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

Official title

A Randomized, Multi-center, Open-label Phase II Trial of Irinotecan and Cetuximab With or Without the Combination of Bevacizumab and Sintilimab in RAS Wild-type, Irinotecan-refractory Metastatic Colorectal Cancer

Overview

Primary endpoint: objective response rate Secondary endpoints: PFS, OS and adverse events

Detailed description

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.

Interventions

• Drug Cetuximab
  250mg/m\^2/week with a loading dose of 400mg/m\^2
• Drug Irinotecan
  125mg/m\^2 on D1 and D8 every three weeks
• Drug Bevacizumab
  7.5mg/kg every three weeks
• Drug Sintilimab
  200mg every three weeks

Primary outcome measures

• Objective Response Rate [Time frame: 12 months]

Secondary outcome measures (3)

• Progression-free Survival [Time frame: 12 months]
• Overall Survival [Time frame: 18 months]
• Adverse Events [Time frame: 18 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Lipsyc-Sharf M, Ou FS, Yurgelun MB, Rubinson DA, Schrag D, Dakhil SR, Stella PJ, Weckstein DJ, Wender DB, Faggen M, Zemla TJ, Heying EN, Schuetz SR, Noble S, Meyerhardt JA, Bekaii-Saab T, Fuchs CS, Ng K. Cetuximab and Irinotecan With or Without Bevacizumab in Refractory Metastatic Colorectal Cancer: BOND-3, an ACCRU Network Randomized Clinical Trial. Oncologist. 2022 Apr 5;27(4):292-298. doi: 10.1 PMID 35380713

Identifiers

NCT: NCT07722754 · KY2024-373-05

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