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

Duke University

Status and phase: Terminated; Phase 2

Conditions: Breast Cancer

Treatments: Drug: Paclitaxel; Drug: CPT-11; Drug: Bevacizumab; Drug: Vinorelbine Tartrate; Drug: Docetaxel; Drug: Gemcitabine

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00476827

Pro00014926

9597-07-4R0 (Other Identifier)

AVF4124s

Details and patient eligibility

About

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.

Full 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.

Enrollment: 16 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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16 participants in 6 patient groups

Bevacizumab / Capecitabine

Active Comparator group

Description:

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.

Treatment:

Drug: Bevacizumab

Bevacizumab / Docetaxel

Active Comparator group

Description:

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.

Treatment:

Drug: Docetaxel

Bevacizumab /Irinotecan (Camptosar®, CPT-11)

Active Comparator group

Description:

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.

Treatment:

Drug: CPT-11

Bevacizumab / Paclitaxel

Active Comparator group

Description:

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.

Treatment:

Drug: Paclitaxel

Bevacizumab /Vinorelbine Tartrate

Active Comparator group

Description:

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.

Treatment:

Drug: Vinorelbine Tartrate

Bevacizumab / Gemcitabine

Active Comparator group

Description:

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.

Treatment:

Drug: Gemcitabine