A Phase Ⅲ Study of Rilvegostomig in Combination With Fluoropyrimidine and Trastuzumab Deruxtecan as the First-line Treatment for HER2-positive Gastric Cancer

Phase 3

Not yet recruiting

• Conditions: HER2-positive Gastric Cancer; Gastroesophageal Junction Adenocarcinoma
• Interventions: Drug: Rilvegostomig; Drug: Trastuzumab; Drug: Trastuzumab deruxtecan; Drug: Pembrolizumab; Drug: 5-fluorouracil; Drug: Capecitabine; Drug: Cisplatin; Drug: Oxaliplatin

• Registration Number: NCT06764875
• Lead Sponsor: AstraZeneca

Brief Summary

This is a Phase Ⅲ, randomized, open-label, Sponsor-blinded, 3-arm, global, multicenter study assessing the efficacy and safety of rilvegostomig in combination with fluoropyrimidine and T-DXd (Arm A) compared to trastuzumab, chemotherapy, and pembrolizumab (Arm B) in HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma participants whose tumors express PD L1 CPS ≥ 1. Rilvegostomig in combination with trastuzumab and chemotherapy will be evaluated in a separate arm (Arm C) to assess the contribution of each component in the experimental arm.

Detailed Description

The purpose of this study is to assess the efficacy and safety of rilvegostomig in combination with fluoropyrimidine and T-DXd (Arm A) compared to trastuzumab, chemotherapy, and pembrolizumab (Arm B) in HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma participants whose tumors express PD L1 CPS ≥ 1. Rilvegostomig in combination with trastuzumab and chemotherapy will be evaluated in a separate arm (Arm C) to assess the contribution of each component in the experimental arm.

This study will be conducted at up to 200-250 sites globally in approximately 25 countries.

Study Timeline

• Study First Submitted: 2024-12-12
• Status Verified: 2025-01
• Study First Submitted QC: 2025-01-07
• Last Update Submitted: 2025-01-07
• Study First Posted: 2025-01-09
• Last Update Posted: 2025-01-09
• Study Start: 2025-03-28
• Primary Completion: 2029-04-27
• Study Completion: 2030-12-09

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 840

Inclusion Criteria

• HER2 positive for gastric cancer on a tumor biopsy.
• PD-L1 combined positive score (CPS) ≥ 1.
• Provision of tumor tissue sample from recent biopsy adequate for HER2 and PD-L1 testing.
• Previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma.
• WHO or Eastern Cooperative Oncology Group performance status of 0 or 1.
• Have measurable target disease assessed by the Investigator based on RECIST v1.1.
• Have adequate organ and bone marrow function within 14 days before randomization.
• LVEF ≥ 55% within 28 days before randomization.
• Adequate treatment washout period before randomization.

