Klinische Studien

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Sebastian Bauer

sebastian.bauer@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Scandinavian Sarcoma Group, Schweden

Einschlusskriterien
1. Age ≥ 18 years.
2. Morphological and immunohistological documentation of GIST (immunostaining for KIT [CD117] and/or DOG-1 positive, or mutation of KIT or PDGFRA present in tumour tissue).
3. Macroscopically complete surgical resection of GIST (either R0 or R1 resection).
4. Mutation analysis of KIT and PDGFR genes has been carried out.
5. A high risk of tumour recurrence following surgery and 3 years of adjuvant imatinib defined as one of the following:
1) gastric GIST with mitotic count >10/50 HPFs HPF, high Power field of the microscope) or >10/5mm2, or
2) non-gastric GIST with mitotic count >5/50 HPFs or >5/5 HPFs mm2, or
3) non-gastric GIST treated with neoadjuvant imatinib and initially larger than 10 cm, or
4) tumour rupture
Tumour rupture may have occurred before or at surgery. Tumour rupture is defined by spillage of the tumour contents into the abdominal cavity. A core needle biopsy from the tumour, or tumour bleed with no apparent spillage of the tumour contents, are not considered ruptures.

If only a small amount of pretreatment tumour tissue is available from a core needle biopsy, it is acceptable to multiply the mitotic count obtained from fewer than 50 HPFs to approximate the counts obtained from 50 HPFs in surgical biopsies, or to multiply the count obtained from a tumour tissue area less than 5 mm2 to approximate the counts obtained from the 5 mm2 area. However, if only minimal amount of tumour tissue is available from a core needle biopsy (from 5 or fewer HPFs, or only 1 mitosis can be identified), multiplication should not be attempted and is not considered acceptable. For further explanation of this expanded high risk classification, please see section 3.2.3.
6. ECOG performance status ≤ 2.
7. Adequate organ function, defined as serum total bilirubin <1.5 x ULN (upper limit of normal), serum AST (SGOT) and ALT (SGPT) <2.5 x ULN, creatinine <1.5 x ULN; blood ANC (neutrophil count) ≥1.0 x 109/L, platelet count ≥100 x 109/L.
8. Female patients of childbearing potential must have a negative pregnancy test within 14 days before initiation of study drug dosing. Postmenopausal women must have amenorrhoea for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.
9. Patient willing to be followed up at the study site regardless of the result of randomisation.
10. Patient has provided a written, voluntary informed consent prior to study-specific screening procedures.

Ausschlusskriterien
1. Presence of distant metastases or local recurrence of GIST.
2. Not willing to donate tumour tissue and/or blood samples for the study molecular studies.
3. Presence of a substitution mutation at PDGFRA codon D842 (usually D842V).
4. Administration of adjuvant imatinib longer than for 3 years is planned regardless of the result of randomisation, or “life long” imatinib administration is planned.
5. Prior adjuvant (+ neoadjuvant) therapy with imatinib mesylate for at least 35 months has not been completed, or the total duration of prior adjuvant (+ neoadjuvant) imatinib administration exceeds the total duration of 38 months.
6. Neoadjuvant imatinib for a duration that exceeds 12 months.
7. Longer than 4-week break during adjuvant imatinib administration.
8. The dose of imatinib at completion of 3 years of adjuvant imatinib was 200 mg per day or less or greater than 800 mg per day.
9. Patient has received any investigational anti-cancer agents during adjuvant imatinib or between completion of adjuvant imatinib and the date of randomisation.
10. Patient has been free of another malignancy for less than 5 years except if the other malignancy is not currently clinically significant nor requiring active intervention, or if the other malignancy is one of the following: basal cell skin cancer, a cervical carcinoma in situ, a small (2 cm or less in diameter) node-negative breast cancer (pT1N0M0), a low Gleason score (<8) local (T1 or T2) prostate cancer. Recent existence of any other malignant disease is not allowed.
11. Patient with Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., congestive heart failure, myocardial infarction within 6 months of study entry).
12. Female patients who are pregnant or breast-feeding.
13. Severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, severe chronic renal disease, or active uncontrolled infection).
14. Known diagnosis of human immunodeficiency virus (HIV) infection.
15. Patient with a significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes, Mesotheliom, GIST - Gastrointestinaler Stromatumor

Medizinischer Befund
gastrointestinal stromal tumor (GIST)

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Jens Siveke

jens.siveke@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

F. Hoffmann- La Roche Ltd.

Einschlusskriterien
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Histologically or cytologically confirmed metastatic PDAC
- For patients in Cohort 1: no prior systemic treatment for PDAC
- For patients in Cohort 2: disease progression during administration of either of 5-fluorouracil or gemcitabine-based first-line chemotherapy in the metastatic or locally advanced setting and, for patients treated in the locally advanced setting, occurrence of metastasis within 6 months after initiation of chemotherapy
- Life expectancy >=3 months
- Availability of a representative tumor specimen that is suitable for determination of programmed death ligand 1 (PD-L1) and/or additional biomarker status via central testing
- Measurable disease (at least one target lesion) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Adequate hematologic and end-organ function test results
- Tumor accessible for biopsy
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive, and agreement to refrain from donating eggs, measures as outlined for each specific treatment arm
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm

Ausschlusskriterien
- Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
- History of leptomeningeal disease
- Active or history of autoimmune disease or immune deficiency
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
- Positive HIV test at screening or at any time prior to screening
- Active hepatitis B or C virus infection or active tuberculosis
- Severe infection within 4 weeks prior to initiation of study treatment
- Prior allogeneic stem cell or solid organ transplantation
- History of malignancy other than pancreatic carcinoma within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren der Leber und Bauchspeicheldrüse und der Gallenwege

Medizinischer Befund
Pancreatic ductal adenocarcinoma

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Anja Welt

anja.welt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

F. Hoffmann-La Roche AG

Einschlusskriterien
Stage 1
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Metastatic or inoperable locally advanced, histologically documented TNBC
- For patients in the 1L PD-L1 positive cohort: no prior systemic treatment for metastatic or inoperable locally advanced TNBC
- For patients in the 2L CIT-naïve cohort: Eligible for capecitabine monotherapy
- For patients in the 2L CIT-naïve cohort: Radiologic/objective evidence of recurrence or disease progression after 1L treatment with chemotherapy (chemo) for a total of one line of therapy for inoperable locally advanced or metastatic breast cancer
- Life expectancy>= 3 months
- Availability of a representative tumor specimen that is suitable for determination of Programmed death-ligand 1and/or additional biomarker status via central testing
- For patients in the 1L PD-L1 positive cohort: positive PD-L1 expression, defined as >= 1%of the tumor area occupied by PD-L1- expressing tumor-infiltrating immune cells of any intensity Stage 1 and Stage 2
- Measurable disease according to Response Evaluation Criteria in Solid Tumors 1.1
- Tumor accessible for biopsy
- Adequate hematologic and end-organ function
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen during the 14 days prior to initiation of study treatment
- Negative HIV test, hepatitis B surface antigen at screening, and hepatitis C virus (HCV) antibody test or positive HCV antibody test followed by a negative HCV RNA test at screening
- Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL at screening
- For women of childbearing potential: agreement to remain abstinent or use treatment arm-specific contraceptive measures and agreement to refrain from breastfeeding and donating eggs
- For men: agreement to remain abstinent or use treatment arm- specific contraceptive measures, and agreement to refrain from donating sperm for a treatment arm-specific time period Stage 2
- ECOG Performance Status of 0, 1, or 2
- Patients randomly allocated to the control arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity, provided that Medical Monitor approval for entry into Stage 2 is obtained, or disease progression per RECIST v1.1 while receiving control treatment
- Patients randomly allocated to an experimental arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related to atezolizumab (Atezo), disease progression per RECIST v1.1, or loss of clinical benefit as determined by the investigator while receiving Stage 1 treatment
- Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1

Ausschlusskriterien
Stage 1
- Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies
- Treatment with investigational therapy within 28 days prior to C1D1
- Biologic treatment or other systemic treatment within 2 weeks (wks) prior to C1D1
- Eligibility only for the control arm Stage 1 (2L CIT naïve cohort only)
- Prior treatment with capecitabine
Stage 1, 2
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, tumor-related pain and uncontrolled or symptomatic hypercalcemia
- Symptomatic, untreated, or actively progressing central nervous system metastases.
- History of leptomeningeal disease, idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis or tuberculosis on screening and malignancy other than breast cancer within 2 years prior to screening.
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- History of autoimmune disease or immune deficiency
- Grade >= 3 hemorrhage or bleeding event within 28 days prior to
C1D1
- Severe infection within 4 wks prior C1D1
- Major surgical procedure within 4wks
- Treatment with antibiotics or live, attenuated vaccine within 2 wks or 4wks prior to C1D1 respectively
- Treatment with systemic immunostimulatory agents within 4wks or 5 half-lives of the drug prior to C1D1
- Patients entering Stage 2: immunotherapy-related adverse events that have not resolved to Grade 1 or better or to baseline at the time of consent Ipatasertib (Ipat) - Containing arm (Stage 1)
- Prior treatment with ipat or other Akt inhibitors
- Grade >= 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceremia
- History of Type I or Type II diabetes mellitus requiring insulin
- Congenital long QT syndrome or screening QT interval corrected through use of Fridericia's formula > 480ms
- Treatment with strong CYP3A4 inducers or inhibitors within 2wks or 5 drug-elimination half-lives prior to C1D1. SGN-LIV1A - Containing arm (Stage 1)
- Prior treatment with SGN-LIV1A or MMAE -based biologic
- Grade>= 2 neuropathy
- Radiotherapy within 2wks prior to C1D1
- AST/ALT > 1.5 x ULN, or 3 x ULN if liver metastases present
- Documented history of a cerebrovascular event, unstable angina, myocardial infarction, or cardiac symptoms consistent with congestive heart failure, within 6 months prior to study enrollment. Bevacizumab (Bev) - Containing arm (Stage 1)
- Inadequately controlled arterial hypertension
- History of hypertensive crisis or hypertensive encephalopathy
- Significant vascular disease within 6 months prior to C1D1
- History of hemoptysis within 1 month prior to C1D1 and abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intraabdominal abscess and intestinal obstruction and/or clinical signs or symptoms of GI obstruction and intra-abdominal inflammatory process within 6 months prior to C1D1.
- Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to C1D1
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to C1D1; or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to C1D1 Selicrelumab (Seli)– containing arm (Stage 1)
- Soluble CD25 > 2 x ULN
- Serum ferritin > 1000 ng/mL
- Known hereditary or acquired coagulopathy
- Concomitant treatment with anticoagulants Chemo – containing arm (Stage 2)
- Inability to tolerate atezo during Stage 1 and Patients with congenital long QT syndrome
Exclusion Criteria for the Nab-Paclitaxel-Containing Arms (Stage 1)
- Grade >= 2 neuropathy related to taxanes
Exclusion Criteria for the Tocilizumab-Containing Arm (Stage 1)
- Preexisting CNS demyelinating or seizure disorders
- History of diverticulitis, chronic ulcerative lower GI disease, or other symptomatic lower GI conditions that might predispose a patient to GI perforation
- Current liver disease unrelated to the underlying cancer diagnosis
- Active current infection or history of recurrent bacterial, viral, fungal, mycobacterial, or other infection, including, but not limited to, TB, atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail bed
- Active TB as documented by a positive purified protein derivative (PPD) skin test or TB blood test and confirmed by a positive chest X-ray within 3 months prior to initiation of study treatment
- Untreated latent TB
- History of, or currently active, primary or secondary immunodeficiency
- ALT or AST > 1.5 xULN or, for patients with liver metastases, > 3 x ULN
- Total bilirubin > ULN
Exclusion Criteria for the Sacituzumab Govitecan- Containing Arm (Stage 1)
- Prior treatment with a topoisomerase 1 inhibitor

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Brustkrebs

Medizinischer Befund
Triple-negative breast cancer (TNBC)

MedDRA Term
Triple negative breast cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Jens Siveke

jens.siveke@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GWT-TUD GmbH, Dresden

Einschlusskriterien
1. Patients must have histologically confirmed PDAC
2. Patients must have metastatic disease (stage IV) and not received prior chemotherapy for stage IV disease (adjuvant/additive chemotherapy is allowed if completed at least 6 months prior to study inclusion)
3. Patients must not have received the following drugs before: Azacitidine, Romidepsin, any checkpoint-inhibitor or immunomodulating agents such as IMiDs (Lenalidomide)
4. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v. 1.1
5. Male or female, age ≥ 18 years
6. Body weight > 30 kg for inclusion into Part 2 (according to Durvalumab treatment)
7. ECOG performance status 0 or 1
8. Patients must have normal organ and marrow function as defined below
• Leukocytes ≥ 2,5*10^9/L
• Absolute neutrophil count ≥ 1,5*10^9/L
• Platelets ≥ 100*10^9/L
• Haemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
• Asparate aminotransferase/alanine aminotransferase (AST/ALT) (SGOT/SGPT) ≤ 2.5 x ULN and ≤ 5 in the case of liver metastasis
• Measured creatinine clearance (CL) >60 mL/min or Calculated creatinine CL>60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
9. Patients must be recovered from the effects of any prior surgery
10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
11. All subjects must agree to refrain from donating blood while on study drug and for 90 days after discontinuation from this study treatment
12. All subjects must have a life expectancy of at least 12 weeks
13. All subjects must agree not to share medication.
14. Females of childbearing potential (FCBP) must
• Understand the potential teratogenic risk to the unborn child
• Understand the need and agree to utilize two reliable forms of contraception simultaneously without interruption for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 90 days after study treatment discontinuation
• Understand and agree to inform the investigator if a change or stop of method of contraception is needed
• Be capable of complying with effective contraceptive measures
• Be informed and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy
• Understand the need to commence the study treatment as soon as study drug is dispensed following a negative pregnancy test
• Understand the need and accept to undergo pregnancy testing based on the frequency outlined in this protocol
• Acknowledges that she understands the hazards Lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of Lenalidomide
• Females must agree to abstain from breastfeeding during study participation and for at least 90 days after study drug discontinuation
15. Males must
• Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a FCBP
• Agree to use a latex condom during any sexual contact with FCBP or a pregnant female while participating in the study and for 90 days following discontinuation from this study, even if he has undergone a successful vasectomy. For treatment with Gemcitabine and nab-Paclitaxel men must avoid fathering a child/ use a condom up to 6 months after their last dose. Depending on duration of Lenalidomide/Durvalumab treatment this period can be longer than 90 days after study discontinuation
• Agree to refrain from donating semen or sperm while on the study drugs and for 90 days after discontinuation from this study treatment. For treatment with nab-Paclitaxel and Gemcitabine male subjects must agree not to father a child or donate semen for at least 6 month afterlast intake of medication
• Agree not to father a child during the course of the trial and for at least 90 days after last administration of study drugs. For Gemcitabine and nab-Paclitaxel treatment up to 6 month after last drug intake.
16. Females of non-childbearing potential:
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhea for at least 24 consecutive months without an alternative medical cause

Ausschlusskriterien
1. Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events from agents administered more than 4 weeks earlier
2. Patients receiving any other investigational agents
3. Patients who have previously received Romidepsin, Azacitidine, Lenalidomide or Durvalumab or any PD1 or PD-L1 inhibitor or participate currently on an other clinical trial, unless it is an observational clinical study or during the follow-up period of an interventional study
4. Patients with untreated or uncontrolled brain metastases or leptomeningeal disease
5. Presence of other active illnesses
6. Any known cardiac abnormalities such as:
• Congenital long QT syndrome
• QTc interval = 470 milliseconds. Calculated from 3 ECGs using Fridericias Correction
7. Myocardial infarction within 6 months of C1D1
8. Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia
9. Symptomatic coronary artery disease, e.g., angina Canadian Class II-IV
10. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or known ejection fraction <40% by MUGA or <50% by echocardiogram and/or MRI
11. A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD)
12. Concomitant use of any drug known to prolong QT interval
13. Concomitant use of strong CYP3A4 inhibitors
14. Lactating, pregnant or breast feeding
15. Patients with any other medical or psychological condition deemed by the investigator to be likely to interfere with a patient’s ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
16. Diagnosis of immunodeficiency or any condition that requires systemic steroid therapy or other forms of immunosuppressive therapy
17. Prior thromboembolic events
18. History of other malignancies, except:
• Malignancy treated with curative intent and with no known active disease present for = 5 years before the first dose of study drug and felt to be at low risk for recurrence by investigator.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without current evidence of disease
19. Any uncontrolled active systemic infection
20. Major surgery within 4 weeks of first dose of study drug
21. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
22. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
23. History of interstitial lung disease, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis
24. Unable to swallow oral medication or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
25. Concomitant use of warfarin or other Vitamin K antagonists
26. Known allergy or hypersensitivity to any study drug or any of the study drug excipients
27. Unwilling or unable to participate in all required study evaluations and procedures. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information
28. Current or prior use of immunosuppressive medication within 14 days (use 28 days if combining Durvalumab with a novel agent) before the first dose of Durvalumab
29. Active or prior documented autoimmune or inflammatory disorders
30. Any unresolved toxicity NCI CTCAE Grade = 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria .
• Patients with Grade = 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Durvalumab may be included only after consultation with the Study Physician.
31. History of allogenic organ transplantation
32. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus
33. Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP
34. Subject is an employee of GWT-TUD GmbH

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren der Leber und Bauchspeicheldrüse und der Gallenwege

Medizinischer Befund
Pancreas Cancer\nPancreatic Adenocarcinoma\nPancreatic Ductal Adenocarcinoma

Institute
Klinik und Poliklinik für Strahlentherapie, Innere Klinik (Tumorforschung), Ruhrlandklinik - Thorakale Onkologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Wilfried Eberhardt

wilfried.eberhardt@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
1. Body weight >30 kg
2. Age = 18 years and < 75 years
3. Male or female patients. Female (as well as male) patients have to take care of effective measures of anticonception
4. Histologically proven non-small cell lung cancer
5. Selected patients with non-small cell lung cancer stages IIIA and IIIB:
• IIIA: one or more lymph node levels involved at EBUS/mediastinoscopy
• IIIA: bulky N2-disease histologically proven at EBUS/cervical mediastinoscopy / parasternal mediastinotomy, not diffuse mediastinal involvement
• selected IIIB: N3-disease with contralateral mediastinal nodes involved at EBUS / mediastinoscopy
• potentially resectable T4-disease:
o involvement of the pulmonary artery (angiogr.-CT/MRI/TEE),
o involvement of the carina (histologically proven),
o involvement of the left atrium (angiogr.-CT/MRI/TEE),
o involvement of the vena cava (angiogr.-CT/MRI/TEE),
o involvement of ipsilateral intrapulmonary satellite nodules,
o mediastinal involvement (not diffuse)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Resectable disease at the time of inclusion
8. Fulfillment of adequate criteria for functional and medical resectability as described in the ERS/ESTS guidelines [Brunelli et al 2009] and acceptable general clinical condition for multimodality treatment (interdisciplinary committee)
9. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
10. Must have a life expectancy of > 12 weeks
11. Adequate normal organ and marrow function as defined below:
o Haemoglobin = 9.0 g/dL
o Absolute neutrophil count (ANC) > 1.5 x 109/L (> 1500 per mm3)
o Platelet count = 100 x 109/L (= 100.000 per mm3)
o Serum bilirubin = 1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
o AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal
o Measured creatinine clearance (CL) > 40 mL/min or Calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause
13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
14. Stable cardiac function (no Myocardial infarction (MI) within 6 months, no heart failure NYHA III-IV)

Ausschlusskriterien
1. resectable IIB or selected IIIA
2. unresectable disease pre-treatment
3. mixed histology with areas of small cell carcinoma
4. clinically symptomatic vena cava superior syndrome
5. diffuse mediastinal involvement
6. patients with T3N3 and T4N3 tumors
7. invasion of the thoracic aorta
8. invasion of the heart
9. invasion of the esophagus
10. invasion of spine
11. Pancoast-syndrome in tumors of the superior sulcus
12. malignant pericardial effusion
13. malignant pleural effusion
14. involvement of the contralateral hilar nodes
15. endobronchial tumor extension to the contralateral main stem bronchus
16. ipsi- or contralateral supraclavicular nodes
17. lung or heart function not allowing at the time of inclusion the intended surgical procedure
18. previous administration of chemotherapy and/or radiotherapy
19. previous immunotherapy
20. insufficient patients compliance
21. loss of weight > 10 % in the last six months
22. missing written informed consent or definitive refusal for participation
23. Participation in another clinical study with an investigational product during the last 12 months
24. Concurrent enrolment in another clinical study, unless it is an observational clinical study or during the follow-up period of an interventional study
25. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day
26. History of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan
27. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions is acceptable
28. Major surgical procedure within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
29. History of allogenic organ transplantation
30. History of a stem cell transplantation
31. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]).
32. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
33. History of another primary malignancy
34. History of active primary immunodeficiency
35. Active infection including tuberculosis hepatitis B, hepatitis C, or human immunodeficiency virus. Patients with a past or resolved HBV infection are eligible. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for HCV RNA
36. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
37. Current or prior use of immunostimulatory agents within 14 days before the first dose of durvalumab
38. Receipt of live attenuated vaccine within 90 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP
39. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy
40. Known allergy or hypersensitivity to durvalumab or any excipientFor full text exclusion criteria and exceptions please refer to study protocol section 4.2

