Novel Combinations in Participants With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Study Overview
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Brief Summary
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This is a Phase II, open-label, multi-drug, multi-centre study designed to assess the efficacy, safety, tolerability, pharmacokinetics, and immunogenicity of novel combination therapies in participants with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.

Detailed Description
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Approximately 240 participants will be assigned across 6 substudies, with approximately 40 evaluable participants of the confirmed recommend dose by SRC for study intervention in each corresponding substudy.

Official Title
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An Open-Label, Multi-Drug, Multi-Centre, Phase II Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Immunogenicity of Novel Combinations in Participants With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: Rilvegostomig
* Drug: Volrustomig
* Drug: FOLFOX
* Drug: XELOX
* Drug: AZD7789
* Drug: AZD0901
* Drug: 5-Fluorouracil
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older at the time of signing the ICF. Body weight > 35 kg. Previously untreated for unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Has measurable target disease assessed by the Investigator based on RECIST 1.1. ECOG PS zero or one. Life expectancy of at least 12 weeks. Adequate organ and bone marrow function. Has central lab confirmed Claudin18.2 status at screening from archival tumour collected within past 24 months or from a fresh biopsy when Substudy 3, Substudy 4 or Substudy 6 is open for recruitment. Exclusion Criteria: Participants with HER2-positive (3+ by IHC, or 2+ by IHC and positive by in situhybridisation) or indeterminate gastric or GEJ carcinoma. Untreated or progressive CNS metastatic disease, any leptomeningeal disease, or cord compression. Participants with ascites which cannot be controlled with appropriate interventions. Active infectious diseases, including tuberculosis, HIV infection, or hepatitis B/C. Uncontrolled intercurrent illness. Active or prior documented autoimmune or inflammatory disorders requiring systemic treatment with steroids or other immunosuppressive treatment. History of another primary malignancy. Previous treatment with an immune-oncology agent. Previous treatment with any modalities of Claudin18.2 target therapy or MMAE exposure (when Substudy 3, Substudy 4, or Substudy 6 is open for recruitment).

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Substudy 1<br>Volrustomig plus XELOX (oxaliplatin and capecitabine) or FOLFOX (oxaliplatin and 5-FU/CF) | Drug: Volrustomig<br>* an anti PD-1 and anti CTLA-4 bispecific antibody; IV infusion<br>Drug: FOLFOX<br>* 5-fluorouracil 400 mg/m^2 IV, oxaliplatin 85 mg/m^2, leucovorin 400 mg/m^2 (or levoleucovorin 200 mg/m^2 when locally preferred and available), day 1, 5-fluorouracil 1200 mg/m^2 IV 24 h day 1-2<br>Drug: XELOX<br>* capecitabine 1000 mg/m^2 BID, days 1 to 14, oxaliplatin 130 mg/m^2, day 1<br>|
| Experimental: Substudy 2<br>Rilvegostomig plus XELOX (oxaliplatin and capecitabine) or FOLFOX (oxaliplatin and 5-FU/CF) | Drug: Rilvegostomig<br>* an anti PD-1 and anti-TIGIT bispecific antibody; IV infusion<br>Drug: FOLFOX<br>* 5-fluorouracil 400 mg/m^2 IV, oxaliplatin 85 mg/m^2, leucovorin 400 mg/m^2 (or levoleucovorin 200 mg/m^2 when locally preferred and available), day 1, 5-fluorouracil 1200 mg/m^2 IV 24 h day 1-2<br>Drug: XELOX<br>* capecitabine 1000 mg/m^2 BID, days 1 to 14, oxaliplatin 130 mg/m^2, day 1<br>|
| Experimental: Substudy 3<br>AZD0901 plus volrustomig and 5-fluorouracil or capecitabine | Drug: Volrustomig<br>* an anti PD-1 and anti CTLA-4 bispecific antibody; IV infusion<br>Drug: AZD0901<br>* an anti Claudin18.2 ADC; IV infusion<br>Drug: 5-Fluorouracil<br>* 5-FU, IV infusion, Q3W<br>Drug: Capecitabine<br>* Oral take, Q3W<br>|
| Experimental: Substudy 4<br>AZD0901 plus rilvegostomig and 5-fluorouracil or capecitabine | Drug: Rilvegostomig<br>* an anti PD-1 and anti-TIGIT bispecific antibody; IV infusion<br>Drug: AZD0901<br>* an anti Claudin18.2 ADC; IV infusion<br>Drug: 5-Fluorouracil<br>* 5-FU, IV infusion, Q3W<br>Drug: Capecitabine<br>* Oral take, Q3W<br>|
| Experimental: Substudy 5<br>AZD7789 plus XELOX (oxaliplatin and capecitabine) or FOLFOX (oxaliplatin and 5-FU/CF) | Drug: FOLFOX<br>* 5-fluorouracil 400 mg/m^2 IV, oxaliplatin 85 mg/m^2, leucovorin 400 mg/m^2 (or levoleucovorin 200 mg/m^2 when locally preferred and available), day 1, 5-fluorouracil 1200 mg/m^2 IV 24 h day 1-2<br>Drug: XELOX<br>* capecitabine 1000 mg/m^2 BID, days 1 to 14, oxaliplatin 130 mg/m^2, day 1<br>Drug: AZD7789<br>* an anti PD 1 and anti TIM 3 bispecific antibody; IV infusion<br>|
| Experimental: Substudy 6<br>AZD0901 plus AZD7789 and 5-fluorouracil or capecitabine | Drug: AZD7789<br>* an anti PD 1 and anti TIM 3 bispecific antibody; IV infusion<br>Drug: AZD0901<br>* an anti Claudin18.2 ADC; IV infusion<br>Drug: 5-Fluorouracil<br>* 5-FU, IV infusion, Q3W<br>Drug: Capecitabine<br>* Oral take, Q3W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR (per RECIST 1.1 as assessed by Investigator) | the proportion of participants who have a confirmed complete response or confirmed partial response, as determined by the Investigator at local site per RECIST 1.1. | Through substudy completion, an average of 2 years | 
| PFS6 (per RECIST 1.1 as assessed by Investigator) | the proportion of participants alive and progression-free at 6 months. | Through substudy completion, an average of 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS per RECIST 1.1 as assessed by the Investigator | the time from the start of study intervention until progression per RECIST 1.1 as assessed by the Investigator at the local site or death due to any cause in the absence of progression. | Through substudy completion, an average of 2 years | 
| OS | the time from the start of study intervention until the date of death due to any cause. | Through substudy completion, an average of 2 years | 
| other safety related endpoints | Incidence of AEs, AESIs, and SAEs | Through substudy completion, an average of 2 years | 
| DoR per RECIST 1.1 based on Investigator assessment. | the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 by the Investigator at local site or death due to any cause in the absence of disease progression. | Through substudy completion, an average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced, Metatstatic, Gastric adenocarcinoma, GEJ adenocarcinoma, GEMINI-Gastric