Phase 1b/2 Study of S095029 and Pembrolizumab in MSI-H/dMMR Gastroesophageal Junction and Gastric Cancer

The primary objective of this study is to evaluate the **safety** and tolerability of the combination therapy involving S095029, an anti-NKG2A antibody, in participants with locally advanced and unresectable or metastatic MSI-H/dMMR gastroesophageal junction/gastric cancer. This evaluation is crucial for determining the recommended Phase 2 dose (RP2D) of S095029, which is essential for ensuring patient safety and optimizing therapeutic efficacy in subsequent trials.

Secondary objectives include:

• Phase 1b: Assessing the antitumor activity of S095029 in combination therapy using RECIST v1.1 and iRECIST criteria, characterizing the pharmacokinetic profile, and evaluating the immunogenicity of the combination therapy.
• Phase 2: Further assessing the antitumor activity through duration of responses, survival, and clinical benefit, evaluating the antitumor activity as per iRECIST criteria, characterizing the pharmacokinetic profile, and evaluating the immunogenicity of the combination therapy.

The clinical trial involves a total of **26 participants** diagnosed with **MSI-H/dMMR gastric cancer** or **MSI-H/dMMR gastroesophageal-junction cancer**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on a confirmed diagnosis of locally advanced, unresectable, or metastatic gastric or gastroesophageal junction adenocarcinoma, with tumors exhibiting MSI-H/dMMR status as per institutional guidelines or the College of American Pathologists. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and ethical treatment. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection criteria emphasize the histological or cytological confirmation of the disease and the specific tumor status, ensuring a focused and relevant study cohort.

The clinical trial is an **open-label**, non-randomized, Phase 1b/2 study designed to evaluate the safety, tolerability, and antitumor activity of **S095029** (anti-NKG2A antibody) as part of a combination therapy in participants with locally advanced and unresectable or metastatic **MSI-H/dMMR gastroesophageal junction/gastric cancer**. The trial is structured into two phases: Phase 1b, which focuses on assessing the safety and tolerability of the combination therapy and determining the recommended Phase 2 dose (RP2D) of S095029, and Phase 2, which aims to evaluate the antitumor activity and further assess the safety profile of the combination therapy. The trial is expected to commence recruitment on April 15, 2024, and conclude by June 1, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically or cytologically confirmed diagnosis of locally advanced and unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with MSI-H/dMMR status. Following the screening, participants will receive the investigational product via **intravenous use**. The study will include regular follow-up visits to monitor safety, tolerability, and antitumor activity, with assessments including the incidence of dose-limiting toxicities, frequency and severity of adverse events, and changes in safety laboratory values and vital signs. The end-of-study visit will mark the completion of the participant's involvement in the trial.

The expected length of participant involvement will vary depending on individual response and tolerability, with conditions for early termination including the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent. Primary endpoints include the incidence of dose-limiting toxicities and adverse events, while secondary endpoints focus on objective response, duration of response, progression-free survival, and overall survival. The trial will utilize **RECIST v1.1** and **iRECIST** criteria for assessing antitumor activity. The investigational products, S095029 and **pembrolizumab**, will be administered as solutions for infusion, with the trial aiming to provide comprehensive data on the combination therapy's efficacy and safety in the specified patient population.

The clinical trial involves the administration of **S095029**/**Sym025**, an experimental medication formulated as a **solution for infusion**. The active substance, **SYM025**, is a protein of non-specified origin, developed by the Institut de Recherches Internationales Servier (I.R.I.S). This investigational drug is administered via **intravenous use**. The trial aims to evaluate the safety, tolerability, and antitumor activity of S095029 in combination therapy for participants with locally advanced and unresectable or metastatic MSI-H/dMMR gastro-esophageal junction/gastric cancer. The dosing schedule and frequency of administration are determined based on the trial phase and participant response, with compliance monitored through standard clinical trial procedures.

In addition to the experimental treatment, the trial includes the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. Pembrolizumab is a humanized anti-PD-1 monoclonal antibody of the IgG4/kappa isotype, provided by Merck Sharp & Dohme B.V. It is also administered via **intravenous use**. This medication is used as a comparator treatment to assess the efficacy of the experimental drug in combination therapy. The dosing regimen for KEYTRUDA follows established guidelines for its use in oncology, with participant adherence monitored throughout the study.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for both Phase 1b and Phase 2 include the incidence of dose-limiting toxicities (DLTs), the frequency and severity of adverse events (AEs) and laboratory abnormalities according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0), the incidence of AEs leading to dose interruption, modification, delays, and permanent treatment discontinuation, and changes from baseline to the end of the study in safety laboratory values and vital signs. Additionally, for Phase 2, the objective response (OR) will be evaluated per investigator assessment using RECIST v1.1.

Secondary endpoints for Phase 1b include objective response (OR), duration of response (DoR), progression-free survival (PFS), and disease control (DC) according to RECIST v1.1 and iRECIST as assessed by the investigator. For both Phase 1b and Phase 2, overall survival (OS) will be assessed per investigator assessment, along with serum concentrations of **S095029** and the concentration of potential antibodies directed against **S095029**. In Phase 2, additional assessments will include DoR, PFS, and DC according to RECIST v1.1, as well as OR, DoR, PFS, and DC according to iRECIST criteria as per investigator assessment.