Clinical trial NCT00028990: Paclitaxel With or Without Bevacizumab in Treating Patients With Locally Recurrent or Metastatic Breast Cancer
Official title: A Randomized Phase III Tial Of Paclitaxel Versus Paclitaxel Plus Bevacizumab (rhuMAb VEGF) As First-Line Therapy For Locally Recurrent or Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage IV breast cancer
recurrent breast cancer
male breast cancer
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: North Central Cancer Treatment Group
name: NCIC Clinical Trials Group
name: NSABP Foundation Inc
First posted: 2003-01-27
Enrollment: 722
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. It is not yet known whether paclitaxel works better with or without bevacizumab in treating breast cancer.

PURPOSE: This randomized phase III trial is to see if paclitaxel works better with or without bevacizumab in treating patients who have locally recurrent or metastatic breast cancer.

Detailed description: OBJECTIVES:

* Compare the time to treatment failure in patients with locally recurrent or metastatic breast cancer treated with paclitaxel with or without bevacizumab.
* Compare the objective response rate, duration of response, overall survival, and time to progression in patients treated with these regimens.
* Compare the toxicity of these regimens in these patients.
* Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to disease-free interval (no more than 24 months vs more than 24 months), number of metastatic sites (less than 3 vs 3 or more), treatment with prior adjuvant chemotherapy (yes vs no), and estrogen receptor status (positive vs negative vs unknown). Patients are randomized to one of two treatment arms.

* Arm I: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 followed by bevacizumab IV over 30-90 minutes on days 1 and 15.
* Arm II: Patients receive paclitaxel as in arm I. In both arms, courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and on day 1 of weeks 17 and 33.

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

PROJECTED ACCRUAL: A total of 316-650 patients (158-325 per treatment arm) will be accrued for this study within 31 months.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed adenocarcinoma of the breast
* Locally recurrent disease that is not amenable to surgical resection with curative intent OR
* Metastatic disease
* No HER-2-overexpressing (3+) breast cancer unless previously treated with trastuzumab (Herceptin)

  * Unknown HER-2 status allowed provided herceptin-based therapy inappropriate or not indicated
* No prior or radiologic evidence of CNS metastases, including previously treated, resected, or asymptomatic brain lesions or leptomeningeal involvement by head CT scan or MRI
* Hormone receptor status:

  * Not specified

PATIENT CHARACTERISTICS:

Age:

* 18 and over

Sex:

* Male or female

Menopausal status:

* Not specified

Performance status:

* ECOG 0-1

Life expectancy:

* Not specified

Hematopoietic:

* Absolute neutrophil count at least 1,500/mm\^3
* Platelet count at least 100,000/mm\^3
* No prior bleeding diathesis

Hepatic:

* Bilirubin no greater than 1.5 mg/dL
* SGOT no greater than 2 times upper limit of normal (ULN) (5 times ULN for known liver involvement)
* PT/PTT no greater than 1.5 times normal
* INR no greater than 1.5 times normal

Renal:

* Creatinine no greater than 2.0 mg/dL
* No proteinuria by dipstick urinalysis
* Trace proteinuria allowed
* Proteinuria less than 500 mg by 24-hour urine collection if proteinuria at least 1+ by urinalysis

Cardiovascular:

* No clinically significant cardiovascular disease
* No myocardial infarction within the past 12 months
* No unstable angina
* No prior deep vein thrombosis
* No grade 2 or greater peripheral vascular disease
* No uncontrolled congestive heart failure
* No uncontrolled hypertension (systolic blood pressure greater than 170 mmHg and diastolic blood pressure greater than 95 mm Hg)
* No prior cerebrovascular accident

Pulmonary:

* No prior pulmonary embolism

Other:

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective non-hormonal contraception
* No history of seizures
* No non-healing wound or fracture
* No hypersensitivity to paclitaxel, Cremophor EL, Chinese hamster ovary cell products, or other recombinant human antibodies
* No active infection requiring parenteral antibiotics

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* See Disease Characteristics

Chemotherapy:

* No prior chemotherapy for locally recurrent or metastatic breast cancer
* At least 12 months since prior adjuvant or neoadjuvant taxane therapy
* At least 3 weeks since prior adjuvant chemotherapy

Endocrine therapy:

* At least 3 weeks since prior hormonal therapy for locally recurrent or metastatic breast cancer

Radiotherapy:

* At least 3 weeks since prior radiotherapy
* No prior radiotherapy to only site of disease
* No concurrent local radiotherapy for pain control or life-threatening situations (e.g, superior vena cava syndrome, spinal cord compression, or CNS metastases)

Surgery:

* At least 4 weeks since prior major surgical procedure except placement of vascular access device or breast biopsy
* At least 7 days since prior minor surgical procedure, including placement of an access device or fine needle aspiration

