Clinical trial NCT00066846: Bevacizumab Plus Fluorouracil and Leucovorin in Treating Patients With Locally Advanced or Metastatic Stage IV Colorectal Cancer That Has Progressed After Standard Chemotherapy
Official title: A Multicenter Study of the Anti-VEGF Monoclonal Antibody Bevacizumab (Avastin®) Plus 5-Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancers That Have Progressed After Standard Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the colon
adenocarcinoma of the rectum
stage IV rectal cancer
recurrent rectal cancer
stage IV colon cancer
recurrent colon cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-08-07
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Bevacizumab may stop the growth of tumor cells by blocking the enzymes necessary for cancer cell growth. Drugs used in chemotherapy such as fluorouracil and leucovorin use different ways to stop tumor cells from dividing so they stop growing or die. Combining bevacizumab with fluorouracil and leucovorin may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combining bevacizumab with fluorouracil and leucovorin in treating patients who have locally advanced or metastatic stage IV colorectal cancer that has progressed after standard chemotherapy.

Detailed description: OBJECTIVES:

* Determine the response rate of patients treated with bevacizumab, fluorouracil, and leucovorin calcium for stage IV colorectal cancer that has progressed after standard chemotherapy.
* Determine the time to progression and overall survival of patients treated with this regimen.
* Determine the safety of administering "bolus" and continuous infusion fluorouracil and leucovorin calcium in patients treated with this regimen.

OUTLINE: This is an open-label, multicenter study. Patients receive 1 of 2 treatment regimens.

* Regimen I: Patients receive bevacizumab IV on days 1, 15, 29, and 42 (every 2 weeks) and leucovorin calcium (CF) IV over 2 hours and fluorouracil (5-FU) IV bolus on days 1, 8, 15, 22, 29, and 36.
* Regimen II: Patients receive bevacizumab as in regimen I and CF IV over 2 hours and 5-FU IV bolus followed by a continuous infusion over 22 hours on days 1, 2, 15, 16, 29, 30, 43, and 44.

For both regimens, courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed for tumor response and survival.

PROJECTED ACCRUAL: Various NCI-designated Clinical Cancer Centers and other medical institutions across the United States will participate in this study. A total of 35-125 patients will be accrued for this study within 3 months.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed colorectal adenocarcinoma

  * Stage IV (metastatic) disease
  * Not curable by surgery or radiotherapy
* Must have received prior standard chemotherapy regimens, including oxaliplatin and irinotecan, and meet both of the following criteria:

  * Disease progression during or after irinotecan-based chemotherapy for metastatic disease OR relapsed disease within 6 months after adjuvant irinotecan-based therapy
  * Disease progression during or after oxaliplatin-based chemotherapy for metastatic disease OR relapsed disease within 6 months after adjuvant oxaliplatin-based therapy
* No brain metastases

PATIENT CHARACTERISTICS:

Age

* 18 and over

Performance status

* ECOG 0-2 OR
* Karnofsky 60-100%

Life expectancy

* Not specified

Hematopoietic

* Absolute granulocyte count at least 1,500/mm\^3
* Platelet count at least 100,000/mm\^3
* Hemoglobin at least 9 g/dL (transfusion allowed)
* No evidence of bleeding diathesis or coagulopathy

Hepatic

* Bilirubin no greater than 1.5 mg/dL
* AST less than 5 times upper limit of normal (ULN)
* Alkaline phosphatase less than 5 times ULN
* PT and INR no greater than 1.5 times ULN
* PTT no greater than ULN

Renal

* Creatinine no greater than 1.5 times ULN
* Proteinuria less than grade 1 OR
* Proteinuria less than 500 mg/24 hours

Cardiovascular

* No prior stroke
* No uncontrolled high blood pressure
* No symptomatic congestive heart failure
* No unstable angina pectoris
* No cardiac arrhythmia
* No myocardial infarction within the past 6 months
* No New York Heart Association class III or IV heart disease
* No thromboembolism within the past 6 months

Other

* Chemonaive
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for at least 3 months after study participation
* No significant traumatic injury within the past 6 weeks
* No prior allergic reaction attributed to compounds of similar chemical or biological composition to bevacizumab or other study agents
* No active infection
* No psychiatric illness or social situation that would preclude study compliance
* No serious nonhealing wound (including wounds healing by secondary intention), ulcer, or bone fracture
* No CNS disease, including either of the following:

  * Primary brain tumor
  * Seizures not controlled with standard medical therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

* At least 8 weeks since prior monoclonal antibody therapy
* No prior bevacizumab

Chemotherapy

* See Disease Characteristics

Endocrine therapy

* Not specified

Radiotherapy

* At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative radiotherapy)

Surgery

* More than 6 weeks since prior major surgical procedure or open biopsy
* More than 7 days since prior fine needle aspiration or core biopsy
* No concurrent surgery

Other

* Recovered from prior therapy
* At least 3 weeks since prior cytotoxic agents
* No concurrent therapeutic anticoagulation

  * Prophylactic anticoagulation of venous access devices allowed provided PT/INR or PTT criteria are met
* No concurrent chronic aspirin (greater than 325 mg/day) or nonsteroidal anti-inflammatory drugs
* No concurrent combination antiretroviral therapy for HIV-positive patients
* No other concurrent investigational or commercial agents for the malignancy

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Providence Alaska Medical Center
state: Alaska
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center, UCLA
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center at University of Colorado Health Sciences Center
state: Colorado
city: New Haven
country: United States
facility: Yale Comprehensive Cancer Center
state: Connecticut
city: Washington
country: United States
facility: Lombardi Cancer Center
state: District of Columbia
city: Atlanta
country: United States
facility: CCOP - Atlanta Regional
state: Georgia
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center, Northwestern University
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Hematology-Oncology
state: Iowa
city: Wichita
country: United States
facility: CCOP - Wichita
state: Kansas
city: Bangor
country: United States
facility: Cancer Care of Maine
state: Maine
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Health System
state: Michigan
city: Duluth
country: United States
facility: St. Mary's/Duluth Clinic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Billings
country: United States
facility: CCOP - Montana Cancer Consortium
state: Montana
city: Las Vegas
country: United States
facility: Southern Nevada Cancer Research Foundation
state: Nevada
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center
state: New Hampshire
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: New York Weill Cornell Cancer Center at Cornell University
state: New York
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Comprehensive Cancer Center at Wake Forest University
state: North Carolina
city: Fargo
country: United States
facility: Meritcare Roger Maris Cancer Center
state: North Dakota
city: Cleveland
country: United States
facility: Ireland Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Abramson Cancer Center of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Kimmel Cancer Center of Thomas Jefferson University - Philadelphia
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sioux Valley Clinics - Oncology
state: South Dakota
city: Burlington
country: United States
facility: Fletcher Allen Health Care - University Health Center Campus
state: Vermont
city: Richmond
country: United States
facility: Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: CCOP - Virginia Mason Research Center
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: NCI - Investigational Drug Branch
name: Helen X. Chen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chen HX, Mooney M, Boron M, Vena D, Mosby K, Grochow L, Jaffe C, Rubinstein L, Zwiebel J, Kaplan RS. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol. 2006 Jul 20;24(21):3354-60. doi: 10.1200/JCO.2005.05.1573.