AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE III STUDY OF SECOND-LINE CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB IN METASTATIC COLORECTAL CANCER PATIENTS WHO HAVE RECEIVED FIRST-LINE CHEMOTHERAPY PLUS BEVACIZUMAB.
AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE III STUDY OF SECOND-LINE CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB IN METASTATIC COLORECTAL CANCER PATIENTS WHO HAVE RECEIVED FIRST-LINE CHEMOTHERAPY PLUS BEVACIZUMAB.
RATIONALE: Drugs used in chemotherapy, such as irinotecan, oxaliplatin, 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. 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. It is not yet known whether combination chemotherapy is more effective with or without bevacizumab in treating metastatic colorectal cancer.
PURPOSE: This randomized phase III trial is studying second-line combination chemotherapy to see how well it works compared with or without bevacizumab in treating patients with metastatic colorectal cancer who have received first-line chemotherapy and bevacizumab.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a multicenter study. Patients are stratified according to participating center, ECOG performance status (0 vs 1-2), disease-free interval from the last administration of first-line chemotherapy for metastatic disease (≤ 3 months vs > 3 months), and type of second-line chemotherapy (irinotecan hydrochloride, leucovorin calcium, and fluorouracil [FOLFIRI] vs oxaliplatin, leucovorin calcium, and fluorouracil [mFOLFOX-6]). Patients are randomized to 1 of 2 treatment arms.
Treatment in both arms repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Existing formalin-fixed paraffin-embedded tumor tissue samples are assessed for pharmacogenomics and markers predictive of response, resistance to, or toxicity from bevacizumab. Samples are analyzed via RT-PCR, array comparative genomic hybridization, fluorescence in situ hybridization, sequencing of candidate genes, and immunohistochemistry.
After completion of study treatment, patients are followed for 1 year.
DISEASE CHARACTERISTICS:
Histologically confirmed colorectal adenocarcinoma
Progressive disease based on the following criteria:
Progression during or after first-line chemotherapy for metastatic disease, including any of the following:
Progression after more than 3 months from the last administration of first-line chemotherapy for metastatic disease with a fluoropyrimidine, irinotecan hydrochloride, and oxaliplatin triplet (FOLFOXIRI) with bevacizumab to which the patient had previously responded
Measurable disease, as assessed by RECIST criteria
No prior or concurrent CNS metastasis
PATIENT CHARACTERISTICS:
ECOG performance status 0-2
Life expectancy > 3 months
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 9 g/dL
INR ≤ 1.5 times upper limit of normal (ULN)
aPTT ≤ 1.5 ULN
Serum bilirubin ≤ 1.5 times ULN
AST and ALT ≤ 2.5 times ULN (< 5 times ULN if liver metastases present)
Alkaline phosphatase ≤ 2.5 times ULN (< 5 times ULN if liver metastases present)
Serum creatinine ≤ 1.5 times ULN
Proteinuria < 2+ OR protein ≤ 1g by 24-hour urine
Not pregnant or nursing
Fertile patients must use effective contraception
No bowel obstruction or subobstruction
No history of inflammatory enteropathy
No prior extensive intestinal resection (i.e., > hemicolectomy or extensive small intestine resection with chronic diarrhea)
No symptomatic peripheral neuropathy > grade 2
No active uncontrolled infection
No active disseminated intravascular coagulation
No prior or concurrent malignancy, except for curatively treated basal cell and squamous cell carcinoma of the skin, or in situ carcinoma of the cervix
No clinically significant cardiovascular disease, including any of the following:
No uncontrolled hypertension
No thromboembolic or hemorrhagic events within the past 6 months
No evidence of bleeding diathesis or coagulopathy
No serious, non healing wound/ulcer or serious bone fracture
No significant traumatic injury within the past 28 days
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
At least 6 weeks since prior radiotherapy
At least 4 weeks since prior surgery
No prior first-line chemotherapy for metastatic disease without bevacizumab
No prior cetuximab or other investigational agents
More than 28 days since prior open biopsy
More than 28 days since prior and no concurrent major surgical procedure
No concurrent therapeutic anticoagulation, antiplatelet agents, or NSAID with anti-platelet activity