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

A Phase I/II Study to Evaluate the Safety, Tolerability, and Efficacy of HSK42360-Na Tablets Combined With Cetuximab With or Without Chemotherapy in Patients With 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.

This is a prospective, multi-center, single-arm, open-label Phase I/II clinical study. The study consists of two stages:

Phase I (Dose Escalation): A 3+3 dose escalation design with 3 pre-specified dose levels of HSK42360-Na tablets (1200 mg QD, 1200 mg BID, 1200 mg TID) in combination with cetuximab (500 mg/m2 IV every 2 weeks). Each dose level enrolls 3-6 evaluable participants. A 28-day cycle comprises the DLT observation period. Backfill cohorts of approximately 6-18 participants per dose level may be enrolled after safety confirmation. The primary objectives are to evaluate safety, tolerability, and determine the DLT, MTD, and RP2D.

Phase II (Cohort Expansion): After RP2D determination, three expansion cohorts are planned:

• Cohort 1: HSK42360-Na + cetuximab (approximately 42 participants with prior systemic therapy)
• Cohort 2: HSK42360-Na + cetuximab + mFOLFOX6 (6-9 safety run-in + approximately 36 expansion)
• Cohort 3: HSK42360-Na + cetuximab + FOLFIRI (6-9 safety run-in + approximately 36 expansion)

Participants continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other termination criteria. Tumor assessment is performed every 6 weeks (every 8 weeks after 18 months) per RECIST 1.1. Safety follow-up occurs 30 days after the last dose, and survival follow-up is conducted every 3 months thereafter.

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) <50%; myocardial infarction, unstable angina, NYHA Class III or IV heart failure within 6 months prior to first dose;

14. Arterial/venous thromboembolic events within 6 months prior to first dose, with uncontrolled risk as judged, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism, etc.; or known familial and/or acquired thrombophilia, such as inherited or acquired deficiencies of anticoagulant proteins, coagulation factors, fibrinolytic proteins, etc.;

15. Severe or uncontrolled diabetes, hypertension (poorly controlled despite standard antihypertensive regimen, with systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg at screening), active bleeding, epilepsy (except when caused by intracranial tumor), chronic obstructive pulmonary disease, interstitial pneumonia, pulmonary interstitial fibrosis, Parkinson's disease, etc.;

16. Receipt of live vaccine within 28 days prior to first dose;

17. Any unstable systemic disease (such as severe hepatic, renal, or metabolic diseases: cirrhosis, renal failure, uremia, etc.);

18. Use of strong or moderate CYP3A4 inhibitors or inducers, or foods, within 14 days or 5 half-lives prior to first dose, whichever is longer. Use of CYP3A4, CYP2C9, and CYP2C8 sensitive substrates, OATP1B1, OATP1B3, OAT1, OAT3, P-gp, and BCRP substrates within 5 half-lives prior to first dose (see Appendix 7 for details);

19. Cognitive impairment, unstable moderate to severe psychiatric illness, other uncontrolled concomitant diseases, alcohol dependence, steroid dependence, or drug abuse;

20. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation; major surgery or severe trauma within 4 weeks prior to first dose (excluding needle biopsy performed for sample collection); or planned systemic or local tumor resection during the study;

21. History of immunodeficiency, including: HIV antibody positive, or other acquired or congenital immunodeficiency diseases;

22. Presence of the following serological status reflecting active hepatitis B or hepatitis C infection:

    Hepatitis B surface antigen positive or hepatitis B core antibody positive, and HBV DNA >1000 copies/mL or HBV DNA >200 IU/mL; Hepatitis C virus antibody positive, and HCV RNA > upper limit of normal;

23. Active syphilis infection;

24. History of tuberculosis treatment within 2 years prior to first dose;

25. Active bacterial, fungal, or viral infection prior to first dose (defined as requiring intravenous antibacterial, antifungal, or antiviral drug treatment). Individuals receiving prophylactic anti-infective treatment without clinical manifestations of active infection prior to first dose may be considered for enrollment;

26. Known allergy to or contraindication for any component of the study drug or its excipients at the planned dose;

27. Positive pregnancy test at screening, or lactating patients;

28. The investigator considers the patient unsuitable for participation in this study.