Conversion Therapy of RAS/BRAF Wild-Type Colorectal Cancer Patients With Initially Unresectable Liver Metastases

Conversion Therapy of RAS/BRAF Wild-Type Colorectal Cancer Patients With Initially Unresectable Liver Metastases: mFOLFOXIRI Plus Cetuximab Versus mFOLFOXIRI Plus Bevacizumab

Evidence suggests that the addition of cetuximab or bevacizumab to doublet regimens could improve response rate and resectability rate of liver metastases and survival in colorectal liver metastases (CRLM). Moreover, it is observed that FOLFOXIRI yields higher response and resection rates compared with doublet regimens. However, which is better in conversion therapy of RAS/BRAF wild-type initially unresectable CRLM, FOLFOXIRI plus cetuximab or bevacizumab, remains unknown.

In this study, RAS/BRAF wild-type colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by a local multidisciplinary team (MDT) according to predefined criteria, will be randomised between modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab and mFOLFOXIRI plus bevacizumab. Patient imaging will be reviewed for resectability by MDT, consisting of at least one radiologist and three liver surgeons every assessment. MDT review will be performed prior to randomization as well as during treatment, as described in the protocol.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Liver Metastases
• Intervention / Treatment: Drug: mFOLFOXIRI plus Cetuximab; Drug: mFOLFOXIRI Plus Bevacizumab

Detailed Description

Patients will be stratified for primary tumor location (right-sided or left sided) and numbers of liver metastases (<5 or ≥5).

Patients with RAS mutated primary tumors will be randomized between mFOLFOXIRI plus cetuximab (cetuximab 500 mg/m^2 in 60 minutes i.v., followed by oxaliplatin 85 mg/m^2 i.v. in 120 minutes, followed by irinotecan 165 mg/m^2 i.v. in 60 minutes, together with leucovorin 400 mg/m^2 i.v. in 120 minutes, followed by continuous infusion of 5-fluorouracil 2400 mg/m^2 in 46 hours, every 2 weeks) or mFOLFOXIRI plus bevacizumab (Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by oxaliplatin 85 mg/m^2 i.v. in 120 minutes, followed by irinotecan 165 mg/m^2 i.v. in 60 minutes, together with leucovorin 400 mg/m^2 i.v. in 120 minutes, followed by continuous infusion of 5-fluorouracil 2400 mg/m^2 in 46 hours, every 2 weeks).

Patients will be evaluated every 8 weeks by MRI or CT scan for disease status. The assigned systemic treatment should be continued for at least 6 months or earlier in case of resectability, progression of disease, unacceptable toxicity, or patient refusal. If after 6 months MDT concludes that the patient is still not resectable, it is highly unlikely that resectability will be achieved at all. Therefore the chemotherapy regimen may be reconsidered after 6 months of treatment.

In patients who will become resectable and undergo secondary surgery of liver metastases, the total duration of preoperative and postoperative treatment together should be 6 months. However, the postoperative chemotherapy regimen was determined by the investigator.