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
74 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
non-small cell lung cancer stages IIIA (N2) and selected resectable stages IIIB

MedDRA Term
Non-small cell lung cancer

Institute
Innere Klinik (Tumorforschung), Ruhrlandklinik - Klinik für Thoraxchirurgie und thorakale Endoskopie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
1. Patients with histologically or cytologically (EBUS-TBNA) confirmed non-small cell lung cancer (NSCLC) eligible for anatomic resection, with the following specification:
• Clinical stages I A3, I B, II and selected stage III A (T3 N1, T4 with satellite nodule in the same lung N0/N1, selected T1a-T2b N2 cases considered suitable for primary surgical approach by the multidisciplinary tumor board) according to UICC 8th edition.
• Female and male patients >= 18 years.
Patients in reproductive age must be willing to use adequate contraception during the study and for 6 months after the end of treatment. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test
2. ECOG ≤ 1
3. Exclusion of extensive mediastinal lymph node metastases (multilevel N2, N3) by PET/CT and/or mediastinal lymph node sampling by EBUS/TBNA and/or staging mediastinoscopy.
4. Exclusion of distant metastases by standard of care imaging studies, which include but are not limited to PET/CT or PET/MRI, or CT or MRI of thorax, abdomen, pelvis, and bone scan. Asymptomatic brain metastases will be excluded by MRI or contrast-enhanced CT as indicated by current guidelines.
5. Measurable target tumor prior to immunotherapy using standard imaging techniques.
6. Sufficient pulmonary function to undergo curative lung cancer surgery, ppFEV1>30%, ppDLCO>30%, ppVO2max>=10 ml/min/kg (if CPET was mandated per local guidelines)
7. Adequate hematological, hepatic and renal function parameters:
o Leukocytes ≥ 2,000/mm³, platelets ≥ 100,000/mm³, absolute neutrophil count (ANC) ≥ 1,500/µL, hemoglobin ≥ 9 g/dL (5.58 mmol/L),
o Anti-platelet therapy (such as but not limited to clopidogrel) should be discontinued pre-operative according to local standards. If this therapy cannot but interrupted due to severe cardiovascular comorbidity, patient is ineligible for trial
o Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the upper limit of normal (ULN) (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocoumon or direct oral anticoagulants are to be bridged according to local standards and have achieved stable coagulation profile prior to surgery.
o Serum creatinine ≤ 1.5 x upper limit of normal
o Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.0 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal
8. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

Ausschlusskriterien
1. Active or history of autoimmune disease or immune deficiency,
* Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
* Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
* skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic immunosuppressive treatment, in particular corticosteroids are permitted to enroll
2. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
3. Subjects who have undergone organ transplant or allogeneic stem cell transplantation.
4. FEV<30%, DLCO<30%, ppO2 < 10 ml/min/kg
5. Uncontrolled or significant cardiovascular disease
• History of other clinically significant cardiovascular disease
• Cardiovascular disease-related requirement for daily supplemental oxygen
• History of two or more MIs OR two or more coronary revascularization procedures
• Subjects with history of myocarditis, regardless of etiology
• Troponin T (TnT) or I (TnI) > 2 × institutional ULN
6. Active malignancy or a prior malignancy within the past 3 years
• Patients with completely resected basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and patients with isolated elevation in prostate-specific antigen or low risk prostate cancer managed with active surveillance or watchful waiting in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study.
7. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
8. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV RNA negative).
9. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
10. Peripheral polyneuropathy NCI CTCAE Grade = 2
11. History of gastric perforation or fistulae in past 6 months
12. Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to enrollment.
13. The patient has undergone major surgery within 28 days prior to enrollment except staging mediastinoscopy, diagnostic VATS or implantation of a venous port-system.
14. Any other concurrent antineoplastic treatment including irradiation
15. Breastfeeding women
16. Women of childbearing potential unless women who meet the following criteria:
* Post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum FSH > 40 U/mL)
* Postoperatively (six weeks after bilateral ovariectomy with or without hysterectomy)
* Regular and correct use of a contraceptive method with error rate <1% per year such as implants, depot injections, oral contraceptives or intrauterine devices during the treatment and at least up to 5 months after last treatment
* Sexual abstinence during the treatment and at least up to 5 months after last treatment
* Vasectomy of the partner
17. Men of sexual activity with women of childbearing potential who are not willing to use an effective barrier method of contraception during and up to 7 months after the end of therapy
18. A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.
a. Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after endocrinopathy.
b. Prior treatment with LAG-3 targeted agent.
Other
• Participation in another interventional clinical study within the last 3 months prior to inclusion or simultaneous participation in other clinical studies
• Previous treatment with nivolumab or relatlimab
• Previous immunotherapy for lung cancer
• Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety
• Any contraindications against nivolumab or relatlimab

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
non-small cell lung cancer (NSCLC) of clinical stages I A3, II and selected stage III A

MedDRA Term
Non-small cell lung cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
Key Inclusion Criteria:

- Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at baseline and during on study therapy. Exceptions may be considered after documented discussion with Novartis.
- All patients must have a BRAF V600 mutation confirmed by local assessment.
- Patients with unresectable advanced/metastatic BRAF V600 cancer of the colon or rectum with measurable disease as determined by RECIST v1.1
- Patients must have documented disease progression following, or are intolerant to, 1 or 2 lines of chemotherapy for advanced/metastatic disease

Ausschlusskriterien
Key Exclusion Criteria:

- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in-situ cervical cancer, or other tumors that will not affect life expectancy
- Impairment of gastrointestinal function or gastrointestinal disease that may signficantly alter the absorption of study drugs
- History of or current evidence/risk of retinal verin occlusion or serous retinopathy
- History of or current interstitial lung disease or non-infectious pneumonitis
- Patients with a known history of testing positive for HIV
- Clinically significant cardiac disease at screening
- Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
- Pregnant or lactating women
Other protocol-defined inclusion/exclusion may apply.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
BRAV V600 Colorectal Cancer

Institute
Innere Klinik (Tumorforschung), Ruhrlandklinik - Thorakale Onkologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Marcel Wiesweg

marcel.wiesweg@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
- Phase 1 and Phase 1b lazertinib+Amivantamab combination cohorts: Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) with previously epidermal growth factor receptor (EGFR) mutation (identified locally in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory [or equivalent]) that is metastatic or unresectable, and have progressed after standard of care front-line therapy, and exhausted available options with targeted therapy. A participant who has refused all other currently available therapeutic options is allowed to enroll
- For the Phase 1b Lazertinib, Amivantamab and Platinum-doublet Chemotherapy (LACP) combination cohort: histologically or cytologically confirmed advanced or metastatic EGFR-mutated NSCLC who have progressed on or after an EGFR-TKI as the most recent line of treatment with a maximum of 3 prior lines of therapy in the metastatic setting allowed
- For all expansion cohorts, the EGFR mutation must have been previously histologically or cytologically characterized, as performed by a CLIA-certified (US sites) or an accredited (outside of US) local laboratory, with a copy of the mutation analysis being submitted during screening (Phase 1b expansion Cohort B, C and D)
1. Expansion Cohort A: Participant must have advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) that has progressed on prior treatment with osimertinib in the first or second line, followed by progression on a platinum-based chemotherapy regimen as the last line of therapy prior to study enrollment. Prior use of first or second generation EGFR tyrosine kinase inhibitor (TKI) is allowed if administered prior to osimertinib
2. Expansion Cohort B: Participant must have previously treated, advanced or metastatic NSCLC with documented primary EGFR Exon 20ins activating mutation. Participants should have been treated with standard of care, platinum-based chemotherapy regimens, but may have treated with approved EGFR TKI, investigational EGFR, or immunotherapy agents if refusing front line platinum-based chemotherapy standard of care. Up to 3 lines of prior systemic anti-cancer treatment are allowed
3. Expansion Cohort C: Participant must have advanced or metastatic NSCLC characterized by an uncommon activating mutation Additional uncommon EGFR mutations/alterations, beyond those listed above, may be considered for enrollment after agreement with the medical monitor. Participants may be treatment naïve or have been treated with one prior line of therapy which must be a first or second generation TKI (that is gefitinib, erlotinib, afatinib) in the most recent line of therapy. Prior chemotherapy is allowed if administered prior to EGFR TKI therapy, or as the only systemic anti-cancer therapy prior to study enrollment. Up to 2 lines of prior systemic anti-cancer treatment are allowed
4. Expansion Cohort D: Participant must have advanced or metastatic EGFR-mutated NSCLC (EGFR Exon19 deletion or L858R) that has progressed on prior treatment with osimertinib in the first or second line (after first- or second-generation EGFR TKI), as the immediate prior line of therapy. Only previous treatment in the metastatic setting with a first, second, or third generation EGFR TKI is allowed
- Evaluable disease
- Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1
- Participants must meet the study protocol defined laboratory criteria without having a history of red blood cell transfusion, platelet transfusion, or granulocyte-colony stimulating factor support within 7 days prior to the date of the test
- A woman of childbearing potential: Must have a negative serum beta human chorionic gonadotropin at screening; Must agree not to breast-feed during the study and for 6 months after the last dose of study intervention. (Enrollment is not allowed even if a woman who is breast-feeding stops breast-feeding); Must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study intervention

Ausschlusskriterien
- Participant has an uncontrolled illness, including but not limited uncontrolled diabetes, ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics week prior to study treatment] or diagnosed or suspected viral infection); active bleeding diathesis; Impaired oxygenation requiring continuous oxygen supplementation; Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of study treatment; or psychiatric illness or any other circumstances including (social circumstances) that would limit compliance with study requirements. Any ophthalmologic condition that is either clinically unstable or requires treatment
- Prior treatment with antiPD-1 or anti Programmed death-ligand 1 (PD-L1) antibody within 6 weeks of planned first dose of study intervention
- Untreated brain or other central nervous system (CNS) metastases whether symptomatic or asymptomatic. Participants who have completed definitive therapy, are not on steroids, and have a stable clinical status for at least 2 weeks prior to study treatment may be eligible for Phase 1b expansion cohorts. If brain metastases are diagnosed on Screening imaging, the participant may be enrolled, or rescreened for eligibility, after definitive treatment if above criteria are met
- Any Toxicities from prior anticancer therapy must have resolved to common terminology criteria for adverse events (CTCAE) version 5.0 Grade 1 or baseline level (except for alopecia [any grade], Grade <=2 peripheral neuropathy, and Grade <=2 hypothyroidism stable on hormone replacement therapy)
- Allergies, hypersensitivity, or intolerance to Lazertinib or JNJ-61186372 or their excipients. For the LACP combination cohort: participant has a contraindication for the use of carboplatin or pemetrexed (refer to local prescribing information for each agent). Participant has a history of hypersensitivity to, or cannot take, vitamin B12 or folic acid

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Advanced Non- Small Cell Lung Cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma GmbH

+499112730
infoservice.novartis@novartis.com

Roonstraße 25
90429 Nürnberg

Einschlusskriterien
1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients ≥ 18 years of age
3. Histologically confirmed and documented advanced solid tumors and lymphoma (includes locally advanced malignancies that are not curable by surgery or radiotherapy, and those with metastatic disease) with documented progression following standard therapy, and for whom, no standard therapy is available, tolerated or appropriate. Disease must be measurable as determined by RECIST 1.1 (refer to Appendix 1) or Cheson et al (2014) (refer to Appendix 6).
- Escalation: Patients previously treated with CPI (anti PD-1/PD-L1 and/or anti CTLA-4) who have previously responded and progressed at any time prior to enrollment. Previous response is an initial radiographic CR/PR (a confirmatory scan is not required). If the most recent regimen included CPI, patients with SD lasting ≥ 6 months are also eligible.
- Expansion in melanoma: Patients with cutaneous melanoma previously treated with CPI (anti PD 1/ PD-L1 and/or anti CTLA-4) who have previously responded and progressed at any time prior to enrollment. Previous response is radiographic CR/PR (a confirmatory scan is not required). If the most recent regimen included CPI, patients with SD lasting ≥ 6 months are also eligible.
- Expansion in NSCLC: Patients with locally advanced or unresectable NSCLC who have been treated with up to 2 prior lines of therapies, at least one of which was a CPI-containing regimen (anti PD 1/ PD-L1 and/or anti CTLA-4). Patients must have previously responded to CPI and progressed at any time prior to enrollment. Previous response is radiographic CR/PR (a confirmatory scan is not required). If the most recent regimen included CPI, patients with SD lasting ≥ 6 months are also eligible. Patients with actionable mutations will be excluded.
4. Patients must be willing and able to comply with the protocol for the duration of the study
5. Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening and during therapy on the study.
6. ECOG performance status ≤1 and in the opinion of the investigator, likely to complete at least 28 days of treatment.

Ausschlusskriterien
1. Patients that have received any prior IL-15 treatment.
2. History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients. In addition, patients with a history of immune mediated toxicities from CPI that led to permanent discontinuation of CPI treatment will be excluded.
3. Patients with primary CNS tumors are excluded. Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry. Patients with treated symptomatic brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of = 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
4. Systemic chronic steroid therapy (> 10mg/day prednisone or equivalent) or any immunosuppressive therapy, other than replacement-dose steroids in the setting of adrenal insufficiency, within 7 days of the first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.
5. Malignant disease, other than that being treated in this study, that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy.
6. Patients having out of range lab values during screening and before the first dose of study treatment. Out of range lab values are defined as:
- Absolute neutrophil count (ANC) <1.0 x 109/L
- Platelets <75 x 109/L
- Hemoglobin (Hgb) < 9 g/dL
- Serum creatinine > 1.5 x ULN or creatinine clearance < 60mL/min using Cockcroft-Gault formula (See Appendix 3)
- Total bilirubin > 1.5 x ULN, (except for patients with Gilbert's syndrome > 3.0 x ULN or direct bilirubin > 1.5 x ULN)
- Aspartate transaminase (AST) > 3 x ULN
- Alanine transaminase (ALT) > 3x ULN
-Serum electrolytes = grade 2 despite adequate supplementation.
7. Impaired cardiovascular function or clinically significant cardiovascular disease, including any of the following:
- Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade = 2), uncontrolled hypertension or clinically significant arrhythmia
- QTcF >470 msec on screening ECG or congenital long QT syndrome
- Acute myocardial infarction or unstable angina < 3 months prior to study entry
8. Infection(s):
- HIV infection
- Active HBV or HCV infection (per institutional guidelines). Patients with chronic HBV or HCV disease that is controlled under antiviral therapy are allowed in expansion but not in escalation.
- Documented infection. Patients requiring systemic antibiotics for infection must have completed treatment before screening is initiated.
9. Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur may be considered. Patients previously exposed to CPI treatment who were adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
10. History of or current interstitial lung disease or pneumonitis grade = 2.
11. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative radiotherapy to a limited field. To allow evaluation for response to study treatment, patients enrolled in the expansion must have remaining measurable disease that has not been irradiated.
12. Treatment with cytotoxic or targeted antineoplastics within 3 weeks of initiation of study treatment. For cytotoxic agents that have major delayed toxicities, a washout period of one cycle is indicated (examples are nitrosoureas and mitomycin C which typically require a 6 week washout). Prior antibodies or immunotherapies require a 4 week washout. Ongoing bisphosphonate therapy and growth hormone-releasing hormone (GHRH) agonist therapy is allowed. Supportive therapy with denosumab is allowed. For patients with lymphoma, the following washout criteria may be used:
• Systemic antineoplastic therapy (including cytotoxic chemotherapy, alfa-interferon, kinase inhibitors or other targeted small molecules, and toxin immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment
13. Presence of Grade = 2 toxicity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5.0), from prior cancer therapy with the exception of neuropathy (inclusion of patients with neuropathy of Grade 2 or less is permitted), ototoxicity, and alopecia.
14. Two weeks since major surgery treatment (mediastinoscopy, insertion of a central venous access device and insertion of a feeding tube are not considered major surgery)
15. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
16. Use of hematopoietic growth factors or transfusion support = 2 weeks prior to start of study treatment. If growth factors were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.
17. Any medical condition that would, in the investigator's judgement, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results.
18. Pregnant or nursing (lactating) women.
19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study medication and for 30 days after the last dose of NIZ985 if receiving NIZ985 alone, 120 days after last dose of tislelizumab, or for 150 days after the last dose of spartalizumab. Highly effective methods of contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks before taking investigational drug(s). In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient
- Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example, hormone vaginal ring or transdermal hormone contraception.
- In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
NOTE: Women are considered post-menopausal and not of child-bearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate [generally age from 40 to 59 years], history of vasomotor symptoms [e.g. hot flush]) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.
20. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. Sexually active males receiving NIZ985 as a single agent or in combination with spartalizumab or tislelizumab must use a condom during intercourse for 30 days after their last dose of NIZ985. In addition, male participants must not donate sperm for 30 days after the last dose of NIZ985. Patients should not father a child during this post treatment period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen.
Other protocol-defined inclusion/exclusion criteria may apply

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
HD - Hodgkin Lymphom, NHL - Non-Hodgkin-Lymphom, Solide Tumoren

Medizinischer Befund
solid tumors and lymphoma

Institute
Klinik für Hals-Nasen-Ohrenheilkunde, Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent has to be obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. If laboratory or imaging procedures were performed for alternate reasons prior to signing consent, these can be used for screening purposes with consent of the patient. However, all screening examinations and laboratory results must have been obtained within 14 days before first study drug administration (initial tumor imaging: within 28 days before first study drug administration).
2. Only patients for whom sufficient tumor material to be judged by the local investigator and which is of adequate quality can be included into the trial. Please refer to section 6.5 for further details on quantity and quality of tumor samples.
3. Histologically or cytologically proven SCCHN that is amenable to surgical resection with curative intent.
4. Patients with relapse after primary radio(chemo)-therapy are allowed if a salvage surgery is possible (maximum 20% in each arm). Patients should have recovered from the effects of radiation: AE/sequelae should resolves to ≤ grade 2 (no minimum recovery period required).
5. Male or female, 18 years of age or older on day of signing informed consent
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
7. Life expectancy >12 weeks
8. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
• Absolute neutrophil count (ANC)  1.5  109/L without granulocyte colony-stimulating factor support
• Lymphocyte count  0.5  109/L
• Platelet count  100  109/L without transfusion
• Hemoglobin  90 g/L
o Patients may be transfused to meet this criterion but patients in need of chronic or repeated RBC transfusion should be discussed with the sponsor before.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  2.5  upper limit of normal (ULN)
• Serum bilirubin  1.5  ULN with the following exception:
o Patients with known Gilbert disease: direct serum bilirubin level  ULN for patients with total bilirubin levels>1.5 ULN.
• Serum creatinine  1.5  ULN or Creatinine clearance ≥30 mL/min (calculated using the Cockcroft-Gault formula)
• Serum albumin  2.5 g/dL
• International normalized ratio (INR) or activated Partial Thromboplastin Time (aPTT)  1.5  ULN (This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low−molecular weight heparin or warfarin) should be on a stable dose
9. Women of childbearing potential:
• Should have a negative urine or serum pregnancy test within 14 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Agreement to remain abstinent (refrain from heterosexual intercourse) or use a non-hormonal contraceptive method with a failure rate of  1% per year during the treatment period and for at least 5 months after last study drug administration
• A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state ( 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
• Examples of contraceptive methods with a failure rate of  1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices.
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. For men: with female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 5 months after the last dose in arm A and B to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

Ausschlusskriterien
1. Evidence of metastatic disease
2. Prior treatment with immune checkpoint blockade therapies,
3. Treatment with investigational therapy within 28 days prior to initiation of study treatment
4. Any anti-cancer therapy, including chemotherapy or hormonal therapy, within 4 weeks prior to initiation of study treatment
5. Bilateral pleural effusion
6. Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1, Cycle 1.
7. Treatment with a live-attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study, and for 5 months after the last dose
8. Treatment with systemic immuno-stimulatory agents within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment
9. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
10. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment
11. Uncontrolled hypercalcemia
12. Uncontrolled tumor-related pain.
13. Pregnant and lactating women
14. Acute toxicities from previous therapy that have not resolved to Grade = 1, except for alopecia
15. Infections
a. Positive human immunodeficiency virus (HIV) test Known HIV+ patients may be included
b. Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening.
Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening followed by a negative HBV DNA test, are eligible for the study. The HBV DNA test will be performed only for patients who have a positive total HBcAb test.
c. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at screening.
The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
d. Active tuberculosis
e. Severe infection within 4 weeks prior to initiation of study treatment
f. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
g. Patients receiving prophylactic antibiotics are eligible for the study.
16. Active or history of autoimmune disease or immune deficiency with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) may be eligible
17. Adverse events (AE) related to any previous radiotherapy, chemotherapy, targeted therapy or surgical procedure that have not reolved to Grade =1, except alopecia (any grade) and Grade 2 neuropathy
18. Prior allogeneic stem cell or solid organ transplantation
19. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computer tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
20. Active malignancy or a prior malignancy within the past 3 years. Patients with completely resected basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and patients with isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study.
21. Any Grade ? 3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1
22. Increased corrected QT (QTc) interval (QTc > 470 ms)
23. Family history of long QT syndrome or other risk factors for torsades de pointes
24. History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to Day 1
25. Significant cardiovascular disease
26. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
27. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety
28. Participation in another clinical study within the last 3 months prior to inclusion or simultaneous participation in other clinical studies with an exception of studies evaluating radiological imaging.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Kopf-Hals-Tumore

Medizinischer Befund
local squamous cell carcinoma of the head and neck

MedDRA Term
Squamous cell carcinoma of head and neck, Head and neck cancer

Institute
Innere Klinik (Tumorforschung), Ruhrlandklinik - Thorakale Onkologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
Dose Escalation:
• Patients with advanced (metastatic or unresectable) KRAS G12C mutant solid tumors who have received standard of care therapy or are intolerant or ineligible to approved therapies.
Dose Expansion:
• Patients with advanced (metastatic or unresectable) KRAS G12C mutant non-small cell lung cancer who are in the second or third line treatment setting and who have received a platinum-based chemotherapy regimen and immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy
• Patients with advanced (metastatic or unresectable) KRAS G12C mutant non-small cell lung cancer who are in the third or fourth line treatment setting and have received a platinum-based chemotherapy regimen and immune checkpoint inhibitor therapy, unless patient was ineligible to receive such therapy, followed by one treatment line of a direct KRAS G12C inhibitor given as a single agent and discontinued within 6 months of the first day of study treatment.
• Patients with advanced (metastatic or unresectable) KRAS G12C mutant colorectal cancer who have received standard-of-care therapy, including a fluropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, unless patient was ineligible to such therapy.
All Patients:
• ECOG performance status of 0 or 1.
• Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the institution’s own guidelines and requirements for such procedures.

