Phase 1/2 Study of BMS-986466 with Adagrasib ± Cetuximab in KRAS G12C-Mutant Advanced Solid Tumors

The primary objective of this study is to evaluate the **safety** and tolerability of BMS-986466 in combination with adagrasib, with or without cetuximab, in participants with advanced KRAS G12C-mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic duct adenocarcinoma (PDAC), and biliary tract cancer (BTC). The study aims to identify the Maximum Tolerated Dose (MTD) or, if not reached, the Maximum Administered Dose (MAD), to establish dose levels for further testing. This is clinically relevant as it helps determine the optimal dosing regimen for these combinations, potentially improving therapeutic outcomes for patients with these specific cancer mutations.

Secondary objectives include: - Determining the **pharmacokinetic** profile of BMS-986466 after the first dose and at steady state in combination with adagrasib, with or without cetuximab. - Evaluating the initial effectiveness of these combinations in KRAS G12C mutant NSCLC and CRC, particularly in patients naive to treatment with KRAS G12C inhibitors. - Assessing the safety and tolerability of the combinations in these patient populations. - Studying the **pharmacodynamic** profile of BMS-986466 to understand how the drug affects the body.

The clinical trial involves a total of **337 participants** diagnosed with advanced KRAS G12C mutant **non-small cell lung cancer (NSCLC)**, colorectal cancer (CRC), pancreatic duct adenocarcinoma (PDAC), and biliary tract cancer (BTC). The study population includes both male and female subjects, with an age range primarily between 18 and 65 years. Participants were selected based on a confirmed diagnosis of the specified cancers that have metastasized and are not amenable to surgical removal. The trial includes individuals who have either failed, are intolerant to, or have experienced recurrence after standard treatments. Both genders are represented, and the trial includes a vulnerable population. Participants must have a documented KRAS G12C mutation, verified through an approved test or confirmed by a central laboratory if initial results are unavailable. The study does not specify particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **Phase 1/2 open-label study** to evaluate the safety, tolerability, and efficacy of BMS-986466 in combination with **adagrasib**, with or without **cetuximab**, in participants with advanced solid tumors harboring the **KRAS G12C mutation**. The trial is structured into two parts: Part 1 focuses on determining the **Maximum Tolerated Dose (MTD)** or **Maximum Administered Dose (MAD)**, while Part 2 assesses the treatment's efficacy. The study is not categorized as low intervention and is expected to conclude by December 2028, with recruitment starting in January 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a documented KRAS G12C mutation and previous treatment history. The trial includes follow-up visits to monitor safety and efficacy, with assessments of dose-limiting toxicities, adverse events, and overall response rate per RECIST v1.1 by Blinded Independent Central Review (BICR). The end-of-study visit will conclude the participant's involvement, which is expected to last until the study's completion unless early termination is warranted due to adverse events or other protocol-specified conditions.

Key elements of the research methodology include the administration of BMS-986466 with adagrasib to patients with advanced KRAS G12C mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic duct adenocarcinoma (PDAC), and biliary tract cancer (BTC) in Part 1A. In Part 1B, the combination includes cetuximab for CRC patients. Part 2A compares BMS-986466 with adagrasib against adagrasib alone in KRAS G12C mutant NSCLC, while Part 2B evaluates the combination with or without cetuximab against adagrasib plus cetuximab in CRC. The trial's primary endpoints include the incidence of dose-limiting toxicities and overall response rate, with secondary endpoints assessing pharmacokinetic parameters, progression-free survival, and disease control rate.

The clinical trial involves the administration of **BBP-398**, a small molecule investigational drug, formulated as a **capsule for oral use**. The active substance, BBP-398, is of chemical origin and is provided by Navire Pharma Inc. Participants will receive BBP-398 orally, with the specific dosage and frequency of administration determined based on the study protocol. The trial aims to evaluate the safety and efficacy of BBP-398 in combination with other treatments in patients with KRAS G12C-mutant advanced solid tumors.

**Cetuximab** is utilized as a comparator treatment in this study. It is administered as a **solution for infusion** via the **intravenous route**. Cetuximab is not a chemical substance and is used in combination with other investigational drugs to assess its comparative effectiveness in the treatment of KRAS G12C-mutant colorectal cancer (CRC). The dosing schedule for cetuximab will follow standard clinical guidelines, and participant compliance will be monitored throughout the trial.

**Adagrasib** is another comparator treatment included in the trial, formulated as a **coated tablet** for **oral use**. As a small molecule of chemical origin, adagrasib is administered to participants to evaluate its efficacy both as a monotherapy and in combination with other investigational drugs. The trial will determine the appropriate dosing regimen for adagrasib, ensuring adherence to the study protocol and monitoring participant compliance.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Overall Response Rate (ORR)** as evaluated by RECIST v1.1 criteria through Blinded Independent Central Review (BICR). Additionally, the incidence of dose-limiting toxicities, adverse events, serious adverse events, adverse events leading to discontinuation, and deaths will be monitored. Secondary endpoints will further evaluate efficacy through measures such as Progression Free Survival (PFS), Disease Control Rate (DCR), Duration of Response (DOR), and Time To Response (TTR), all assessed per RECIST v1.1 by BICR. Pharmacokinetic parameters of BMS-986466, including Maximum concentration (Cmax), Time to maximum concentration (Tmax), and Area Under the Curve (AUC(0-T)), will also be summarized from concentration-time data. Additionally, the trial will assess the incidence of dose-limiting toxicities and adverse events, as well as the drug's target engagement capabilities.