A Phase II Safety and Tolerability Study of Bevacizumab When Added to Single-agent Chemotherapy to Treat Patient With Breast Cancer Metastatic to Brain

This study has been terminated.
(Slow accrual)
Sponsor:
Collaborator:
Genentech
Information provided by (Responsible Party):
Duke University
ClinicalTrials.gov Identifier:
NCT00476827
First received: May 18, 2007
Last updated: July 15, 2013
Last verified: July 2013
  Purpose

Our hypothesis is that this study design, in which bevacizumab is added to one of six single agent chemotherapies with proven activity in metastatic breast cancer, will result in regression or stabilization of this disease in a safe and tolerable manner.


Condition Intervention Phase
Breast Cancer
Drug: Bevacizumab
Drug: Docetaxel
Drug: CPT-11
Drug: Paclitaxel
Drug: Vinorelbine Tartrate
Drug: Gemcitabine
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Safety and Tolerability Study of Avastin When Added to Single-agent Chemotherapy to Treat Patient With Breast Cancer Metastatic to Brain

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Safety and Tolerability Will be Assessed According to Standard (CTCAE Version 3.0) Toxicity Reporting Criteria. [ Time Frame: May 2009 ] [ Designated as safety issue: Yes ]
    Primary endpoint has not been analysed secondary to slow and low accrual numbers.

  • Determining the Safety and Tolerability of Adding Avastin to Single Agent Chemotherapy to Treat Patients With Brain Metastasis Originating From Breast Cancer [ Time Frame: trial closure ] [ Designated as safety issue: Yes ]
    Due to slow accrual study was prematurely closed and endpoint not analysed


Secondary Outcome Measures:
  • Assess the Activity of Avastin When Added to Single Agent Chemotherapy, as Measured by Radiographic Response Rate,Progression Free Survival, and Overall Survival. [ Time Frame: 8 to 9 weeks ] [ Designated as safety issue: No ]
    Due to slow accrual study was prematurely closed and endpoint not analysed

  • To Assess the Quality of Life During Treatment With This Therapeutic Approach [ Time Frame: 8 to 9 weeks ] [ Designated as safety issue: No ]
    Due to slow accrual study was prematurely closed and endpoint not analysed


Enrollment: 16
Study Start Date: May 2007
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Bevacizumab / Capecitabine
Bevacizumab 15 mg/kg every 3 weeks in combination with Capecitabine (Xeloda), 2 weeks on and 1 week off on a every 3 week cycle.
Drug: Bevacizumab
Bevacizumab(Avastin) 15 mg/kg every 3 weeks in combination with Capecitabine (Xeloda), 2 weeks on and 1 week off on a every 3 week cycle. until progression or unacceptable toxicity develops
Other Name: Avastin
Active Comparator: Bevacizumab / Docetaxel
Docetaxel (taxotere) 35mg/m² IV over 60 min days 1, 8, and 15 in combination with avastin 10 mg/kg on days 1 and 15 of a 28-day cycle.
Drug: Docetaxel
Docetaxel 35mg/m² IV over 60 min days 1, 8, and 15 in combination with avastin 10 mg/kg on days 1 and 15 of a 28-day cycle. until progression or unacceptable toxicity develops
Other Name: Taxotere
Active Comparator: Bevacizumab /Irinotecan (Camptosar®, CPT-11)
CPT-11 (Irinotecan, Camptosar) - Patients being treated with an enzyme inducing antiepileptic drug (EIAED) will receive 340 mg/m² IV; others will receive 125 mg/m² IV 90 min on days 1 and 15, in combination with avastin 10 mg/kg on days 1 and 15 of a 28-day cycle.
Drug: CPT-11
CPT-11 (Irinotecan, Camptosar) - Patients being treated with an enzyme inducing antiepileptic drug (EIAED) will receive 340 mg/m² IV; others will receive 125 mg/m² IV 90 min on days 1 and 15, in combination with avastin 10 mg/kg on days 1 and 15 of a 28-day cycle.until progression or unacceptable toxicity develops
Other Names:
  • Irinotecan
  • Camptosar
Active Comparator: Bevacizumab / Paclitaxel
Paclitaxel (Taxol)90 mg/m2 IV over 60-90 min days 1, 8, and 15, in combination with avastin 10 mg/kg on days 1 and 15 of a 28-day cycle.
Drug: Paclitaxel
Paclitaxel (Taxol)90 mg/m2 IV over 60-90 min days 1, 8, and 15, in combination with avastin 10 mg/kg on days 1 and 15 of a 28-day cycle.until progression or unacceptable toxicity develops
Other Name: Taxol
Active Comparator: Bevacizumab /Vinorelbine Tartrate
Vinorelbine Tartrate (Navelbine®) 25 mg/m² IV over 10 min days 1, 8 and 15 in combination with avastin 10 mg/kg IV on days 1 and 15 of a 28-day cycle.
Drug: Vinorelbine Tartrate
Vinorelbine Tartrate (Navelbine®) 25 mg/m² IV over 10 min days 1, 8 and 15 in combination with avastin 10 mg/kg IV on days 1 and 15 of a 28-day cycle. until progression or unacceptable toxicity develops
Other Name: Navelbine®
Active Comparator: Bevacizumab / Gemcitabine
Gemcitabine (difluorodeoxycytidine, dFdC) 1000 mg/m2 IV on days 1 and 8 in combination with avastin 15 mg/kg IV on day 1 of a 21-day treatment cycle.
Drug: Gemcitabine
Gemcitabine (difluorodeoxycytidine, dFdC) 1000 mg/m2 IV on days 1 and 8 in combination with avastin 15 mg/kg IV on day 1 of a 21-day treatment cycle.until progression or unacceptable toxicity develops
Other Name: difluorodeoxycytidine

