A Phase II Safety and Tolerability Study of Bevacizumab When Added to Single-agent Chemotherapy to Treat Patient With Breast Cancer Metastatic to Brain
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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 (Avastin) Drug: Bevacizumab (avastin) |
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 |
- • Safety and Tolerability In this study, safety and tolerability will be assessed according to standard (CTCAE version 3.0) toxicity reporting criteria. Adverse events will be monitored at every patient visit and quality of life will be measured at ba [ Time Frame: May 2009 ] [ Designated as safety issue: Yes ]
- To estimate the activity of avastin when added to single agent chemotherapy, as measured by radiographic response rate, PFS, and OS. To assess quality of life during treatment with this therapeutic approach. [ Time Frame: 8 to 9 weeks ] [ Designated as safety issue: No ]
| 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 (Avastin)
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
|
|
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: Bevacizumab (Avastin)
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
|
|
Active Comparator: Bevacizumab / 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: Bevacizumab (avastin)
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
|
|
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: Bevacizumab (avastin)
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
|
|
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: Bevacizumab (avastin)
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
|
|
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: Bevacizumab (avastin)
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
|
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 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 mRNA 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/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 |
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| 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 | |
| Principal Investigator: | Kimberly Blackwell, MD | Duke University |
More Information
Publications:
| Responsible Party: | Duke University |
| ClinicalTrials.gov Identifier: | NCT00476827 History of Changes |
| Other Study ID Numbers: | 9597-07-4R0, AVF4124s |
| Study First Received: | May 18, 2007 |
| Last Updated: | October 4, 2011 |
| 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 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 Immunosuppressive Agents |
ClinicalTrials.gov processed this record on May 22, 2013