New Second-Line Combo Therapy for MSS Metastatic Colorectal Cancer

Prior treatment

• Prior exposure to topoisomerase-I inhibitors or their analogues in first-line therapy.
• Toxicities from prior therapy not resolved to CTCAE v5.0 Grade ≤ 1 (except alopecia or other toxicities deemed by the investigator to pose no safety risk).
• Any anti-cancer therapy (chemotherapy, radiotherapy, biologics, targeted therapy, immunotherapy, etc.) within 4 weeks before first study-dose; major surgery (excluding biopsy) within 4 weeks that has not fully healed.
• Clinically significant cardiovascular disease:
  • Severe/unstable angina, symptomatic congestive heart failure (NYHA ≥ II), clinically significant arrhythmia requiring treatment, arterial thrombosis, acute coronary syndrome, MI, cerebrovascular accident (including TIA) or other Grade ≥ 3 CV event within 6 months prior to first dose.
  • QTcF ≥ 450 ms (men) or ≥ 470 ms (women) on resting 12-lead ECG.
• History or current evidence of leptomeningeal metastases. Active brain metastases: untreated and/or symptomatic, or requiring corticosteroids or anticonvulsants. Subjects treated with surgery or radiotherapy may enter if imaging ≥ 4 weeks shows stable CNS disease, symptoms have resolved, no corticosteroids for ≥ 2 weeks, and acute toxicities have recovered.
• Participation in another clinical drug trial within 4 weeks or less than 5 half-lives of the previous investigational agent, whichever is longer.

Other illness

• Documented hypersensitivity to any study drug or its excipients.
• Severe psychiatric or psychological disorders that could compromise compliance.
• Infection-related:
  • Active infection or unexplained fever \> 38.5 °C on screening or dosing day (tumor fever allowed at investigator's discretion).
  • Serious infection (CTCAE Grade 3, e.g., pneumonia, bacteremia) requiring hospitalization within 4 weeks.
  • Active pulmonary inflammation on baseline imaging or need for systemic antibiotics (prophylactic antibiotics permitted).
• Other severe uncontrolled disorders (e.g., frequent seizures, hepatic failure).
• Other malignancies within 5 years, except adequately treated basal-cell carcinoma of skin or cervical carcinoma in situ.
• Any social or medical condition that, in the investigator's opinion, could interfere with informed consent, study participation, or interpretation of results.

Lab values

• Known HIV-positive, active hepatitis B, or hepatitis C:
  • HBsAg or HBcAb positive: HBV DNA must be ≤ 2.5 × 10³ copies/mL (or ≤ 500 IU/mL, or below LLoQ); HBsAg(+) subjects must receive anti-HBV prophylaxis throughout study treatment.
  • HCV-seropositive allowed only if HCV RNA negative (or below LLoQ).

Other

• Pregnant or breast-feeding women.
• Patients deemed by the investigator to be unsuitable for enrollment.

• Male or female, aged 18-75 years.
• Histologically or cytologically confirmed colorectal adenocarcinoma.
• Unresectable, MSS-type metastatic colorectal cancer that has failed or is intolerant to first-line standard oxaliplatin plus fluoropyrimidine ± targeted therapy.
  • Failure definition: progression during or within 3 months after completing first-line oxaliplatin/fluoropyrimidine ± targeted therapy.
  • Adjuvant setting: progression/recurrence during or within 6 months of completing adjuvant oxaliplatin-based chemotherapy/chemoradiation counts as first-line failure.
• At least one measurable lesion by RECIST 1.1.
• ECOG performance status 0-1.
• Expected survival ≥ 3 months.
• Adequate organ function within 14 days before enrollment (no transfusion or growth-factor support):
  • Hematology: Hb ≥ 90 g/L; WBC ≥ 3.0 × 10⁹/L; ANC ≥ 1.5 × 10⁹/L; PLT ≥ 90 × 10⁹/L.
  • Coagulation: INR ≤ 1.5 × ULN; APTT ≤ 1.5 × ULN (stable anticoagulation at therapeutic range allowed).
  • Renal: Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault).
  • Hepatic:
  • No liver mets: TBIL ≤ 1.5 × ULN, ALT ≤ 2.5 × ULN, AST ≤ 2.5 × ULN.
  • Liver mets: TBIL ≤ 2 × ULN, ALT ≤ 5 × ULN, AST ≤ 5 × ULN.
  • Cardiac: LVEF ≥ 50 %.
• Voluntary written informed consent; willing and able to comply with study procedures and follow-up.
• WOCBP must have a negative serum/urine pregnancy test within 3 days before first study-dose (Cycle 1 Day 1).
• All subjects (men and women) with reproductive potential must use a highly effective contraceptive method (annual failure rate \< 1 %) from screening until 120 days after the last dose of investigational product or 180 days after the last chemotherapy dose, whichever is later.