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Exclusion Criteria

• Lack of physiological integrity of the upper gastrointestinal tract.
• Known dihydropyrimidine dehydrogenase enzyme deficiency.
• Contraindication to pembrolizumab or trastuzumab, contraindications to fluoropyrimidine (5-FU and capecitabine) or platinum (cisplatin and oxaliplatin) treatment as per local label.
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence.
• Persistent toxicities caused by previous anti-cancer therapy.
• Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring corticosteroid or anticonvulsant may be included in the study if they have recovered from the acute toxic effect of radiotherapy.
• Uncontrolled infection including tuberculosis and active hepatitis A infection.
• Uncontrolled infection requiring intravenous (IV) antibiotics, anti-virals, or antifungals.
• Recent receipt of live, attenuated vaccine.
• Chronic/active HBV or HCV infection unless controlled.
• Clinically significant cardiac or psychological conditions.
• Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
• History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Lung-specific intercurrent clinically significant illnesses.
• Any active non-infectious skin disease requiring systemic treatment.
• A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART).
• History of any of the following: drug-induced severe cutaneous adverse reaction.
• Any concurrent antic-ancer treatment with the exception of receptor activator of nuclear factor kappa-B ligand inhibitors.
• Have had major surgical procedure recently (excluding placement of vascular access) or recent significant traumatic injury or an anticipated need for major surgery during the study.
• Current or prior use of immunosuppressive medication within 14 days before study intervention.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A	Rilvegostomig	T-DXd + Rilvegostomig + Fluoropyrimidine (Capecitabine OR 5-FU)
Arm A	Trastuzumab deruxtecan	T-DXd + Rilvegostomig + Fluoropyrimidine (Capecitabine OR 5-FU)
Arm A	5-fluorouracil	T-DXd + Rilvegostomig + Fluoropyrimidine (Capecitabine OR 5-FU)
Arm A	Capecitabine	T-DXd + Rilvegostomig + Fluoropyrimidine (Capecitabine OR 5-FU)
Arm B	Trastuzumab	Pembrolizumab + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm B	Pembrolizumab	Pembrolizumab + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm B	5-fluorouracil	Pembrolizumab + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm B	Capecitabine	Pembrolizumab + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm B	Cisplatin	Pembrolizumab + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm B	Oxaliplatin	Pembrolizumab + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm C	Rilvegostomig	Rilvegostomig + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm C	Trastuzumab	Rilvegostomig + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm C	5-fluorouracil	Rilvegostomig + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm C	Capecitabine	Rilvegostomig + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm C	Cisplatin	Rilvegostomig + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)
Arm C	Oxaliplatin	Rilvegostomig + Trastuzumab + FP (5-FU plus cisplatin) or CAPOX (capecitabine plus oxaliplatin)

Primary Outcome Measures

Name	Time	Method
Progression free survival (PFS)	Up to approximately 6 years	PFS is defined as time from randomization until progression per RECIST v1.1, or death due to any cause.
Overall Survival (OS)	Up to approximately 6 years	OS is defined as time from randomization until the date of death due to any cause.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to approximately 6 years	ORR according to RECIST v1.1. ORR is defined as the proportion of participants who have a complete response (CR) or partial response (PR).
Duration of Response (DoR)	Up to approximately 6 years	DoR according to RECIST v1.1. DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST v1.1 or death due to any cause.
Proportion of all randomized participants alive and progression-free at 6 months (PFS6)	Up to 6 months	Proportion of all randomized participants alive and progression-free at 6 months calculated for progression.
Proportion of all randomized participants alive and progression-free at 12 months (PFS12)	Up to 12 months	Proportion of all randomized participants alive and progression-free at 12 months calculated for progression.
Time to second progression or death (PFS2)	Up to approximately 6 years	PFS2 is defined as the time from randomization to the earliest of the progression event (following the initial progression), after the first subsequent therapy, or death, where the first objective progression includes progression occurring after 2 missed visits.
Occurrence of adverse events (AEs) and serious adverse events (SAEs)	Up to approximately 6 years	Occurrence of AEs and SAEs will be graded according to the revised NCI CTCAE v5.0.
Pharmacokinetics (PK) of rilvegostomig, T-DXd, total anti-HER2 antibody, DXd, 5-FU, and capecitabine in serum	Up to approximately 6 years	PK parameters (peak and trough concentrations).
Increase in enteral feeding assistance and eating difficulties	Up to approximately 6 years	Time to first-confirmed worsening of eating symptoms or initiation of feeding assistance among all participants, as randomized.
Proportion of time on study intervention with high side-effect bother	Up to approximately 6 years	Proportion of time on study intervention with high side-effect bother relative to low side-effect burden as measured by the Patient Global Impression of Treatment Tolerability (PGI-TT).
Overall Survival at 12 months (OS12)	Up to 12 months	Proportion of all randomized participants alive at 12 months.
Overall Survival at 24 months (OS24)	Up to 24 months	Proportion of all randomized participants alive at 24 months.
Immunogenicity of rilvegostomig and T-DXd assessed by the presence of antidrug antibodies (ADAs) for rilvegostomig and T-DXd	Up to approximately 6 years	Presence of antidrug antibodies (ADAs) for rilvegostomig and T-DXd (confirmatory results: titers and neutralizing antibodies for confirmed positive samples).

Trial Locations

Locations (1)

Research Site; 🇻🇳 Vinh, Vietnam