Evaluation of RAS Inhibitor Treatment in Participants With Advanced or Metastatic Solid Tumors Harboring RAS Mutations

This is a first-in-human, open label, multi-center, multiple-ascending dose escalation, phase I study consisting of three parts: Part 1 Dose-Escalation, Part 2 Food Effect Assessment and Part 3 Dose-Expansion (See Figure 1, Figure 2, Figure 3 and Figure 4). The study is designed to evaluate the safety, tolerability, PK, and preliminary efficacy of AN9025, an oral pan-RAS (ON) inhibitor, in participants with advanced or metastatic solid tumors that harbor RAS mutations. In addition, the effect of food intake on the PK of AN9025 will be preliminarily investigated. The study will be conducted in the United States and China. Part 1 Dose-Escalation is designed to identify the Maximum Tolerated Dose (MTD) and/or Recommended Dose for Expansion (RDE) in participants with advanced or metastatic RAS-mutant solid tumors. Participants will be evaluated for Dose-limiting Toxicities (DLTs) in escalating dose and back fill cohorts. Participants enrolled in escalating dose cohorts will receive AN9025 with continuous once daily (QD) dosing or once weekly (QW) dosing in 21-day cycles. Participants enrolled in back fill cohorts will start with a single lead-in dose of AN9025 at least 5 days prior to initiating continuous QD dosing to enable PK sampling during the Single-Dose Lead-in period (Cycle 0). Following the Lead-in period, back fill participants will begin Cycle 1 Day 1 of the standard QD or QW 21-day cycle treatment (Figure 3 A). Part 2 Food Effect Assessment will employ a single-sequence, two-period crossover design in at least 6 participants. Participants will begin with a Food Effect Lead-in period (Cycle 0), receiving a single-dose of AN9025 (at a selected dose level lower than the MTD) under fasting condition, followed by PK sample collection and a washout period. A second single-dose will then be administered under fed conditions, with additional PK sampling and another washout period. Upon completing this lead-in period, participants will transition to the main study treatment, initiating QD dosing from Cycle 1 Day 1 in 21-day cycles (Figure 3 B). Part 3 Dose-Expansion will evaluate the clinical activity of AN9025 in up to two RAS-mutated solid tumor indications using up to two dose levels selected based on the MTD/RDE established during dose escalation. This phase will further characterize the safety, tolerability, and PK of AN9025 in selected tumor types.