Bevacizumab, Sintilimab, Cetuximab and Irinotecan in Refractory RAS Wild-type Metastatic Colorectal Cancer: BOND-4 Trial

This randomized, multi-center, open-label phase II trial studies the efficacy and safety of irinotecan and cetuximab with or without bevacizumab plus sintilimab in the treatment for RAS wild-type metastatic colorectal cancer in third- or later-line setting.

Patients with refractory mCRC have limited treatment options after failure of standard chemotherapies and anti-angiogenic agents. The BOND-3 trial showed that adding bevacizumab to cetuximab and irinotecan may improve outcomes in this setting. Meanwhile, immune checkpoint inhibitors have demonstrated activity in MSI-high tumors but have limited efficacy in MSS mCRC. Preclinical and clinical evidence suggests that anti-VEGF therapy can modulate the tumor immune microenvironment and may synergize with PD-1 blockade. This study therefore tests whether the quadruple combination (bevacizumab + sintilimab + cetuximab + irinotecan) can improve objective response rate compared with cetuximab and irinotecan alone in this heavily pretreated population.

The primary efficacy analysis will be conducted on the intention-to-treat population. Assuming an ORR of 10% in the control arm and 30% in the experimental arm, with a two-sided alpha of 0.05 and power of 80%, the required sample size is approximately 70 patients per arm (total 140), and we enroll 160 to account for 10-15% dropout.

Inclusion criteria

• Metastatic and unresectable colorectal adenocarcinom;
• RAS wild-type and MSS tumor;
• Measurable lesions;
• Failed to at least two lines of standard treatment containing fluoropyrimidine, irinotecan and bevacizumab;
• Eastern Cooperative Oncology Group performance status 2 or less;
• White blood cell≥ 3*10^9/L, neutrophil≥ 1.5*10^9/Lplatelet count≥75*10^9/L, hemoglobin≥60g/L;
• Total serum bilirubin≤upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 2.5*ULN or ≤5*ULN for subjects with liver metastasis;
• Creatinine ≤ ULN or creatinine clearance ≥ 80 mL/min;
• Urinary protein negative or 24-hour urinary protein ≤ 2g;
• Activated partial thromboplastin time≤ULN and international normalized ratio≤1.5;
• Any major surgery ≥ 4 weeks and any minor surgery ≥ 1 week and fully recovered from the procedure;
• Life expectancy > 3 months;
• Provide fully informed written consent;

Exclusion criteria

• Other aggressive malignancies within 3 years (Exceptions: non-melanoma skin cancer or carcinoma-in-situ of the cervix that has been treated);
• Allergy or intolerance to any of the study drugs;
• Human immunodeficiency virus positive;
• Concurrent anti-cancer therapy including radiation therapy, chemotherapy, targeted agents or biological agents not otherwise specified within two weeks;
• Malignant bowel obstruction;
• Prior treatment with PD-1 antibody;
• Autoimmune diseases;
• Significant bleeding events or pre-existing bleeding diathesis within 6 months (unless the source of bleeding has been resected);
• Gastrointestinal perforation within 12 months;
• Serious or non-healing wound, ulcer, or bone fracture;
• Blood pressure >= 160/90 mmHg after active anti-hypertensive therapy;
• Arterial or venous thrombotic or embolic events within 6 months (including but not limited to transient ischemic attack, cerebrovascular accident, unstable angina or myocardial infarction);
• Uncontrolled illness including active infection, symptomatic congestive heart failure, cardiac arrhythmia, respiratory failure, symptomatic pulmonary fibrosis, interstitial pneumonitis or psychiatric illness that may interfere with the conduct of the study;
• Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous meningitis;
• Any of the following: pregnant, nursing, childbearing potential but unwilling to employ contraception.