Phase 1/2 study of FMC-376 an oral KRAS G12C dual inhibitor in participants with locally advanced unresectable or metastatic solid tumors (PROSPER).

TPS3184 Background: FMC-376 is a highly selective, orally bioavailable, dual (ON/OFF) irreversible covalent inhibitor that rapidly and effectively blocks signaling via ON (GTP-bound) mutant KRAS G12C and prevents OFF (GDP-bound) KRAS G12C from being activated. This prevents downstream KRAS G12C signaling without affecting wild-type KRAS protein. Nonclinical pharmacology studies demonstrate that FMC-376 inhibits tumor cell growth and viability in cells harbouring KRAS G12C mutation and results in tumor regression in multiple mouse models including PDX models of NSCLC, PDAC and CRC. FMC-376 demonstrated the ability to overcome mechanisms associated with innate and acquired resistance to the first generation KRASG12C (off) only inhibitors. 1. Methods: This clinical study is global and is designed to evaluate the safety, tolerability, PK/PD and anti-tumor activity of FMC-376. Phase 1A (Dose Escalation) may enroll ~83 participants, Phase 1B (Dose Expansion) in tumor specific cohorts may enroll ~120 participants to optimize dosing and Phase 2 (Cohort Expansion) may enroll multiple tumor specific cohorts. Phase 1A includes participants who have progressed on or are ineligible for available standard approved therapies including KRAS G12C inhibitors. Participants will be enrolled into 1 of 5 escalating dose levels. BOIN design will be employed with a single Cohort, accelerated titration. Key eligibility criteria include histologically or cytologically confirmed locally advanced/unresectable or metastatic solid tumors with KRAS G12C mutations, ECOG 0-1 and adequate hematologic, hepatic and renal function. Participants with stable treated brain metastases may be eligible, but participants with leptomeningeal disease or carcinomatous meningitis are not eligible. FMC-376 will be administered PO QD for 21-day cycles until PD. Key objectives include establishing doses, based on incidence of DLTs, identifying SAEs/AEs and changes in ECG parameters, characterizing the PK profile and evaluating the clinical activity of FMC-376 via RECIST v1.1. In addition, FMC-376 target engagement and changes in expression of RAS pathway genes will be evaluated. A dose escalation and safety committee will be established to oversee the dose escalation portion of the study. The study is open to enrollment as of February 2024, NCT06244771. 1. AACR 2023 Annual Meeting Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRAS G12C Kevin Webster, April 16, 2023. Clinical trial information: NCT06244771 .