Bevacizumab and Combination Chemotherapy as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer That Cannot Be Removed by Surgery (OMEGA)

Phase II Study Evaluating the Efficacy and Tolerance to Chemotherapy With 5-fluorouracil, Folinic Acid, Irinotecan and Bevacizumab as First-line Treatment in Patients With Metastatic Colorectal Cancer

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with combination chemotherapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving bevacizumab together with combination chemotherapy works as first-line therapy in treating patients with metastatic colorectal cancer that cannot be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Genetic: polymorphism analysis; Drug: fluorouracil; Drug: leucovorin calcium; Drug: irinotecan hydrochloride; Biological: bevacizumab

Detailed Description

OBJECTIVES:

Primary

• Determine the efficacy of bevacizumab, irinotecan hydrochloride, leucovorin calcium, and fluorouracil, in terms of partial or complete response, in patients with unresectable metastatic colorectal cancer.

Secondary

• Determine the duration of response in patients treated with this regimen.
• Determine the overall survival and progression-free survival of patients treated with this regimen.
• Determine the tolerability of this regimen in these patients.
• Assess the pharmacogenetics and change in genetic polymorphisms susceptible to modification by this regimen.

OUTLINE: This is a nonrandomized, multicenter study.

Patients receive irinotecan hydrochloride IV over 90 minutes, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

Blood and tissue samples are collected periodically for pharmacogenetic and genetic polymorphism analysis.

PROJECTED ACCRUAL: A total of 61 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Institut Bergonie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum

  • No other histological types

• Metastatic, unresectable disease

  • No bone metastases only
• Unidimensionally measurable metastatic disease
• No CNS metastases

PATIENT CHARACTERISTICS:

• WHO performance status (PS) 0-2 OR Karnofsky PS 70-100%
• Life expectancy ≥ 12 weeks
• ANC > 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL
• Bilirubin ≤ 1.25 times normal (1.5 times normal in presence of hepatic metastases)
• AST and ALT < 3 times normal (5 times normal in presence of hepatic metastases)
• Creatinine < 1.25 times normal
• No proteinuria
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other cancer in the past 5 years except for carcinoma in situ of the uterine cervix or basal cell skin cancer
• No hypersensitivity to fluorouracil
• No hypersensitivity to leucovorin calcium, bevacizumab, or their excipients
• No hypersensitivity to Chinese hamster ovarian cell products or other recombinant humanized or nonhumanized monoclonal antibodies
• No allergy to irinotecan hydrochloride
• No prior reaction to attenuated vaccines (fever, jaundice)
• No poor nutritional status
• No Biermer anemia or other anemia due to vitamin B12 deficiency
• No uncontrolled symptomatic occlusion or subocclusion
• No medullary hypoplasia or severe insufficiency
• No prior chronic intestinal disease
• No Gilbert's syndrome
• No intra-abdominal inflammatory reaction (e.g., gastroduodenal ulcer, diverticulitis, or colitis)
• No chronic intestinal inflammatory disease

• No thromboembolic arterial condition in the past 6 months, including any of the following:

  • Cardiovascular accident
  • Transient ischemic attack
  • Myocardial infarction
• No infection or serious noncancerous disease

• No condition that is unstable or would increase risk to the patient, including any of the following:

  • Unstable angina
  • Poorly controlled hypertension
  • Severe cardiac insufficiency
  • Serious arrhythmia
  • Bleeding diathesis
  • Pulmonary disease at risk of decompensation
• No familial, geographical, social, or psychological condition that would preclude study participation
• No prisoners or patients without guardians

PRIOR CONCURRENT THERAPY:

• At least 8 weeks since prior surgery
• At least 6 months since prior adjuvant chemotherapy
• At least 1 month since prior palliative chemotherapy
• No prior abdominal or pelvic radiotherapy
• At least 30 days since prior participation in another investigational study
• No prior bevacizumab
• No extensive intestinal resection (e.g., partial colectomy or extensive thin resection)
• No concurrent warfarin, Hypericum perforatum (St. John's wort), or prophylactic phenytoin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Folfiri and Bevacizumab; Premedication = Dexchlorpheniramine, 5 mg in slow Direct IntraVeinous (DIV) on D1.; FOLFIRI (simplified LV5FU2 + irinotecan):; Irinotecan (Campto®): 180 mg/m² on D1 by IV infusion in 250 mL of 0.9% saline over 90 minutes.; LV5FU2, in its so-called "simplified" version, will be administered as follows L-folinic acid, as a 2-hour intravenous infusion, at a dose of 200 mg/m², on Day 1, in 500 mL of 5% glucose solution, concomitantly with the irinotecan infusion via a Y-tube, followed by 5 Fluorouracil (5 FU), intravenous bolus, at a dose of 400 mg/m² on D1, followed by 5 Fluorouracil (5 FU) as a 46-hour continuous infusion at a dose of 2400 mg/m² from D1 to D3, either in 1000 mL of 5% glucose solution, or in an electric syringe or pump dispenser; Bevacizumab (Avastin®): 5 mg/kg IV infusion in 100 mL of 0.9% saline over 90 minutes for the first infusion, then 60 minutes for the second infusion if tolerated, and 30 minutes for subsequent infusions if tolerated.

Genetic: polymorphism analysis; Drug: fluorouracil; Drug: leucovorin calcium; Drug: irinotecan hydrochloride; Biological: bevacizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants in Objective Response (Partial or Complete Responses)	Objective response defined as complete or partial responses according to RECIST v1.0. Complete response is defined as the disappearance of all target lesions and partial response is defined as at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD (RECIST V1.0.).Radiologic assessment was carried out every four cycles (8 weeks) with centralized external secondary review.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Duration of Response	Duration of response is defined as the delay between response (complete or partial) and disease progression according to RECIST V1.0. Therefore, this criterion can only be assessed in in subjects who have responded. Complete response is defined as the disappearance of all target lesions and partial response is defined as at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD (RECIST V1.0.). Progression is defined as a 20% increase in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD, or appearance of one or several new lesions (RECIST V1.0) Radiologic assessment was carried out every four cycles (8 weeks) with centralized external secondary review.	24 months

Collaborators and Investigators

• Sponsor: Institut Bergonié

Publications and helpful links

General Publications

• Becouarn Y, Cany L, Pulido M, Beyssac R, Texereau P, Le Morvan V, Bechade D, Brunet R, Aitouferoukh S, Lalet C, Mathoulin-Pelissier S, Fonck M, Robert J. FOLFIRI(R) and bevacizumab in first-line treatment for colorectal cancer patients: safety, efficacy and genetic polymorphisms. BMC Res Notes. 2014 Apr 23;7:260. doi: 10.1186/1756-0500-7-260.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2007
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: April 25, 2007
• First Submitted That Met QC Criteria: April 25, 2007
• First Posted (Estimate): April 27, 2007

Study Record Updates

• Last Update Posted (Actual): November 1, 2022
• Last Update Submitted That Met QC Criteria: October 28, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Bevacizumab; Leucovorin; Irinotecan; Calcium; Levoleucovorin
• Other Study ID Numbers: CDR0000540522; IB-2006-31; IB-OMEGA; INCA-RECF0387; EUDRACT-2006-003901-22