Phase 3 Randomized Study of Zanidatamab with Chemotherapy ± Tislelizumab vs. Trastuzumab with Chemotherapy in HER2-Positive Advanced Gastroesophageal Adenocarcinoma
- Trial ID
- 2023-510319-20-00
- Protocol
- ZWI-ZW25-301
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of **zanidatamab** in combination with chemotherapy, with or without **tislelizumab**, to the efficacy of **trastuzumab** in combination with chemotherapy in subjects with unresectable locally advanced, recurrent, or metastatic **HER2-positive gastroesophageal adenocarcinoma (GEA)**. This comparison is clinically relevant as it aims to determine the most effective treatment regimen for improving outcomes in patients with this aggressive cancer type.
Secondary objectives include:
- Further comparing the efficacy of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab to chemotherapy with trastuzumab.
- Assessing the contribution of components of tislelizumab in combination with zanidatamab and chemotherapy.
- Evaluating the safety and tolerability of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab.
- Evaluating the effect of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab on health-related quality of life (HRQoL).
- Evaluating the pharmacokinetics (PK) of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab.
- Evaluating the PK of tislelizumab in combination with chemotherapy and zanidatamab.
- Evaluating the immunogenicity of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab.
- Evaluating the immunogenicity of tislelizumab in combination with chemotherapy and zanidatamab.
Participants
The clinical trial involves a total of **668 participants** diagnosed with **Gastroesophageal Adenocarcinoma (GEA)**, specifically those with unresectable locally advanced, recurrent, or metastatic HER2-positive conditions. The study population includes both male and female subjects, with age categories spanning from adults to the elderly. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of HER2-positive gastroesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, and adequate organ function. The trial also considers vulnerable populations. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection process ensures that participants have assessable disease as defined by RECIST 1.1 and a left ventricular ejection fraction (LVEF) of at least 50%. The trial aims to evaluate the efficacy of zanidatamab in combination with chemotherapy, with or without tislelizumab, compared to trastuzumab combined with chemotherapy.
Plans and Procedures
The clinical trial is a **randomized**, **multicenter**, **Phase 3** study designed to evaluate the efficacy of **zanidatamab** in combination with chemotherapy, with or without **tislelizumab**, compared to **trastuzumab** in combination with chemotherapy in subjects with unresectable locally advanced, recurrent, or metastatic **HER2-positive gastroesophageal adenocarcinoma** (GEA). The trial employs a **double-blind** and **controlled** design to ensure unbiased results. The estimated duration of the trial is from October 28, 2021, to June 1, 2027, with the primary analysis of progression-free survival (PFS) expected approximately seven months after the last subject is randomized.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed HER2-positive GEA, assessable disease per RECIST 1.1, and adequate organ function. Following randomization, participants will attend regular follow-up visits for treatment administration and monitoring of efficacy and safety endpoints. The primary endpoints include PFS and overall survival (OS), assessed by blinded independent central review (BICR). Secondary endpoints encompass objective response rate (ORR), duration of response (DOR), and changes in health economics and outcomes research/patient-reported outcomes (HEOR/PRO) parameters.
The expected length of participant involvement is up to 756 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial aims to provide comprehensive data on the comparative efficacy of the investigational treatments, contributing to the advancement of therapeutic options for patients with HER2-positive GEA.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Capecitabine** is utilized in the study as a **prodrug** in the form of a film-coated tablet. It is administered orally with a maximum daily dose of 2000 mg/m² and a total dose not exceeding 28000 mg/m² over a treatment period of 756 days. This medication is not a pediatric formulation and is classified under the role of an auxiliary treatment in the trial.
**Tislelizumab** is an investigational drug provided as a solution for infusion. It is administered via intravenous infusion with a maximum daily and total dose of 200 mg. The treatment period is set for 756 days. Tislelizumab is not a pediatric formulation and is categorized as a test product in the trial.
**JZP598**, containing the active substance **zanidatamab**, is provided as a powder for concentrate for solution for infusion. It is administered intravenously with a maximum daily and total dose of 2400 mg over a treatment period of 756 days. This investigational drug is designated as an orphan drug and serves as a test product in the study.
**Loperamide** is used as a chemical auxiliary treatment in the form of hard capsules. It is administered orally with a maximum daily dose of 8 mg and a total dose not exceeding 168 mg over the course of 756 days. This medication is not a pediatric formulation.
**Trastuzumab** is employed as a comparator treatment in the form of a powder for solution for injection. It is administered intravenously with a maximum daily and total dose of 8 mg/kg. The treatment period is set for 756 days. Trastuzumab is classified as a biologic product and is not a pediatric formulation. The product has been relabeled and QP released for the trial.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**, both evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). PFS will be assessed by a blinded independent central review (BICR), and the primary analysis will occur once the target event count is reached, estimated to be 7 months after the last subject is randomized. Interim analyses of OS will also be conducted at this time.
Secondary endpoints encompass a range of measures: the **Confirmed Objective Response Rate (ORR)** and **Duration of Response (DOR)**, both assessed by BICR using RECIST 1.1, and PFS as per investigator assessment. Additionally, changes from baseline in health economics and outcomes research/patient-reported outcomes (HEOR/PRO) parameters will be evaluated. Pharmacokinetic parameters, including serum concentrations for **zanidatamab** and **tislelizumab**, will also be measured.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 1.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 ISHpositivity per central assessment. Subjects with esophageal adenocarcinoma must not be eligible for combined chemoradiotherapy at the time of enrollment. 2.Assessable (measurable or non-measurable) disease as defined by RECIST 1.1. 3.Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, assessed within 3 days prior to randomization 4.Adequate organ function 5.Left ventricular ejection fraction (LVEF) ≥ 50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA)
Exclusion Criteria
- 1.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. 2.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. 3. Prior treatment with systemic antineoplastic therapy or intraperitoneal chemotherapy for unrespectable locally advanced, recurrent or metastatic GEA. 4.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 anticonvulsantsand are neurologically stable with no evidence of radiographic progression for at least 4 weeks prior to randomization). 5.Known history of or ongoing leptomeningeal disease (LMD). 6.Known additional malignancy that is not considered cured or that has required treatment within the past 3 years. 7.Known active hepatitis 8.Any history of human immunodeficiency virus (HIV) infection 9.Known SARS-CoV-2 infection; subjects with prior infection that has resolved per local institutions' requirements and screening guidance are eligible 10.Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF). 11.QTc Fridericia (QTcF) > 470 ms.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 28 Oct 2021 | 18 |
 Estonia | Not Recruiting | 28 Oct 2021 | 2 |
 France | Not Recruiting | 28 Oct 2021 | 41 |
 Germany | Not Recruiting | 28 Oct 2021 | 5 |
 Greece | Not Recruiting | 28 Oct 2021 | 8 |
 Ireland | Not Recruiting | 28 Oct 2021 | 6 |
 Italy | Not Recruiting | 28 Oct 2021 | 34 |
 The Netherlands | Not Recruiting | 28 Oct 2021 | — |
 Poland | Not Recruiting | 28 Oct 2021 | 9 |
 Portugal | Not Recruiting | 28 Oct 2021 | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CAPECITABINE | Other | — | ORAL | 2000 | 756 | SUB12474MIG |
JZP598 | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 2400 | 756 | PRD10444188 |
LOPERAMIDE | Other | — | ORAL | 8 | 756 | SUB08572MIG |
Tislelizumab | Test | SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 200 | 756 | PRD5423108 |
TRASTUZUMAB | Comparator | — | INTRAVENOUS | 8 | 756 | SUB12612MIG |
Oxaliplatin 5 mg/ml concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 130 | 756 | PRD988142 |