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

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

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

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Neoplasms Malignant; Neoplasm, Metastatic
• Intervention / Treatment: Drug: Cetuximab; Drug: Irinotecan; Drug: Bevacizumab; Drug: Sintilimab

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.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jian Xiao, MD; Phone Number: 86-20-83525975; Email: xiaojian@gdph.org.cn
• Study Contact Backup: Name: Xiaoru Lin; Phone Number: 86-20-83525975; Email: 13711114566@139.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CI Arm; Cetuximab: 250mg/m^2/week with a loading dose of 400mg/m^2; Irinotecan: 125mg/m^2 on D1 and D8 every three weeks.	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
Experimental: CIBS Arm; Cetuximab: 250mg/m^2/week with a loading dose of 400mg/m^2; Irinotecan: 125mg/m^2 on D1 and D8 every three weeks; Bevacizumab: 7.5mg/kg every three weeks ; Sintilimab: 200mg every three weeks.	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	the proportion of participants who achieved a complete or partial response according to RECIST 1.1	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	the interval from randomization to first disease progression or death from any cause or last follow-up	12 months
Overall Survival	the interval from randomization to death from any cause or last follow-up	18 months
Adverse Events	reported according to NCI Common Terminology Criteria for Adverse Events 5.0	18 months

Collaborators and Investigators

• Sponsor: Guangdong Provincial People's Hospital
• Investigators: Principal Investigator: Jian Xiao, MD, Guangdong Provincial People's Hospital

Publications and helpful links

General 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: 10.1093/oncolo/oyab025.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): January 31, 2029

Study Registration Dates

• First Submitted: July 20, 2026
• First Submitted That Met QC Criteria: July 20, 2026
• First Posted (Actual): July 23, 2026

Study Record Updates

• Last Update Posted (Actual): July 23, 2026
• Last Update Submitted That Met QC Criteria: July 20, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Bevacizumab; Cetuximab; Irinotecan; Immune checkpoint inhibitors
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Colonic Diseases; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Colonic Neoplasms; Neoplasm Metastasis; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds; Camptothecin; Alkaloids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Bevacizumab; Irinotecan; Cetuximab; sintilimab
• Other Study ID Numbers: KY2024-373-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No