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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00476827
• Other study ID #: Pro00014926
• Secondary ID: AVF4124s9597-07-
• Status: Terminated
• Phase: Phase 2
• First received: May 18, 2007
• Last updated: July 15, 2013
• Start date: May 2007
• Est. completion date: May 2011

Study information

• Verified date: July 2013
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: May 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Neoplasms
• Breast Cancer
• Breast Neoplasms

Intervention

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
• 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
• 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
• 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
• 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
• 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

Locations

Country	Name	City	State
United States	Presbyterian Health Care	Charlotte	North Carolina
United States	Duke University Medical Center	Durham	North Carolina
United States	Virginia Oncology Associates	Newport News	Virginia
United States	Palm Beach Cancer Center Institute	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Duke University	Genentech, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (37)

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* Note: There are 37 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and Tolerability Will be Assessed According to Standard (CTCAE Version 3.0) Toxicity Reporting Criteria.	Primary endpoint has not been analysed secondary to slow and low accrual numbers.	May 2009	Yes
Primary	Determining the Safety and Tolerability of Adding Avastin to Single Agent Chemotherapy to Treat Patients With Brain Metastasis Originating From Breast Cancer	Due to slow accrual study was prematurely closed and endpoint not analysed	trial closure	Yes
Secondary	Assess the Activity of Avastin When Added to Single Agent Chemotherapy, as Measured by Radiographic Response Rate,Progression Free Survival, and Overall Survival.	Due to slow accrual study was prematurely closed and endpoint not analysed	8 to 9 weeks	No
Secondary	To Assess the Quality of Life During Treatment With This Therapeutic Approach	Due to slow accrual study was prematurely closed and endpoint not analysed	8 to 9 weeks	No