A Safety and Efficacy Study of Treatment Combinations With and Without Chemotherapy in Adult Participants With Advanced Upper Gastrointestinal Tract Malignancies

Study Overview
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Brief Summary
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This is a Phase 2, open-label, parallel 3-cohort, multicenter study to evaluate the safety and preliminary clinical activity of treatment combinations with and without chemotherapy in participants with locally advanced unresectable or metastatic gastric, GEJ, and esophageal adenocarcinoma. Chemotherapy will consist of FOLFOX (oxaliplatin, leucovorin, fluorouracil).

Official Title
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A Phase 2 Trial to Evaluate the Safety and Efficacy of Combination Therapies in Patients With Advanced Upper Gastrointestinal Tract Malignancies (EDGE-Gastric)

Conditions
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Gastrointestinal Tract Malignancies

Intervention / Treatment
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* Drug: Domvanalimab
* Drug: Quemliclustat
* Drug: Zimberelimab
* Drug: Fluorouracil
* Drug: Leucovorin
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with histologically confirmed diagnosis of locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma with life expectancy ≥3 months as assessed by the Investigator Eastern cooperative oncology group (ECOG) Performance Score of 0-1 At least one measurable target lesion per RECIST v1.1. Adequate organ and marrow function Able to provide an archival tumor sample that is representative of the cancer under investigation and suitable for central PD-L1 testing Exclusion Criteria: Participants with underlying medical conditions that, in the Investigator's or Sponsor's opinion, will make the administration of investigational products hazardous Only for Cohort A: Known Human Epidermal Growth Factor Receptor 2 (HER-2) positive tumor Known untreated, symptomatic, or actively progressing central nervous system (brain) metastases. Participants with leptomeningeal metastases are excluded from enrollment. Discontinued use of prior immune checkpoint therapy due to immune related adverse events; received prior treatment with an anti-TIGIT monoclonal antibody. History of trauma or major surgery within 28 days prior to enrollment. Other protocol defined Inclusion/Exclusion criteria may apply.

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: A1: First Line - Treatment Naïve Participants<br>Domvanalimab and zimberelimab once every 4 weeks (Q4W) in addition to FOLFOX chemotherapy by intravenous (IV) infusion once every 2 weeks (Q2W) | Drug: Domvanalimab<br>* Administered as specified in the treatment arm<br>Drug: Zimberelimab<br>* Administered as specified in the treatment arm<br>Drug: Fluorouracil<br>* Administered as specified in the treatment arm<br>Drug: Leucovorin<br>* Administered as specified in the treatment arm<br>Drug: Oxaliplatin<br>* Administered as specified in the treatment arm<br>|
| Experimental: A2: First Line - Treatment Naïve Participants<br>Zimberelimab Q4W in addition to chemotherapy with FOLFOX administered by IV infusion Q2W | Drug: Zimberelimab<br>* Administered as specified in the treatment arm<br>Drug: Fluorouracil<br>* Administered as specified in the treatment arm<br>Drug: Leucovorin<br>* Administered as specified in the treatment arm<br>Drug: Oxaliplatin<br>* Administered as specified in the treatment arm<br>|
| Experimental: B1: Second Line or greater Checkpoint Inhibitor Naïve Participants<br>Domvanalimab and zimberelimab administered once every three weeks (Q3W) by IV infusion | Drug: Domvanalimab<br>* Administered as specified in the treatment arm<br>Drug: Zimberelimab<br>* Administered as specified in the treatment arm<br>|
| Experimental: B2: Second Line or greater Checkpoint Inhibitor Naïve Participants<br>Quemliclustat Q2W and zimberelimab Q4W administered by IV infusion | Drug: Quemliclustat<br>* Administered as specified in the treatment arm<br>Drug: Zimberelimab<br>* Administered as specified in the treatment arm<br>|
| Experimental: Cohort C1: Second Line or greater - Checkpoint Inhibitor Experienced Participants<br>Domvanalimab and zimberelimab Q3W administered by IV infusion | Drug: Domvanalimab<br>* Administered as specified in the treatment arm<br>Drug: Zimberelimab<br>* Administered as specified in the treatment arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incidence and severity of adverse events (AEs), serious adverse events (SAEs), and any Clinically meaningful trends in safety parameters |  | Up to 18 months | 
| Objective Response Rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 |  | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) as measured by PD-L1 Expression Level |  | Up to 18 months | 
| Overall survival (OS) |  | From date of first dose until the date of death due to any cause (approximately 18 months) | 
| Progression-free survival (PFS) as determined by the Investigator according to RECIST v1.1 |  | Up to 18 months | 
| Disease Control (complete response, partial response, or stable disease) for greater than equal to 12 weeks |  | Up to 18 months | 
| Duration of response (DOR) as determined by the Investigator according to RECIST v1.1 |  | Up to 18 months | 
| Plasma concentration of domvanalimab |  | Up to 18 months | 
| Plasma concentration of zimberelimab |  | Up to 18 months | 
| Plasma concentration of quemliclustat |  | Up to 18 months | 
| Percentage of participants with anti-drug antibodies to domvanalimab |  | Up to 18 months | 
| Percentage of participants with anti-drug antibodies to zimberelimab |  | Up to 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Domvanalimab, Quemliclustat, Zimberelimab, Esophageal adenocarcinoma, Gastric adenocarcinoma, Gastric cancer, Gastroesophageal junction cancer, Anti-PD-1 antibody, Anti-CD73, anti-TIGIT antibody