Phase 1/2a Study of Relatlimab and Nivolumab in Advanced Solid Tumors: Safety, Tolerability, and Efficacy Evaluation

The primary objective of this study is to evaluate the **safety**, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD) of BMS-986016, an anti-LAG-3 monoclonal antibody, both as a monotherapy and in combination with nivolumab, an anti-PD-1 monoclonal antibody, in subjects with advanced solid tumors. This assessment is crucial for determining the therapeutic potential and safety profile of BMS-986016, which could lead to improved treatment options for patients with these malignancies.

Secondary objectives include:

• Characterizing the pharmacokinetics (PK) of BMS-986016 alone and in combination with nivolumab.
• Investigating preliminary objective response rate (ORR) and/or disease control rate (DCR) of BMS-986016 alone and with nivolumab in subjects with advanced solid tumors.
• Characterizing the immunogenicity of BMS-986016 alone and with nivolumab.
• Assessing the effect of BMS-986016 alone and with nivolumab on QTc interval.
• Evaluating duration of response (DOR), DCR, and progression-free survival (PFS) rates at pre-specified time points based on blinded independent central review (BICR) assessments using RECIST v1.1 in advanced melanoma subjects with varying levels of LAG-3 expression.
• Evaluating ORR, DCR, DOR, and PFS rates at pre-specified time points based on investigator assessments using RECIST v1.1 in advanced melanoma subjects with varying levels of LAG-3 expression.
• Assessing the 1-year and 2-year landmark overall survival (OS) in advanced melanoma subjects.
• Assessing the safety and tolerability of a more convenient dosing regimen in advanced melanoma subjects.
• Evaluating the clinical benefit of a 480 mg BMS-986016 plus 480 mg nivolumab Q4W regimen using DOR in melanoma subjects.

The clinical trial involves a total of **997 participants** diagnosed with **neoplasms by site**, focusing on advanced solid tumors and melanoma. The study population includes both male and female subjects, with an age range encompassing young adults, adults, and the elderly. Participants were selected based on specific inclusion criteria, such as having an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and possessing at least one lesion with measurable disease at baseline. The trial includes individuals who have progressed or been intolerant to at least one standard treatment regimen, except for those in first-line cohorts. The study also considers subjects naive to immuno-oncology agents for certain cancer types, such as cervical, ovarian, bladder, and others, as well as those who have progressed on or after therapy with anti-PD1/anti-PDL-1. The trial population includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Participants are required to provide an existing tumor biopsy sample and consent to a pre-treatment tumor biopsy.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the safety, tolerability, and efficacy of the **anti-LAG-3 monoclonal antibody** (BMS-986016) administered alone and in combination with the **anti-PD-1 monoclonal antibody** (nivolumab) in patients with advanced solid tumors. The trial is structured in multiple parts, each with specific objectives, including dose escalation and cohort expansion phases. The primary endpoints focus on the proportion of subjects experiencing adverse events, serious adverse events, and laboratory abnormalities, as well as the objective response rate, disease control rate, and duration of response. Secondary endpoints include pharmacokinetic parameters such as maximum observed serum concentration and area under the concentration-time curve, along with immunogenicity and overall survival rates.

The trial is expected to span from November 2013 to August 2026, with participants involved for varying durations depending on their response to treatment and the specific phase of the trial they are enrolled in. Study visits are sequenced to include an initial screening visit to assess eligibility based on criteria such as ECOG performance status and the presence of measurable disease. Follow-up visits are scheduled to monitor safety, efficacy, and pharmacokinetic parameters, with the end-of-study visit marking the conclusion of a participant's involvement. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or disease progression.

Participants are required to have progressed or been intolerant to at least one standard treatment regimen, except for those in first-line cohorts. The trial includes subjects with various types of cancer, such as melanoma, non-small cell lung cancer, and renal cell carcinoma, among others. The study aims to gather preliminary efficacy information and establish a more convenient dosing regimen, with the ultimate goal of demonstrating significant clinical benefits in terms of increased objective response rates.

The clinical trial involves the administration of **Nivolumab** and **Relatlimab** as part of the investigational treatment regimen. The experimental medication, identified as "Nivo 240 mg and Rela 80 mg per vial," is a **solution for infusion**. This combination product contains the active substances **Nivolumab** and **Relatlimab**, both of which are proteins of biotechnological origin. The medication is administered via **intravenous use**. The dosing schedule involves the administration of 240 mg of Nivolumab and 80 mg of Relatlimab per vial, with the frequency of administration determined by the specific protocol of the study. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the treatment protocol.

In addition to the combination product, the trial also utilizes "OPDIVO 10 mg/mL concentrate for solution for infusion," which contains the active substance **Nivolumab**. This product is also a **solution for infusion** and is administered via **intravenous use**. The concentration of Nivolumab in this formulation is 10 mg/mL, and the dosing schedule is aligned with the study's protocol requirements. The administration of this product is carefully monitored to ensure accurate dosing and participant compliance.

The trial further includes the administration of "Relatlimab," a **solution for injection** containing the active substance **Relatlimab**. This product is administered through **intravenous infusion**. The dosing regimen for Relatlimab is specified in the study protocol, and the administration is conducted under controlled conditions to maintain participant safety and treatment efficacy. Compliance with the dosing schedule is tracked to ensure adherence to the study's requirements.

Throughout the trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus remains on evaluating the safety, tolerability, and efficacy of the investigational products in participants with advanced solid tumors. The trial is conducted under the sponsorship of Bristol-Myers Squibb International Corporation, with all products being of biological or biotechnological origin. The study protocol includes detailed monitoring of drug administration and participant compliance to ensure the integrity of the trial data.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary efficacy endpoints include the **Objective Response Rate (ORR)**, **Disease Control Rate (DCR)**, and **Duration of Response (DOR)**. These parameters will be measured to evaluate the preliminary efficacy of the investigational drug BMS-986016, both alone and in combination with nivolumab, across multiple tumor types. The ORR will be determined by the proportion of subjects achieving a complete or partial response to the treatment, as assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 criteria.

Secondary efficacy endpoints will include pharmacokinetic parameters such as the maximum observed serum concentration (Cmax), time of maximum observed serum concentration (Tmax), and area under the concentration-time curve (AUC) of BMS-986016, both alone and in combination with nivolumab. Additional secondary endpoints include progression-free survival (PFS) rates, overall survival (OS), and the best overall response (BOR). These endpoints will be measured at various time points throughout the trial to provide a comprehensive assessment of the treatment's efficacy.