ctDNA-Guided Cetuximab or Bevacizumab Plus Trifluridine/Tipiracil in RAS/BRAF Wild-Type mCRC

NCT ID: NCT07012954

Last Updated: 2025-06-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 64 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-06-01
• Study Completion Date: 2030-12-31

Brief Summary

The objective of this randomized controlled clinical trial is to evaluate the efficacy of ctDNA-guided rechallenge with cetuximab plus trifluridine/tipiracil compared with bevacizumab plus trifluridine/tipiracil in patients with treatment-refractory, RAS/BRAF wild-type metastatic colorectal cancer.

Detailed Description

Colorectal cancer (CRC) remains a major public health challenge in China, where its incidence and mortality continue to rise. Although surgical resection is the cornerstone of curative treatment, metastatic disease develops in 30-40% of patients. Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies such as cetuximab and panitumumab are pivotal therapeutic agents for patients with RAS wild-type metastatic colorectal cancer (mCRC), exerting antitumor effects through inhibition of the EGFR pathway and activation of antibody-dependent cell-mediated cytotoxicity.

Recent evidence from phase II trials and retrospective analyses has suggested that rechallenge with anti-EGFR monoclonal antibodies in later-line settings may confer clinical benefit in selected patients who previously responded to first-line anti-EGFR-based therapy. Studies such as CRICKET and CHRONOS have highlighted the feasibility of this approach, with emerging data supporting the utility of circulating tumor DNA (ctDNA) to guide patient selection based on RAS, BRAF, and EGFR extracellular domain mutation status. Notably, the VELO study demonstrated improved progression-free survival (PFS) with third line panitumumab plus trifluridine/tipiracil compared to trifluridine/tipiracil alone, particularly in patients with ctDNA-confirmed RAS/BRAF wild-type status. Similarly, the ongoing PARERE and recently reported CITRIC studies have further emphasized the value of molecular stratification using liquid biopsy to refine anti-EGFR rechallenge strategies and optimize treatment sequencing.

The current study builds upon these findings and aims to evaluate and compare the efficacy and safety of cetuximab plus trifluridine/tipiracil versus bevacizumab plus trifluridine/tipiracil as later-line treatments in Chinese patients with RAS/BRAF wild-type mCRC, with treatment selection informed by ctDNA profiling. By integrating real-world clinical data and contemporary molecular diagnostics, this study seeks to assess the potential benefit of cetuximab-based rechallenge therapy in a population with limited therapeutic options and to contribute further evidence supporting the implementation of personalized, biomarker-guided strategies in later-line mCRC management.

Conditions

Colorectal Cancer Metastatic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

cetuximab plus trifluridine/tipiracil

Trifluridine/tipiracil 35 mg/m² (orally for 5 days, followed by 9 days off) plus cetuximab 500 mg/m² intravenous drip (IVD) once every two weeks.

Group Type: EXPERIMENTAL

Cetuximab (Erbitux, C225)

Intervention Type: DRUG

cetuximab 500 mg/m² repeated every two weeks.

trifluridine/tipiracil

Intervention Type: DRUG

Trifluridine/tipiracil 35 mg/m² (orally for 5 days, followed by 9 days off)

bevacizumab plus trifluridine/tipiracil

Trifluridine/tipiracil 35 mg/m² (orally for 5 days, followed by 9 days off) plus bevacizumab 5 mg/kg administered by intravenous drip (IVD), repeated every two weeks.

Group Type: ACTIVE_COMPARATOR

trifluridine/tipiracil

Intervention Type: DRUG

Trifluridine/tipiracil 35 mg/m² (orally for 5 days, followed by 9 days off)

Bevacizumab ( Avastin)

Intervention Type: DRUG

bevacizumab 5 mg/kg

Interventions

Cetuximab (Erbitux, C225)

cetuximab 500 mg/m² repeated every two weeks.

Intervention Type: DRUG

trifluridine/tipiracil

Trifluridine/tipiracil 35 mg/m² (orally for 5 days, followed by 9 days off)

Intervention Type: DRUG

Bevacizumab ( Avastin)

bevacizumab 5 mg/kg

Intervention Type: DRUG

Other Intervention Names

Erbitux; C225

Eligibility Criteria

Inclusion Criteria

• Histologically confirmed colorectal adenocarcinoma
• Initial RAS/BRAF wild-type status
• Received first-line treatment with FOLFOX, FOLFIRI, or FOLFOXIRI combined with cetuximab, with documented clinical benefit (CR/PR/SD) and progression-free survival (PFS) ≥ 6 months
• Disease progression occurred during or within 3 months after cetuximab-based first-line therapy
• Experienced further tumor progression after receiving second-line or subsequent treatments
• At least 4 months have elapsed since the last administration of cetuximab
• At least one measurable lesion according to RECIST v1.1
• RAS/BRAF wild-type status confirmed by blood-based ctDNA testing
• Normal hematologic function (platelets > 90 × 10⁹/L; white blood cells > 3 × 10⁹/L; neutrophils > 1.5 × 10⁹/L; hemoglobin > 10.0 g/100 ml)
• Serum bilirubin ≤ 1.5 × upper limit of normal (ULN), transaminases ≤ 5 × ULN
• No ascites, normal coagulation function, serum albumin ≥ 35 g/L
• Child-Pugh class A liver function
• Serum creatinine below ULN or calculated creatinine clearance > 50 ml/min (using the Cockcroft-Gault formula)
• ECOG performance status of 0-1
• Expected survival > 3 months
• Signed written informed consent
• Willing and able to undergo follow-up until death, study completion, or study termination

Exclusion Criteria

• Presence of RAS or BRAF gene mutations
• Severe arterial embolism or ascites
• Bleeding tendency or coagulation disorders
• Hypertensive crisis or hypertensive encephalopathy
• Severe and uncontrolled systemic complications such as infections or diabetes
• Clinically significant cardiovascular diseases, including cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), uncontrolled hypertension despite appropriate medical therapy, unstable angina, congestive heart failure (NYHA class II-IV), or arrhythmias requiring medical treatment History of or physical examination indicating central nervous system diseases (e.g., primary brain tumor, epilepsy not controlled with standard therapy, any brain metastases, or history of stroke)
• History of other malignancies within the past 5 years (excluding adequately treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, and/or thyroid cancer)
• Known allergy to any of the study drugs
• Pregnant or breastfeeding women
• Women of childbearing potential (within 2 years of last menstruation) or men with reproductive potential who are not using or refuse to use effective non-hormonal contraception (e.g., intrauterine device, barrier method with spermicidal gel, or sterilization)
• Inability or unwillingness to comply with the study protocol
• Any other disease, functional impairment caused by metastatic lesions, or suspicious findings on physical examination that may indicate contraindications to study treatment or place the patient at high risk of treatment-related complications

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sun Yat-sen University

OTHER

Sponsor Role: lead

Responsible Party

Deshen Wang

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, China

Site Status: RECRUITING

Countries

China

Central Contacts

Deshen Wang, PhD

Role: CONTACT

wangdsh@sysucc.org.cn

87342487 ext. 020

Ruihua Xu, PhD

Role: CONTACT

xurh@sysucc.org.cn

87342479 ext. 020

Facility Contacts

Deshen Wang, PhD

Role: primary

wangdsh@sysucc.org.cn

87342487 ext. 020

Other Identifiers

RECHALLENGE-CRC

Identifier Type: -

Identifier Source: org_study_id