This is a Phase I/II, single-arm, open-label, multi-center study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of HSK42360-Na tablets combined with cetuximab with or without chemotherapy in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC). The Phase I stage uses a 3+3 dose escalation design to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of HSK42360-Na in combination with cetuximab. The Phase II stage evaluates the efficacy and safety of HSK42360-Na combined with cetuximab alone or with mFOLFOX6/FOLFIRI chemotherapy in expansion cohorts.
Age ≥18 years; voluntarily participate in this clinical trial, understand the study procedures, and have signed the informed consent form;
ECOG performance status 0-1;
Estimated survival time >3 months;
Histologically or cytologically confirmed metastatic and unresectable colorectal adenocarcinoma. For Phase I, Phase II Cohort 1, and the safety lead-in period of Cohorts 2/3: previously received one or more systemic treatments for metastatic colorectal cancer, and failed standard treatment, or have no standard treatment option, or standard treatment is not applicable at this stage; for the subsequent expansion phase of Phase II Cohorts 2/3: no prior systemic treatment for metastatic colorectal cancer;
History of other malignancies within the past 2 years (excluding skin basal cell carcinoma, skin squamous cell carcinoma, cervical carcinoma in situ, papillary thyroid carcinoma, and other low-grade malignancies that have undergone radical treatment);
Known RAS mutation;
Known MSI-H/dMMR or unknown MSI/MMR status; if the participant has dMMR/MSI-H mCRC and is unable to receive immune checkpoint inhibitors due to existing medical conditions, enrollment is permitted (only for the subsequent expansion phase of Cohorts 2 and 3);
Prior treatment with any BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib, etc.) or any EGFR inhibitor (e.g., cetuximab, etc.) prior to screening;
Parallel
HSK42360-Na Tablets
DrugHSK42360-Na tablets administered orally once, twice, or three times daily depending on the assigned dose level, in 28-day treatment cycles.
Cetuximab (EGFR inhibitor)
DrugCetuximab 500 mg/m2 administered by intravenous infusion every 2 weeks.
mFOLFOX6 Regimen (Oxaliplatin/Leucovorin/5-FU)
DrugOxaliplatin 85 mg/m2 IV over 2 hours (Day 1), Leucovorin 400 mg/m2 IV over 2 hours (Day 1), 5-FU 400 mg/m2 IV bolus (Day 1) followed by 1200 mg/m2/day continuous IV infusion over 46-48 hours (total 2400 mg/m2), repeated every 2 weeks.
FOLFIRI Regimen (Irinotecan/Leucovorin/5-FU)
DrugIrinotecan 180 mg/m2 IV over 30-90 minutes (Day 1), Leucovorin 400 mg/m2 IV over 2 hours (Day 1), 5-FU 400 mg/m2 IV bolus (Day 1) followed by 1200 mg/m2/day continuous IV infusion over 46-48 hours (total 2400 mg/m2), repeated every 2 weeks.
dose-limiting toxicities (DLTs)
Incidence and severity of dose-limiting toxicities (DLTs) during the first 28-day treatment cycle.
Maximum tolerated dose (MTD)
recommended Phase II dose (RP2D)
Tmax
Objective response rate (ORR)
Progression-free survival (PFS)
Overall survival (OS)
Changes in circulating tumor DNA (ctDNA) levels from baseline.
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