Combination Chemotherapy and Bevacizumab With or Without Bevacizumab Maintenance Therapy in Treating Patients With Metastatic Colorectal Cancer

Federation Francophone de Cancerologie Digestive

Status and phase: Completed; Phase 3; Phase 2

Conditions: Colorectal Cancer

Treatments: Drug: FOLFIRI regimen; Drug: irinotecan hydrochloride; Drug: fluorouracil; Biological: bevacizumab; Drug: leucovorin calcium

Study type: Interventional

Funder types: Other

Identifiers

NCT00952029

PRODIGE 9

EUDRACT-2009-017996-11

EU-21030

EUDRACT-2008-007928-25

FFCD-0802

EU-20912

FFCD-PRODIGE-9

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet known whether giving more than one drug (combination chemotherapy) is more effective when given with or without bevacizumab in treating patients with metastatic colorectal cancer.

PURPOSE: This randomized phase III trial is studying giving combination chemotherapy with or without bevacizumab to see how well it works in treating patients with metastatic colorectal cancer.

Full description

OBJECTIVES:

Primary

• Compare disease-control duration in patients with metastatic colorectal cancer receiving FOLFIRI chemotherapy in combination with bevacizumab with or without bevacizumab maintenance therapy.

Secondary

• Determine objective response rate.
• Determine non-hematologic grade 3-4 (except alopecia) toxicity rate.
• Determine overall toxicity rate.
• Determine duration of chemotherapy-free interval.
• Determine progression-free survival.
• Determine overall survival.
• Determine time-to-treatment failure.
• Determine quality of life (EORTC QLQ-C30).
• Complete geriatric evaluation.

OUTLINE: This is a multicenter study. Patients are stratified according to cancer center, primary tumor (resected vs unresected), and Köhne criteria (low vs intermediate vs high). Patients are randomized to 1 of 2 treatment arms.

• Arm A: Patients receive FOLFIRI chemotherapy comprising irinotecan hydrochloride IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours on days 1-2. Chemotherapy treatment repeats every 2 weeks for 12 courses. Patients also receive bevacizumab IV over 30-90 minutes once every 2 weeks during chemotherapy. Patients then receive bevacizumab maintenance therapy once every 2 weeks during the chemotherapy-free interval.
• Arm B: Patients receive FOLFIRI chemotherapy and bevacizumab as in arm A. Patients receive no treatment during the chemotherapy-free interval.

In all arms, the chemotherapy treatment and the chemotherapy-free interval treatment repeats in the absence of disease progression during the chemotherapy portion or unacceptable toxicity. Patients who progress during the chemotherapy-free interval will receive 12 more courses of chemotherapy.

All patients complete quality of life questionnaires (QLQ-30) and patients ≥ 75 also complete the geriatric questionnaire at baseline and every 8 weeks during study treatment.

After completion of study treatment, patients are followed up every 8 weeks.

Enrollment: 492 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer

  • Metastatic disease

• Not a candidate for curative surgery

• At least 1 tumor target measurable by RECIST criteria

• No metastasis potentially resectable after receiving chemotherapy

• No occlusive tumors

• No macronodular peritoneal carcinomatosis

• No known or suspected CNS metastases

PATIENT CHARACTERISTICS:

• OMS status 0-2
• Life expectancy ≥ 3 months
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of hepatic metastases)
• Creatinine ≤ 1.5 times ULN
• Proteinuria ≤1 g
• Not pregnant or nursing
• No gastroduodenal ulcer, wound, or fractured bone
• No acute or subacute intestinal occlusion or history of inflammatory bowel disease or large resection of small bowel
• No clinically relevant coronary artery disease or a history of a myocardial infarction within the last 6 months
• No uncontrolled hypertension while receiving chronic medication
• No other malignancy within the past 5 years except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix
• No medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study

PRIOR CONCURRENT THERAPY:

• See Patient Characteristics

• No prior chemotherapy for metastatic disease

  • Adjuvant chemotherapy allowed provided it was completed > 6 months ago

• No prior irinotecan or other antiangiogenic therapy

• At least 4 weeks since surgery (except for diagnostic biopsy) or irradiation

• No other drugs not allowed for medical reasons

• Concurrent oral anticoagulants (e.g., coumadin, warfarin) allowed provided the INR is closely monitored

  • A change of anticoagulants to low-molecular weight heparin is preferred

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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492 participants in 2 patient groups

Maintenance with bevacizumab

Experimental group

Description:

FOLFIRI + Avastin and during the chemotherapy-free interval maintenance with bevacizumab

Treatment:

Drug: fluorouracil

Biological: bevacizumab

Drug: leucovorin calcium

Drug: FOLFIRI regimen

Drug: irinotecan hydrochloride

No maintenance with bevacizumab

Active Comparator group

Description:

FOLFIRI + Avastin and during the chemotherapy-free interval NO maintenance

Treatment:

Drug: fluorouracil

Biological: bevacizumab

Drug: leucovorin calcium

Drug: FOLFIRI regimen

Drug: irinotecan hydrochloride