口服RAS(ON)多重三复合物抑制剂BPI-572270治疗RAS突变晚期实体瘤患者的首次人体I/II期研究

Background: KRAS mutations are common oncogenic drivers across various tumor types. Despite KRAS G12C inhibitors have been approved for treating a subset of lung cancer, no inhibitors targeting non-G12C KRAS mutations have gained market approval. BPI-572270 is an orally bioavailable, Cyclophilin A-dependent RAS(ON) multi-inhibitor that targets GTP-bound RAS proteins. In preclinical studies, BPI-572270 potently suppressed tumor cell proliferation across KRAS-, NRAS-, and HRAS-mutant models with sub-nanomolar IC 50 , and induced marked tumor growth suppression and regression in KRAS G12V , KRAS G12D , and KRAS G12R pancreatic cancer xenograft models at 0.3-3 mg/kg oral doses. A phase I/II clinical study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of BPI-572270 in patients with RAS-mutated advanced solid tumors. Methods: This first-in-human, open-label, multicenter, phase I/II study aims to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential antitumor activity of BPI-572270 monotherapy in patients with advanced solid tumors harboring RAS mutations. The study comprises 3 parts: dose escalation (part A); dose expansion (part B); phase 2 (part C). Key eligibility criteria include aged ≥ 18 years; histologically confirmed metastatic or locally advanced solid tumors refractory to, intolerant of, or lacking standard therapies; confirmed RAS mutation status; ECOG PS score of 0-1; and adequate organ function. Patients who had received prior treatment with KRAS G12X inhibitor or other RAS inhibitor are excluded, except in the dose-escalation phase, where prior KRAS G12C inhibitor-treated patients are permitted. In Part A, dose escalation follows a backfilling Bayesian optimal interval (BF-BOIN) design. BPI-572270 will be administered orally once daily with sequential dose escalation from 1 mg/day up to 20 mg/day (planned dose levels: 1, 2, 4, 8, 12, 16, and 20 mg/day) to evaluate safety and determine the maximum tolerated dose (MTD), with a 21-day window to assess dose-limiting toxicities (DLTs). Part B aims to further evaluate the safety and tolerability of selected dose levels from Part A to determine the recommended phase II dose (RP2D). Expansion cohorts will be enrolled for patients with RAS-mutated advanced cancers, including pancreatic cancer, non-small-cell lung cancer, colorectal cancer, and others. In Part C, patients are enrolled into expansion cohorts at the RP2D to further assess the antitumor activity according to RECIST v1.1. The primary endpoints include safety and tolerability in part A, determination of the RP2D in part B, and investigator-assessed objective response rate per RECIST v1.1 in part C. Conclusion: The study has been initiated with anticipated first patient dosing in the first quarter 2026.