Clinical trial NCT00476827: A Phase II Safety and Tolerability Study of Bevacizumab When Added to Single-agent Chemotherapy to Treat Patient With Breast Cancer Metastatic to Brain
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Breast Cancer
Metastatic
Brain
Anti-angiogenesis
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2007-05-22
Enrollment: 16
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Safety and Tolerability Will be Assessed According to Standard (CTCAE Version 3.0) Toxicity Reporting Criteria.
timeFrame: May 2009
measure: Determining the Safety and Tolerability of Adding Avastin to Single Agent Chemotherapy to Treat Patients With Brain Metastasis Originating From Breast Cancer
timeFrame: trial closure
Secondary outcomes:
measure: Assess the Activity of Avastin When Added to Single Agent Chemotherapy, as Measured by Radiographic Response Rate,Progression Free Survival, and Overall Survival.
timeFrame: 8 to 9 weeks
measure: To Assess the Quality of Life During Treatment With This Therapeutic Approach
timeFrame: 8 to 9 weeks
Other outcomes:
Locations:
city: West Palm Beach
country: United States
facility: Palm Beach Cancer Center Institute
state: Florida
city: Charlotte
country: United States
facility: Presbyterian Health Care
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Newport News
country: United States
facility: Virginia Oncology Associates
state: Virginia
Study officials:
affiliation: Duke University
name: Kimberly Blackwell, MD
role: PRINCIPAL_INVESTIGATOR
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