Bemarituzumab Plus Chemotherapy and Nivolumab Versus Chemotherapy and Nivolumab for FGFR2b Overexpressed Untreated Advanced Gastric and Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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The main objective of Part 1 is to evaluate the safety and tolerability of bemarituzumab plus 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) and nivolumab. The main objective Part 2 is to compare efficacy of bemarituzumab plus chemotherapy (mFOLFOX6 or capecitabine combined with oxaliplatin (CAPOX)) and nivolumab to placebo plus chemotherapy (mFOLFOX6 or CAPOX) and nivolumab as assessed by overall survival.

Official Title
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A Phase 1b/3 Study of Bemarituzumab Plus Chemotherapy and Nivolumab Versus Chemotherapy and Nivolumab Alone in Subjects With Previously Untreated Advanced Gastric and Gastroesophageal Junction Cancer With FGFR2b Overexpression

Conditions
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Gastric Cancer, Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
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* Drug: Bemarituzumab
* Drug: Nivolumab
* Drug: Chemotherapy
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Part 1 and Part 2: Adult with unresectable, locally advanced or metastatic (not amenable to curative therapy) histologically documented gastric or gastroesophageal junction adenocarcinoma Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Measurable disease or non-measurable, but evaluable disease, according to Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) Participant has no contraindications to nivolumab and either mFOLFOX6 or CAPOX chemotherapy as per local prescribing information. Participants in Part 1 must have no contraindications to mFOLFOX6. Participants in Part 2 with contraindications to mFOLFOX6 are permitted and may be administered the CAPOX regimen, if no contraindications for this regimen exist. Participants in Part 2 with contraindications to CAPOX are permitted and may be administered the mFOLFOX6 regimen, if no contraindications for this regimen exist Adequate organ function as follows: Absolute neutrophil count ≥ 1.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Hemoglobin ≥ 9 g/dL without red blood cell (RBC) transfusion within 7 days prior to the first dose of study treatment Aspartate aminotransaminase (AST) and Alanine aminotransaminase (ALT) <3 x upper limit of normal (ULN) (or < 5 x ULN if liver involvement) Total bilirubin <1.5 x ULN (or < 2 x ULN if liver involvement or Gilbert's disease) Part 1 only: Calculated or measured creatinine clearance (CrCl) of ≥ 50 mL/minute calculated using the formula of Cockcroft and Gault ([140 - Age] × Mass [kg]/[72 × Creatinine mg/dL]) (x 0.85 if female). Part 2 only: Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault ([140 - Age] × Mass [kg]/[72 × Creatinine mg/dL]) (x 0.85 if female). INR or prothrombin time (PT) < 1.5 × ULN except for participants receiving anticoagulation, who must be on a stable dose of anticoagulant therapy for 6 weeks prior to enrollment Additional Inclusion Criteria Part 2: No prior treatment for metastatic or unresectable disease except for a maximum of 1 dose of chemotherapy with or without nivolumab; prior adjuvant, neo-adjuvant, and peri-operative therapy is allowed, provided it has been completed more than 6 months prior to the first dose of study treatment Fibroblast growth factor receptor 2b (FGFR2b) ≥ 10% 2+/3+ tumor cells (TC) as determined by centrally performed immunohistochemistry (IHC) testing, based on tumor sample either archival (obtained within 6 months/180 days prior to signing pre-screening informed consent) or a fresh biopsy. Exclusion Criteria: Prior treatment with any selective inhibitor of the fibroblast growth factor (FGF)-FGFR pathway Known positive human epidermal growth factor receptor 2 (HER2) status Untreated or symptomatic central nervous system disease metastases and leptomeningeal disease Peripheral sensory neuropathy grade 2 or higher Clinically significant cardiac disease Other malignancy within the last 2 years (exceptions for definitively treated disease) Chronic or systemic ophthalmologic disorders Major surgery or other investigational study within 28 days prior to randomization Palliative radiotherapy within 14 days prior to randomization Abnormalities of the cornea that may pose an increased risk of developing a corneal ulcer 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a Phase 1b/3 study: Phase 1b (Part 1) is a single-arm open-label study, which will enroll about 20 participants Phase 3 (Part 2) is a randomized double-blind 2-arm study, which will enroll 508 participants
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Safety Lead-in: Bemarituzumab with mFOLFOX6 and Nivolumab<br>Participants will be administered bemarituzumab at different doses with mFOLFOX6 and nivolumab to determine the recommended phase 3 dose (RP3D) based on occurrence of dose-limiting toxicities (DLTs), and on an evaluation of the overall safety, tolerability, and pharmacokinetics (PK). | Drug: Bemarituzumab<br>* Bemarituzumab will be administered as intravenous (IV) infusion.<br>* Other names: AMG 552;Drug: Nivolumab<br>* Nivolumab will be administered as IV infusion.<br>Drug: Chemotherapy<br>* mFOLFOX6: 5-fluorouracil, leucovorin, and oxaliplatin will be administered as IV infusion. OR CAPOX: oxaliplatin will be administered as IV infusion and capecitabine will be administered orally.<br>|
