Paclitaxel With or Without Bevacizumab in Treating Patients With Locally Recurrent or Metastatic Breast Cancer

A Randomized Phase III Tial Of Paclitaxel Versus Paclitaxel Plus Bevacizumab (rhuMAb VEGF) As First-Line Therapy For Locally Recurrent or Metastatic Breast Cancer

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: bevacizumab; Drug: Paclitaxel

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.

• Study Type: Interventional
• Enrollment (Actual): 722
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • British Columbia Cancer Agency
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
• United States
  • Alabama
    • Mobile, Alabama, United States, 36607
      • MBCCOP - Gulf Coast
  • Arizona
    • Scottsdale, Arizona, United States, 85259-5404
      • CCOP - Mayo Clinic Scottsdale Oncology Program
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30342-1701
      • CCOP - Atlanta Regional
  • Illinois
    • Peoria, Illinois, United States, 61602
      • CCOP - Illinois Oncology Research Association
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Iowa
    • Cedar Rapids, Iowa, United States, 52403-1206
      • CCOP - Cedar Rapids Oncology Project
    • Des Moines, Iowa, United States, 50309-1016
      • CCOP - Iowa Oncology Research Association
    • Sioux City, Iowa, United States, 51101-1733
      • Siouxland Hematology-Oncology
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • CCOP - Ochsner
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • CCOP - Michigan Cancer Research Consortium
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • CCOP - Duluth
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
    • Saint Cloud, Minnesota, United States, 56303
      • CentraCare Health Plaza
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
  • Nebraska
    • Omaha, Nebraska, United States, 68106
      • CCOP - Missouri Valley Cancer Consortium
  • North Dakota
    • Bismarck, North Dakota, United States, 58501-5505
      • Medcenter One Health System
    • Fargo, North Dakota, United States, 58122
      • CCOP - Merit Care Hospital
    • Grand Forks, North Dakota, United States, 58201
      • Altru Cancer Center
  • Ohio
    • Dayton, Ohio, United States, 45429
      • CCOP - Dayton
    • Toledo, Ohio, United States, 43623-3456
      • CCOP - Toledo Community Hospital
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • CCOP - Oklahoma
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-2001
      • CCOP - Geisinger Clinic and Medical Center
    • Pittsburgh, Pennsylvania, United States, 15212-4772
      • Allegheny General Hospital
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • CCOP - Upstate Carolina
  • South Dakota
    • Rapid City, South Dakota, United States, 57709
      • Rapid City Regional Hospital
    • Sioux Falls, South Dakota, United States, 57104
      • CCOP - Sioux Community Cancer Consortium
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • CCOP - St. Vincent Hospital Cancer Center, Green Bay

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Paclitaxel	Drug: Paclitaxel; 90 mg/m2 IV infusion over 1 hour every week for 3 weeks followed by 1 week rest
Active Comparator: Paclitaxel + Bevacizumab	Drug: bevacizumab; 10 mg/kg following paclitaxel treatment on weeks 1 and 3 of every 4-week cycle; Other Names: Avastin; Drug: Paclitaxel; 90 mg/m2 IV infusion over 1 hour every week for 3 weeks followed by 1 week rest

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-Free Survival	Assessed every 3 months for 2 years, then every 6 months for 3 years

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI); NCIC Clinical Trials Group; North Central Cancer Treatment Group; NSABP Foundation Inc
• Investigators: Study Chair: Kathy Miller, MD, Indiana University Melvin and Bren Simon Cancer Center; Robin Zon, MD, Elkhart General Hospital; Study Chair: Tamara N. Shenkier, MD, British Columbia Cancer Agency; Study Chair: Edith A. Perez, MD, Mayo Clinic; Study Chair: Melody A. Cobleigh, MD, Rush University Medical Center

Publications and helpful links

General Publications

• 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.
• 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. Erratum In: J Clin Oncol. 2009 Jun 20;27(18):3070.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2002
• Primary Completion (Actual): November 1, 2006
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: January 4, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimated): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 14, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer; male breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Paclitaxel; Bevacizumab
• Other Study ID Numbers: CDR0000069156; E2100; NCCTG-E2100; CAN-NCIC-MAC3; NSABP-E2100