A Phase II Study of Bevacizumab + Sorafenib in Metastatic Breast Cancer

Study Overview
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Brief Summary
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Prior clinical trials involving bevacizumab and sorafenib have demonstrated single agent activity in previously treated advanced breast cancer. This trial will test combined VEGF inhibition with sorafenib and bevacizumab in less heavily pre-treated patients with advanced breast cancer.

Detailed Description
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OUTLINE: This is a multi-center study. Sorafenib 200mg po daily Bevacizumab 5mg/kg every other week 1 Cycle = 4 weeks Imaging every third cycle Acceptable toxicity and non-PD = Protocol therapy will continue Un-acceptable toxicity or PD = Protocol therapy will be discontinued ECOG Performance Status 0-1 Life Expectancy: at least 12 weeks Hematopoietic: Platelets > 100 K/mm3 Absolute neutrophil count (ANC) > 1.5 K/mm3 Hemoglobin > 10 g/dL Hepatic: Total Bilirubin < 1.5 x ULN Aspartate aminotransferase (AST, SGOT) < 2 x ULN (up to 5 x ULN in patients with known liver involvement) Renal: Creatinine < 1.5 x ULN No proteinuria as demonstrated by either Urine protein:creatinine (UPC) ratio < 1.0 or Urine dipstick for proteinuria < 2+ Cardiovascular: No known myocardial infarction, unstable angina, > grade II New York Heart Association (NYHA) classification, congestive heart failure, uncontrolled hypertension defined as SBP >150 or DBP >100, > grade II peripheral vascular disease or significant vascular disease (e.g. aortic aneurysm, aortic dissection) within 12 months prior to being registered for protocol therapy. No uncontrolled or clinically significant arrhythmia. NOTE: Controlled atrial fibrillation is allowed. LVEF ≥ LLN by MUGA or ECHO as obtained within 28 days prior to being registered for protocol therapy. Pulmonary: No pulmonary hemorrhage/bleeding event ≥ CTCAE grade 2 within 28 days prior to being registered for protocol therapy.

Official Title
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A Phase II Study of Combined VEGF Inhibitor (Bevacizumab + Sorafenib) in Patients With Metastatic Breast Cancer: Hoosier Oncology Group BRE06-109

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Sorafenib
* Drug: Bevacizumab
* Other: Imaging


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic diagnosis of breast cancer with evidence of metastatic disease. NOTE: Patients with Her-2 positive (3+ by IHC or gene amplification by FISH) are eligible only if they have had prior trastuzumab therapy. Must have measurable or non-measurable lesions as defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Two or fewer prior chemotherapy regimens in any disease setting. NOTE: All adjuvant and neoadjuvant chemotherapy will be considered one regimen. NOTE: Prior hormonal therapy for metastatic disease is allowed. NOTE: Prior radiation therapy is allowed as long as the irradiated area is not the only source of evaluable disease. Age > 18 years at the time of consent. Written informed consent and HIPAA authorization for release of personal health information. Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 8 weeks after treatment discontinuation. Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for protocol therapy. Ability to comply with study and/or follow-up procedures. Exclusion Criteria: No prior therapy with bevacizumab, sorafenib or any other known VEGF inhibitors. No known hypersensitivity to any component of the study drugs. No other forms of cancer therapy including radiation, chemotherapy and hormonal therapy within 21 days prior to being registered for protocol therapy. No history or radiologic evidence of CNS metastases including previously treated, resected, or asymptomatic brain lesions or leptominigeal involvement. A head CT or MRI must be obtained within 28 days prior to being registered for protocol therapy. No other participation in another clinical drug study within 28 days prior to being registered for protocol therapy. No known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C No major surgical procedure within 28 days prior to being registered for protocol therapy or anticipation of need for major surgical procedure during the course of the study. Placement of a vascular access device and breast biopsy will not be considered major surgery. No minor surgical procedure within 7 days prior to being registered for protocol therapy. No known history of cerebrovascular disease including TIA, stroke or subarachnoid hemorrhage. No known history of ischemic bowel. No known history of deep venous thrombosis or pulmonary embolism. No history of hypertensive crisis or hypertensive encephalopathy. No non-healing wound or fracture. No active infection requiring parenteral antibiotics. No other hemorrhage/bleeding event ≥ CTCAE grade 3 within 28 days prior to being registered for protocol therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm A<br>Sorafenib 200mg po daily, Bevacizumab 5mg/kg every other week, 1 Cycle = 4 weeks. Imaging every third cycle | Drug: Sorafenib<br>* Sorafenib 200mg po daily<br>Drug: Bevacizumab<br>* Bevacizumab 5mg/kg every other week 1 Cycle = 4 weeks<br>Other: Imaging<br>* Imaging every third cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | The primary objective was to assess the Progression-Free Survival of sorafenib combined with bevacizumab in patients with metastatic breast cancer. Progression is defined by RECIST as a 20% increase in the sum of the longest diameters of target measurable lesions over the smallest sum observed (over baseline if no decrease during therapy) or by the appearance of a new lesion. | From the start of the treatment until the criteria for disease progression is met (or death occurs) maximum of 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Clinical Benefit Response: the Proportion of Patients With Clinical Benefit (CR+PR+SD > 6 Months Duration) Will be Assessed at the Completion of the Study. |  | 6 months | 
| Assess the Overall Response Rate. |  | 24 months | 
| Determine the Adverse Event Profile of Sorafenib Combined With Bevacizumab in This Patient Population. |  | 24 months |