HSK42360-Na Tablets Combined With Cetuximab With or Without Chemotherapy in BRAF V600-Mutant Metastatic Colorectal Cancer

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.

Inclusion Criteria: 1. Age ≥18 years; voluntarily participate in this clinical trial, understand the study procedures, and have signed the informed consent form; 2. ECOG performance status 0-1; 3. Estimated survival time \>3 months; 4. 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; 5. Genetic testing documentation (limited to PCR or NGS-based assays) must be provided prior to enrollment to demonstrate BRAF V600 mutation positivity; 6. Agree to provide tumor tissue and/or blood samples; 7. At least one measurable lesion according to RECIST 1.1 criteria; 8. Laboratory values meeting the following standards: Absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelets (PLT) ≥100×10⁹/L; hemoglobin (HB) ≥90 g/L (no transfusion or growth factor support within 7 days prior to testing); Total serum bilirubin ≤1.5×ULN; AST and/or ALT ≤2.0×ULN; if liver metastases are present, or if Gilbert syndrome (unconjugated hyperbilirubinemia) is clearly documented, AST and/or ALT ≤3.0×ULN, total bilirubin ≤1.5×ULN; Serum creatinine (Scr) ≤1.5×ULN, or creatinine clearance ≥50 mL/min (measured or calculated using the Cockcroft-Gault equation); Coagulation: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤1.5×ULN; 9. Men and women of childbearing potential must agree to use appropriate contraceptive methods (hormonal, barrier method, or abstinence) during the study and for 3 months after the last dose; women of childbearing potential must have a negative pregnancy test within 7 days prior to dosing; male participants must not donate sperm from the start of treatment until 90 days after stopping treatment; 10. Fully understand this clinical trial and voluntarily sign the written informed consent form. Exclusion Criteria: 1. 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); 2. Known RAS mutation; 3. 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); 4. Prior treatment with any BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib, etc.) or any EGFR inhibitor (e.g., cetuximab, etc.) prior to screening; 5. History of acute or chronic pancreatitis within 6 months prior to the start of study treatment, or history of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention within 12 months prior to the start of study treatment; 6. Impaired liver function, Child-Pugh Class B or C; 7. Uncontrolled (including but not limited to requiring repeated drainage, symptomatic) moderate or larger pleural effusion, pericardial effusion, or ascites, as determined by the investigator; 8. Known symptomatic central nervous system metastasis or leptomeningeal metastasis, or other evidence indicating that the individual's CNS metastasis or leptomeningeal metastasis is not controlled, and the investigator judges that the patient is unsuitable for enrollment; 9. Individuals receiving long-term immunosuppressive therapy (e.g., cyclosporine) or requiring daily systemic corticosteroid therapy (e.g., \>20 mg prednisone or equivalent), excluding those using topical corticosteroids via nasal spray, inhalation, or other local routes; 10. Systemic chemotherapy within 28 days prior to first dose, or immunotherapy (e.g., interleukin, interferon, thymosin, etc.), hormonal therapy, targeted therapy, or any investigational intervention within 14 days or 5 half-lives prior to first dose, whichever is shorter; 11. Toxicity from prior antineoplastic therapy that has not resolved to CTCAE Grade ≤1 (excluding alopecia, skin toxicity, or other toxicities that the investigator considers to have no safety risk); 12. Any condition affecting drug swallowing and severely affecting absorption of the study drug or pharmacokinetic parameters, including but not limited to active peptic ulcer disease, chronic gastroesophageal reflux disease (GERD), etc.; 13. Severe or uncontrolled cardiac disease requiring treatment, including any of the following (but not limited to): QT interval prolongation on ECG corrected using Fridericia's formula, QTcF \>450 msec for males or \>470 msec for females; various clinically significant arrhythmias, including but not limited to ventricular arrhythmias requiring clinical intervention, second- to third-degree atrioventricular block, etc.; echocardiogram indicating left ventricular ejection fraction (LVEF) \