Ausschlusskriterien
• Tumors harboring driver mutations that have approved therapies or tumors with known activating KRAS, NRAS, HRAS, BRAF, or PTPN11 (SHP2) mutations, with the exception of KRAS G12C mutations.
• Prior treatment with a KRAS G12C inhibitor is excluded for patients in the single agent dose escalation arm and a subset of groups in dose expansion.
• Prior treatment with a SHP2 or SOS1 inhibitor is not allowed for NSCLC patients enrolled into the dose expansion parts of the JDQ443 single agent and JDQ443 plus TNO155 expansion arms.
• Active brain metastases, i.e. symptomatic brain metastases or known leptomeningeal disease
• Clinically significant cardiac disease or risk factors at screening
• Insufficient bone marrow, hepatic or renal function at screening

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Multientity/Biomarker driven

Medizinischer Befund
advanced solid tumors harboring the KRAS G12C mutation

MedDRA Term
Malignant solid tumor

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Jens Siveke

jens.siveke@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
Subjects must fulfill all of the following criteria for study entry:
1) Signed informed consent form
2) Age ≥ 18 years by the time of inclusion in the study
3) Ability to comply with the study protocol, in the investigator’s judgment
4) Histologically confirmed advanced BTC
5) Patient must have received at least one prior line of systemic therapy in advanced-stage BTC
6) Adjuvant or neoadjuvant chemotherapy is allowed, provid it is completed at least 6 months before start of study treatment
7) Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
8) Life expectancy > 12 weeks
9) Measurable disease, according to RECIST v1.1. Lesions intended to be biopsied should not be defined as target lesions
10) Tumor must be accessible for biopsies and patient willing to provide tissue from a newly obtained biopsy of a tumor lesion
11) Adequate hematologic and end-organ function
12) For women of childbearing potential: Negative serum pregnancy test within 21 days prior to Cycle 1 Day 1 (C1D1). Agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of ≤ 1% per year during the treatment period and for at least 180 days after the last study treatment
13) For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below:
o With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 180 days after the last dose of study treatment. Men must refrain from donating sperm during this same period.

Ausschlusskriterien
1) Malignancies other than BTC within 3 years prior to C1D1 with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival > 90%) treated with expected curative outcome
2) Patients with known microsatellite instability high (MSI-H) status.
3) Untreated central nervous system (CNS) metastases. Treatment of brain metastases, either by surgical or radiation techniques must have been completed at least 4 weeks prior to initiation of study treatment.
4) Radiation therapy within 21 days prior to C1D1 and/or persistence of radiation-related adverse effects
5) Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past
6) Spinal cord compression not definitively treated with surgery and/or radiation
7) Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
8) Uncontrolled tumor pain. Patients who require narcotic pain medication during screening should be on a stable dose regimen prior to C1D1. Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth should be considered for loco-regional therapy if appropriate prior to enrollment.
9) Treatment with any investigational agent or approved therapy within 28 days or two investigational agent half-lives (whichever is longer) prior to C1D1
10) Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-PD-1 and anti-PD-L1, or VEGF/VEGFR inhibitors
11) Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene polymorphism predisposing the patient for 5-fluorouracil (5-FU) toxicity
12) History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
13) Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any components of atezolizumab or bevacizumab formulations
14) Current or recent (within 10 days of study enrollment) use of acetylsalicylic acid (> 325 mg/day), clopidogrel (> 75 mg/day) or thrombolytic agents for therapeutic purposes
15) History of clinically significant cardiac or pulmonary dysfunction.
16) History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
17) Major surgical procedure within 4 weeks prior to C1D1 or anticipation of need for a major surgical procedure during the course of the study
18) Evidence of tumor invading or abutting major blood vessels
19) Serious non-healing wound, active ulcer or untreated bone fracture
20) History of abdominal fistula or gastrointestinal perforation within 6 months prior to C1D1
21) History of hemoptysis (= ½ teaspoon of bright red blood per episode), or any other serious hemorrhage, or at risk of bleeding
22) INR > 1.5 and aPTT > 1.5 x ULN within 7 days prior to C1D1 (excluding patients on prophylactic or therapeutic anticoagulation)
23) History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding
24) Proteinuria at screening as demonstrated by urine dipstick = 2+ or 24-hour proteinuria > 1.0 g
25) Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
26) Systemic immunostimulatory agents are prohibited within 4 weeks or five half-lives of the drug (whichever is longer) prior to C1D1
27) Autoimmune conditions: History of autoimmune disease
28) Infectious diseases
o Severe infection within 4 weeks prior to initiation of C1D1
o Treatment with therapeutic oral or intravenous antibiotics within 2 weeks prior to initiation of study treatment
o Patients with active hepatitis B
o Patients with past hepatitis B virus (HBV) infection or resolved HBV infection are eligible. HBV DNA test must be performed in these patients prior to C1D1.
o Patients with active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
o Positive HIV test at screening or at any time prior to screening
o Known active tuberculosis
o Patients must not receive any kind of living, attenuated vaccine (e.g. Fluenz® Tetra) within 4 weeks prior to C1D1 or at any time during the study and for at least 5 months after the last dose of study drug.
29) Pregnant or lactating or intending to become pregnant during the study or within 5 months after final dose for atezolizumab or 6 months for bevacizumab.
30) Uncontrolled serious medical or psychiatric illness

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
advanced-stage biliary tract cancer

MedDRA Term
Cholangiocarcinoma

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Martin Metzenmacher

martin.metzenmacher@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

AIO-Studien-gGmbH, Berlin

Einschlusskriterien
Patients who meet all of the following criteria are eligible for the project:

Age ≥ 18 years
Able to understand and willing to sign written Informed Consent and to complete patient-reported-outcome assessment instruments
Main project (Metatstatic NSCLC):

Confirmed non-small cell lung cancer (NSCLC)
Informed consent no later than four weeks after start of first-line systemic treatment
Stage IV, or stage IIIB/C (UICC8) if patient is ineligible for curative surgery and/or radiochemotherapy
Systemic therapy
Satellite Stage II/III (NSCLC):

Confirmed non-small cell lung cancer (NSCLC)
Informed consent no later than four weeks after start of first anti-tumor treatment
Stage II, stage IIIA, or stage IIIB/C (UICC8) if patient is eligible for curative surgery and/or radiochemotherapy
Systemic (chemo)therapy and/or radiation therapy and/or surgery
Satellite SCLC

Confirmed Small cell lung cancer (SCLC)
Informed consent no later than four weeks after start of first anti-tumor treatment or no later than four weeks after diagnosis for patients receiving "best supportive care only" (i.e. no anti-tumor treatment = no surgery, radiotherapy or systemic therapy)
Systemic (chemo)therapy and/or radiation therapy and/or surgery or best supportive care

Ausschlusskriterien
none

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Metastatic Non-small Cell Lung Cancer (NSCLC)\nNon-small Cell Lung Cancer Metastatic\nNon-small Cell Lung Cancer Stage I\nNon-small Cell Lung Cancer Stage II\nNon Small Cell Lung Cancer Stage III\nSmall-cell Lung Cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
1. Signed informed consent must be obtained prior to participation in the study.
2. Age 18 years (or older, if required by local regulations) at the time of informed consent.
3. Histologically or cytologically confirmed (by local laboratory and local clinical guidelines) metastatic colorectal adenocarcinoma that is not amenable to potentially curative surgery in the opinion of the investigator and progressed on or within 6 months after the last dose of one prior line of systemic anti-cancer therapy administered for metastatic disease.
4. Presence of at least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
6. Adequate organ function as defined by the following laboratory values (assessed by central laboratory for eligibility except where indicated):
• Absolute neutrophil count ≥ 1.5 × 109/L
• Platelets count ≥ 100 × 109/L
• Hemoglobin ≥ 9 g/dL
• Calculated creatinine clearance ≥ 60 mL/min (e.g. by using Cockcroft-Gault equation)
• Albumin ≥ 3 g/dL
• PT/INR and PTT ≤ 1.5 x ULN. Participants requiring therapeutic anticoagulants are eligible if coagulation parameters are within therapeutic range.
• Total bilirubin ≤ 1.5 X ULN
• Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase /serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 3.0 x ULN (≤5 x ULN in presence of liver metastasis). In participants with elevated ALT or AST, the values must be stable for at least 2 weeks and with no evidence of biliary obstruction by imaging.
7. Women of child-bearing potential must have negative pregnancy tests during the screening period and before starting study treatment.
8. Able to adhere to study visit schedule and other protocol requirements.
9. Participant must have recovered from treatment related toxicities of prior anticancer therapies to grade ≤1 (CTCAE v5.0) at the time of screening, except alopecia.

Ausschlusskriterien
1. Previously administered systemic TGF-ß targeted therapies.
2. Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAFV600 mutation positive colorectal cancer (tests performed by local laboratory and per local guidelines).
3. Known complete or partial dipyrimidine dehydrogenase (DPD) enzyme deficiency (testing for DPD enzyme deficiency is not mandatory unless required by local regulations and can be conducted at a local laboratory).
4. For participants treated with irinotecan: Known history or clinical evidence of reduced UGT1A1 activity (testing for UGT1A1 status is not mandatory unless required by local regulations and can be conducted at a local laboratory).
5. Presence of symptomatic CNS metastases, or CNS metastases that requires directed therapy (such as focal radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry. Participants with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study entry, and at a dose of = 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
6. Known history of severe allergy or hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes (e.g. monoclonal antibodies), or contraindication to any of the study drugs as outlined in the ‘Contraindications’ or ‘Warnings and Precautions’ sections of the SOC local prescribing information
7. Participant is currently receiving other anti-cancer therapy (medication or radiotherapy), or received other investigational product within 30 days or 5 half-lives prior to initiation of study treatment, whichever is longer.
8. Participant is currently receiving any of the prohibited medications as outlined in the protocol or in the SOC anti-cancer therapy local prescribing information, and these cannot be discontinued = 7 days or 5 half-lives, whichever is longer, before the first dose of that drug.
9. Participant has not recovered from a major surgery performed prior to start of study treatment or has had a major surgery within 4 weeks days prior to start of study treatment.
10. Radiation therapy = 4 weeks or brain-radiotherapy = 4 weeks prior to start of study treatment
11. Impaired cardiac function or clinically significant cardio-vascular disease, such as:
• Congestive heart failure requiring treatment (NYHA grade =2), or clinically significant arrhythmia (including uncontrolled atrial flutter/fibrillation)
• Acute myocardial infarction, unstable angina pectoris, coronary stenting, or bypass surgery <6 months prior to study entry
• LVEF < 50%
• Elevated cardiac enzymes troponin I > 2 x ULN
• Cardiac valvulopathy= grade 2
• Uncontrolled hypertension defined by a systolic blood pressure =160 mg and/or diastolic blood pressure =100 mg Hg
12. History of positive test for human immunodeficiency virus (HIV) infection
13. Active or chronic hepatitis B virus (HBV) or hepatitis C virus infections.
14. Active untreated or uncontrolled systemic fungal, bacterial or viral infection (including COVID-19), which in the opinion of the investigator places the study participant at an unacceptable risk.
15. Use of hematopoietic growth factors or transfusion support = 2 weeks prior to start of study treatment.
16. Participant has conditions that are considered to have a high risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding.
17. Serious non-healing wounds.
18. Stroke or transient ischemic attack, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before start of study treatment.
19. Concurrent malignancy other than the disease under investigation with exception of malignancy that was treated curatively and has not recurred within 2 years prior to the date of screening. Fully resected basal or squamous cell skin cancers and any carcinoma in situ are eligible.
20. Any significant medical condition, laboratory abnormality or psychiatric or social condition that would constitute unacceptable safety risks to the participants, contraindicate participant participation in the clinical study, limit the participant’s ability to comply with study requirements, or compromise participant’s compliance with the protocol and all requirements of the study as stated in the Informed Consent Form.
21. Women of child-bearing potential, unless they are willing to use highly effective methods of contraception during treatment with study drugs and for 90 days after stopping NIS793 whichever is latest.
22. Pregnant or breast-feeding women.

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
metastatic colorectal cancer (mCRC)

MedDRA Term
Colorectal cancer, Colorectal cancer metastatic

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

AIO-Studien-gGmbH, Berlin

Einschlusskriterien
1. Written informed consent including participation in translational research and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
2. Male or female ≥ 18 years of age
3. Histologically confirmed adenocarcinoma of the colon or rectum
4. For the main study: Pathological Stage III disease For the perioperative sub-study: Clinical stage III disease
5. For the main study: R0-resected primary tumor For the perioperative sub-study: Resectable primary tumor; R0 resection anticipated (R1-resected patients can remain on study.)
6. Tumor is MSI-high (MSI-H) or MMR-deficient (dMMR) For the main study: assessed from biopsy or from resected tumor tissue For the perioperative sub-study: assessed from biopsy
7. ECOG status 0 – 2
8. Ineligible for oxaliplatin-based adjuvant chemotherapy or patient’s refusal of oxaliplatin-based adjuvant chemotherapy
9. Adequate blood count, liver enzymes, and renal function – re-testing can be undergone once in case of initial results near cutoff
- White blood cell count ≥ 3.5 x 106/mL
- Platelet count ≥ 100 x 109/L (>100,000 per mm3)
- Hemoglobin ≥ 9 g/dL (blood transfusion > 2 weeks before testing is permitted)
- AST (SGOT)/ALT (SGPT) ≤ 5 x institutional upper limit of normal
- Serum Creatinine ≤ 1.5 x institutional ULN and a calculated glomerular filtration rate ≥ 30 mL per minute
10. Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and PTT < 1.5 ULN within 7 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of randomization
11. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
12. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly-effective contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for up to 6 months after the last dose of study drug.

Ausschlusskriterien
1. Severe infection within 4 weeks prior to randomization e.g. hospitalization for complications of infection, bacteremia, known active pulmonary disease with hypoxia, or severe pneumonia or any active infection requiring systemic therapy within 4 weeks prior to randomization. Patients with positive test result for SARS-CoV2 should be managed as per local institutional guidelines
2.For the main study: Distant metastases or residual disease/For the perioperative sub-study: Distant metastases or macroscopic residual disease (R2 resection status)
3. Neoadjuvant radiotherapy or radio-chemotherapy (rectal cancer patients without prior radio- or radio-chemotherapy allowed); prior neoadjuvant radio-chemotherapy or radiotherapy for rectal cancer is allowed if >5 years and secondary colorectal cancer
4. Prior adjuvant chemotherapy for colorectal cancer; allowed if >5 years and secondary colorectal cancer
5. Prior treatment with atezolizumab or any other checkpoint inhibitor
6. Prior exposure to IMM-101
7. Treatment with systemic immunosuppressive medication within 2 weeks prior to treatment start, or anticipation of need for systemic immunosuppressive medication during study treatment
8. Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment.
9. History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins.
10. Known hypersensitivity to CHO cell products or any component of the atezolizumab formulation.
11. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. If any of these lung diseases is suspected based on the patient’s history or the integrated evaluation of clinical and radiological records, an additional spirometry should be conducted.
12. Active HBV infection (chronic or acute), defined as having a positive HBsAg test at screening. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total HBcAb test at screening followed by a negative HBV DNA test, are eligible for the study. The HBV DNA test will be performed only for patients who have a positive total HBcAb test. Patients are also eligible if HBV DNA < 500 IU/mL obtained within 28 days prior to initiation of study treatment, AND anti-HBV treatment for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study
13 Anti-viral therapy against HCV during the trial (allowed prior to trial)
14. Positive HIV test. As an exception, known HIV+ patients may be included if they have: A stable regimen of HAART; No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections; A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests
15. a) Treatment with a live, attenuated vaccine within 4 weeks prior to first dose of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the last dose of study treatment. b) Treatment with any vaccine during screening and the first cycle of treatment.
16. Active tuberculosis
17. Active or history of autoimmune disease or immune deficiency e.g. myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis
18. Prior (<3 years) or concurrent malignancy that either progresses or requires active treatment. Exceptions: basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a or T1b prostate carcinoma, superficial urinary bladder tumor
19. History of hypersensitivity to any of the study drugs or any excipient IMM-101
20. History of allergic reaction to any mycobacterial product
21. Prior allogeneic stem cell or solid organ transplantation requiring immunosuppressive therapy or other major immunosuppressive therapy
22. Severe non-healing wounds, ulcers or bone fractions
23. Evidence of bleeding diathesis or coagulopathy
24. Major gastrointestinal bleeding within 4 weeks prior to treatment start, unless cause of bleeding was resected tumor
25. Major surgical procedures other than primary tumor resection, except open biopsy, nor significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgical procedure during the course of the study except for surgery of central intravenous line placement for chemotherapy administration.
26. Medication that is known to interfere with any of the agents applied in the trial.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Patients with MSI-high or MMR-deficient stage III colorectal cancer who are ineligible for or who refuse oxaliplatin-based chemotherapy after R0 tumor resection (main study) or planned resection (sub-study)

