Combination Chemotherapy With or Without Bevacizumab Compared With Bevacizumab Alone in Treating Patients With Advanced or Metastatic Colorectal Cancer That Has Been Previously Treated

National Cancer Institute (NCI)

Status and phase

Completed

Phase 3

Conditions

Stage IV Rectal Cancer

Stage III Rectal Cancer

Recurrent Colon Cancer

Stage IV Colon Cancer

Adenocarcinoma of the Colon

Adenocarcinoma of the Rectum

Stage III Colon Cancer

Recurrent Rectal Cancer

Treatments

Drug: fluorouracil

Drug: oxaliplatin

Biological: bevacizumab

Drug: leucovorin calcium

Study type

Interventional

Funder types

NIH

Identifiers

NCT00025337

NCI-2012-02417

E3200

CDR0000068951 (Registry Identifier)

U10CA021115 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without bevacizumab in treating patients who have advanced or metastatic colorectal cancer that has been previously treated. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as bevacizumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining monoclonal antibody therapy with combination chemotherapy may kill more tumor cells. It is not yet known if bevacizumab is more effective with or without combination chemotherapy in treating colorectal cancer

Full description

OBJECTIVES:

I. Compare the response, time to progression, and overall survival of patients with previously treated advanced or metastatic colorectal adenocarcinoma treated with oxaliplatin, leucovorin calcium, and fluorouracil with or without bevacizumab versus bevacizumab only. (Arm III closed to accrual as of 03/11/2003).

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

OUTLINE: This is a randomized study. Patients are stratified according to ECOG performance status (0 vs 1 or 2), and prior radiotherapy (yes vs no). Patients are randomized to 1 of 3 treatment arms.

Arm I: Patients receive bevacizumab IV over 30-90 minutes and oxaliplatin IV over 2 hours on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil (5-FU) IV over 22 hours on days 1 and 2.

Arm II: Patients receive oxaliplatin, leucovorin calcium, and 5-FU as in arm I.

Arm III: Patients receive bevacizumab as in arm I. (Arm closed to accrual as of 03/11/2003).

Courses in all arms repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response may receive 2 additional courses.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Enrollment

880 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

Histologically confirmed adenocarcinoma of the colon or rectum
- Advanced or metastatic disease
- Must have received a fluoropyrimidine-based regimen and an irinotecan-based regimen, either alone or in combination, for advanced disease
- May have relapsed within 6 months of adjuvant therapy with fluorouracil (5-FU) (or combination 5-FU and irinotecan) and progressed after single-agent irinotecan
Measurable disease
No known brain metastases
Performance status - ECOG 0-2
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
No history of thrombotic or hemorrhagic disorders
Bilirubin no greater than 1.5 times upper limit of normal (ULN)
AST no greater than 5 times ULN
INR no greater than 1.5
PTT no greater than ULN
Creatinine no greater than 1.5 times ULN
Proteinuria less than 1+ (i.e., 0 or trace)
Protein less than 500 mg by 24-hour urine collection
Proteinuria secondary to ureteral stents allowed
- No proteinuria secondary to nephropathy
Controlled hypertension (less than 150/100 mm Hg) allowed if on a stable antihypertensive regimen
No prior myocardial infarction
No uncontrolled congestive heart failure
No unstable angina within the past 3 months
No serious nonhealing wound, ulcer, or bone fracture
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No prior bevacizumab
See Disease Characteristics
Recovered from prior chemotherapy
No prior oxaliplatin
At least 2 weeks since prior radiotherapy and recovered
At least 28 days since prior major surgical procedure
At least 10 days since prior aspirin dose of more than 325 mg/day
No concurrent therapeutic anticoagulation except prophylactic anticoagulation of venous access device
No concurrent antiplatelet agents (e.g., dipyridamole, ticlopidine, clopidogrel, or cilostazol)
No concurrent oral cryotherapy on day 1 of oxaliplatin administration

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

880 participants in 3 patient groups

Arm I (bevacizumab, oxaliplatin, leucovorin, fluorouracil)

Experimental group

Description:

Patients receive bevacizumab IV over 30-90 minutes and oxaliplatin IV over 2 hours on day 1. Patients also receive leucovorin calcium IV over 2 hours and fluorouracil (5-FU) IV over 22 hours on days 1 and 2.

Treatment:

Drug: leucovorin calcium

Biological: bevacizumab

Drug: fluorouracil

Drug: oxaliplatin

Arm II (oxaliplatin, leucovorin calcium, fluorouracil)

Experimental group

Description:

Patients receive oxaliplatin, leucovorin calcium, and 5-FU as in arm I.

Treatment:

Drug: leucovorin calcium

Drug: fluorouracil