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

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

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.