A Study of Zanidatamab in Combination With Chemotherapy Plus or Minus Tislelizumab in Patients With HER2-positive Advanced or Metastatic Gastric and Esophageal Cancers

Study Overview
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Brief Summary
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This study is being done to find out if zanidatamab, when given with chemotherapy plus or minus tislelizumab, is safe and works better than trastuzumab given with chemotherapy. The patients in this study will have advanced human epidermal growth factor 2 (HER2)-positive stomach and esophageal cancers that are no longer treatable with surgery (unresectable) or chemoradiation, and/or have grown or spread to other parts of the body (metastatic).

Official Title
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A Randomized, Multicenter, Phase 3 Study of Zanidatamab in Combination With Chemotherapy With or Without Tislelizumab in Subjects With HER2-positive Unresectable Locally Advanced or Metastatic Gastroesophageal Adenocarcinoma (GEA)

Conditions
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Gastric Neoplasms, Gastroesophageal Adenocarcinoma, Esophageal Adenocarcinoma

Intervention / Treatment
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* Drug: Zanidatamab
* Drug: Tislelizumab
* Drug: Trastuzumab
* Drug: Capecitabine
* Drug: Oxaliplatin
* Drug: Cisplatin
* Drug: 5-Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed unresectable locally advanced, recurrent or metastatic HER2-positive gastroesophageal adenocarcinoma (adenocarcinomas of the stomach or esophagus, including the gastroesophageal junction), defined as 3+ HER2 expression by IHC or 2+ HER2 expression by IHC with ISH positivity per central assessment. Subjects with esophageal adenocarcinoma must not be eligible for combined chemoradiotherapy at the time of enrollment Assessable (measurable or non-measurable) disease as defined by RECIST 1.1 Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, assessed within 3 days prior to randomization Adequate organ function Left ventricular ejection fraction (LVEF) ≥ 50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA) Exclusion Criteria: Prior treatment with a HER2-targeted agent, with the exception of subjects who received HER2-targeted treatment for breast cancer > 5 years prior to initial diagnosis of GEA Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Prior treatment with systemic antineoplastic therapy or intraperitoneal chemotherapy for unresectable locally advanced, recurrent or metastatic GEA Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks prior to randomization. Stable, treated brain metastases are allowed (defined as subjects who are completely off steroids and anticonvulsants and are neurologically stable with no evidence of radiographic progression for at least 4 weeks prior to randomization) Known history of or ongoing leptomeningeal disease (LMD) Known additional malignancy that is not considered cured or that has required treatment within the past 3 years Known active hepatitis Any history of human immunodeficiency virus (HIV) infection Known SARS-CoV-2 infection; subjects with prior infection that has resolved per local institutions' requirements and screening guidance are eligible QTc Fridericia (QTcF) > 470 ms Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF)

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multi-cohort, open-label, multicenter study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>Trastuzumab (Herceptin®) plus physician's choice of capecitabine plus oxaliplatin (CAPOX) or 5-fluorouracil (5-FU) plus cisplatin (FP) | Drug: Trastuzumab<br>* Administered intravenously (IV)<br>* Other names: Herceptin®;Drug: Capecitabine<br>* Administered orally (PO bid)<br>Drug: Oxaliplatin<br>* Administered IV<br>Drug: Cisplatin<br>* Administered IV<br>Drug: 5-Fluorouracil<br>* Administered IV<br>|
| Experimental: Arm B<br>Zanidatamab plus physician's choice of CAPOX or FP | Drug: Zanidatamab<br>* Administered IV<br>* Other names: JZP598;Drug: Capecitabine<br>* Administered orally (PO bid)<br>Drug: Oxaliplatin<br>* Administered IV<br>Drug: Cisplatin<br>* Administered IV<br>Drug: 5-Fluorouracil<br>* Administered IV<br>|
| Experimental: Arm C<br>Zanidatamab and tislelizumab plus physician's choice of CAPOX or FP | Drug: Zanidatamab<br>* Administered IV<br>* Other names: JZP598;Drug: Tislelizumab<br>* Administered IV<br>Drug: Capecitabine<br>* Administered orally (PO bid)<br>Drug: Oxaliplatin<br>* Administered IV<br>Drug: Cisplatin<br>* Administered IV<br>Drug: 5-Fluorouracil<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) by blinded independent central review (BICR) | The time from randomization to the date of documented disease progression (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) as assessed by BICR or death from any cause | Up to 2.5 years | 
| Overall survival | The time from randomization to death due to any cause | Up to 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed objective response rate (ORR) by BICR | Number of patients who achieved a best overall response of complete response (CR) or (PR) as determined per RECIST 1.1 as assessed by BICR | Up to 2.5 years | 
| Duration of response (DOR) by BICR | The time from the first objective response (CR or PR) per BICR to documented progressive disease per RECIST 1.1 as assessed by BICR or death from any cause | Up to 2.5 years | 
| PFS per Investigator assessment | The time from randomization to the date of documented disease progression (per RECIST 1.1) as assessed by Investigator or death from any cause | Up to 2.5 years | 
| Confirmed ORR per Investigator assessment | Number of patients who achieved a best overall response of CR or PR as determined per RECIST 1.1 as assessed by Investigator | Up to 2.5 years | 
| DOR per Investigator assessment | The time from the first objective response (CR or PR) per Investigator to documented progressive disease per RECIST 1.1 as assessed by Investigator or death from any cause | Up to 2.5 years | 
| Incidence of adverse events | Number of subjects who experienced adverse events or serious adverse events | Up to 2 years | 
| Incidence of clinical laboratory abnormalities | Number of patients who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 | Up to 2 years | 
| Health-related quality of life (HRQoL) as assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (core cancer questionnaire) C30 (QLQ-C30) | Changes from baseline in the EORTC QLQ-C30 scores | Up to 2.5 years | 
| HRQoL as assessed by the EORTC Quality of Life Questionnaire (oesophago-gastric module) OG25 (QLQ-OG25) | Changes from baseline in the EORTC QLQ-OG25 scores | Up to 2.5 years | 
| HRQoL as assessed by the EuroQol 5-dimensions 5-levels (EQ-5D-5L) questionnaire | Changes from baseline in the EORTC EQ-5D-5L questionnaire scores | Up to 2.5 years | 
| Serum concentration of zanidatamab and tislelizumab |  | Up to 2 years | 
| Incidence of anti-drug antibodies (ADAs) | Number of patients who develop ADAs | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, Bispecific antibody, Biparatopic antibody, Immunotherapy, Gastric cancers, Esophageal cancers, Chemotherapy, FP, Capecitabine, Cisplatin, 5-FU, Oxaliplatin, Gastroesophageal adenocarcinoma, CAPOX, Programmed cell death receptor 1 (PD-1), Anti-PD-1, Anti PD-1, JZP598