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

Liver Metastases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04781270
• Other study ID #: BECOME2
• Status: Recruiting
• Phase: Phase 3
• Start date: April 15, 2021
• Est. completion date: March 30, 2026

Study information

• Verified date: March 2021
• Source: Fudan University
• Contact: Jianmin Xu, MD, Ph.D.
• Phone: 021-64041990
• Email: xujmin[@]aliyun.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 308
• Est. completion date: March 30, 2026
• Est. primary completion date: March 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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;

Related Conditions & MeSH terms

• Colorectal Carcinoma
• Colorectal Neoplasms
• Liver Metastases
• Neoplasm Metastasis

Intervention

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
• 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
• Bevacizumab
5 mg/kg on day 1

Locations

Country	Name	City	State
China	Zhongshan Hospital, Fudan University	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Fudan University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	conversion resection rate	R0 resection rate upon conversion treatment with chemotherapy plus bevacizumab	up to 6 months
Secondary	Overall survival (OS)	from the first day of assigned treatment to death or last known to be alive	up to 2 years
Secondary	Progression-free survival (PFS)	from the first day of assigned treatment to progression or death whichever comes first	up to 2 years
Secondary	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
Secondary	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
Secondary	overall response	Response according to RECIST 1.1	up to 6 months
Secondary	proportion of no evidence of disease	Response according to RECIST 1.1	up to 6 months
Secondary	Best deepness of response	The maximum tumor shrinkage rates by Response Evaluation Criteria in Solid Tumors (RECIST) throughout the treatments	up to 6 months
Secondary	Early tumor shrinkage	The rates of tumor shrinkage by RECIST at 8 weeks	at 8 weeks