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
Patients must meet the following criteria to be eligible for enrollment into the study:
1. Aged ≥18 years old.
2. Able to provide informed consent obtained before any study related activities and according to local guidelines.
3. Patient has histologically and/or cytologically-confirmed HNSCC.
4. Patient has archival or new tumor tissue for the analysis of biomarkers and confirmation of HPV status (if unknown). One tumor block (preferred) or a recommended minimum of 5 unstained slides for patients with known HPV status (for tumor DNA characterization) or a recommended minimum of 10 slides for patients whose HPV status is unknown (5 slides for HPV testing plus 5 slides needed for biomarker testing).
Enrollment in the study is contingent on confirmation of the availability of an adequate amount of tumor tissue, except in rare special circumstances, which must be reviewed and approved by the sponsor.
5. Patient has either progressive or recurrent disease after treatment with PDL1/PD1 based therapy for recurrent or metastatic disease:
a. PDLl/PD1 therapy alone for metastatic (monotherapy) disease
b. PDL1/PD1 in combination with chemotherapy for metastatic and recurrent disease
c. PDL1/PD1 used for metastatic disease, after or prior to receiving a platinum agent for locally advanced or metastatic disease.
6. Patient has received no more than two prior lines of systemic treatment for HNSCC (single agent chemotherapy used as a radiosensitizer is not counted as a prior line of therapy).
7. Patient has measurable disease as determined per RECIST version 1.1. If the only site of measurable disease is a previously irradiated lesion, documented progression of disease and a four-week period since radiotherapy completion is required.
8. Patient has adequate bone marrow function and organ function as shown by the following:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
b. Hemoglobin ≥ 9 g/dL (which may be reached by transfusion).
c. Platelets ≥ 100 x 109/L (which may be reached by transfusion).
d. International normalized ratio (INR) ≤ 1.5.
e. Calcium (corrected for serum albumin) within normal limits (WNL) or ≤ grade 1 severity according to NCI-CTCAE version 5.0 if judged clinically not significant by the Investigator. Patients concomitantly taking bisphosphonates or denosumab for calcium correction are eligible.
f. Normal potassium and magnesium levels
g. Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 1.5 x upper limit of normal (ULN) or < 3.0 x ULN if liver metastases are present.
h. Total serum bilirubin ≤ ULN or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin below or within normal range in patients with well documented Gilbert’s Syndrome. Gilbert’s syndrome is defined as presence of episodes of unconjugated hyperbilirubinemia with normal results from cells blood count (including normal reticulocyte count and blood smear), normal liver function test results, and absence of other contributing disease processes at the time of diagnosis.
i. Serum creatinine ≤ 1.5 x ULN or calculated or directly measured creatinine clearance (CrCL) > 30 mL/min.
j. Haemoglobin A1c (glycosylated hemoglobin; HbA1c) ≤8%.
9. Patient has Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
10. Patient is able to swallow and retain oral medication. Patients able to swallow oral medication but mostly self-nourished through gastric or jejunal feeding tube are eligible.
11. For inclusion criteria 11 on contraception please refer to the protocol

Ausschlusskriterien
Patients meeting any of the following criteria will not be eligible for participation in the study:
1. Patient has received previous treatment with any protein kinase B (PKB/AKT), mammalian target of rapamycin (mTOR) inhibitors, or phosphatidylinositol 3 kinase (PI3K) pathway inhibitors.
2. Patient received treatment with a taxane as part of prior treatment for recurrent or metastatic disease.
3. Patient has symptomatic CNS metastases. Patients with asymptomatic CNS metastases may participate in this study. Patient must have completed any prior local treatment for CNS metastases = 28 days prior to the start of study treatment (including radiotherapy) and must be on a stable low dose of corticosteroid therapy. Radiosurgery must have been completed at least 14 days prior to start of study treatment.
4. Patient has received wide field radiotherapy = 4 weeks or limited field radiation for palliation = 2 weeks prior to starting study treatment or who have adverse events which have not recovered to grade 1 or better from previous chemotherapy treatment (except alopecia, autoimmune endocrine events must be stable and controlled).
5. Patient has grade = 2 neuropathy, colitis, pneumonitis, and uncontrolled endocrinopathies (e.g., hypothyroidism, diabetes with hemoglobin A1c > 8%) from previous treatment.
6. Patient has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects.
7. Patient is currently receiving increasing or chronic treatment (>5 days) with corticosteroids or another immunosuppressive agent. The following uses of corticosteroids are permitted: single doses; standard premedication for paclitaxel, topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops, or local injections (e.g., intra-articular), or < 10 mg prednisolone or equivalent.
8. Patient is being treated at start of study treatment with any of the following drugs:
a. Drugs known to be strong or moderate inhibitors or inducers of isoenzyme cytochrome P450 3A4 (CYP3A4) including herbal medications. b. Drugs with a known risk of inducing Torsades de Pointes.
9. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant, for treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), fondaparinux or new oral anticoagulants (NOACs) is allowed.
10. Patient has a known hypersensitivity and/or contraindication to paclitaxel, standard premedication for paclitaxel, or other products containing Cremophor®.
11. Patient has other concurrent severe and/or uncontrolled medical conditions that would, in the Investigator’s judgment, contraindicate patient participation in the clinical study.
12. Patient has a known history of HIV infection (testing not mandatory).
13. Patient has any of the following cardiac abnormalities:
a.Symptomatic congestive heart failure within 12 months of the screening period , History of documented congestive heart failure or documented cardiomyopathy and left ventricular ejection fraction (LVEF) 450 msec for males and > 470 msec for females, on the screening ECG, Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
14. Patient has impairment of GI function or GI disease that may significantly alter the absorption of study treatment.
15. Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation or active severe personality disorders are not eligible.
For exclusion criteria 16-20 please refer to the protocol

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Kopf-Hals-Tumore

Medizinischer Befund
Head and Neck Squamous Cell Carcinoma (HNSCC)

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Charité - Universitätsmedizin Berlin

Einschlusskriterien
1. Patient’s signed informed consent.
2. Patient’s age ?18 years at the time of signing the informed consent.
3. Histologically confirmed adenocarcinoma of the colon or rectum.
4. Resected (R0 or R1) and/or effectively treated metastases (all techniques allowed) of colorectal cancer within 3-10 weeks before randomization AND resected primary tumor (synchronous or metachronous).
5. Absence of significant active wound healing complications (if applicable) prior to randomization. Resolved wound healing complications after resection/ablation are acceptable for inclusion into the trial.
6. No radiographic evidence of active metastatic disease at study entry in a CT and/or MRI scan not older than 8 weeks. Pre-surgery/ablation images are eligible for the study if all lesions have been addressed in the interval.
7. ECOG performance status 0-2.
8. Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results:
• Absolute neutrophil count ? 1.5 x 109/L (1500/µL)
• Hemoglobin ? 80 g/L (8 g/dL)
• Platelet count ? 100 x109/L (100000/µL) without transfusion
• Total serum bilirubin of ? 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST/GOT) ? 3.0 × ULN.
• Calculated glomerular filtration rate (GFR) according to Cockcroft-Gault formula or according to MDRD ? 50 mL/min or serum creatinine ? 1.5 x ULN
9. Patients without anticoagulation need to present with an INR < 1.5 x ULN and PTT < 1.5 x ULN. Patient with prophylactic or therapeutic anticoagulation are allowed into the trial.
10. Proficient fluorouracil metabolism as defined:
a) Prior treatment with 5-FU or capecitabine without unusal toxicity
or
b) If tested, normal DPD deficiency test according to the standard of the study site
or
c) If tested, in patients with DPD deficiency test with a CPIC activity score of 1.0-1.5 fluoropyrimidine dosage should be reduced by 50%
11. For women of childbearing potential (WOCBP): negative pregnancy test within 14 days before randomization and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study treatment.
A woman is considered to be of childbearing potential if she is post-menarcheal, has not reached a postmenopausal state (? 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
For men: With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication to avoid exposing the embryo.

Ausschlusskriterien
1. Treatment of metastases greater than 3 cm with radio-frequency/microwave ablation within 24 months prior to study entry if applicable.
2. Treatment of metastases greater than 5 cm with radiation (stereotactic/ brachytherapy) within 24 months prior to study entry if applicable.
3. Previous chemotherapy for metastatic or localized disease with > 6 cycles of FOLFOX (or FOLFOXIRI) or > 4 cycles of CAPOX/XELOX.
4. New York Heart Association Class III or greater heart failure by clinical judgement.
5. Myocardial infarction within 6 months prior to randomization; percutaneous transluminal coronary angioplasty (PTCA) with or without stenting within 6 months prior to randomization.
6. Unstable angina pectoris.
7. Unstable cardiac arrhythmia > grade 2 NCI CTCAE despite anti-arrhythmic therapy.
8. Ongoing toxicities > grade 2 NCI CTCAE, in particular peripheral neuropathy.
9. Active uncontrolled infection by investigator’s perspective.
10. Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
11. Known hypersensitivity to 5-FU, leucovorin, irinotecan or oxaliplatin or to any of the other excipients listed in section 6.1 of the corresponding SmPC.
12. Bone marrow depression after radio- or chemotherapy.
13. Severe kidney dysfunction (creatinine clearance < 30 ml/min) or changes in blood count.
14. Recent or concomitant treatment with brivudine.
15. Peripheral sensitive neuropathy with functional impairment (> grade 1 acc. to CTCAE version 5.0 (see appendix)).
16. Inflammatory bowel disease and/or bowel obstruction.
17. Simultaneous application of Johannis herbs preparations.
18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
19. If tested, DPD deficiency test with a CPIC activity score <1.
20. Major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to randomization, or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 21 days prior to randomization or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure.
21. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
22. Medical history of malignant disease other than mCRC with the following exceptions:
- patients who have been disease-free for at least three years before randomization
- patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer
- patients with any treated or untreated malignant disease that is associated with a 5-year survival prognosis of ? 90% and does not require active therapy
23. Known alcohol or drug abuse.
24. Pregnant or breastfeeding females.
25. Participation in a clinical trial or experimental drug treatment within 28 days prior to potential inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to potential inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
26. Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
27. Limited legal capacity.

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Metastatic colorectal cancer after definite interventional therapy of all lesions

MedDRA Term
Metastatic colorectal cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Martin Metzenmacher

martin.metzenmacher@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma GmbH

+499112730
infoservice.novartis@novartis.com

Roonstraße 25
90429 Nürnberg

Indikation
Lungenkrebs

Medizinischer Befund
advanced Mesothelioma and other solid tumors

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Bristol-Myers Squibb International Corporation, Belgien

Einschlusskriterien
• Fresh pre-treatment and on-treatment tumor biopsy must be provided for biomarker analysis
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and at least 1 lesion accessible for biopsy
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Radiographically documented progressive disease on or after the most recent therapy
• Received standard-of-care therapies, including an available programmed death (ligand)-1 inhibitor known to be effective in the tumor type for which they are being evaluated
• Parts 1A, 1B, and 2A: Advanced or metastatic non-small cell lung cancer, squamous cell carcinoma of head and neck, microsatellite stable colorectal cancer, gastric/ gastroesophageal junction adenocarcinoma, or cervical cancer, and have received, be refractory to, not be a candidate for, or be intolerant of existing therapies known to provide clinical benefit for the condition of the participant

Ausschlusskriterien
• Women who are pregnant or breastfeeding
• Primary central nervous system (CNS) malignancy
• Untreated CNS metastases
• Leptomeningeal metastases
• Concurrent malignancy requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study treatment
• Active, known, or suspected autoimmune disease
• Condition requiring systemic treatment with either corticosteroids within 14
days or other immunosuppressive medications within 30 days of the first dose of study treatment
• Prior organ or tissue allograft
• Uncontrolled or significant cardiovascular disease
• Major surgery within 4 weeks of study drug administration
• History of or with active interstitial lung disease or pulmonary fibrosis
Other protocol-defined inclusion/exclusion criteria apply

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Multientity/Biomarker driven

Medizinischer Befund
Male and female participants = 18 years of age with advanced or metastatic cancers .\n\nCervical Cancer\nGastric\/Gastroesophageal Junction Adenocarcinoma\nMicrosatellite Stable Colorectal Cancer\nNon-Small-Cell Lung Cancer\nSquamous Cell Carcinoma of Head and Neck\nCarcinoma, Renal Cell\nUrothelial Carcinoma\nPancreatic Adenocarcinoma\nMelanoma\nOvarian Neoplasms\nTriple Negative Breast Neoplasms

MedDRA Term
Advanced cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Michael Pogorzelski

michael.pogorzelski@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Amgen Inc, USA

Einschlusskriterien
101 Subject has provided informed consent prior to initiation of any study-specific
activities/procedures.
102 Age ≥ 18 years
103 Subjects with histologically or cytologically confirmed ES-SCLC and no prior
systemic treatment for ES-SCLC other than first-line therapy described below.
Subjects with prior treatment for limited-stage SCLC are permitted
 Parts 1 to 4: Subject must have received 1 cycle of platinum chemotherapy,
etoposide, and PD-L1 inhibitor. Subjects who did not have access to PD-L1
inhibitor are eligible.
 Parts 5 and 6: Subjects must have completed 4 cycles of first-line platinum
chemotherapy, etoposide, and PD-L1 inhibitor and not have experienced
disease progression. If there is no access to first-line PD-L1 inhibitor,
subjects who received 4 to 6 cycles of platinum chemotherapy plus etoposide
are eligible.
104 Measurable disease by modified RECIST 1.1 (Parts 1 to 4 only).
105 Eastern Cooperative Oncology Group (ECOG) 0 to 1
106 Subjects with treated asymptomatic brain metastases are eligible provided they
meet the following criteria:
 Only supratentorial and cerebellar metastasis permitted
 Stereotactic radiosurgery must have completed at least 7 days prior to first
planned dose of study treatment
Product: Tarlatamab (AMG 757)
Protocol Number: 20200469
Date: 15 October 2021 Page 68 of 177
CONFIDENTIAL
 No requirement for corticosteroids and off or on stable doses of anti-epileptic
drugs
 No evidence of radiographic CNS progression following definitive therapy at
the time of study screening
 New or asymptomatic CNS metastasis detected as part of screening
assessments must receive radiation or surgery for CNS metastasis. A repeat
radiographic assessment is not required if all of the above criteria are met.
107 Adequate organ function per local laboratory, defined as follows:
 Absolute neutrophil count ≥ 1.5 x 109/L
 Platelet count ≥ 100 x 109/L
 Hemoglobin ≥ 9 g/dL
 Estimated glomerular filtration rate based on Modification of Diet in Renal
Disease calculation > 60 mL/min/1.73 m2
 Aspartate aminotransferase and alanine aminotransferase  3 x upper limit of
normal (ULN) (or  5 x ULN for subjects with liver involvement)
 Total bilirubin  1.5 x ULN (or  2 x ULN for subjects with liver metastases)
 Prothrombin time (PT)/international normalized ratio and partial
thromboplastin time or activated partial thromboplastin time
 1.5 x institutional ULN
Note: Subjects on stable anticoagulation therapy are allowed.
108 Pulmonary function:
 No clinically significant pleural effusion on study day 1. Treatment of pleural
effusions to meet eligibility are permitted.
 Baseline oxygen saturation > 90% on room air.
109 Cardiac function:
 Cardiac ejection fraction ≥ 50%
110 Subjects must submit tumor tissue sample. Fresh tumor biopsies may be
performed if subject has a readily accessible tumor lesion and consents to the
biopsies. If fresh biopsies cannot be obtained, archival tumor samples are
acceptable. Exceptions may be permitted if a biopsy is not feasible due to safety
reasons.
111 Minimum life expectancy of 12 weeks

Ausschlusskriterien
Disease Related
201 Untreated or symptomatic brain metastases and/or leptomeningeal disease
Other Medical Conditions
202 History of other malignancy within the past 2 years, with the following exceptions:
Product: Tarlatamab (AMG 757)
Protocol Number: 20200469
Date: 15 October 2021 Page 69 of 177
CONFIDENTIAL
? Malignancy treated with curative intent and with no known active disease
present for 2 years before enrollment and felt to be at low risk for recurrence
by the treating physician.
? Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease.
? Adequately treated cervical carcinoma in situ without evidence of disease.
? Adequately treated breast ductal carcinoma in situ without evidence of
disease.
? Prostatic intraepithelial neoplasia without evidence of prostate cancer.
? Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in
situ.
203 History or evidence of interstitial lung disease or active, noninfectious
pneumonitis
204 Subject who experienced recurrent grade 2 pneumonitis or severe or
life-threatening immune-mediated adverse events or infusion-related reactions
including those that lead to permanent discontinuation while on treatment with
immuno-oncology agents
205 History of allergic reactions or acute hypersensitivity reaction to antibody
therapies
206 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or
any other form of immunosuppressive therapy within 7 days prior to the first dose
of study treatment
207 History of any immune-related colitis. Infectious colitis is allowed if evidence of
adequate treatment and clinical recovery exists and at least 3 months interval
observed since diagnosis of colitis.
208 Presence of fungal, bacterial, viral, or other infection requiring systemic oral or IV
antimicrobials for management within 7 days of first dose of study treatment
209 Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube,
biliary drain, or pericardial catheter)
? Note: a pleural or peritoneal catheter for management of pleural effusion or
ascites or dedicated central venous access catheters such as a Port-a-Cath
or Hickman catheter are permitted
210 History of hypophysitis or pituitary dysfunction
211 Major surgery within 28 days of study day 1
212 History of arterial thrombosis (eg, stroke or transient ischemic attack) within
6 months of enrollment
213 Myocardial infarction and/or symptomatic congestive heart failure (New York
Heart Association > class II) or unstable angina within 6 months of study day 1.
Unstable cardiac arrhythmia within 3 months of study day 1. Clinically significant
pericardial effusion.
214 Positive/non-negative test for human immunodeficiency virus; has known active
Hepatitis B (eg, hepatitis B antigen [HBsAg] reactive) or Hepatitis C (eg, hepatitis
C virus RNA [qualitative] is detected)
Product: Tarlatamab (AMG 757)
Protocol Number: 20200469
Date: 15 October 2021 Page 70 of 177
CONFIDENTIAL
215 Active autoimmune disease that has required systemic treatment (except
replacement therapy) within the past 2 years or any other diseases requiring
immunosuppressive therapy while on study. Subjects with Type I diabetes,
vitiligo, psoriasis, hypo- or hyper-thyroid disease not requiring
immunosuppressive treatment are permitted.
216 History or evidence of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection and meeting the following criteria:
? No acute symptoms of COVID-19 disease within 14 days prior to the first
dose of study treatment (counted from day of positive test for asymptomatic
subjects)
Prior/Concomitant Therapy
217 Live vaccine therapy within 4 weeks prior to study drug administration
218 History of solid organ transplantation
Prior/Concurrent Clinical Study Experience
219 Currently receiving treatment in another investigational drug study, or less than
4 weeks since ending treatment on another investigational drug study.
Other Exclusions
220 Subject has known sensitivity to any of the products or components to be
administered during dosing.
221 Subject likely to not be available to complete all protocol-required study visits or
procedures, and/or to comply with all required study procedures (eg, Clinical
Outcome Assessments) to the best of the subject and investigator’s knowledge.
222 History or evidence of any other clinically significant disorder, condition or
disease (with the exception of those outlined above) that, in the opinion of the
investigator or Amgen physician, if consulted, would pose a risk to subject safety
or interfere with the study evaluation, procedures or completion.
223 Female subjects of childbearing potential unwilling to use protocol-specified
method of contraception (see Section 11.5) during treatment and for an
additional:
? 42 days following the last dose of tarlatamab
? 3 months following the last dose of carboplatin and/or etoposide
? 5 months following the last dose of atezolizumab
224 Female subjects who are breastfeeding or who plan to breastfeed while on study
through:
? 42 days following the last dose of tarlatamab
? 3 months following the last dose of carboplatin and/or etoposide
? 5 months following the last dose of atezolizumab
225 Female subjects planning to become pregnant while on study through
? 42 days following the last dose of tarlatamab
? 3 months following the last dose of carboplatin and/or etoposide
Product: Tarlatamab (AMG 757)
Protocol Number: 20200469
Date: 15 October 2021 Page 71 of 177
CONFIDENTIAL
? 5 months following the last dose of atezolizumab
226 Female subjects of childbearing potential with a positive pregnancy test
assessed at screening by a highly sensitive urine or serum pregnancy test.
227 Male subjects with a female partner of childbearing potential who are unwilling to
practice sexual abstinence (refrain from heterosexual intercourse) or use
contraception during treatment and for an additional:
? 90 days following the last dose of tarlatamab
? 3 months following the last dose of carboplatin and/or etoposide
? 5 months following the last dose of atezolizumab
228 Male subjects with a pregnant partner who are unwilling to practice abstinence or
use a condom during treatment and for an additional:
? 90 days following the last dose of tarlatamab
? 3 months following the last dose of carboplatin and/or etoposide
? 5 months following the last dose of atezolizumab
229 Male subjects unwilling to abstain from donating sperm during treatment and for
an additional:
? 90 days following the last dose of tarlatamab
? 3 months following the last dose of carboplatin and/or etoposide
? 5 months following the last dose of atezolizumab

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Extensive Stage Small Cell Lung Cancer

Institute
Innere Klinik (Tumorforschung), Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. Uta Dirksen

+49 (0)201 723-82025
uta.dirksen@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

German Pediatric Oncology Group, GPOH gGmbH, Berlin

Einschlusskriterien
•Histologically (and molecularly) diagnosed primary localised (SR) or metastatic (HR) Ewing sarcoma or so called Ewing-like sarcoma ( i.e. translocation-positive small blue round cell sarcoma other than Rhabdomyosarcoma) of bone and / or soft tissue; pathological diagnosis can be performed at the investigational site
•Any sex, age >2 and < 50 years by the date of diagnostic biopsy
•Informed consent must be obtained according to national and GCP guidelines and signed prior to trial entry. Subjects and when applicable parental or legal representative(s) must understand and voluntarily provide permission to the ICF, prior to conducting any trial-related assessments / procedures. Willingness and ability to comply with scheduled visits and trial procedures are required.
•White blood cell (WBC) count > 2000/µl*
•Assessment of cardiac function including LVEF > 40% and SF > 28%*
•Serum creatinine < 1.5 X ULN*
•For patients of childbearing potential, a negative pregnancy test must be documented prior to enrolment and repeated every month during therapy. Female and male patients, who are fertile and sexually active, must agree to use an effective form of contraception from the time of signing the ICF until 6 months after the end of treatment.
*Parameters must be checked within the screening phase of 45 days from biopsy biopsy / surgery and after diagnosis of metastatic disease to registration.

Ausschlusskriterien
•Treatment of more than one cycle of chemotherapy prior to registration in the SR group
•Concurrent treatment within any other clinical trials, excluding trials with different endpoints, which, due to the nature of their endpoints, must run parallel to iEuroEwing trial, e.g. studies on antiemetics, antimycotics, antibiotics, strategies for psychosocial support, etc.
•Clinically significant and uncontrolled, or active cardiac disease
•Evidence of invasive fungal infection or other severe systemic infection requiring systemic / parenteral therapy
•Hypersensitivity to the active substance or other excipients contained in the investigational medical products listed in the summary of product characteristics (SmPC) or investigators brochure (IB).
•Secondary malignancy
•Pregnancy or lactation
•Female and male subjects with child-bearing potential, who avoid using highly effective contraceptive methods
•Any other medical, psychiatric, or social condition which is incompatible with the protocol treatment
•Contraindications according to the respective applicable SmPCs

Additional exclusion criteria iEuroEwing-SR-RT part:
•Primary diagnosed and histologically confirmed metastatic (HR) Ewing sarcoma or Ewing-like sarcoma of bone and/or soft tissue
•Patients who receive preoperative RTX
•Patients who receive Brachytherapy
•Patients who have been diagnosed with pleural effusion
•Patients with previous RT in the same region

Studienteilnehmende Mindestalter
12 Jahr(e)

Studienteilnehmende Höchstalter
64 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Ewing Sarcoma

Institute
Innere Klinik (Tumorforschung), Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Stefan Schönberger

stefan.schoenberger@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Aachen

Einschlusskriterien
- Histologisch bestätigtes, neu diagnostiziertes NPC bei Patienten ab 3 bis 17 Jahren oder Histologisch bestätigtes, neu diagnostiziertes NPC bei Patienten ab 18 Jahren, EBV positiv, WHO Stadium II, III
- AJCC Stadium ≥ II (Kinder), ≥ III (Erwachsene)
- Messbare Erkrankung per MRT via RECIST 1.1
- Ausreichendes Tumorgewebe für Referenz und PD L1 Staining
- Vorliegen einer Einwilligungserklärung

Ausschlusskriterien
- NPC Stadium I, Rezidiv oder NPC als Sekundärmalignom
- Vorherige Chemotherapie oder Radiotherapie
- Vorliegen einer weiteren aktiven malignen Erkrankung
- Vorherige Behandlung mit einem anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 Antikörper oder einem anderen Antikörper oder Medikament, das die T-Zell-Co-Stimulation oder Checkpoint-pathways anspricht
- Erhalt eines anderen Studienmedikaments bis zu 30 Tage vor Einschluss in diese Studie
- Vorliegen einer aktiven, bekannten Autoimmunerkrankung
- Systemische Behandlung mit Kortikosteroiden (größer 10 mg tägliches Prednison Äquivalent) oder Immunsuppressiva innerhalb von 14 Tagen vor Start der Studienmedikation.
- Nachweis einer akuten oder chronischen Hepatitis B oder Hepatitis C
- Nachweis einer HIV-Infektion
- Unzureichende hämatologische, renale oder hepatische Funktion
- Hörverlust von mehr als 20dB bei 3kHz
- Bekannte Allergie oder Hypersensibilität gegen ein Studienmedikament
- Vorliegen einer anderen Erkrankung, die nach Meinung des Investigators ein nicht akkzeptables Risiko für den/die Teilnehmende bedeuten würde,
- Vorliegen einer Schwangerschaft oder stillende Frauen; sexuell aktive Teilnehmende müssen einverstanden sein, eine ausreichende Kontrazeption vorzunehmen.

Studienteilnehmende Mindestalter
3 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
EBV positives Nasopharynx Karzinom

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Sebastian Bauer

sebastian.bauer@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Boehringer Ingelheim Pharma GmbH & Co. KG

Einschlusskriterien
1. Provision of signed and dated, written informed consent form ICF in accordance with ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or analyses.
2. Male or female patients ≥18 years old at the time of signature of the ICF. Women of childbearing potential and men able to father a child must be ready and able to use 2 medically acceptable methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at screening, during trial participation, and until 6 months and 12 days after last dose for women and 102 days after last dose for men.
3. Histologically proven locally advanced or metastatic, unresectable (surgery morbidity
would outweigh potential benefits), progressive or recurrent DDLPS. Locally performed histopathological diagnosis will be accepted for entry into this trial but will be confirmed by independent pathological review while the patients receive treatment in this trial.
4. Written pathology report indicating the diagnosis of DDLPS with positive MDM2 immunohistochemistry or MDM2 amplification as demonstrated by fluorescence in situ hybridization or NGS must be available.
5. Formalin fixed paraffin embedded tumor blocks or slides must be available for retrospective histopathological central review.
6. Presence of at least one measurable target lesion according to RECIST version 1.1. In patients who only have one target lesion, the baseline imaging must be performed at least 2 weeks after any biopsy of the target lesion.
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
8. Patient must be willing to donate blood samples for the pharmacokinetics, pharmacodynamics, and tumor mutation analysis.
9. Patient willing to undergo a mandatory tumor biopsy at the time point specified in the flowchart unless exempt.
10. Adequate organ function

Ausschlusskriterien
1. Known mutation in the TP53 gene (screening for TP53 status is not required).
2. Major surgery (major according to the investigator’s assessment) performed within
4 weeks prior to randomization or planned within 6 months after screening.
3. Prior systemic therapy for liposarcoma in any setting (including adjuvant, neoadjuvant, maintenance, palliative).
4. Previous or concomitant malignancies other than DDLPS or WDLPS, treated within the previous 5 years, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ, and prostate cancer.
5. Previous treatment with anthracyclines in any setting (systemic treatment with other anticancer agents is allowed if completed at least 5 years prior to study entry with the exception of hormone therapy).
6. Patients who must or intend to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
7. Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s) or receiving other investigational treatment(s).
8. Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition that, in the investigator’s opinion, makes the patient an unreliable trial participant).

Further criteria apply.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Sarkome

Medizinischer Befund
advanced dedifferentiated liposarcoma

MedDRA Term
Dedifferentiated liposarcoma

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Isabel Virchow

isabel.virchow@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Pierre Fabre Pharma GmbH, Freiburg

Einschlusskriterien
Inclusion Criteria:

Written informed consent of the patient with regard to the pseudonymized documentation of his/her data in the frame of this non-interventional study
Legally capable patient ≥ 18 years of age (no upper limit)
Metastatic colorectal carcinoma with BRAFV600E-mutation, pretreated with systemic therapy
Decision was taken to treat the patient with the doublet therapy (encorafenib and cetuximab) in accordance with the current SmPC and by prescription; this decision was taken prior to and independent from the inclusion into the study;
Treatment with the doublet therapy (encorafenib plus cetuximab) has been started ≤ 3 months prior to providing written informed consent for this study or is planned to be started in the near future.

Ausschlusskriterien
Exclusion Criteria:

More than 2 prior systemic regimens in the metastatic setting (adjuvant systemic therapy with relapse = 6 months will be counted as metastatic treatment line; maintenance treatment will not be counted as separate metastatic treatment line)
Prior treatment with any RAF-inhibitor or MEK-inhibitor.
Presence of any contraindication with regard to the doublet therapy (encorafenib plus cetuximab) as specified in the corresponding SmPCs
Current or upcoming participation in an interventional clinical trial
Current or upcoming systemic treatment of any other tumor than metastatic colorectal carcinoma
Prisoners or persons who are compulsorily detained (involuntarily incarcerated).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Metastatic Colorectal Carcinoma

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Bristol-Myers Squibb Research and Development, USA

Einschlusskriterien
- Histologically confirmed previously treated CRC with adenocarcinoma histology with metastatic or recurrent unresectable disease at study entry.
- Participants must have:
a) progressed during or within approximately 3 months following the last administration of approved standard therapies (at least 1, but not more than 4 prior lines of therapies), which must include a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF therapy, and anti-EGFR therapy (if KRAS wild-type), if approved in the respective country, or;
b) been intolerant to prior systemic chemotherapy regimens if there is documented evidence of clinically significant intolerance despite adequate supportive measures.
- Participants must have sufficient tumor tissue & evaluable PD-L1 expression to meet the study requirements. Participants with indeterminate PD-L1 results will be stratified with those participants assessed to be PD-L1 negative by CPS (see next slide for details).
- Participants must have historically or locally confirmed tumor MSS/pMMR status to enroll in this study.
- KRAS mutation status must be documented based on available historical or local testing results as part of medical history prior to study enrollment.
- Participants must have measurable disease per RECIST v1.1. Participants with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately.

Ausschlusskriterien
- Prior treatment with either an immunotherapy (anti-LAG-3, anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) or with regorafenib or with TAS-102.
- Untreated CNS metastases. Participants are eligible if CNS metastases have been treated and participants have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment)
- Participants with history of refractory hypertension not controlled with anti-hypertensive therapy, myocarditis (regardless of etiology), uncontrolled arrhythmias, acute coronary syndrome within 6 months prior to dosing, Class II congestive heart failure (as per the New York Heart Association Functional Classification), interstitial lung disease/pneumonitis or an active, known or suspected autoimmune disease.
- In the case of prior SARS-CoV-2 infection, acute symptoms must have completely resolved and based on investigator assessment in consultation with the clinical trial physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Metastatic Colorectal Cancer

MedDRA Term
Metastatic colorectal cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Marcel Wiesweg

marcel.wiesweg@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Frankfurt

Einschlusskriterien
Pre-Screening Phase:
1. Provision of written informed consent for the pre-screening phase.
2. Age ≥ 18 years
3. Histologically confirmed stage IIIB or IV NSCLC
4. Tumor positive for Ex19del or L858R EGFR mutation assessed according to local standard.
5. Planned treatment with osimertinib 80mg/d 1st-line as SoC or ongoing treatment for a maximum of 28 days
6. Available radiographic chest and abdominal CT or MRI scans performed up to 42 days before initial osimertinib treatment
7. Previously untreated with systemic treatment given as primary therapy for advanced or metastatic disease, except for osimertinib for a maximum of 28 days (see above)
8. At least one measurable site of disease as defined by RECISTv1.1 criteria
9. Female subjects of childbearing potential (WOCBP) should be using highly effective contraceptive measures and must have a negative urine or serum pregnancy test within 7 days prior to start of study treatment and must not be breast-feeding prior to start of trial.
10. Non-child-bearing potential must be evidenced by fulfilling one of the following criteria at screening:
• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
• Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution.
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation

Treatment Phase:
1. Provision of informed consent for the screening and treatment phase prior to any study specific procedures, including screening evaluations that are not SoC.
2. Persistent mEGFR ctDNA signal 21 to 28 days after osimertinib initiation for advanced of metastatic ex19del or L858R EGFR mutation positive NSCLC as assessed by a liquid biopsy during the pre-screening phase of the trial in the central laboratory.
3. ECOG performance status 0-2.
4. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
5. Osimertinib no longer than 10 weeks before start of chemotherapy in the treatment phase

Ausschlusskriterien
Pre-Screening Phase
1. History of another primary malignancy. Exceptions are:
• Malignancy treated with curative intent and with no known active disease =6 months before the first dose of IMP, and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
2. History of leptomeningeal carcinomatosis
3. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study
4. Previous enrolment in the present study.

Treatment Phase
1. Symptomatic CNS metastases. [Patients with asymptomatic brain metastases may be included.]
2. Currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3 weeks prior) ). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
3. Osimertinib had to be withheld or administered at reduced dosage for toxicity management for more than 7 days or persistent unresolved toxicities which preclude study treatment.
4. Any unresolved toxicities other than osimertinib from prior therapy greater than CTCAE grade 1 at the time of starting study treatment, with the exception of alopecia and grade 2 prior platinum-therapy–related neuropathy.
5. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib. History of hypersensitivity to any of the chemotherapy drugs used.
6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
7. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
8. Any of the following cardiac criteria:
a. Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value
b. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block.
c. Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, electrolyte abnormalities (including: Serum/plasma potassium < LLN; Serum/plasma magnesium < LLN; Serum/plasma calcium < LLN), congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes. [Note: Electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia) can be corrected to be within normal ranges prior to first dose. No more than two re-tests may be performed in order to meet this criterion.]
9. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
10. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
a. Absolute neutrophil count below lower limit of normal (<LLN) *
b. Platelet count below lower limit of normal (<LLN) *
c. Hemoglobin <90 g/L *
* The use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted.
d. Alanine aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases;
e. Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases;
f. Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert’s Syndrome [unconjugated hyperbilirubinaemia] or liver metastases;
g. Serum creatinine >1.5 times ULN concurrent with creatinine clearance 1.5 times ULN.
h. INR = 1.4 or aPTT = 40 sec during the last 7 days before chemotherapy [Subjects under therapeutic anticoagulation are permitted.]
11. Women who are pregnant or breast-feeding

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Advanced NSCLC with common EGFR-Mutation\nfortgeschrittenes nicht-kleinzelliges Lungenkarzinom mit EGFR-Mutation

MedDRA Term
Non-small cell lung cancer stage IIIB, Non-small cell lung cancer stage IV

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Tanja Gromke

tanja.gromke@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
1. Patients in the dose escalation part must be ≥ 18 years of age at the time of informed consent (ICF) signature. In the phase II part, patients ≥ 12 years of age at the time of informed consent may be eligible for enrollment (not applicable in countries where enrollment is restricted by the local health authority to patients ≥ 18 years of age). Patients must have a minimum weight of 40 kg.
2. ECOG performance status ≤ 1 for patients ≥ 18 years of age; Karnofsky performance status ≥ 70 for patients ≥ 16 and < 18 years of age; Lansky performance status ≥ 70 for patients ≥ 12 and < 16 years of age
3. Patients must be suitable and willing to undergo study required biopsies according to the treating institution’s own guidelines and requirements, if medically feasible.
For all patients in Dose Escalation
4. MUM: uveal melanoma with histologically or cytologically confirmed metastatic disease. Patient must be either treatment naive or have received any number of prior lines and progressed on most recent therapy
5. Non-MUM: advanced cutaneous or mucosal melanoma with histologically or cytologically confirmed metastatic disease that has progressed following all standard therapies or that has no satisfactory alternative therapies and has evidence of GNAQ/11 mutation based on local data
For patients in Phase II
6. Tebentafusp naïve group: Diagnosis of uveal melanoma with histologically or cytologically confirmed metastatic disease that has progressed following standard therapies or that has no satisfactory alternative therapies
7. Tebentafusp pre-treated group: Diagnosis of uveal melanoma with histologically or cytologically confirmed metastatic disease. Patients must be previously treated with tebentafusp and have progressed
8. Non-MUM: patients with diagnosis of cutaneous or mucosal melanomas harboring GNAQ/11 mutations based on local data, with histologically or cytologically confirmed metastatic disease that has progressed following all standard therapies or that has no satisfactory alternative therapies

Ausschlusskriterien
1. Malignant disease, other than that being treated in this study.
2. Active brain metastases, i.e. symptomatic brain metastases or known leptomeningeal disease.
3. Evidence of active bleeding or bleeding diathesis or significant coagulopathy (including familial) or a medical condition requiring long term systemic anticoagulation that would interfere with biopsies.
4. History of anaphylactic or other severe hypersensitivity / infusion reactions to ADCs or monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction.
5. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
= 2 weeks for fluoropyrimidine therapy
= 4 weeks for radiation therapy or limited field radiation for palliation within = 2 weeks prior to the first dose of study treatment.
= 4 weeks or = 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
= 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C.
= 4 weeks for immuno-oncologic therapy, such as CTLA-4, PD-1, or PD-L1 antagonists.
6. Clinically significant and / or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA grade = 2) or clinically significant arrhythmia despite medical treatment.

Other protocol defined criteria may apply.

Studienteilnehmende Mindestalter
12 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Melanom

Medizinischer Befund
metastatic uveal melanoma (MUM)\nother GNAQ\/11 mutant melanomas

MedDRA Term
Uveal melanoma, Metastatic melanoma, Ocular melanomas

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
1. Signed informed consent must be obtained prior to participation in the study.
2. Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow-up.
3. Adult men and women ≥ 18 years of age.
4. Histologically confirmed and documented advanced malignancies (locally advanced malignancies, non-curable by surgery or radiotherapy and metastatic disease). Disease must be measurable, including presence of at least one measurable lesion, as determined by RECIST v1.1 (Refer to Appendix
5. In the opinion of the treating investigator, patients must have received, but are not benefitting from standard therapies, be intolerant or ineligible to receive such therapy, or have no standard therapy option. At minimum the following therapies listed below must
have been given in the past for the respective disease type, as well as any other therapies deemed to be standard by local/institutional standard.
• Non-small cell lung cancer: Histologically confirmed non-squamous or squamous histology with historic PD-L1 ≥ 1% by local IHC staining. Patients must have received prior treatment that includes anti-PD(L)-1 and a platinum-based chemotherapy regimen, either in combination or in sequence, unless patient was ineligible to receive such therapy. Tumors must not have known activating alterations in EGFR, ALK, ROS1, or RET.
• Esophageal squamous cell carcinoma: Histologically confirmed esophageal squamous cell carcinoma with historic PD-L1 ≥ 1% by local IHC staining. Patients must have received prior treatment that includes a platinum-based chemotherapy regimen and if appropriate, anti- Programmed cell death protein 1 (PD-1) therapy, either in combination or separately, unless patient was ineligible to receive such therapy.
• Renal cell carcinoma: Histologically confirmed renal cell carcinoma. For clear cell histology, patients must have received prior treatment including anti-PD-(L)1 and VEGFR TKI, either in combination or in sequence, unless patient was ineligible to receive such therapy.
For dose expansion, only clear cell histology is allowed.
• HPV-associated head and neck squamous cell carcinoma: Histologically confirmed head and neck squamous cell carcinoma with historic positive p16 and PD-L1 ≥ 1% by local IHC staining. Patients must have received prior treatment that includes platinum-based chemotherapy regimen, and if appropriate, anti-PD-1 therapy, either in combination or separately, unless patient was ineligible to receive such therapy.
6. Must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution’s guidelines. The patient must be willing to undergo a new tumor biopsy at screening and during treatment. Exceptions may be granted following a documented discussion with Novartis medical monitor. Refer to Section 8.8.1 for further details regarding biopsy requirements. For the screening biopsy, exceptions may be made for patients who have recently undergone a fresh tumor biopsy outside of the screening window after documented discussion with Novartis who meet the following provisions:
• Biopsy was collected ≤ 3 months before screening
• No anti-cancer treatment was given to the patient since collection of biopsy.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Patients must have a life expectancy of 3 months or more.

