Breast Cancer
Conditions
Keywords
Breast Cancer, Metastatic, Brain, Anti-angiogenesis
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.
Interventions
DRUGBevacizumab
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
DRUGDocetaxel
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
DRUGCPT-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
DRUGPaclitaxel
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
DRUGVinorelbine 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
DRUGGemcitabine
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
Sponsors
Genentech, Inc.
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability Will be Assessed According to Standard (CTCAE Version 3.0) Toxicity Reporting Criteria. | May 2009 | 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 | trial closure | Due to slow accrual study was prematurely closed and endpoint not analysed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assess the Activity of Avastin When Added to Single Agent Chemotherapy, as Measured by Radiographic Response Rate,Progression Free Survival, and Overall Survival. | 8 to 9 weeks | Due to slow accrual study was prematurely closed and endpoint not analysed |
| To Assess the Quality of Life During Treatment With This Therapeutic Approach | 8 to 9 weeks | Due to slow accrual study was prematurely closed and endpoint not analysed |
Countries
United States
Participant flow
Recruitment details
Subjects will be identified in cancer center outpatient clinics multi-site. The study will be introduced by a physician or caregiver known to the patient. We will need to review protected health information in order to identify subjects, and information resulting from this activity will be used only to assess eligibility of a subject.
Pre-assignment details
to meet inclusion must be 2 wks from prior hormonal chemotherapy and radio-static surgery, 4 weeks since major surgery and 8 weeks from neuro surgery. excluded for prior tx with avastin or other anti-angiogenic therapy. Central Nervous system hemorrhage
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3 |
| 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. | 0 |
| 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. | 1 |
| 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. | 0 |
| 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. | 2 |
| 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. | 2 |
| Total | 8 |
Baseline characteristics
| Characteristic | Bevacizumab / CPT-11 | Bevacizumab /Vinorelbine Tartrate | Bevacizumab / Capecitabine | Bevacizumab / Gemcitabine | Total |
|---|---|---|---|---|---|
| Age Categorical <=18 years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age Categorical >=65 years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age Categorical Between 18 and 65 years | 1 participants | 2 participants | 3 participants | 2 participants | 8 participants |
| Age Continuous | 42 years | 52.5 years | 48.3 years | 56.5 years | 50.6 years STANDARD_DEVIATION 5.8 |
| Gender Female | 1 participants | 2 participants | 3 participants | 2 participants | 8 participants |
| Gender Male | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 1 participants | 2 participants | 3 participants | 2 participants | 8 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 1 / 1 | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 2 / 3 | 1 / 1 | 1 / 2 | 0 / 2 |
Outcome results
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
Time frame: trial closure
Population: Due to slow accrual study was prematurely closed and endpoint not analysed
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.
Time frame: May 2009
Population: Endpoint has not been analysed secondary to slow and low accrual numbers.
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
Time frame: 8 to 9 weeks
Population: Due to slow accrual study was prematurely closed and endpoint not analysed
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
Time frame: 8 to 9 weeks