An Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Gastric or Gastroesophageal Junction Carcinoma

Study Overview
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Brief Summary
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This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in participants with advanced gastric carcinoma (GC) or gastroesophageal junction carcinoma (GEJC). The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, and modify the participant population. Cohort 1 will enroll participants with inoperable locally advanced, metastatic, or advanced GC or GEJC, with adenocarcinoma confirmed as the predominant histology, who have not received prior systemic therapy for advanced or metastatic disease. Eligible participants will initially be randomly assigned to one of treatment arms (Stage 1). Participants who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may be eligible to receive treatment with a different treatment combination (Stage 2). When a Stage 2 treatment combination is available, this will be introduced by amending the protocol.

Official Title
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A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Gastric or Gastroesophageal Junction Carcinoma (MORPHEUS C-Gastric and Gastroesophageal Junction Carcinoma)

Conditions
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Gastric and Gastroesophageal Junction Carcinoma

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Capecitabine
* Drug: Oxaliplatin
* Drug: Tiragolumab
* Drug: AB011


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Stage 1: ECOG Performance Status of 0 or 1 Inoperable locally advanced, metastatic, or advanced GC or GEJC, with adenocarcinoma confirmed as the predominant histology No prior systemic treatment for advanced or metastatic disease Life expectancy >= 3 months, as determined by the investigator Human epidermal growth factor receptor 2 (HER2)-negative tumors Measurable disease according to RECIST v1.1 Adequate hematologic and end-organ function Patients without hepatitis B virus (HBV) infection at screening Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening Negative HIV test at screening For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, as outlined for each specific treatment arm For men: agreement to remain abstinent or use contraception, and agreement to refrain from donating sperm, as outlined for each specific treatment arm Exclusion Criteria for Stage 1: Prior treatment with CD137 agonists or immune checkpoint blockade therapies Treatment with investigational therapy within 28 days prior to initiation of study treatment Any contraindications to any of the study drugs of the chemotherapy regimen Eligible only for the control arm Patients with a signet ring cells dominant carcinoma Symptomatic, untreated, or actively progressing CNS metastases History of leptomeningeal disease Active or history of autoimmune disease or immune deficiency Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina History of malignancy other than GC or GEJC within 2 years prior to initiation of study treatment, with the exception of malignancies with a negligible risk of metastasis or death Exclusion Criteria for Tiragolumab-Containing Arm: Prior treatment with an anti-TIGIT agent Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Atezo + CAPOX (capecitabine + oxaliplatin)<br>Participants in the atezolizumab plus capecitabine plus oxaliplatin in Stage 1 will receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV infusion on Day 1 of each 21 day cycle. Treatment until progressive disease.<br>* Other names: Tecentriq;Drug: Capecitabine<br>* Capecitabine is administered orally twice daily on Days 1-14 of each 21 day cycle. Treatment for up to six cycles.<br>Drug: Oxaliplatin<br>* Oxaliplatin is administered by IV infusion on Day 1 of each 21 day cycle. Treatment for up to six cycles.<br>|
| Experimental: Atezo + CAPOX +Tir<br>Participants in the atezolizumab plus capecitabine plus oxaliplatin plus tiragolumab arm in Stage 1 will receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV infusion on Day 1 of each 21 day cycle. Treatment until progressive disease.<br>* Other names: Tecentriq;Drug: Capecitabine<br>* Capecitabine is administered orally twice daily on Days 1-14 of each 21 day cycle. Treatment for up to six cycles.<br>Drug: Oxaliplatin<br>* Oxaliplatin is administered by IV infusion on Day 1 of each 21 day cycle. Treatment for up to six cycles.<br>Drug: Tiragolumab<br>* Tiragolumab is administered by IV infusion on Day 1 of each 21 day cycle.<br>|
| Experimental: Atezo + CAPOX + AB011<br>Participants in the atezolizumab plus capecitabine plus oxaliplatin plus AB011 arm in Stage 1 will receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab is administered by IV infusion on Day 1 of each 21 day cycle. Treatment until progressive disease.<br>* Other names: Tecentriq;Drug: AB011<br>* AB011 is administered by IV infusion on Day 1 of each 21 day cycle. Treatment until progressive disease.<br>|
| Active Comparator: CAPOX + AB011<br>Participants in the capecitabine plus oxaliplatin plus AB011 arm in Stage 1 will receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator. | Drug: AB011<br>* AB011 is administered by IV infusion on Day 1 of each 21 day cycle. Treatment until progressive disease.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants with a complete response or a partial response on two consecutive occasions >= 4 weeks apart during Stage 1, as determined by the investigator according to RECIST v1.1. | Up to approximately 3-5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS after randomization is defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) in Stage 1, as determined by the investigator according to RECIST v1.1. | Randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) (up to approximately 3-5 years) | 
| Overall Survival (OS) | OS after randomization, defined as the time from randomization to death from any cause, regardless of stage. | Randomization to death from any cause (up to approximately 3-5 years) | 
| Overall Survival (OS) | OS at specific timepoints. | At specific timepoints (up to approximately 3-5 years) | 
| Duration of Response (DOR) | DOR is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first) in Stage 1, as determined by the investigator according to RECIST v1.1. | First occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first) (up to approximately 3-5 years) | 
| Disease Control Rate | Disease control rate is defined as the proportion of participants with stable disease for >= 12 weeks or a complete or a partial response, as determined by the investigator according to RECIST v1.1. | Up to approximately 3-5 years | 
| Percentage of Participants with Adverse Events in Stage 1 | Percentage of participants with adverse events in Stage 1. | Baseline through approximately end of study (approximately 3-5 years) | 
| Percentage of Participants with Adverse Events in Stage 2 | Percentage of participants with adverse events in Stage 2. | Baseline through approximately end of study (approximately 3-5 years) |