Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Closed	18 and over	Pharmaceutical / Industry	GENENTECH-AVF2192g NCT00012272

Objectives

I. Compare the efficacy of fluorouracil and leucovorin calcium with and 
without bevacizumab, in terms of duration of survival, objective response 
rate, duration of response, time to disease progression, and change in quality 
of life, in patients with previously untreated metastatic colorectal cancer.

II. Compare the safety of these regimens in these patients.

III. Assess the safety and preliminary efficacy of bevacizumab combined with 
irinotecan in these patients.

IV. Assess the pharmacokinetics of irinotecan in these patients.
 

Entry Criteria

Disease Characteristics:

Histologically confirmed, previously untreated, metastatic colorectal
carcinoma

Bidimensionally measurable disease (minimum of two lesions)

Not an optimal candidate for first-line irinotecan

Must meet at least one of the following criteria:
 Age 65 years or over
 ECOG performance status 1-2
 Albumin no greater than 3.5 g/dL
 Prior radiotherapy to the abdomen or pelvis

No CNS disease (e.g., primary brain tumor, seizures not controlled with
standard therapy, or any brain metastases)

No clinically detectable ascites

Prior/Concurrent Therapy:

Biologic therapy:
 No prior biologic therapy for colorectal cancer
 No concurrent immunotherapy

Chemotherapy:
 See Disease Characteristics
 At least 12 months since prior adjuvant fluoropyrimidines in combination with
  leucovorin calcium and/or levamisole
 No other prior chemotherapy
 No concurrent chemotherapy

Endocrine therapy:
 Not specified

Radiotherapy:
 See Disease Characteristics
 No prior radiotherapy to target lesions
 At least 12 months since prior administration of fluoropyrimidines as a
  radiosensitizer during pelvic radiotherapy for rectal cancer completed less
  than 12 months prior to study
 At least 14 days since prior radiotherapy
 No concurrent radiotherapy

Surgery:
 At least 28 days since prior major surgery
 At least 7 days since prior fine needle aspiration
 No concurrent open biopsy or anticipated need for major surgery

Other:
 At least 10 days since prior chronic use of oral or parenteral anticoagulants
  (except as needed to maintain patency of indwelling IV catheters) or
  thrombolytic agents
 At least 28 days since participation in other experimental drug study
 No concurrent oral or parenteral anticoagulants (except as needed to maintain
  patency of indwelling IV catheters) or thrombolytic agents
 No concurrent chronic daily aspirin or nonsteroidal anti-inflammatory
  medications known to inhibit platelet function

Patient Characteristics:

Age:
 See Disease Characteristics 
 18 and over

Performance status:
 See Disease Characteristics
 ECOG 0-2

Life expectancy:
 More than 3 months

Hematopoietic:
 Absolute neutrophil count at least 1,500/mm3
 Platelet count greater than 75,000/mm3
 Hemoglobin at least 9 g/dL (transfusion allowed)
 No bleeding diathesis or coagulopathy

Hepatic:
 See Disease Characteristics
 Bilirubin no greater than 2.0 mg/dL
 AST/ALT no greater than 2.5 times upper limit of normal (ULN)(less than 5
  times ULN if liver metastases present)
 INR less than 1.5

Renal:
 No history of proteinuria
 No clinically significant impairment of renal function
 Creatinine no greater than 2.0 mg/dL

Cardiovascular:
 No uncontrolled hypertension, myocardial infarction, or unstable angina
  within the past year
 No New York Heart Association class II or higher congestive heart failure
  within the past year
 No serious cardiac arrhythmia requiring medication or grade II or higher
  peripheral vascular disease within the past year
 
Other:
 Able to tolerate CT scan contrast dye
 Not pregnant or nursing
 Negative pregnancy test
 Fertile patients must use effective contraception
 No other malignancy within the past 5 years except basal cell carcinoma
  of the skin
 No serious nonhealing wound, ulcer, significant traumatic injury, or bone
  fracture
 No concurrent active infection requiring parenteral antibiotics
 No metabolic dysfunction or other medical condition that would preclude study

Expected Enrollment

A total of 200 patients (100 per arm) will be accrued for this study.

Outline

This is a randomized, double-blind, active-controlled, multicenter study.  
Patients are stratified according to ECOG performance status (0 vs 1 or 
higher), site of primary disease (colon vs rectum), and number of metastatic 
sites (1 vs more than 1).  Patients are randomized to one of two treatment 
arms.

Arm I: Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV 
over 1 hour weekly for the first 6 weeks of each 8 week course.  Study drug, 
bevacizumab is administered IV over 30-90 minutes every 2 weeks.  Courses 
repeat every 8 weeks in the absence of disease progression or unacceptable 
toxicity.

Arm II: Patients receive leucovorin calcium and fluorouracil as in arm I and 
placebo IV over 30-90 minutes every 2 weeks.

Treatment continues for up to a total of 48 doses of bevacizumab or a maximum 
of 96 weeks of therapy.  Patients on arm I who have disease progression may 
continue bevacizumab with or without irinotecan IV over 90 minutes weekly for 
4 weeks, with courses repeating every 6 weeks.  Patients on arm II who have 
disease progression may not receive second-line bevacizumab.   Patients on 
either arm who have disease progression may receive irinotecan alone as 
second-line treatment.

Quality of life is assessed every 3-5 weeks.

Patients are followed every 4 months for survival.

Kabbinavar FF, Schulz J, McCleod M, et al.: Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 23 (16): 3697-705, 2005.[PUBMED Abstract]

Cassidy J, Saltz LB, Giantonio BJ, et al.: Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. J Cancer Res Clin Oncol : , 2009.[PUBMED Abstract]

Kabbinavar FF, Hurwitz HI, Yi J, et al.: Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol 27 (2): 199-205, 2009.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Genentech Incorporated

Brent Perrou, MD, Protocol chair		Ph: 650-225-1752; 800-626-3553

Registry Information
Official Title		A Phase II, Multicenter, Double-Blind, Randomized, Active-Controlled Clinical Trial to Evaluate the Efficacy and Safety of rhuMAb VEGF, A Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor in Combination with 5-Fluorouracil and Leucovorin Chemotherapy in Subjects with Metastatic Colorectal Cancer who are Not Optimal Candidates for First-Line CPT-11
Trial Start Date		2000-06-01
Registered in ClinicalTrials.gov		NCT00012272
Date Submitted to PDQ		2001-01-25
Information Last Verified		2009-11-13

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