Other:

* At least 10 days since prior anticoagulant therapy (low-dose anticoagulant therapy to maintain patency of a vascular access device allowed)
* At least 10 days since prior and no concurrent daily aspirin (more than 325 mg/day) or other non-steroidal anti-inflammatory medication known to inhibit platelet function
* No concurrent dipyridamole, ticlopidine, clopidogrel, or cilostazol

Primary outcomes:
measure: Progression-Free Survival
timeFrame: Assessed every 3 months for 2 years, then every 6 months for 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: Mobile
country: United States
facility: MBCCOP - Gulf Coast
state: Alabama
city: Scottsdale
country: United States
facility: CCOP - Mayo Clinic Scottsdale Oncology Program
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Atlanta
country: United States
facility: CCOP - Atlanta Regional
state: Georgia
city: Peoria
country: United States
facility: CCOP - Illinois Oncology Research Association
state: Illinois
city: Urbana
country: United States
facility: CCOP - Carle Cancer Center
state: Illinois
city: Cedar Rapids
country: United States
facility: CCOP - Cedar Rapids Oncology Project
state: Iowa
city: Des Moines
country: United States
facility: CCOP - Iowa Oncology Research Association
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Hematology-Oncology
state: Iowa
city: New Orleans
country: United States
facility: CCOP - Ochsner
state: Louisiana
city: Ann Arbor
country: United States
facility: CCOP - Michigan Cancer Research Consortium
state: Michigan
city: Duluth
country: United States
facility: CCOP - Duluth
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Saint Cloud
country: United States
facility: CentraCare Health Plaza
state: Minnesota
city: Saint Louis Park
country: United States
facility: CCOP - Metro-Minnesota
state: Minnesota
city: Omaha
country: United States
facility: CCOP - Missouri Valley Cancer Consortium
state: Nebraska
city: Bismarck
country: United States
facility: Medcenter One Health System
state: North Dakota
city: Fargo
country: United States
facility: CCOP - Merit Care Hospital
state: North Dakota
city: Grand Forks
country: United States
facility: Altru Cancer Center
state: North Dakota
city: Dayton
country: United States
facility: CCOP - Dayton
state: Ohio
city: Toledo
country: United States
facility: CCOP - Toledo Community Hospital
state: Ohio
city: Tulsa
country: United States
facility: CCOP - Oklahoma
state: Oklahoma
city: Danville
country: United States
facility: CCOP - Geisinger Clinic and Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Spartanburg
country: United States
facility: CCOP - Upstate Carolina
state: South Carolina
city: Rapid City
country: United States
facility: Rapid City Regional Hospital
state: South Dakota
city: Sioux Falls
country: United States
facility: CCOP - Sioux Community Cancer Consortium
state: South Dakota
city: Green Bay
country: United States
facility: CCOP - St. Vincent Hospital Cancer Center, Green Bay
state: Wisconsin
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
Study officials:
affiliation: Indiana University Melvin and Bren Simon Cancer Center
name: Kathy Miller, MD
role: STUDY_CHAIR
affiliation: Elkhart General Hospital
name: Robin Zon, MD
affiliation: Mayo Clinic
name: Edith A. Perez, MD
role: STUDY_CHAIR
affiliation: British Columbia Cancer Agency
name: Tamara N. Shenkier, MD
role: STUDY_CHAIR
affiliation: Rush University Medical Center
name: Melody A. Cobleigh, MD
role: STUDY_CHAIR
References:
citation: Gray R, Giantonio BJ, O'Dwyer PJ, et al.: The safety of adding angiogenesis inhibition into treatment for colorectal, breast, and lung cancer: the Eastern Cooperative Oncology Group's (ECOG) experience with bevacizumab (anti-VEGF). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-825, 2003.
citation: Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, Flockhart DA, Hancock B, Davidson N, Gralow J, Dickler M, Perez EA, Cobleigh M, Shenkier T, Edgerton S, Miller KD; ECOG 2100. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol. 2008 Oct 1;26(28):4672-8. doi: 10.1200/JCO.2008.16.1612.
citation: Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. doi: 10.1056/NEJMoa072113.
citation: Cella D, Wang M, Wagner L, Miller K. Survival-adjusted health-related quality of life (HRQL) among patients with metastatic breast cancer receiving paclitaxel plus bevacizumab versus paclitaxel alone: results from Eastern Cooperative Oncology Group Study 2100 (E2100). Breast Cancer Res Treat. 2011 Dec;130(3):855-61. doi: 10.1007/s10549-011-1725-6. Epub 2011 Aug 27.
citation: Miller KD, Wang M, Gralow J, et al.: A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-3, 2005.
citation: Miller KD. E2100: a phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer. 2003 Feb;3(6):421-2. doi: 10.3816/CBC.2003.n.007. No abstract available.