• Study Type: Interventional
• Enrollment (Anticipated): 386
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jianmin Xu, MD, Ph.D.; Phone Number: 692011 86-21-64041990; Email: xujmin@aliyun.com
• Study Contact Backup: Name: Wentao Tang, MD, Ph.D.; Phone Number: 86-21-64041990; Email: tangwt1988@163.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Zhongshan Hospital, Fudan University
      • Principal Investigator: Tao Zhang, M.D. Ph.D
      • Contact: Jianmin Xu, MD,Ph.D
      • Principal Investigator: Zhen Lou, M.D. Ph.D
      • Principal Investigator: Zhigang Wang, M.D. Ph.D
      • Principal Investigator: Sheng Wang, M.D. Ph.D
      • Principal Investigator: Kejing Huang, M.D. Ph.D
      • Principal Investigator: Minhao Yu, M.D. Ph.D
      • Principal Investigator: Zihua Chen, M.D. Ph.D
      • Principal Investigator: Rui Zhang, M.D.
      • Principal Investigator: Yifei Pan, M.D.
      • Principal Investigator: Chunkang Yang, M.D.
      • Principal Investigator: Yijiu Shi, M.D.
      • Principal Investigator: Guiying Wang, M.D.
      • Principal Investigator: Zhenning Wang, M.D.
      • Principal Investigator: Lingjun Zhu, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The primary tumor was confirmed by histology as colorectal adenocarcinoma
2. Initially unresectable liver metastases suggested by MDT
3. RAS/BRAF gene wild-type states
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Life expectancy ≥ 3 months
6. Good hematological function: neutrophil ≥ 1.5x109 / L and platelet count ≥ 100x109 / L; HB ≥ 9g / dl (within one week before randomization)
7. Normal liver and kidney function: serum bilirubin ≤ 1.5x normal upper limit (ULN), alkaline phosphatase ≤ 5x ULN, serum transaminase (AST or ALT) ≤ 5x ULN (within one week before randomization);
8. Sign the written informed consent to participate in the experiment

Exclusion Criteria:

1. Patients with liver metastases from colorectal cancer who have previously received targeted therapy, chemotherapy, radiotherapy or interventional therapy
2. Known or suspected extrahepatic metastasis
3. Patients with known hypersensitivity to any component of the study treatment
4. Clinical related coronary heart disease or history of myocardial infarction in the last 12 months or left ventricular ejection fraction below normal range
5. Acute or subacute intestinal obstruction
6. Pregnancy (no pregnancy confirmed by serum / urine β - hCG) or breastfeeding.
7. Other malignant tumors within 5 years, except for those with skin basal cell carcinoma or cervical cancer
8. Known drug / alcohol abuse
9. No legal capacity or limited legal capacity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: mFOLFOXIRI plus Cetuximab	Drug: mFOLFOXIRI plus Cetuximab; cetuximab 500mg/m2 + oxaliplatin 85 mg/m2 + irinotecan 165 mg/m2 + folinic acid 400 mg/m2 + 5-fluorouracil 2400 mg/m2 46h infusion starting on day 1, every 2 weeks
EXPERIMENTAL: mFOLFOXIRI plus Bevacizumab	Drug: mFOLFOXIRI Plus Bevacizumab; bevacizumab 5mg/kg + oxaliplatin 85 mg/m2 + irinotecan 165 mg/m2 + folinic acid 400 mg/m2 + 5-fluorouracil 2400 mg/m2 46h infusion starting on day 1, every 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conversion resection rate of liver metastases	Rate of conversion from initially unresectable liver metastases to resectable ones	up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Incidence of adverse events	up to 6 months
Early tumor shrinkage	The rates of tumor shrinkage by RECIST at 8 weeks	at 8 weeks
Objective Response Rate	rate of objective response for therapy	up to 6 months
Progression-Free Survival	Progression free survival	up to 3 years
Overall Survival	overall survival	up to 3 years
Best deepness of response	the maximum tumor shrinkage rates by RECIST during the treatment of the study	up to 6 months
time interval from chemotherapy to hepatectomy	Time interval from the beginning of treatment to hepatectomy	up to 6 months

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Jianmin Xu, MD, Ph.D., Fudan University

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 14, 2021
• Primary Completion (ANTICIPATED): December 31, 2023
• Study Completion (ANTICIPATED): December 31, 2026

Study Registration Dates

• First Submitted: December 27, 2020
• First Submitted That Met QC Criteria: December 27, 2020
• First Posted (ACTUAL): December 29, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 15, 2022
• Last Update Submitted That Met QC Criteria: June 11, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Bevacizumab; Colorectal Cancer; Cetuximab; Liver Metastases; Triplet Chemotherapeutic Regimen
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Liver Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Liver Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Cetuximab
• Other Study ID Numbers: TRUST

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