Ausschlusskriterien
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. Presence of symptomatic Central Nervous System (CNS) metastases or CNS metastases that require local CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids =2 weeks prior to study entry. Patients with treated symptomatic brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study entry) and at a dose of =10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment.
2. History of allogeneic bone marrow or solid organ transplant.
3. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
• = 4 weeks for radiation therapy or limited field radiation for palliation within = 2 weeks prior to the first dose of study treatment.
• = 4 weeks or = 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
• = 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C.
• Patients who have undergone major surgery = 4 weeks prior to first dose of study treatment or who have not recovered for the surgical procedure.
4. Active previously documented or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur should not be excluded. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
5. Patients with a history of or current interstitial lung disease (ILD) or pneumonitis = Grade 2.
6. Patients who discontinued prior anti-PD-1 therapy due to an anti-PD-1-related toxicity
7. Patients who required discontinuation of treatment due to treatment-related toxicities during prior therapy directed against the same target as the drug under study in this protocol
8. Clinically significant cardiac disease or risk factors at screening including any of the following:
• Clinically significant and / or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA grade = 2), uncontrolled hypertension, defined by blood pressure = 140/90 mmHg at rest (average of 3 consecutive readings) despite medical treatment or clinically significant arrhythmia despite medical treatment.
• QT corrected with Fredericia’s (QTcF) > 470 ms on screening ECG or congenital long QT syndrome
• Acute myocardial infarction or unstable angina pectoris < 3 months prior to study entry.
9. History of severe hypersensitivity reactions to any ingredient of study drug(s) and/or their excipients which in the opinion of the investigator may pose an increased risk of serious infusion reaction.
10. Insufficient bone marrow function at screening:
a. Laboratory value meeting any of the following:
• Absolute Neutrophil Count (ANC) < 1.5 x 109/L
• Hemoglobin (Hgb) < 9.0 g/dL (without transfusion support within 7 days prior to the first dose of study drug)
• Platelets < 75 x 109/L without transfusion support within 7 days prior to the first dose of study drug
OR
b. Use of hematopoietic colony-stimulating factors (e.g. G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics, or erythroid stimulating agents =2 weeks prior to start of study treatment. If growth factors were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained
11. Insufficient hepatic or renal function at screening:
• Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN or > 5 x ULN if liver metastases are present
• Creatinine clearance < 45 mL/min (calculated using Cockcroft-Gault equation)
12. Patients who have not had resolution, except where otherwise stated in the inclusion/exclusion criteria, of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade =1 (except for alopecia, vitiligo, residual hypothyroidism requiring only hormone replacement or other endocrinopathies adequately treated with replacement therapy, ototoxicity, or peripheral neuropathy (both ototoxicity and peripheral neuropathy) if present, must be = Grade 2)
13. Malignant disease, other than that is being treated in this study. Exceptions to this criterion include the following: malignancies that were treated curatively and have not recurred within two years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
14. Patients who are taking a prohibited medication that cannot be discontinued at least seven days prior to the first dose of study treatment and for the duration of the study (see Section 6.8.2).
15. Any medical condition that would, in the investigator’s judgement, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures. Any severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgement of the investigator, would make the patient inappropriate for the study.
Novartis Confidential Page 41 of 166
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16. Infections:
• Known history of testing positive for Human Immunodeficiency Virus (HIV) infection. For countries where known HIV status is mandatory: Test HIV status during screening using a local test.
• Active Hepatitis B (HBV) and / or Hepatitis C (HCV).
a. Active HBV is defined by positive HBsAg and detectable HBV DNA level in serum. Patients with positive HBsAg and HBV DNA level below the limit of quantification can be enrolled with concurrent antiviral therapy.
b. Active HCV is defined by quantitative HCV RNA results greater than the lower detection limits of the assay.
• Active, documented COVID-19 infection
• Known history of tuberculosis
• Any serious uncontrolled (untreated or unresponsive to treatment) infection (acute or chronic), such as but not limited to those caused by bacteria, viruses, or fungi, confirmed by clinical evidence, imaging, and/or relevant positive laboratory tests (e.g., blood cultures, polymerase chain reaction (PCR) for DNA/RNA, etc).
17. Use of any live or attenuated vaccines against infectious diseases within 4 weeks of initiation of study treatment.
18. Participation in any additional, parallel, investigational drug or device studies.
19. Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy, other than replacement-dose steroids in the setting of adrenal insufficiency, within 7 days of the first dose of study treatment. Topical, inhaled, and ophthalmic steroids are allowed.
20. Pregnant or breast-feeding (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
21. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 90 days after stopping study treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), or total hysterectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
Novartis Confidential Page 42 of 166
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• Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate (generally age from 40 to 59 years), history of vasomotor symptoms (i.e., hot flush)). Women are considered not of child bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered to be not of child bearing potential.
NOTE: If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the Informed Consent form (ICF).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Phase I Studie

Medizinischer Befund
advanced solid tumors

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Bristol-Myers Squibb

Einschlusskriterien
Patients fulfilling the following criteria will be enrolled in the study:
• adult patients (at least 18 years of age at time of treatment decision)
• diagnosis of advanced or metastatic HER2 negative gastric, gastro-oesophageal junction or oesophageal adenocarcinoma whose tumours express PD-L1 with a CPS ≥5
or
• diagnosis of unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma (ESCC) with tumour cell PD-L1 expression ≥ 1%
• whose physician has decided to start a treatment with nivolumab plus chemotherapy or nivolumab plus ipilimumab (according to the German marketing authorization) for the treatment of GC, GEJ adenocarcinoma, EAC or ESCC and prior to study participation
• who provided written informed consent to participate in the study

Ausschlusskriterien
• previous malignancy within 3 years or concomitant malignancy, except: those with a 5-year overall survival rate of more than 90%, e.g. non-melanomatous skin cancer or adequately treated in situ cervical cancer.
• patients currently included in an interventional clinical trial for his/her advanced or metastatic GC, GEJ adenocarcinoma, EAC or ESCC. Patients who have completed their participation in an interventional clinical trial or who are not receiving any study drug anymore and who are only in the follow-up phase for OS can be enrolled. For blinded studies, the study drug administered needs to be known at the time of enrolment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
gastric cancer\nadvanced or metastatic gastric, gastro-oesophageal junction or oesophageal adenocarninoma

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Gemeinsamer Bundesausschuss GBA InnoFonds

info@if.g-ba.de

Gutenbergstraße 13
10587 Berlin

Indikation
Lungenkrebs

Medizinischer Befund
fortgeschrittenes nicht-kleinzelliges Lungenkarzinom\nNSCLC

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GlaxoSmithKline Research & Development Limited, Großbritannien

Einschlusskriterien
- Histologically or cytologically confirmed diagnosis of locally advanced unresectable NSCLC not eligible for curative surgery and/or definitive radiotherapy with or without chemotherapy or metastatic NSCLC (squamous or non squamous)
- No prior systemic therapy for their locally advanced or metastatic NSCLC
- Provides a fresh tumor tissue sample or archival sample collected within 6 months of screening
- PD-L1-high (TC/TPS ≥ 50%) tumor
- Measurable disease based on RECIST 1.1, as determined by the investigator
- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
- Adequate baseline organ function
- Female participants of childbearing potential must use adequate contraception

Ausschlusskriterien
- Presence of Epidermal growth factor receptor (EGFR) mutations, Anaplastic lymphoma kinase (ALK) translocations, or other known genomic aberrations or oncogenic driver mutations for which a locally approved therapy is available. All participants with non squamous histology must have been tested for EGFR mutation and ALK translocation status.
- Had major surgery within 4 weeks or lung radiation therapy within 6 months of the first dose of study intervention
- Received prior therapy with any immune checkpoint inhibitors
- Never smoker, defined as smoking <100 tobacco cigarettes in a lifetime
- History of invasive malignancy other than the disease under study within the last 5 years
- Symptomatic, untreated, or actively progressing brain metastases and/or leptomeningeal disease
- Autoimmune disease or syndrome that required systemic treatment within the past 2 years
- Receiving any form of immunosuppressive medication
- Received any live vaccine = 30 days prior to first dose of study intervention
- Any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis
- History or evidence of cardiac abnormalities = 3 months prior to enrollment
- Current unstable liver or biliary disease
- Severe infection within 4 weeks prior to randomization
- Positive for tuberculosis, human immunodeficiency virus infection, hepatitis B, or hepatitis C

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Non-small Cell Lung Cancer

MedDRA Term
Non-small cell lung cancer metastatic

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Sebastian Bauer

sebastian.bauer@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

IDRx, Inc

info@IDRX.COM

Einschlusskriterien
Phase 1
1. Male or female participants ≥18 years of age
2. Histologically or cytologically confirmed metastatic and/or surgically unresectable GIST
3. Documented progression on imatinib (Phase 1)
4. Documented pathogenic mutation in KIT OR any PDGFRA mutation other than exon 18 mutations, determined through local testing
5. At least one measurable lesion by mRECIST v1.1 for participants with GIST
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Resolution of any toxicities from prior treatment(s) to ≤ Grade 1 by NCI CTCAE v5.0 criteria, or have resolved to baseline, at the time of first dose of study drug.
8. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.

Additional for Phase 1b Exploratory Cohorts
1. For Cohort 1, progressed on imatinib only (second line therapy)
2. For Cohort 2, progressed on both imatinib and sunitinib (third line therapy) or progressed on imatinib, sunitinib, and an additional agent (i.e., regorafenib or ripretinib) (fourth line therapy)
3. For Cohort 3, progressed on at all U.S. -approved TKI therapies for KIT-mutant GIST [imatinib, sunitinib, regorafenib, and ripretinib] (fifth line or greater therapy)

Ausschlusskriterien
1. Any prior exposure to the following investigational agents NB003 or THE-630 or bezuclastinib plus sunitinib combination.
2. GIST with no documented mutation in both KIT and PDGFRA genes.
3. Any prior primary CNS malignancy or known untreated or active central nervous system metastases.
4. Has an active uncontrolled infection, including, but not limited to, the requirement for intravenous antibiotics.
5. Has significant, uncontrolled, or active cardiovascular disease.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Phase I Studie, GIST - Gastrointestinaler Stromatumor

Medizinischer Befund
Gastrointestinal Stromal Tumor (GIST)\nDigestive System Disease\nGastrointestinal Diseases\nMetastatic Cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Gilead Sciences, Inc., USA

+1 650 574 3000

Lakeside Drive 333
94404 Foster City

Einschlusskriterien
Members of all genders, races, and ethnic groups are eligible for this study.
Participants must meet all of the following inclusion criteria to be eligible for participation in this study (no waivers for participant eligibility will be permitted).
1) Participants assigned male at birth and participants assigned female at birth, 18 years of age or older, able to understand and give written informed consent.
2) Life expectancy ≥ 3 months.
3) Pathologically documented NSCLC that meets both of the criteria below:
a) Have documented evidence of Stage IV NSCLC disease at the time of enrollment (based on AJCC, Eighth Edition).
b) Have documented negative test results for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations.
Note:Tumor testing for EGFR or ALK mutations is required if status is unknown
4) Have no known genomic alterations in ROS proto-oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF), RET mutations, or other actionable driver oncogenes with approved therapies (actionable genomic alteration). Testing is not required if status is unknown.
5) Provide adequate tumor tissue from locations not radiated prior to biopsy to evaluate PD-L1 status prior to randomization.
6) Have not received prior systemic treatment for metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the start of study treatment.
7) Measurable disease by CT or MRI as per RECIST v1.1 criteria by investigator assessment.
8) ECOG PS score of 0 or 1.
9) Organ function requirement.
10) Participants assigned male at birth and participants assigned female at birth of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
11) Willing and able to comply with the requirements and restrictions in this protocol.

Ausschlusskriterien
Participants who meet any of the following exclusion criteria at screening/Day -1 are not eligible to be enrolled in this study (no waivers for participant eligibility will be offered or permitted):
1) Have mixed small-cell lung cancer (SCLC) and NSCLC histology.
2) Positive serum pregnancy test or participants who are breastfeeding or have plans to breastfeed during the study period and for the required duration of contraception use after the last dose of study drug.
3) Received prior treatment with any anti-PD-1, anti-PD-L1, or any other antibody targeting an immune checkpoint. Participants who received PD-(L)1 inhibitors as a part of treatment for early stage NSCLC including in neoadjuvant/adjuvant setting are not eligible.
4) Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
5) Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.6.3.
6) Have an active second malignancy or have had an active second malignancy within 3 years prior to enrollment. Participants with a history of malignancy that has been completely treated, with no evidence of active cancer for at least 3 years prior to enrollment, or with surgically cured tumors with low risk of recurrence (eg, nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll.
7) Have an active autoimmune disease that required systemic treatment in past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
8) Are receiving chronic systemic steroids. Use of topical, inhalational, intra-nasal, and intra-ocular steroids will be permitted.
9) Have significant third-space fluid retention (eg, ascites or pleural effusion) and is not amenable for required repeated drainage
10) Have known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to enrollment and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases and are not requiring use of steroids for at least 14 days prior to the start of study treatment. All participants with carcinomatous meningitis are excluded regardless of clinical stability.
11) Meet any of the following criteria for cardiac disease:
a) Myocardial infarction or unstable angina pectoris within 6 months of enrollment.
b) History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation.
c) NYHA Class III or greater congestive heart failure or known left ventricular ejection fraction less than 40%.
12) Active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or gastrointestinal perforation within 6 months of enrollment.
13) Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
14) Has received radiotherapy within 2 weeks prior to first dose of study intervention or radiotherapy to the lung that is > 30 Gy within 6 months of the first study treatment. Participants must have recovered to = Grade 1 from all radiation-related toxicities, not requiring corticosteroids, and have not had radiation pneumonitis.
15) Has had an allogenic tissue/solid organ transplant.
16) Have received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted.
17) Have active infection requiring treatment (eg, antibiotics).
18) Have known history of HIV-1 or 2 with uncontrolled viral load (ie, = 200 copies/mL or CD4+ T cell count < 350 cells/µL), or taking medications that may interfere with metabolism of study drugs. No HIV testing is required unless mandated by local health authority.
19) Have known acute hepatitis B, known chronic hepatitis B infection with active untreated disease, or known active hepatitis C infection. In participants with a history of HBV or HCV, participants with detectable viral loads will be excluded. No hepatitis testing is required unless mandated by local health authority.
20) Have other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Metastatic Non–Small Cell Lung Cancer With No Epidermal Growth Factor Receptor or Anaplastic Lymphoma Kinase Genomic Tumor Aberrations

MedDRA Term
Non-small cell lung cancer metastatic

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Marcel Wiesweg

marcel.wiesweg@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Janssen Research & Development, LLC

Einschlusskriterien
• Previously diagnosed with histologically or cytologically confirmed unresectable Stage IV (metastatic) non-small cell lung cancer (NSCLC) (any histology)

• May have: definitively, locally treated brain metastases that are clinically stable and asymptomatic for greater than (>) 2 weeks and who are off or receiving low-dose corticosteroid treatment (less than or equal to [<=]10 milligrams (mg) prednisone or equivalent) for at least 2 weeks prior to start of study treatment

• May have a prior malignancy (other than the disease under study) the natural history or treatment of which is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s)

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• A female participant of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study

Ausschlusskriterien
• Medical history of (non-infectious) interstitial lung disease (ILD)/pneumonitis, or has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening

• Participant has impairment of the gastrointestinal function that could affect absorption of capmatinib or is unable or unwilling to swallow tablets

• Participant has symptomatic central nervous system (CNS) metastases which are neurologically unstable or have required increasing doses of steroids >10 mg prednisone or equivalent within the 2 weeks prior to study entry to manage CNS symptoms

• Participant has uncontrolled tumor-related pain: Symptomatic lesions amenable to palliative radiotherapy (example, bone metastases, or metastases causing nerve impingement) should be treated more than 7 days prior to the administration of the first study treatment

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Lung Cancer\nNon-Small Cell Lung Cancer (NCSLC)

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Amgen Inc, USA

Einschlusskriterien
- Participant has provided informed consent prior to initiation of any study specific activities/procedures.
- Age ≥ 18 years (or legal adult age within country, whichever is older) at the time of signing the informed consent.
- Histologically or cytologically confirmed relapsed/refractory SCLC.
- Participants who progressed or recurred following 1 platinum-based regimen.
- Provision of evaluable tumor sample for central testing.
- Measurable disease as defined per RECIST 1.1 within the 21-day screening period.
- Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1.
- Minimum life expectancy of 12 weeks.
- Adequate organ function.

Ausschlusskriterien
Disease Related
- Untreated or symptomatic central nervous system (CNS) metastases with exceptions defined in the protocol.
- Diagnosis or evidence of leptomeningeal disease.
- Prior history of immune checkpoint inhibitors resulting in events defined in the protocol.

Other Medical Conditions
- Active autoimmune disease that has required systemic treatment (except replacement therapy) within the past 2 years or any other diseases requiring immunosuppressive therapy.
- History of solid organ transplantation.
- History of other malignancy within the past 2 years, with exceptions defined in the protocol.
- Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months prior to first dose of study treatment.
- History of arterial thrombosis (eg, stroke or transient ischemic attack) within 12 months prior to first dose of study treatment.
- Exclusion of HIV and hepatitis infection based on criteria per protocol.
- Receiving systemic corticosteroid therapy or any other form of immunosuppressive therapy within 7 days prior to first dose of study treatment.
- Symptoms and/or radiographic signs that indicate an acute and/or uncontrolled active systemic infection requiring antibiotics within 7 days prior to the first dose study treatment.
- Evidence of interstitial lung disease or active, non-infectious pneumonitis.
Prior/Concomitant Therapy
- Prior therapy with tarlatamab or any of the standard of care chemotherapy included as part of this trial.
- Prior therapy with any selective inhibitor of the DLL3 pathway.
- Participant received more than one prior systemic therapy regimen for SCLC.
- Prior anti-cancer therapy within 21 days prior to first dose of study treatment with exceptions defined in protocol.
- Current anti-cancer therapy such as chemotherapy, immunotherapy, or targeted therapy with exceptions.
- Use of herbal or prescription/non-prescription medications known to inhibit membrane transporters P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) within 7 days prior to the first dose of study treatment.
- Use of herbal or prescription/non-prescription medications known to be moderate or strong inhibitors of cytochrome P450 3A (CYP3A) enzymes within 7 days prior to the first dose of study treatment.
- Use of herbal or prescription/non-prescription medications known to be moderate or strong inducers of CYP3A enzymes within 28 days prior to first dose of study treatment.
- Participants who have reached the limit dose of prior treatment with cardiotoxic drugs.
- Major surgical procedures within 28 days prior to first dose of study treatment.
- Live and live-attenuated vaccines within 14 days prior to the start of study treatment.
- Inactive vaccines and live viral non-replicating vaccines within 3 days prior to the first dose of study treatment.
- Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.
Diagnostic Assessments
- Any previous diagnosis of transformed non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) activating mutation positive NSCLC that has transformed to SCLC, or mixed SCLC NSCLC histology.
Other Exclusions
- Female participants of childbearing potential unwilling to use protocol specified method of contraception during treatment and for an additional 72 days after the last dose of tarlatamab.
- Female participants who are breastfeeding or who plan to breastfeed while on study through 72 days after the last dose of tarlatamab.
- Female participants planning to become pregnant or donate eggs while on study through 72 days after the last dose of tarlatamab.
- Female participants of childbearing potential with a positive pregnancy test assessed at screening by a serum pregnancy test.
- Male participants with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 132 days after the last dose of tarlatamab.
- Male participants with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 132 days after the last dose of tarlatamab.
- Male participants unwilling to abstain from donating sperm during treatment and for an additional 132 days after the last dose of tarlatamab.
- Contraception requirements for male and female participants receiving SOC therapies are based on regional prescribing information.
- Breastfeeding restrictions for female participants receiving SOC therapies are based on regional prescribing information.
- Participant has known sensitivity or is contraindicated to any of the products or components to be administered during dosing.
- Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures.
- History or evidence of any other clinically significant disorder, condition or disease determined by the investigator or Amgen physician that would pose a risk to the subject safety or interfere with the study evaluation.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Small Cell Lung Cancer (SCLC)

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Marcel Wiesweg

marcel.wiesweg@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

AMGEN GmbH

+49 89 149096 0

Riesstraße 24
80992 München

Einschlusskriterien
101 Subject has provided informed consent prior to initiation of any study specific activities/procedures.
102 Age = 18 years.

Part 2 Cohort H:
- Pathologically documented, metastatic pancreatic cancer with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIA-certified laboratory
- Subjects may not have received treatment with a KRAS G12C inhibitor in the past
- Subjects must have had at least 1 prior treatment for metastatic disease or have refused standard of care chemotherapy or standard of care chemotherapy is contraindicated
- Neoadjuvant or adjuvant therapy will count as a line of therapy for metastatic disease if the subject progressed on or within 6 months of completion of neoadjuvant or adjuvant therapy administration.

