mFOLFOXIRI+Bev vs. mFOLFOX6+Bev for RAS Mutant Unresectable Colorectal Liver-limited Metastases

mFOLFOXIRI Plus Bevacizumab Versus mFOLFOX6 Plus Bevacizumab for the First Line Treatment of RAS Mutant Unresectable Colorectal Liver-limited Metastases

Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by conversion therapy. However, the optimal regimen of conversion therapy for RAS mutant patients has not been defined.

In this study colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by a local multidisciplinary team (MDT) according to predefined criteria, will be tested for RAS and BRAF tumor mutation status. Patients with RAS mutant and BRAF wild type will be randomised between modified FOLFOXIRI (mFOLFOXIRI) plus bevacizumab and modified FOLFOX6 (mFOLFOX6) 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: Liver Metastases; Colorectal Carcinoma
• Intervention / Treatment: Drug: mFOLFOXIRI regimen; Drug: Bevacizumab; Drug: mFOLFOX regimen

Detailed Description

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

Patients with RAS mutated primary tumors will be randomized between mFOLFOXIRI plus bevacizumab (Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by irinotecan 165 mg/m^2 i.v. in 60 minutes, followed by oxaliplatin 85 mg/m^2 i.v. 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 mFOLFOX6 plus bevacizumab (Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by oxaliplatin 85 mg/m^2 i.v. together with leucovorin 400 mg/m^2 i.v. in 120 minutes, followed by bolus 5FU 400 mg/m^2, all on day 1, 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. These patients will continue with bevacizumab plus fluoropyrimidine until progression or unacceptable toxicity.

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, in these patients mFOLFOXIRI should not be continued after surgery and replaced by mFOLFOX6. Bevacizumab will continued after surgery for both groups.

• Study Type: Interventional
• Enrollment (Anticipated): 308
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jianmin Xu, MD, Ph.D.; Phone Number: 021-64041990; Email: xujmin@aliyun.com
• Study Contact Backup: Name: Wentao Tang, MD, Ph.D.; Phone Number: 021-64041990; Email: tangwt1988@163.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Zhongshan Hospital, Fudan University
      • Contact: Jianmin Xu, M.D. Ph.D; Email: xujmin@aliyun.com
      • Contact: Wentao Tang, M.D. Ph.D; Email: tangwt1988@163.com
      • Principal Investigator: Kefeng Ding, M.D. Ph.D
      • Principal Investigator: Shan Zeng, M.D. Ph.D
      • Principal Investigator: Zhenning Wang, M.D. Ph.D
      • Principal Investigator: Tao Zhang, M.D. Ph.D
      • Principal Investigator: Lechi Ye, M.D. Ph.D
      • Principal Investigator: Chunkang Yang, M.D. Ph.D
      • Principal Investigator: Guiying Wang, M.D. Ph.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:

• Histological proof of colorectal adenocarcinoma;
• Age ≥ 18 years and ≤75 years;
• Simultaneous liver-limited metastases;
• Initially unresectable liver metastases determined by a local MDT;
• RAS mutation and BRAF V600E wild-type;
• At least one measurable liver metastasis;
• Initially resectable primary tumor or primary tumor already resected;
• World Health Organization (WHO) performance status 0-1;
• Life expectancy ≥ 3 months;
• Adequate hematologic function: absolute neutrophil count (ANC)≥1.5×109/l, platelets≥100×109/l, and hemoglobin(HB) ≥ 9g/dl;
• Adequate liver and renal function: total bilirubin ≤2.0 mg/dl, serum transaminases ≤ 5x upper limit of normal(ULN), and serum creatinine ≤ 1.5x ULN and creatinine clearance ≥ 30 ml/min;
• Written informed consent.

Exclusion Criteria:

• Previous systemic treatment for metastatic disease;
• Previous surgery for metastatic disease;
• Extrahepatic metastases;
• Unresectable primary tumor;
• Major cardiovascular events (myocardial infarction, severe/unstable angina, congestive heart failure, CVA) within 12 months before randomisation;
• Acute or subacute intestinal obstruction;
• Second primary malignancy within the past 5 years;
• Drug or alcohol abuse;
• No legal capacity or limited legal capacity;
• Pregnant or lactating women;
• Uncontrolled hypertension, or unsatisfactory blood pressure control with ≥3 antihypertensive drugs;
• Peripheral neuropathy;

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: mFOLFOXIRI+Bev; Patients will receive mFOLFOXIRI plus bevacizumab once every two weeks as the first-line treatment. Drug: mFOLFOXIRI plus Bevacizumab Bevacizumab (5 mg/kg on day 1) plus mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1). A local MDT will assess the efficiency every 4 cycles of the treatment. The maximum period of conversion therapy is 12 cycles.	Drug: mFOLFOXIRI regimen; oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, and folinic acid 400 mg/m2 followed by 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1; Drug: Bevacizumab; 5 mg/kg on day 1
ACTIVE_COMPARATOR: mFOLFOX6+Bev; Patients will receive mFOLFOX6 plus bevacizumab once every two weeks as the first-line treatment. Drug: mFOLFOX6 Plus Bevacizumab mFOLFOX6 (oxaliplatin 85 mg/m2, and folinic acid 400 mg/m2 followed by bolus 5-fluorouracil 400 mg/m2 and 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1). A local MDT will assess the efficiency every 4 cycles of the treatment. The maximum period of conversion therapy is 12 cycles.	Drug: Bevacizumab; 5 mg/kg on day 1; Drug: mFOLFOX regimen; oxaliplatin 85 mg/m2, and folinic acid 400 mg/m2 followed by bolus 5-fluorouracil 400 mg/m2 and 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
conversion resection rate	R0 resection rate upon conversion treatment with chemotherapy plus bevacizumab	up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	from the first day of assigned treatment to death or last known to be alive	up to 2 years
Progression-free survival (PFS)	from the first day of assigned treatment to progression or death whichever comes first	up to 2 years
Toxicity (AE)	Patients will be evaluated for Adverse Events at the start of each treatment cycle according to CTCAE version 5.0	up to 6 months
postoperative complication	Patients will be evaluated for surgical morbidity during 1 month. Postoperative morbidity will be scored according 'Clavien-Dindo Grade'.	After surgery during one month
overall response	Response according to RECIST 1.1	up to 6 months
proportion of no evidence of disease	Response according to RECIST 1.1	up to 6 months
Best deepness of response	The maximum tumor shrinkage rates by Response Evaluation Criteria in Solid Tumors (RECIST) throughout the treatments	up to 6 months
Early tumor shrinkage	The rates of tumor shrinkage by RECIST at 8 weeks	at 8 weeks

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): April 15, 2021
• Primary Completion (ANTICIPATED): March 30, 2024
• Study Completion (ANTICIPATED): March 30, 2026

Study Registration Dates

• First Submitted: March 1, 2021
• First Submitted That Met QC Criteria: March 1, 2021
• First Posted (ACTUAL): March 4, 2021

Study Record Updates

• Last Update Posted (ACTUAL): September 27, 2021
• Last Update Submitted That Met QC Criteria: September 22, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: BECOME2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No