Detailed Description:

There is an unmet clinical need for effective therapy of breast cancer that has metastasized to the brain. In this scenario, median survival is around 12 months using currently available therapeutic interventions. The majority of chemotherapy-based clinical trials have considered the presence of central nervous system metastasis an exclusion criterion due to the risk of toxicities, the inability of chemotherapeutic agents to cross the blood brain barrier, and the limited overall survival within this patient population.

The preclinical data regarding the safety and activity of bevacizumab in vascular endothelial growth factor(VEGF)-expressing tumors provide a good rationale for its study in patients with breast cancer with metastasis to the brain. Yano, et al. illustrated that tumor cell expression of VEGF messenger ribonucleic acid and protein directly correlated with angiogenesis and growth of brain metastasis in a nude mouse model. Transfecting the experimental cell lines known to produce visceral metastasis with an anti-sense VEGF-gene significantly reduced the incidence of brain metastasis. Kim, et al. illustrated that a murine model specific for brain metastases originating from breast cancer showed elevated expression of the angiogenic and permeability-inducing factor VEGF-A. The growth of the brain metastases in this model was attenuated by the addition of a VEGF-tyrosine kinase inhibitor via induction of apoptosis and decreased angiogenesis. VEGF has also been implicated in the development of brain edema, a significant source of the morbidity and mortality associated with brain metastasis. Enhanced levels of VEGF and its receptors have been reported in a murine model after induction of cortical ischemia. Finally, antagonism of VEGF was demonstrated to reduce both immediate and delayed volume of infarct.

The optimal dose of bevacizumab has been extensively studied in phase I trials alone and in combination with chemotherapy. The safe and effective dose has been established as 10 mg/kg q 14 days or 15 mg/kg Q 21 days. In addition to irinotecan and paclitaxel, it has been previously used in phase II/III settings in combination with capecitabine, vinorelbine, gemcitabine, and docetaxel. Phase III studies showed an overall survival advantage when bevacizumab was added to an irinotecan/Fluorouracil (5FU)-based regimen for metastatic colorectal cancer, and when added to weekly paclitaxel for metastatic breast cancer.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Female, 18+, with evaluable metastatic breast cancer and stable brain metastases
  • Must have received definitive radiotherapy
  • No evidence, or history of, central nervous system hemorrhage
  • Adequate organ and hematological function

Exclusion Criteria:

  • Active infection, non-healing wound, or history of any bleeding diathesis or coagulopathy
  • Uncontrolled hypertension, congestive heart failure, peripheral vascular disease
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00476827

Locations
United States, Florida
Palm Beach Cancer Center Institute
West Palm Beach, Florida, United States, 33401-3406
United States, North Carolina
Presbyterian Health Care
Charlotte, North Carolina, United States, 28204
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Virginia
Virginia Oncology Associates
Newport News, Virginia, United States, 23606
Sponsors and Collaborators
Duke University
Genentech
Investigators
Principal Investigator: Kimberly Blackwell, MD Duke University
  More Information

Publications:
Lin N, et al. CNS metastasis in breast cancer. J Clin Oncol 2004;22(17):3608-17.
Engel J, et al. Determinants and prognosis of locoregional and distant progression in breast cancer. Int J Radiat Oncol Biol Phys 2003;55(5):1186-95.
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285:1182-6.
Schneider BP, Miller KD. Angiogenesis and breast cancer. J Clin Oncol 2005;23:1782- 90.
Miller KD, et al. E2100: a randomized phase III trial of paclitaxel vs paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Proc: ASCO 2005; (#3) (Abstract).
Vrendenburgh JJ, et al. Bevacizumab, a monoclonal antibody to VEGF, and irinotecan for the treatment of malignant gliomas. Proc: ASCO 2006;24(18S):1506.
Burstin HJ, et al. Phase II trial of anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Can Res Treat 2002;76(supp 1):S115.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat Assoc 1958;43:457-81.

Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00476827     History of Changes
Other Study ID Numbers: Pro00014926, AVF4124s, 9597-07-4R0
Study First Received: May 18, 2007
Results First Received: December 10, 2012
Last Updated: July 15, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
Breast Cancer
Metastatic
Brain
Anti-angiogenesis

Additional relevant MeSH terms:
Breast Neoplasms
Brain Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Anticonvulsants
Gemcitabine
Capecitabine
Irinotecan
Vinorelbine
Docetaxel
Bevacizumab
Vinblastine
Paclitaxel
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 22, 2014