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

Phase 3RecruitingNCT06764875

AstraZeneca840 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

840

Conditions

HER2-positive Gastric Cancer Gastroesophageal Junction Adenocarcinoma

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. HER2 positive for gastric cancer on a tumor biopsy. 2. PD-L1 combined positive score (CPS) ≥ 1. 3. Provision of tumor tissue sample from recent biopsy adequate for HER2 and PD-L1 testing. 4. Previously untreated, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma. 5. WHO or Eastern Cooperative Oncology Group performance status of 0 or 1. 6. Have measurable target disease assessed by the Investigator based on RECIST v1.1. 7. Have adequate organ and bone marrow function. 8. LVEF ≥ 50% within 28 days before randomization. 9. Adequate treatment washout period before randomization. Exclusion Criteria: 1. Lack of physiological integrity of the upper gastrointestinal tract. 2. Known dihydropyrimidine dehydrogenase enzyme deficiency. 3. Contraindication to pembrolizumab or trastuzumab, contraindications to fluoropyrimidine (5-FU and capecitabine) or platinum (cisplatin and oxaliplatin) treatment as per local label. 4. 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. 5. Persistent toxicities caused by previous anti-cancer therapy. 6. 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. 7. Uncontrolled infection including tuberculosis and active hepatitis A infection. 8. Uncontrolled infection requiring intravenous (IV) antibiotics, anti-virals, or antifungals. 9. Recent receipt of live, attenuated vaccine. 10. Chronic/active HBV or HCV infection unless controlled. 11. Clinically significant cardiac or psychological conditions. 12. Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment. 13. History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. 14. Lung-specific intercurrent clinically significant illnesses. 15. Any active non-infectious skin disease requiring systemic treatment. 16. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). 17. History of any of the following: drug-induced severe cutaneous adverse reaction. 18. Any concurrent antic-ancer treatment with the exception of receptor activator of nuclear factor kappa-B ligand inhibitors. 19. 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. 20. Current or prior use of immunosuppressive medication within 14 days before study intervention.

Outcomes

Primary Outcomes

Progression free survival (PFS)

PFS is defined as time from randomization until progression per RECIST v1.1, or death due to any cause.

Time frame: Up to approximately 6 years

Overall Survival (OS)

OS is defined as time from randomization until the date of death due to any cause.

Time frame: Up to approximately 6 years

Secondary Outcomes

Objective Response Rate (ORR)

ORR according to RECIST v1.1. ORR is defined as the proportion of participants who have a complete response (CR) or partial response (PR).

Time frame: Up to approximately 6 years

Duration of Response (DoR)

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.

Time frame: Up to approximately 6 years

Proportion of all randomized participants alive and progression-free at 6 months (PFS6)

Proportion of all randomized participants alive and progression-free at 6 months calculated for progression.

Time frame: Up to 6 months

Proportion of all randomized participants alive and progression-free at 12 months (PFS12)

Proportion of all randomized participants alive and progression-free at 12 months calculated for progression.

Time frame: Up to 12 months

Time to second progression or death (PFS2)

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.

Time frame: Up to approximately 6 years

Occurrence of adverse events (AEs) and serious adverse events (SAEs)

Occurrence of AEs and SAEs will be graded according to the revised NCI CTCAE v5.0.

Time frame: Up to approximately 6 years

Pharmacokinetics (PK) of rilvegostomig, T-DXd, total anti-HER2 antibody, DXd, 5-FU, and capecitabine in serum

Concentration of rilvegostomig, T-DXd, total anti-HER2 antibody, DXd, fluoropyrimidine, and capecitabine in serum or plasma.

Time frame: Up to approximately 6 years

Immunogenicity of rilvegostomig and T-DXd assessed by the presence of antidrug antibodies (ADAs) for rilvegostomig and T-DXd

Presence of antidrug antibodies (ADAs) for rilvegostomig and T-DXd (confirmatory results: titers and neutralizing antibodies for confirmed positive samples).

Time frame: Up to approximately 6 years

Increase in enteral feeding assistance and eating difficulties

Time to first-confirmed worsening of eating symptoms or initiation of feeding assistance among all participants, as randomized.

Time frame: Up to approximately 6 years

Proportion of time on study intervention with high side-effect bother

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).

Time frame: Up to approximately 6 years

Overall Survival at 12 months (OS12)

Proportion of all randomized participants alive at 12 months.

Time frame: Up to 12 months

Overall Survival at 24 months (OS24)

Proportion of all randomized participants alive at 24 months.

Time frame: Up to 24 months

Pharmacokinetics (PK) of rilvegostomig, T-DXd, total anti-HER2 antibody, DXd, 5-FU, and capecitabine in serum

PK parameters (peak and trough concentrations).

Time frame: Up to approximately 6 years

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

Overview

Conditions

Interventions

Eligibility

Locations (302)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts