A PHASE 1/2 STUDY OF REGN5668 (MUC16 × CD28, A COSTIMULATORY BISPECIFIC ANTIBODY) ADMINISTERED IN COMBINATION WITH OTHER AGENTS IN MUC16+ MALIGNANCIES

The primary objective of this study is to evaluate the **safety**, tolerability, and pharmacokinetics (PK) of REGN5668, both as a monotherapy and in combination with cemiplimab or REGN4018, during the Dose Escalation Phase. This assessment aims to determine the maximally tolerated dose (MTD) or recommended phase 2 dose (RP2D) for these combinations. In the Dose Expansion Phase, the primary objective shifts to assessing the preliminary efficacy of REGN5668 in combination with cemiplimab or REGN4018, as determined by the objective response rate (ORR) using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. These objectives are clinically relevant as they aim to establish a safe and effective dosing regimen for patients with Primary Peritoneal Cancer, Fallopian Tube Cancer, and Ovarian Cancer, potentially improving therapeutic outcomes.

Secondary objectives include: - In the Dose Escalation Phase, assessing the preliminary efficacy of REGN5668 in combination with cemiplimab or REGN4018, as determined by ORR by RECIST 1.1. - In the Dose Expansion Phase, characterizing the safety profile in each expansion cohort and the PK of REGN5668 in combination with cemiplimab or REGN4018. - In both phases, assessing preliminary efficacy using immune-based therapy RECIST (iRECIST), best overall response (BOR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) based on RECIST 1.1 and iRECIST. - Evaluating changes in cancer antigen 125 (CA-125) levels from baseline after treatment with REGN5668 in combination with cemiplimab or REGN4018. - Assessing the immunogenicity of REGN5668, both alone and in combination with cemiplimab or REGN4018.

The clinical trial involves a total of **225 participants** diagnosed with **Primary Peritoneal Cancer**, **Fallopian Tube Cancer**, or **Ovarian Cancer**. The study population is exclusively female, with an age range that includes adults and older adults. Participants were selected based on specific inclusion criteria, such as having a histologically or cytologically confirmed diagnosis of advanced epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer, and having received at least one line of platinum-based systemic therapy. Additionally, participants are required to have a serum CA-125 level of at least two times the upper limit of normal, adequate organ and bone marrow function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial does not include vulnerable populations. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants have a life expectancy of at least three months, and for expansion cohorts, at least one lesion measurable by RECIST 1.1 is required.

The clinical trial is designed to evaluate the safety, tolerability, and preliminary efficacy of **REGN5668** in combination with **cemiplimab** or **REGN4018** in patients with advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. This study is structured as a Phase 1/2 trial with a randomized, double-blind, and controlled design. The trial is expected to commence on July 31, 2023, and conclude by July 30, 2027. The trial is divided into two phases: a dose escalation phase to determine the maximally tolerated dose or recommended phase 2 dose, and a dose expansion phase to assess the objective response rate as per RECIST 1.1 criteria.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of the specified cancers, adequate organ function, and a life expectancy of at least three months. Follow-up visits will be scheduled to monitor safety, pharmacokinetics, and efficacy outcomes. The end-of-study visit will conclude the participant's involvement, which is expected to last until the trial's completion or until early termination criteria are met. Conditions for early termination include the occurrence of dose-limiting toxicities, serious adverse events, or withdrawal of consent.

The primary endpoints include the incidence of dose-limiting toxicities, treatment-emergent adverse events, and serious adverse events during the dose escalation phase. Secondary endpoints focus on pharmacokinetic measurements, objective response rates, and the presence of anti-drug antibodies. Participants will be monitored for laboratory abnormalities and changes in CA-125 levels. The trial aims to provide comprehensive data on the safety and efficacy of the investigational combinations, contributing to the development of new therapeutic options for these cancer types.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, routes, and frequencies of administration. **Sarilumab** is provided as a **solution for injection** and is administered via **intravenous administration**. The active substance, sarilumab, is a monoclonal antibody produced by Regeneron Pharmaceuticals, Inc. The dosing schedule and frequency are determined based on the study protocol, and participant compliance is monitored throughout the trial.

**Cemiplimab** is another monoclonal antibody used in the study, provided as a **solution for infusion**. It is administered through **intravenous infusion**. The product has undergone modifications, including a different vial cap color and packaging site compared to the marketed product. The administration schedule is designed to optimize safety and efficacy, with compliance monitoring in place.

**REGN4018**, also known as **Ubamatamab**, is a bispecific antibody available in multiple forms, including a **solution for injection** and **lyophilized powder**. It is administered via **intravenous infusion**. The active substance, ubamatamab, is a bispecific T-cell engager targeting MUC16 and CD3. The dosing regimen is tailored to achieve the desired therapeutic outcomes, with adherence monitored throughout the study.

**REGN5668** is another bispecific antibody used in the trial, provided as both a **lyophilisate for solution for injection** and a **solution for infusion**. It is administered through **intravenous infusion**. The active substance, REGN5668, is designed to engage specific immune pathways, and its administration is carefully scheduled to ensure participant safety and study integrity.

Throughout the trial, participant compliance with the dosing schedules is closely monitored to ensure the accuracy and reliability of the study results. The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. All medications are developed and supplied by Regeneron Pharmaceuticals, Inc., and are not formulated for pediatric use. The trial aims to assess the safety, tolerability, and preliminary efficacy of these investigational products in combination therapies.

The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. This evaluation will be conducted separately for each cohort and combination of treatments, specifically REGN5668 in combination with cemiplimab or REGN4018. The ORR will be measured during the dose expansion phase, with secondary assessments during the dose escalation phase. Additionally, secondary efficacy endpoints include the ORR based on iRECIST, Best Overall Response (BOR), Duration of Response (DOR), Disease Control Rate (DCR), and Progression-Free Survival (PFS), all evaluated using RECIST 1.1 and iRECIST criteria. Changes in CA-125 levels from baseline after treatment with REGN5668 in combination with cemiplimab or REGN4018 will also be monitored. The presence or absence of anti-drug antibodies against REGN5668, REGN4018, and cemiplimab will be assessed during both the dose escalation and expansion phases. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the therapeutic impact of the investigational treatments.