Phase 3 Randomized Study of Zolbetuximab, Pembrolizumab, and Chemotherapy in HER2-Negative, CLDN18.2-Positive, PD-L1-Positive Gastric Adenocarcinoma

The primary objective of this study is to evaluate the **efficacy** of **zolbetuximab** in combination with **pembrolizumab** and chemotherapy (CAPOX or mFOLFOX6) compared with placebo plus pembrolizumab and chemotherapy as a first-line treatment for patients with locally advanced unresectable or metastatic **gastric adenocarcinoma** or **gastroesophageal junction adenocarcinoma**. This evaluation is clinically relevant as it aims to determine the potential benefits of adding zolbetuximab to the current standard treatment regimen, potentially improving outcomes for patients with HER2-negative, Claudin 18.2-positive, and PD-L1-positive tumors.

Secondary objectives include:

• Evaluating the activity and efficacy of zolbetuximab plus pembrolizumab and chemotherapy compared with placebo plus pembrolizumab and chemotherapy.
• Assessing the safety and tolerability of zolbetuximab in combination with pembrolizumab and chemotherapy.
• Evaluating the pharmacokinetics of zolbetuximab in combination with pembrolizumab and chemotherapy.
• Evaluating the immunogenicity profile of zolbetuximab in combination with pembrolizumab and chemotherapy.

The clinical trial involves a total of **299 participants** diagnosed with **Gastric Adenocarcinoma**, **Gastric Cancer**, or **Gastroesophageal Junction Adenocarcinoma**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a positive PD-L1 expression in their tumors, histologically confirmed gastric or gastroesophageal adenocarcinoma, and radiographically confirmed locally advanced, unresectable, or metastatic disease. The trial excludes vulnerable populations and requires participants to have an Eastern Cooperative Oncology Group performance status of 0 to 1, a predicted life expectancy of at least 12 weeks, and a HER2-negative tumor. Additionally, participants must be candidates for mFOLFOX6 or CAPOX chemotherapy combined with pembrolizumab. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the efficacy of **zolbetuximab** in combination with **pembrolizumab** and chemotherapy (CAPOX or mFOLFOX6) compared to a placebo in the first-line treatment of locally advanced unresectable or metastatic **gastric adenocarcinoma** or **gastroesophageal junction adenocarcinoma**. The trial aims to assess overall survival as the primary endpoint, with secondary endpoints including progression-free survival, objective response rate, duration of response, and safety and tolerability. The trial is expected to commence recruitment on July 1, 2025, and conclude by January 31, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, tumor characteristics, and disease status. Following randomization, participants will receive treatment and attend regular follow-up visits to monitor efficacy and safety outcomes. These visits will include assessments such as imaging studies, laboratory tests, and evaluations of adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected length of participant involvement in the study is determined by the treatment regimen, with a maximum treatment period of up to 14 cycles for certain chemotherapy agents. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on the participant's best interest. The study will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of several experimental and non-experimental treatments for the first-line treatment of locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. The experimental medication **Zolbetuximab** is administered as a **powder for concentrate for solution for infusion**. It is a chimeric monoclonal antibody targeting claudin-18 splice variant 2, with a maximum daily dose of 800 mg/m². The route of administration is **intravenous use**, and the treatment period is limited to 1 cycle. Zolbetuximab is of biological/biotechnological origin and is designated as an orphan drug.

**Pembrolizumab**, marketed as Keytruda, is another experimental treatment used in this trial. It is provided as a **concentrate for solution for infusion** with a maximum daily dose of 400 mg. The administration route is **intravenous infusion**, and the treatment period is 1 cycle. Pembrolizumab is a protein-based therapeutic agent.

The chemotherapy regimen includes **Oxaliplatin**, **Fluorouracil**, **Folinic Acid**, and **Capecitabine**. Oxaliplatin is administered as a **solution for infusion** with a maximum daily dose of 130 mg/m², delivered via **infusion** over a treatment period of 2 cycles. Fluorouracil is provided as a **solution for injection** with a maximum daily dose of 2400 mg/m², administered through **intravenous bolus injection/IV infusion** over 2 cycles. Folinic Acid is also administered as a **solution for injection** with a maximum daily dose of 400 mg/m² via **infusion** over 2 cycles. Capecitabine is given as a **film-coated tablet** with a maximum daily dose of 2000 mg/m², administered **orally** over a treatment period of 14 days.

Additionally, **Sodium chloride 0.9% intravenous infusion** is used as a non-experimental treatment, serving as a placebo in the trial. It is administered as needed to maintain hydration and electrolyte balance during the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy of the combination of Zolbetuximab, Pembrolizumab, and chemotherapy compared to placebo plus Pembrolizumab and chemotherapy in the specified patient population.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival**, defined as the time from the date of randomization until the documented date of death from any cause. Secondary endpoints include **Progression-free Survival**, which is the time from randomization until radiologic progressive disease or death, and **Objective Response Rate**, defined as the proportion of participants achieving a complete or partial response. Additionally, the **Duration of Response** will be measured from the first response until disease progression or death. Safety and tolerability will be evaluated through adverse events, electrocardiogram, vital signs, Eastern Cooperative Oncology Group performance status, and safety laboratory assessments according to NCI-CTCAE version 5.0. Serum concentrations of **zolbetuximab** will be measured at the end of infusion and immediately prior to dosing at multiple time points. The frequency of antidrug antibody-positive participants will also be assessed.