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

• ClinicalTrials.gov Identifier: NCT04781270
• Recruitment Status: Recruiting
• First Posted: March 4, 2021
• Last Update Posted: September 27, 2021
• Sponsor: Fudan University
• Information provided by (Responsible Party): Fudan University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Carcinoma; Liver Metastases	Drug: mFOLFOXIRI regimen; Drug: mFOLFOX regimen; Drug: Bevacizumab	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 308 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: mFOLFOXIRI Plus Bevacizumab Versus mFOLFOX6 Plus Bevacizumab for the First Line Treatment of RAS Mutant Unresectable Colorectal Liver-limited Metastases
• Actual Study Start Date: April 15, 2021
• Estimated Primary Completion Date: March 30, 2024
• Estimated Study Completion Date: March 30, 2026

Arms and Interventions

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: 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; Drug: Bevacizumab; 5 mg/kg on day 1

Outcome Measures

Primary Outcome Measures :

1. conversion resection rate [ Time Frame: up to 6 months ]
   R0 resection rate upon conversion treatment with chemotherapy plus bevacizumab

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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;

Contacts and Locations

Contacts

Contact: Jianmin Xu, MD, Ph.D.; 021-64041990; xujmin@aliyun.com

Contact: Wentao Tang, MD, Ph.D.; 021-64041990; tangwt1988@163.com

Locations

China, Shanghai

Zhongshan Hospital, Fudan University; Recruiting

Shanghai, Shanghai, China, 200032

Contact: Jianmin Xu, M.D. Ph.D xujmin@aliyun.com

Contact: Wentao Tang, M.D. Ph.D 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

Sponsors and Collaborators

Fudan University

Investigators

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

More Information

• Responsible Party: Fudan University
• ClinicalTrials.gov Identifier: NCT04781270
• Other Study ID Numbers: BECOME2
• First Posted: March 4, 2021
• Last Update Posted: September 27, 2021
• Last Verified: March 2021

• 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

Additional relevant MeSH terms:

Neoplasm Metastasis; Colorectal Neoplasms; Neoplastic Processes; Neoplasms; Pathologic Processes; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Bevacizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors