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.
18 Years
75 Years
Both
Colorectal Cancer
Trial Information
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.
OBJECTIVES:
Primary
- To compare the progression-free survival of second-line chemotherapy with or without
bevacizumab in patients with metastatic colorectal cancer who have received first-line
chemotherapy with bevacizumab.
Secondary
- To compare the overall survival, response rate, and safety profile of second-line
chemotherapy of these regimens in these patients.
- To conduct pharmacogenomics assessment of candidate variants in the VEGF gene and
evaluate their association with progression-free survival and other study outcomes.
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.
- Arm I: Patients receive either irinotecan hydrochloride over 1 hour or oxaliplatin over
1 hour on day 1. Patients also receive leucovorin calcium IV over 2 hours and
fluorouracil IV over 46 hours continuously beginning on day 1.
- Arm II: Patients receive combination chemotherapy as in arm I and bevacizumab IV on day
1.
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.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Histologically confirmed colorectal adenocarcinoma
- Metastatic or unresectable disease
- Progressive disease based on the following criteria:
- Progression during or after first-line chemotherapy for metastatic disease,
including any of the following:
- Fluoropyrimidine-based monotherapy with bevacizumab
- Fluoropyrimidine and irinotecan hydrochloride-based doublet with
bevacizumab
- Fluoropyrimidine and oxaliplatin-based doublet with bevacizumab
- 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:
- Cerebrovascular accident within the past 6 months
- Myocardial infarction within the past 6 months
- Unstable angina
- NYHA class II-IV chronic heart failure
- Uncontrolled arrhythmia
- 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
- Acetylsalicylic acid ≤ 325 mg/day allowed
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Progression-free survival
Outcome Time Frame:
last progression of the last patient
Safety Issue:
No
Principal Investigator
Alfredo Falcone, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Presidio Ospedaliero di Livorno
Authority:
Italy: Agenzia Italiana del Farmaco (AIFA)
Study ID:
CDR0000598567
NCT ID:
NCT00720512
Start Date:
June 2008
Completion Date:
March 2014
Related Keywords:
- Colorectal Cancer
- adenocarcinoma of the colon
- adenocarcinoma of the rectum
- recurrent colon cancer
- recurrent rectal cancer
- stage IV colon cancer
- stage IV rectal cancer
- stage III rectal cancer
- stage III colon cancer
- Colorectal Neoplasms
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