| Experimental: Part 2: Bemarituzumab with chemotherapy (mFOLFOX6 or CAPOX) and Nivolumab<br>Participants will be administered bemarituzumab at the RP3D determined from Part 1 in combination with mFOLFOX6 and nivolumab on a 14-day cycle. Or participants will be administered bemarituzumab in combination with CAPOX and nivolumab on a 21-day cycle. | Drug: Bemarituzumab<br>* Bemarituzumab will be administered as intravenous (IV) infusion.<br>* Other names: AMG 552;Drug: Nivolumab<br>* Nivolumab will be administered as IV infusion.<br>Drug: Chemotherapy<br>* mFOLFOX6: 5-fluorouracil, leucovorin, and oxaliplatin will be administered as IV infusion. OR CAPOX: oxaliplatin will be administered as IV infusion and capecitabine will be administered orally.<br>|
| Placebo Comparator: Part 2: Placebo with chemotherapy (mFOLFOX6 or CAPOX) and Nivolumab<br>Participants will be administered placebo comparator in combination with mFOLFOX6 and nivolumab on a 14-day cycle. Or participants will be administered placebo comparator in combination with CAPOX and nivolumab on a 21-day cycle. | Drug: Nivolumab<br>* Nivolumab will be administered as IV infusion.<br>Drug: Chemotherapy<br>* mFOLFOX6: 5-fluorouracil, leucovorin, and oxaliplatin will be administered as IV infusion. OR CAPOX: oxaliplatin will be administered as IV infusion and capecitabine will be administered orally.<br>Other: Placebo<br>* Placebo will be administered as IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants Who Experienced DLTs |  | 28 days | 
| Part 1: Number of Participants Who Experienced One or More Treatment-Emergent Adverse Events (TEAEs) |  | Up to 4.5 years | 
| Part 1: Number of Participants Who Experienced One or More Related TEAEs |  | Up to 4.5 years | 
| Part 1: Number of Participants With Clinically Significant Changes in Vital Signs |  | Up to 4.5 years | 
| Part 1: Number of Participants With Clinically Significant Changes in Visual Acuity |  | Up to 4.5 years | 
| Part 1: Number of Participants With Clinically Significant Changes in Physical Examinations |  | Up to 4.5 years | 
| Part 1: Number of Participants with Clinically Significant Changes in Clinical Laboratory Tests |  | Up to 4.5 years | 
| Part 2: Overall Survival in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Up to 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Objective Response (OR) |  | Up to 4.5 years | 
| Part 1: Duration of Response (DoR) |  | Up to 4.5 years | 
| Part 1: Disease Control Rate (DCR) |  | Up to 4.5 years | 
| Part 1: Progression Free Survival (PFS) |  | Up to 4.5 years | 
| Part 1: Overall Survival |  | Up to 4.5 years | 
| Part 1: Maximum Observed Concentration (Cmax) of Bemarituzumab |  | Day 1 to up to 4.5 years | 
| Part 1: Area Under the Concentration Time Curve (AUC) of Bemarituzumab |  | Day 1 to up to 4.5 years | 
| Part 1: Observed Concentration at the End of a Dose Interval (Ctrough) of Bemarituzumab |  | Day 1 to up to 4.5 years | 
| Part 1: Number of Participants With Anti-Bemarituzumab Antibody Formation |  | Day 1 to up to 4.5 years | 
| Part 2: PFS in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Up to 4.5 years | 
| Part 2: OR in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Up to 4.5 years | 
| Part 2: Number of Participants Who Experienced One or More TEAEs |  | Up to 4.5 years | 
| Part 2: Number of Participants With Clinically Significant Changes in Vital Signs |  | Up to 4.5 years | 
| Part 2: Number of Participants With Clinically Significant Changes in Visual Acuity |  | Up to 4.5 years | 
| Part 2: Number of Participants with Clinically Significant Changes in Clinical Laboratory Tests |  | Up to 4.5 years | 
| Part 2: Overall Survival in All Randomized Participants |  | Up to 4.5 years | 
| Part 2: PFS in All Randomized Participants |  | Up to 4.5 years | 
| Part 2: Objective Response Rate (ORR) in All Randomized Participants |  | Up to 4.5 years | 
| Part 2: DoR in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Up to 4.5 years | 
| Part 2: DCR in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Up to 4.5 years | 
| Part 2: Mean Score in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Version 3.0 (QLQ-C30) Individual Scores in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Up to 4.5 years | 
| Part 2: Change From Baseline in EORTC QLQ-C30 Individual Scores in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Baseline to up to 4.5 years | 
| Part 2: Mean Score in Stomach Cancer Related Symptoms Measured by EORTC Quality of Life Questionnaire-Stomach 22 (QLQ-STO22) in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Up to 4.5 years | 
| Part 2: Change From Baseline in Stomach Cancer Related Symptoms Measured by EORTC QLQ-STO22 in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Baseline to up to 4.5 years | 
| Part 2: Mean Score of Visual Analogue Scale (VAS) Scores as Measured by EuroQol 5-dimensional (EQ-5D-5L) in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Up to 4.5 years | 
| Part 2: Change From Baseline of VAS Scores as Measured by EQ-5D-5L in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Baseline to up to 4.5 years | 
| Part 2: Time to Deterioration in Stomach Cancer Related Symptoms Measured by EORTC QLQ-STO22 in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Day 1 to up to 4.5 years | 
| Part 2: Time to Deterioration in Health-Related Quality of Life (HRQoL) Scores in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Day 1 to up to 4.5 years | 
| Part 2: Time to Deterioration in Physical Function Scores in FGFR2b ≥ 10% 2+/3+ Tumor Cell Staining Participants |  | Day 1 to up to 4.5 years | 
| Part 2: Cmax of Bemarituzumab |  | Day 1 to up to 4.5 years | 
| Part 2: Ctrough of Bemarituzumab |  | Day 1 to up to 4.5 years | 
| Part 2: Number of Participants With Anti-Bemarituzumab Antibody Formation |  | Day 1 to up to 4.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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5-Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6), Nivolumab, AMG 552, Bemarituzumab, Gastric Cancer, Gastroesophageal Junction Adenocarcinoma, FGFR2b Overexpression, Capecitabine and Oxaliplatin (CAPOX)