Part 2 Cohort G:
- Pathologically documented, metastatic CRC with KRAS p.G12C mutation identified through molecular testing performed according to in-country requirements. In the United States, this test must be performed in a CLIAcertified laboratory
- Subjects may not have received treatment with a KRAS G12C inhibitor in the past
- Subjects must have received at least one prior systemic therapy for metastatic disease.
104 Subjects must be willing to undergo pretreatment tumor biopsy and tumor biopsy on treatment, if clinically feasible. If a tumor biopsy prior to treatment is not medically feasible, or if the sample has insufficient tissue for testing, subjects must be willing to provide archived tumor tissue samples (ie, formalin-fixed, paraffin-embedded [FFPE] sample) collected within the past 5 years, if available. Subjects with prior molecularly confirmed KRAS p.G12C mutation who do not have archived tissue available can be allowed to enroll without undergoing tumor biopsy upon agreement with investigator and the Medical Monitor if a tumor biopsy is not clinically feasible.
105 Measurable disease per RECIST 1.1 criteria (see Section 11.9)
106 Eastern Cooperative Oncology Group (ECOG) Performance Status of = 2.
107 Life expectancy of > 3 months, in the opinion of the investigator.
108 Ability to take oral medications and willing to record daily adherence to investigational product.
109 Corrected QT interval (QTc) = 470 msec for females and QTc = 450 msec for males (based on average of screening electrocardiogram [ECG] triplicates).
110 Adequate hematological laboratory assessments, as follows:
- Absolute neutrophil count (ANC) = 1.5 x 109/L
- Platelet count = 100 x 109/L
- Hemoglobin = 9 g/d
111 Adequate renal laboratory assessments, as follows:
- Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation = 60 ml/min/1.73 m2
112 Adequate hepatic laboratory assessments, as follows:
- AST = 2.5 x upper limit of normal (ULN) (if liver metastases are present, =5 x ULN)
- ALT = 2.5 x ULN (if liver metastases are present, = 5 x ULN)
- Total bilirubin = 1.5 x ULN for Part 1 Cohort A, Part 2 Cohorts A to E and Cohort H
- Total bilirubin = 1 x ULN for Part 1 Cohort B, Part 2 Cohort F and
Cohort G
113 Adequate coagulation laboratory assessments as follows:
- Prothrombin time (PT) or partial thromboplastin time (PTT) or activated partial thromboplastin time < 1.5 x ULN, OR international normalized ratio (INR) < 1.5 x ULN or within target range if on prophylactic anticoagulation therapy.

Ausschlusskriterien
201 Primary brain tumor
202 Active brain metastases and/or carcinomatous meningitis from non-brain tumors. Subjects who have had brain metastases or have received radiation therapy ending at least 4 weeks prior to study day 1 are eligible if they meet all of the following criteria:
a) residual neurological symptoms grade = 2;
b) on stable doses of dexamethasone, if applicable; and
c) follow-up MRI performed within 30 days shows no new lesions appearing.
Other Medical Conditions
203 History or presence of hematological malignancies unless curatively treated with no evidence of disease = 2 years
204 History of other malignancy within the past 2 years, with the following exceptions:
- Malignancy treated with curative intent and with no known active disease present for > 2 years before enrollment and felt to be at low risk for recurrence by the treating physician.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated cervical carcinoma in situ without evidence of disease.
- Adequately treated breast ductal carcinoma in situ without evidence of disease.
- Prostatic intraepithelial neoplasia without evidence of prostate cancer.
- Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ.
205 Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association [NYHA] > class II), unstable angina, or cardiac arrhythmia requiring medication
206 Gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous IV alimentation, uncontrolled inflammatory GI disease (eg, Crohn’s disease, ulcerative colitis)
207 Exclusion of hepatitis infection based on the following results and/or criteria
- Positive Hepatitis B Surface Antigen (HepBsAg) (indicative of chronic Hepatitis B or recent acute hepatitis B)
- Negative HepBsAg with a positive for hepatitis B core antibody (Hepatitis B core antibody testing is not required for screening, however if this is done and is positive, then hepatitis B surface antibody [anti-HBs] testing is necessary. Undetectable anti-HBs in this setting would suggest unclear and possible infection and needs exclusion).
- Positive Hepatitis C virus antibody: Hepatitis C virus RNA by polymerase chain reaction (PCR) is necessary. Detectable Hepatitis C virus RNA suggests chronic hepatitis C
208 Known positive test for human immunodeficiency virus (HIV)
209 History of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis
210 Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose = 1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
211 Has an active infection requiring systemic therapy.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Advanced Solid Tumors with KRAS p.G12C Mutation

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Viktor Grünwald

+49 (0)201 723-3213
urologie.studien@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Amgen Inc, USA

Einschlusskriterien
- Parts 1, 2, and 5: prior taxane exposure Participants with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (eg, abiraterone acetate and/or enzalutamide, apalutamide, darolutamide, bicalutamide, or equivalent) and have failed at least 1 (but not more than 2) taxane regimens including for mHSPC (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen). Note: A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane.
1. Dose exploration phase: Novel antiandrogen therapy must have been given for treatment of metastatic disease.
2. Dose expansion phase: participants must not have had more than 2 NHTs and 2 taxane regimens in any setting, and an additional up to 2 other systemic anti-cancer treatments are allowed (eg, anti-PD1, PARP inhibitors, radioligand therapies, sipuleucel-T, experimental agents) Note: Combinations are considered one systemic anti-cancer treatment.
- Parts 4A and 4B: prior taxane exposure
1. Participants with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide, bicalutamide or equivalent) given for hormone-sensitive prostate cancer (HSPC) or non-metastatic CRPC and have failed up to 1 taxane regimen which must have been given for HSPC only (or who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen).
2. 4A: Participants planning to receive abiraterone acetate for the first time (participants who received prior abiraterone acetate are not eligible).
3. 4B: Participants planning to receive enzalutamide for the first time (participants who received prior enzalutamide/apalutamide or daralutamide are not eligible).
- Parts 3 and 4C: no prior taxane exposure
a. Participants with histologically or cytologically confirmed mCRPC who are refractory to a novel antiandrogen therapy (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide, bicalutamide or equivalent) given in any disease setting and who are deemed medically unsuitable to be treated with a taxane regimen or have actively refused treatment with a taxane regimen.
- Participants must have undergone bilateral orchiectomy or be on continuous androgen-deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist.
- Total serum testosterone <= 50 ng/dL or 1.7 nmol/L.
- Evidence of progressive disease, defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria:
1. PSA level >= 1 ng/mL that has increased on at least 2 successive occasions at least 1 week apart.
2. nodal or visceral progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with PCGW3 modifications.
3. appearance of 2 or more new lesions in bone scan.
- Eastern Cooperative Oncology Group performance status of 0-1.
- Adequate organ function, defined as follows:
1. Hematological function:
a. absolute neutrophil count >= 1 x 10^9/L (without growth factor support within 7 days from screening assessment).
b. platelet count >= 75 x 10^9/L (without platelet transfusion within 7 days from screening assessment).
c. hemoglobin >= 9 g/dL (90 g/L) (without blood transfusion within 7 days from screening assessment).
2. Renal function:
1. estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation >= 30 ml/min/1.73 m^2.
3. Hepatic function:
a. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) (or < 5 x ULN for participants with liver involvement).
b. total bilirubin (TBL) < 1.5 x ULN (or < 2 x ULN for participants with liver metastases).
4. Cardiac function:
a. left ventricular ejection fraction > 50% (2-D transthoracic echocardiogram [ECHO] is the preferred method of evaluation; multi-gated acquisition scan is acceptable if ECHO is not available).
b. Baseline electrocardiogram (ECG) QTcF <= 470 msec.

Ausschlusskriterien
- Pathological finding consistent with pure small cell, neuroendocrine carcinoma of the prostate or any other histology different from adenocarcinoma.
- Radiation therapy within 4 weeks of first dose (or local or focal radiotherapy within 2 weeks of first dose).
- Untreated central nervous system (CNS) metastases or leptomeningeal disease. Participants with a history of treated CNS metastases are eligible if there is radiographic evidence of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study.
- Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy.
- History of arterial or venous thrombosis (eg, stroke, transient ischemic attack, pulmonary embolism, or deep vein thrombosis); for arterial thrombosis within 12 months of AMG 509 initiation; for venous thrombosis, 6 months and stable on anti-coagulation.
- Myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of AMG 509 with the exception of ischemia or non-ST segment elevation myocardial infarction controlled with stent placement and confirmed by a cardiologist more than 6 months prior to first dose of AMG 509.
- Any anti-cancer therapy or immunotherapy within 4 weeks of start of first dose, not including luteinizing hormone-releasing hormone (LHRH)/GnRH analogue (agonist/antagonist). Participants on a stable bisphosphonate or denosumab regimen for >= 30 days prior to enrollment are eligible.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
Prostate Cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
- Non-small cell lung cancer with historic PD-L1 ≥ 1%, as determined locally using a clinically accepted assay. Patients must have experienced benefit from previous anti-PD(L)1-containing therapy for at least 4 months based on investigator-assessed disease stability or response prior to developing documented disease progression.
- Renal cell carcinoma, clear cell histology, previously treated with anti-PD(L)1-containing therapy and a VEGF targeted therapy as monotherapy or in combination. Patients should have documented disease progression following anti-PD(L)1-containing therapy.
- Cutaneous melanoma, previously treated with anti-PD(L)1-containing therapy. Patients should have documented disease progression following anti-PD(L)1-containing therapy.
- Ovarian cancer, high-grade serous histology, naive to anti-PD(L)1 therapy, no more than 3 prior lines of systemic therapy for recurrent/metastatic disease.
- Nasopharyngeal carcinoma, non-keratinizing locally advanced recurrent or metastatic, naive to anti-PD(L)1 therapy.
- Locally advanced unresectable or metastatic anal cancer (squamous), thymic carcinoma, MSI-H CRC, esophagogastric cancer, mesothelioma, and HNSCC, all naive to anti-PD(L)1 therapy.
- Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening, and during therapy on the study, if medically feasible. Exceptions may be considered after documented discussion with Novartis. Patients with archival tumor tissue obtained ≤ 6 months prior to study treatment initiation do not need to undergo a new tumor biopsy at screening, if the patient has not received any anti-cancer therapy since the biopsy was taken, and if adequate tissue is available.
- Patients must have body weight > 36 kg.

Ausschlusskriterien
- Impaired cardiac function or clinically significant cardiac disease.
- Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of study.
- History of severe hypersensitivity reactions to any ingredient of study drug(s) and other mAbs and/or their excipients.
- Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur may be considered. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.
- Any evidence of interstitial lung disease (ILD) or pneumonitis, or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
- Patients who discontinued prior anti-PD-(L)1 therapy due to an anti-PD-(L)1-related toxicity (applicable to the KFA115 in combination with tislelizumab treatment arms).
- Patients with symptomatic peripheral neuropathy limiting instrumental activities of daily living.
Other protocol-defined inclusion/exclusion criteria may apply

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Phase I Studie

Medizinischer Befund
Carcinoma, Non-Small-Cell Lung\nCutaneous Melanoma\nCarcinoma, Renal Cell\nCarcinoma, Ovarian Epithelial\nNasopharyngeal Carcinoma\nCarcinoma, Thymic\nAnal Cancer\nMesothelioma\nEsophagogastric Cancer\nHigh Microsatellite Instability Colorectal Carcinoma\nSquamous Cell Carcinoma of Head and Neck

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharmaceuticals

+1 888-669-6682
novartis.email@novartis.com

1000 S Pine Island Rd #410
33324 Florida

Einschlusskriterien
* Patients with advanced unresectable or metastatic MSIhi or MMR deficient (dMMR) solid tumors who have progressed after or are intolerant to prior standard therapy.
- Arm A and C: Patients must have progressed on the most recent therapy for advanced disease including one prior line of immune checkpoint inhibitor therapy.
- Arm B: Patients may have received prior chemotherapy or targeted therapy but should not have or without prior treatment with immune checkpoint inhibitors.
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
* Measurable disease as determined by RECIST version 1.1
* HRO761 s.a. (Arm A) dose finding only: Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patients must be willing to undergo a new tumor biopsy at screening, and during therapy on the study. A biopsy from the same lesion is preferred if safe and medically feasible. Exceptions may be considered after documented discussion with Novartis.
* All patients (Arm A, B and C) will have available archival tumor tissue obtained prior to study treatment initiation (in addition to newly obtained tumor biopsy at screening for Arm A), to allow retrospective MSIhi/dMMR status confirmation.

Ausschlusskriterien
* Impaired cardiac function or clinically significant cardiac disease
* Clinically significant eye impairment
* Patients with a primary Central Nervous System (CNS) tumor or tumor metastatic to the CNS
* Human Immunodeficiency Virus (HIV) infection
* Active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Tuberculosis infection. Patients whose disease is controlled under antiviral therapy should not be excluded.
* History of severe hypersensitivity reactions to any ingredient of study drug(s)
* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., severe ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection), except for prior gastrectomy.

Indikation
Solide Tumoren

Medizinischer Befund
MSIhi or dMMR Advanced Unresectable or Metastatic Solid Tumors, Including Colorectal Cancers

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Institut für Klinische Krebsforschung IKF GmbH, Frankfurt

Einschlusskriterien
1. Has provided written informed consent
2. Patient* 18 years or older at time of signing informed consent form
3. Histologically confirmed NSCLC of squamous or non-squamous histology
4. Resectable clinical stage II, IIIA and IIIB (T3N2 only) NSCLC (according to UICC 8)
5. Adequate disease staging by PET and/or CT as per SOC (performed ≤ 42 days prior initiation of the study treatment)
6. At least 1 measurable lesion according to RECIST v1.1
7. ECOG performance status ≤ 1
8. Adequate lung and cardiac function for curative intend lung resection (R0) according to German S3 guideline
9. Eligibility to receive a platinum-based neoadjuvant chemotherapy
10. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
11. The patient is willing and able to provide liquid and tissue samples for the accompanying translation project.
12. Adequate bone marrow and renal function including the following:
o Hemoglobin ≥ 9.0 g/dL
o Absolute neutrophil count ≥ 1.0 x 109/L
o Platelets ≥ 75 x 109/L
o Calculated creatinine clearance ≥ 30 mL/min as determined by the Cockcroft-Gault equation
13. Adequate hepatic function (with stenting for any obstruction, if required) including the following:
o Serum bilirubin ≤ 3 x institutional upper limit of normal (ULN)
o AST (SGOT) / ALT (SGPT) and alkaline phosphatase ≤ 2.5x ULN
14. Female patients who are considered as women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
15. Female patients who are considered as WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as up to 5 months after the last dose of IMP. Male patients who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year during the treatment as well as at least 5 months after the last dose of IMP. Female patients who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile, see section 5.1.5) as well as azoospermic male patients do not require contraception.

Ausschlusskriterien
1. Treatment in any other clinical trial with an investigational product within 30 days before screening
2. Clinical stage I, IIIB (T4N2), IIIC, nodal NSCLC stage cN3 and stage IV NSCLC
3. Positive testing of activating (TKI-responsive) EGFR-mutation, ROS1-mutation or known ALK fusion oncogene
4. Expected pneumonectomy at baseline to achieve curative intend resection
5. Any concurrent chemotherapy, investigational product (IMP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g. hormone replacement therapy) is acceptable.
6. Malignancies other than NSCLC within 3 years prior to study inclusion with the exception of malignancies with a negligible risk of metastases or death (5-year OS > 90%) like localized prostate cancer, ductal carcinoma in situ, adequately treated carcinoma in situ of the cervix, Stage I uterine cancer, in-situ bladder cancer treated by BCG-Instillation, or non-melanoma skin carcinoma
7. History of allogeneic tissue / solid organ transplant or allogeneic stem cell transplantation
8. History of active primary immunodeficiency.
9. Clinical diagnosis of active tuberculosis.
10. Positive testing for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus (HCV) RNA indicating acute or chronic infection. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
11. Positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
12. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 5 months after the last dose of atezolizumab/tiragolumab.
13. Active or prior documented autoimmune or inflammatory disorders (including but not limited to diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis, or Wegener's syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptions to this criterion:
o Patients with vitiligo or alopecia
o Patients with hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement
o Patients with controlled Type I diabetes mellitus on an insulin regimen
o Any chronic skin condition that does not require systemic therapy
o Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
14. Active, uncontrolled inflammatory bowel disease [e.g. ulcerative colitis or Crohn's disease]. Patients in stable remission for more than 1 year may be included.
15. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, interstitial lung disease, gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
16. Current or prior use of immunosuppressive medication within 14 days before the first dose of atezolizumab/tiragolumab. The following are exceptions to this criterion:
o Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection)
o Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
o Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
17. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
18. History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia, drug-induced pneumonitis, or evidence of active pneumonitis on screening chest Computed Tomography (CT) scan.
19. Prior treatment with CD137 agonist or immune checkpoint blockade therapies, such as anti-TIGIT, anti-PD-1 and anti-PD-L1 therapeutic antibody
20. Live vaccine within 30 days prior to first dose of trial treatment
21. Known allergy or hypersensitivity to any component of the chemotherapy regimen or to the IMP or any constituents of the products
22. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
23. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.
24. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Non-small Cell Lung Cancer (NSCLC)

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Isabel Virchow

isabel.virchow@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

IKF Klinische Krebsforschung GmbH am Krankenhaus Nordwest

Einschlusskriterien
1. Have provided written informed consent
2. In the investigator’s judgement, is willing and able to comply with the study protocol including the planned surgical treatment
3. Female and male patients* ≥ 18 years of age
4. Diagnosed with histologically confirmed adenocarcinoma of the GEJ (Type I-III) or the stomach (cT2, cT3, cT4, any N category, M0), or (any T, N+, M0) that:
a. is not infiltrating any adjacent organs or structures by CT or MRI evaluation
b. does not involve peritoneal carcinomatosis
c. is considered medically and technically resectable
Note: the absence of distant metastases must be confirmed by CT or MRI of the thorax and abdomen, and, if there is clinical suspicion of osseous lesions, a bone scan. If peritoneal carcinomatosis is suspected clinically, its absence must be confirmed by laparoscopy. Diagnostic laparoscopy is mandatory in patients with T3 or T4 tumors of the diffuse type histology in the stomach.
5. No prior cytotoxic or targeted therapy
6. No prior partial or complete esophagogastric tumor resection
7. ECOG ≤ 1
8. Availability of a representative tumor specimen that is suitable for determination of PD-L1 and MSI status via central testing; PD-L1 and MSI assessment will be performed prior to randomization. The analysis requires paraffin embedded biopsy samples. Patients are included in the trial upon available results only.
9. Females of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 5 months after the last study treatment.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (has not had ≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
10. Males must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree to refrain from donating sperm, as defined below:
a. With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of 1% per year during the treatment period and for at least 3 months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period. Men with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.
11. Adequate hematological, hepatic and renal function as indicated by the following parameters:
o Leukocytes ≥ 3.000/mm³, platelets ≥ 100.000/mm3 without transfusion, absolute neutrophil count (ANC) ≥ 1500/mm3 without granulocyte colony-stimulating factor support, Hemoglobin ≥ 90 g/L (9 g/dL) - Patients may be transfused to meet this criterion.
o Bilirubin ≤ 1.5 x upper limit of normal, aspartate transaminase and alanine transaminase ≤ 2.5 x upper limit of normal, alkaline phosphatase ≤ 2.5 x upper limit of normal
o Serum creatinine ≤ 1.5 x upper limit of normal, or glomerular filtration rate > 45 ml/min (calculated using the Cockcroft-Gault formula)
o Serum albumin ≥ 25 g/L (2.5 g/dL)
o For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN; for patients receiving therapeutic anticoagulation: stable anticoagulant regimen

Ausschlusskriterien
1. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein; Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
2. Any known contraindication (including hypersensitivity) to docetaxel, 5-FU, leucovorin, or oxaliplatin.
3. Active or History of autoimmune disease including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
4. Prior allogeneic bone marrow transplantation or prior solid organ transplantation
5. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
Note: History of radiation pneumonitis within the radiation field (fibrosis) is permitted.
6. Positive test for human immunodeficiency virus (HIV)
7. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C
Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid (RNA).
8. Active tuberculosis
9. Known Dihydropyrimidine dehydrogenase (DPD) deficiency
10. Uncontrolled tumor-related pain; Patients requiring pain medication must be on a stable regimen at study entry
11. Administration of a live, attenuated vaccine within four weeks prior to start of enrollment, or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after the last dose of atezolizumab
12. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibodies
13. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is longer, prior to study enrollment
14. Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to study enrollment. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.
15. Requirement for use of denosumab during the study. Patients who are receiving denosumab for any reason (including hypercalcemia) must be willing and eligible to receive a bisphosphonate instead while in the study.
16. Significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina.
17. Clinically significant valvular defect
18. History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
19. Known central nervous system metastases
20. Peripheral polyneuropathy = NCI CTCAE grade 2
21. Serum albumin < 2.5 g/dL.
22. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
23. Serious infection requiring oral or IV antibiotics within 14 days prior to study enrollment
24. Chronic inflammatory bowel disease
25. Clinically significant active gastrointestinal bleeding
26. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment
27. Evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of any of the study medications, puts the patient at higher risk for treatment-related complications or may affect the interpretation of study results
28. Participation in another interventional clinical study = 30 days prior to study enrollment or planned participation in such a study at the same time as this study
29. Receipt of an investigational drug within 28 days prior to initiation of study drug
30. Pregnancy or breast feeding, or planning to become pregnant within 5 months after the end of treatment.
Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
locally advanced resectable adenocarcinoma of the oesophagogastric junction or the stomach

MedDRA Term
Gastrooesophageal cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Sebastian Bauer

sebastian.bauer@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Deciphera Pharmaceuticals, LLC, USA

Einschlusskriterien
1. Male or female ≥18 years of age.
2. Histologic diagnosis of GIST with co-occurring KIT exons 11+17/18 mutations confirmed by ctDNA sample.
3. Participants must have advanced GIST and radiologic progression on imatinib treatment.
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2 at screening.
5. Female participants of childbearing potential must have a negative pregnancy test at screening and prior to the first dose of study drug.
6. Participants of reproductive potential must agree to follow contraception requirements.
7. Participants must have at least 1 measurable lesion according to mRECIST v1.1 within 21 days prior to the first dose of study drug.
8. Adequate organ function and bone marrow reserve based on laboratory assessments performed at screening.
9. Resolution of all toxicities from prior therapy to Grade ≤1 (or participant baseline) within 1 week prior to the first dose of study drug.

Ausschlusskriterien
1. History of KIT exon 9 mutation or detection of KIT exon 9, 13, or 14 mutations in a ctDNA sample.
2. Has known active central nervous system metastases.
3. New York Heart Association Class II-IV heart disease, myocardial infarction within 6 months of Cycle 1 Day 1, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, or congestive heart failure.
4. Use of strong or moderate inhibitors or inducers of cytochrome P450 (CYP) 3A prior to the first dose of study drug, and consumption of grapefruit or grapefruit juice within 14 days prior to the first dose of study drug.
5. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study drug.
6. Known human immunodeficiency virus or hepatitis C infection only if the participant is taking medications that are excluded per protocol, acute or chronic hepatitis B, or acute or chronic hepatitis C infection.
7. Gastrointestinal abnormalities including, but not limited to:
- inability to take oral medication
- malabsorption syndromes
- requirement for intravenous alimentation
8. Any active bleeding excluding hemorrhoidal or gum bleeding.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes, GIST - Gastrointestinaler Stromatumor

Medizinischer Befund
Gastro-intestinale Stroma-Tumore (GIST)

Institute
Klinik für Nuklearmedizin, Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ken Herrmann

+49 (0) 201 723 2032
ken.herrmann@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Institut für Klinische Krebsforschung IKF GmbH, Frankfurt

Einschlusskriterien
1. Fully-informed written consent and locally required authorization (European Union [EU]: General Data Privacy Regulation (GDPR)) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.
2. Age ≥ 18 years.
3. Histologically documented diagnosis of locally-advanced OR limited metasized intrahepatic BTC not amenable to curative treatment (tumor resection or ablation), specified as
- Tumor being confined to the liver or
- In case of presence of extrahepatic lesions, metastasis must be stable AND of limited extent* AND patient must have a potential benefit from study participation in comparison to standard of care systemic therapy per local tumor board evaluation.
*Limited extent is defined in this protocol as presence of
-- EITHER ≤3 malignant extrahepatic lymph nodes (short axis diameter ≥3cm)
-- OR metastatic lesions in one organ other than liver (if only single lesion is present diameter MUST be < 3cm; if up to 3 lesions in one organ each lesion MUST be ≤ 1cm).
-- Presence of peritoneal or brain metastatsis excludes patients from study participation (see exclusion criterion #4)
- Tumor tissue (block or at least 4 slides) is available for translational research.
4. Patients with prior chemotherapy can be enrolled if ONE of the following criteria is met:
- Capecitabin or gemcitabine+cisplatin in the adjuvant setting
- Experienced progressive disease under gemcitabine+cisplatin therapy in the advanced setting
- Stable disease after 3 months of gemcitabine+cisplatin treatment
5. Has been considered candidate for standard-of-care Y-90 SIRT therapy per Investigator decision and after prior consultation with the tumor board if available at site and does not display contraindications against SIRT.
Contraindications against SIRT would be
- hepatic tumor load > 50%
- any Gastrointestinal deposition that cannot be corrected via angiographic techniques
- irreversibly elevated serum bilirubin
- renal insufficiency
- increased pulmonary shunt fraction being able to deliver > 16.5 mCi to the lungs
- gastrointestinal ulceration
- hepatic dysfunction
- biliary complications
- portal hypertension
- vascular injury and lymphopenia.
6. Performance status (PS) ≤ 1 (ECOG scale).
7. Body weight >30 kg
8. At least one measurable site of disease as defined by RECIST 1.1 criteria.
9. Adequate bone marrow and renal function
10. Adequate hepatic function (with stenting for any obstruction, if required)
11. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
13. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
14. Must have a life expectancy of at least 12 weeks.
15. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, meets the following criteria:
- Patients with HBV or HCV infection should be monitored for viral levels during study participation.
- Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment guidelines.
Controlled (treated) hepatitis B subjects will be allowed if they started treatment at the time point of enrollment into the study by the latest and treatment is continued during study participation and for ≥ 6 months after end of study treatment.
- HCV patients with advanced BTC are mostly not treated for their HCV infection. However, patients treated for HCV are considered suitable for inclusion if antiviral therapy has been completed ≥ 30 days prior to first administration of study drug.

Ausschlusskriterien
1. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study.
2. Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment.
3. Prior immunotherapy or use of other investigational agents, including prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4) antibody, therapeutic cancer vaccines.
4. Presence of peritoneal carcinomatosis or brain metastases.
5. Any unresolved toxicity NCI CTCAE Grade = 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
6. Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable.
7. Prior radiotherapy treatment before the first dose of any study drug.
8. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent (e.g. surgery of isolated lesions, per-cutaneous biliary drainage or biliary stenting) is acceptable.
9. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis].
10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, , serious active, uncontrolled, gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
11. History of non-infectious pneumonitis requiring steroids, or patients with Grade = 2 pneumonitis.
12. History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease = 5 years before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
13. History of leptomeningeal carcinomatosis
14. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a CT/ MRI of the brain prior to study entry.
15. History of active primary immunodeficiency
16. History of allogenic organ transplantation.
17. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies) or active hepatitis B/hepatitis C co-infection.
18. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab.
19. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 180 days after the last dose of durvalumab.
20. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product.
21. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
22. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
23. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
24. Receipt of live attenuated vaccine within 30 days prior to the first administration of any of the IMPs and without need to receive any live attenuated vaccines during study conduct and for up to 30 days after end of Durvalumab treatment or 90 days after end of Tremelimumab treatment respectively.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Tumoren der Leber und Bauchspeicheldrüse und der Gallenwege

Medizinischer Befund
Intrahepatic Biliary Tract Carcinoma

MedDRA Term
Cholangiocarcinoma non-resectable, Intrahepatic cholangiocarcinoma

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Amgen Inc, USA

Einschlusskriterien
101 Subject has provided informed consent prior to initiation of any pre-screening
study specific activities/procedures.
102 Subjects with histologically or cytologically documented malignant solid tumor
diseases co-expressing CDH3 and MSLN (by mRNA in the Cancer Genome
Atlas Program [TCGA] database), including CRC, NSCLC, mesothelioma, PDAC,
GC, HNSCC, EOC, cervical carcinoma, uterine endometrial carcinoma, and triple
negative breast cancer that is locally advanced or metastatic at pre-screening.
103 Subject has provided inform consent to the main study prior to initiation of any
study specific activities/procedures.
104 Male or female subjects age ≥ 18 years (or  legal age within the country if it is
older than 18 years) at the time of the earliest signing of the informed consent
105 Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
106 Subjects with histologically or cytologically documented malignant solid tumor
diseases that is locally advanced or metastatic at the time of screening, including
CRC, NSCLC, mesothelioma, PDAC, GC, HNSCC, EOC, cervical carcinoma,
uterine endometrial carcinoma, and triple negative breast cancer. Subjects must
have exhausted available standard of care (SOC) systemic therapy or must not
be candidates for such available therapy.
- For subjects enrolling in cohorts 5 or higher dose cohort, available positive
test result for both MSLN and CDH3 expression resulting from testing of
either an available archival tissue sample in pre-screening or screening or a
sample obtained from biopsy in a screening procedure.
- Backfill subjects must have tumor tissue that is accessible by endoscopic
biopsy or endobronchial ultrasound (EBUS) and biopsy or by core biopsy
using minimally invasive procedures.
- For subjects enrolling in cohorts 1 through 4 during dose escalation, consent
to provide archival tissue slides for IHC assessment is sufficient and
enrollment is not dependent on availability of the MSLN and CDH3
expression test result.
- Requested archival tissue sample fulfills the following criteria: A minimum of
20 freshly cut, serially sectioned, unstained slides of archived tumor tissue
(formalin fixed, paraffin embedded [FFPE] sample) or an archival block must
be available. The archival sample must have tumor content review with
 20% of tumor material pre-submission. See also Section 8.8.
107 For Part B dose expansion: subjects with at least 1 measurable lesion  10 mm
which has not undergone biopsy within 3 months of screening scan. This lesion
cannot be biopsied at any time during the study.
108 Life expectancy  3 months.
109 Adequate organ function, defined as follows:
 Hematological function:
 absolute neutrophil count  1 x 109/L (without growth factor support within
7 days from screening assessment)
 platelet count  75 x 109/L (without platelet transfusion within 7 days from
screening assessment)
 hemoglobin 10 g/dL (100 g/L) (without blood transfusion or growth factor
support within 7 days from screening assessment)
 Renal function:
 Estimated glomerular filtration rate based on Modification of Diet in Renal
Disease (MDRD) calculation  30 ml/min
 Hepatic function:
 aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
 3 x upper limit of normal ([ULN] or  5 x ULN for subjects with liver
involvement)
 total bilirubin (TBL)  1.5 x ULN (or  2 x ULN for subjects with liver
metastases); in subjects with Gilberts syndrome, enrollment will be
allowed if the level of TBL falls within the Common Terminology Criteria
for Adverse Events (CTCAE) grade 2 (ie,  3 x ULN)
 Cardiac function:
 left ventricular ejection fraction  50 (2-D transthoracic echocardiogram
[ECHO] is the preferred method of evaluation; multigated acquisition scan
[MUGA] is acceptable if ECHO is not available)
 baseline ECG Fridericia Correction Formula (QTcF)  470 msec (as
average of 3 ECGs)
110 Subjects with resolved toxicities from prior anti-tumor therapies to CTCAE
version 5.0 grade 1 or better, with the exception of:
 alopecia
 grade 2 peripheral neuropathy, which has been unchanged within the
last 2 months AND there is agreement to allow by both the investigator
and sponsor
111 For France only: Subjects affiliated to a social security scheme

Ausschlusskriterien
201 Untreated central nervous system (CNS) metastases, leptomeningeal disease, or
spinal cord compression. Subjects with a history of treated CNS metastases are
eligible if there is radiographic evidence of improvement upon the completion of
CNS-directed therapy and no evidence of interim progression between the
completion of CNS-directed therapy and the screening radiographic study.
Other Medical Conditions
202 History of other malignancy within the past 2 years, with the following exceptions:
? Malignancy treated with curative intent and with no known active disease
present for ? 2 years before enrollment and felt to be at low risk for
recurrence by the treating physician.
? Adequately treated nonmelanoma skin cancer or lentigo maligna without
evidence of disease.
? Adequately treated cervical carcinoma in situ without evidence of disease.
? Adequately treated breast ductal carcinoma in situ without evidence of
disease.
? Prostatic intraepithelial neoplasia without evidence of prostate cancer.
? Adequately treated urothelial papillary noninvasive carcinoma or carcinoma
in situ.
203 Ongoing or active infection requiring IV anti-infective therapy less than 1 week
prior to administration of a first dose of AMG 305.
Note: Simple urinary tract infections and uncomplicated bacterial pharyngitis are
permitted if responding to active treatment and after consultation with sponsor.
Screening for chronic infectious conditions is not required.
225 Subject with symptoms and/or clinical signs and/or radiographic signs that
indicate an acute and/or uncontrolled active systemic infection within 14 days
prior to the first dose of investigational product administration.
205 Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures.
206 Known interstitial lung disease.
207 Positive test for human immunodeficiency virus (HIV).
208 Exclusion of hepatitis infection based on the following results and/or criteria:
? Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic
hepatitis B or recent acute hepatitis B).
? Negative HBsAg and positive for hepatitis B core antibody: Hepatitis B virus
DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis
B virus DNA (HBV-DNA) suggests occult hepatitis B (subjects with positive
hepatitis B core antibody [HBcAb] and/or hepatitis B surface antibody
[HBsAb] accompanied by a negative HBV-DNA can be screened for
enrollment into the study, but HBV-DNA needs to be monitored every
2 months).
? Positive Hepatitis C virus antibody (HCVAb): Hepatitis C virus RNA by PCR
is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C.
226 Myocardial infarction, unstable angina, uncontrolled cardiac arrhythmia,
and/or symptomatic congestive heart failure (New York Heart Association
? class III) within 6 months of first dose of AMG 305.
Prior/Concomitant Therapy
227 Anticancer therapies including radiotherapy (with the exception of palliative
radiation, see Section 6.1.6), chemotherapy, or molecularly-targeted treatments
or tyrosine kinase inhibitors (TKI) within 4 weeks or 5 half-lives (whichever is
longer) of administration of a first dose of study treatment;
immunotherapies/monoclonal antibodies within 3 weeks of administration of a
first dose of study treatment.
210 Has had a major surgery within 4 weeks of administration of a first dose of study
treatment (excluded: biopsies and central venous catheter insertion).
211 Prior treatment with MSLN-or CDH3-targeted agent or cell therapy.
212 Autoimmune disorders requiring chronic systemic steroid therapy or any other
form of immunosuppressive therapy while on study (eg, ulcerative colitis, Crohn’s
disease). Recent or current use of inhaled steroids or physiological substitution
in case of adrenal insufficiency is not exclusionary.
228 Live and/or live-attenuated vaccines received within 28 days (or longer, if
required locally) prior to the first dose of AMG 305 with the exception of a live
viral nonreplicating vaccine for Monkeypox infection (eg, Jynneos) in
accordance with local standard of care and institutional guidelines.
Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) vaccinations
should be avoided during screening (within a minimum of 3 days from first dose
of AMG 305).

Indikation
Phase I Studie

Medizinischer Befund
Solid tumors

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
non-small cell lung cancer (NSCLC) stages I B, II or selected stages III A harboring oncogenic EGFR mutations

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Indikation
Kopf-Hals-Tumore

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Martin Schuler

martin.schuler@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

F. Hoffmann-La Roche AG

Einschlusskriterien
- Unequivocal histologically or cytologically confirmed diagnosis of unresectable Stage IIIc, per the American Joint Committee on Cancer staging system (AJCC) (Amin et al. 2017) not amenable to treatment with combined modality chemoradiation (advanced) or Stage IV (metastatic) NSCLC
- Disease progression during or after treatment with at least one prior systemic therapy but no more than three lines of prior systemic therapy in the metastatic setting
- Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- Documentation of the presence of a KRAS G12C mutation
- Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or 10-15 (15 preferred) unstained, freshly cut, serial slides with an associated pathology report
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of >= 12 weeks

Ausschlusskriterien
- Known hypersensitivity to any of the components of divarasib, or sotorasib or adagrasib
- Malabsorption syndrome or other condition that would interfere with enteral absorption
- Known concomitant second oncogenic driver
- Mixed small-cell lung cancer or large cell neuroendocrine histology
- Known and untreated, or active central nervous system (CNS) metastases
- Leptomeningeal disease or carcinomatous meningitis
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently
- Any infection that, in the opinion of the investigator, could impact patient safety, or treatment with therapeutic oral or IV antibiotics within 14 days prior to Day 1 of Cycle 1
- Prior treatment with any KRAS G12C inhibitor or pan-KRAS/RAS inhibitor
- More than 30 Gy of radiotherapy to the lung within 6 months of randomization
- Uncontrolled tumor-related pain
- Unresolved toxicities from prior anticancer therapy
- History of malignancy within 5 years prior to screening, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Non small-cell lung cancer\nKRAS G12C Lung Cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Marcel Wiesweg

marcel.wiesweg@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Daiichi Sankyo Deutschland GmbH, München

Einschlusskriterien
- Sign and date the Main Informed Consent Form (ICF), prior to the start of any study- specific qualification procedures.
- Adults ≥18 at the time the Main ICF is signed.
- Has tumor with PD-L1 TPS <50% as determined by PD-L1 IHC 22C3 pharmDx assay by central testing.
- Has provided a formalin-fixed tumor tissue sample for the measurement of TROP2 protein expression and for the assessment of other exploratory biomarkers.
- Has not been treated with systemic anticancer therapy for advanced or metastatic non-squamous NSCLC.
- Has measurable disease based on local imaging assessment using RECIST v1.1.
- Histologically documented NSCLC that meets all of the following criteria:
-- Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition).
-- Documented negative test results for epidermal growth factor receptor (EGFR), lymphoma kinase (ALK), and proto-oncogene1 (ROS1) actionable genomic alterations based on analysis of tumor tissue.
-- No known actionable genomic alterations in neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF), rearranged during transfection (RET), mesenchymal-epithelial transition factor (MET), or other actionable driver kinases with locally approved therapies.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening.
- Has an adequate treatment washout period before Cycle 1 Day 1.
- Is willing and able to participate in the collection of patient-reported outcomes (PRO) data.

Ausschlusskriterien
- Has received prior systemic treatment for advanced/metastatic NSCLC.
- Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant (for NSCLC) setting:
-- Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I.
TROP2-targeted therapy.
-- Any anti-programmed death receptor-1 (PD-1), anti-PD-L1, or anti-PD-ligand 2 (L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).
-- Any other immune checkpoint inhibitors.
- Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. For any participant receiving an approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine, please follow the vaccine label and/or local guidance.
- Has spinal cord compression or clinically active untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Uncontrolled or significant cardiovascular disease, including:
-- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >470 msec regardless of sex.
-- Myocardial infarction within 6 months prior to randomization.
-- Uncontrolled angina pectoris within 6 months prior to randomization.
-- LVEF <50% by ECHO or MUGA scan within 28 days before randomization.
-- New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening.
-- Uncontrolled hypertension within 28 days before randomization.
- Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
- History of another primary malignancy (beyond NSCLC) except for:
-- Malignancy treated with curative intent and with no known active disease =3 years before the first dose of study treatment and of low potential risk for recurrence.
-- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
-- Adequately treated carcinoma in situ without evidence of disease.
-- Participants with a history of prostate cancer (tumor/node/metastasis stage) of Stage =T2cN0M0 without biochemical recurrence or progression.
- Has a history of severe hypersensitivity reactions to either the drugs or inactive ingredients of Dato-DXd, pembrolizumab, carboplatin, cisplatin or pemetrexed.
- Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
- Has known human immunodeficiency virus (HIV) infection that is not well controlled.
- Has active or uncontrolled hepatitis B or C infection.
- Female who is pregnant or breastfeeding or intends to become pregnant.
- Any other medical conditions, including cardiac disease or psychological disorders, and/or substance abuse.
- Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
- Has active, known, or suspected autoimmune disease.
- Has clinically significant corneal disease.
- Has had an allogeneic tissue/solid organ transplantation.
- Has received prior radiotherapy =4 weeks of start of study intervention or more than 30 Gy to the lung within 6 months of Cycle 1 Day 1.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Lungenkrebs

Medizinischer Befund
Metastatic Non Small Cell Lung Cancer

Institute
Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Stefan Kasper-Virchow

+49 (0) 201 723-2040
stefan.kasper-virchow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Amgen Inc, USA

Einschlusskriterien
* Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
* Histologically or cytologically confirmed diagnosis of metastatic and/or unresectable (locally advanced) adenocarcinoma of the pancreas.
* Tumor tissue (FFPE sample) or an archival block must be available. Participants without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before dosing.
* Homozygous MTAP-deletion.
* Disease measurable as defined by RECIST v1.1.
* Adequate organ function as defined in the protocol

Ausschlusskriterien
* Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.
* Radiation therapy within 28 days of first dose.
* Major surgery within 28 days of first dose of AMG 193.
* Cardiovascular and pulmonary exclusion criteria as defined in the protocol.
* Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn's disease, ulcerative colitis).
* History of solid organ transplantation.

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
100 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Tumoren des Magen-Darm-Traktes

Medizinischer Befund
Advanced Gastrointestinal, Biliary Tract, and Pancreatic Cancers