Sorafenib and Paclitaxel in Treating Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with paclitaxel may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects of giving sorafenib together with paclitaxel and to how well it works in treating patients with metastatic breast cancer.

Detailed Description
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OBJECTIVES: Primary To evaluate the efficacy of sorafenib tosylate and paclitaxel by measuring tumor response, as defined by RECIST criteria, in patients with metastatic, HER2-negative breast cancer. Secondary To evaluate time to disease progression in patients treated with this regimen. To evaluate six-month progression-free survival of patients treated with this regimen. To evaluate time to treatment failure in patients treated with this regimen. To evaluate clinical benefit rate (tumor response and stable disease) at 24 weeks in patients treated with this regimen. To evaluate duration of response in patients treated with this regimen. To evaluate the tolerability of this regimen in these patients. To examine the relationship of gene expression and tissue/serum protein markers, where available, related to response to therapy focusing on growth factor receptor pathways. OUTLINE: This is a multicenter study. Patients receive oral sorafenib tosylate twice daily on days 1-28 and paclitaxel IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 4 weeks.

Official Title
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Phase II Trial of Sorafenib and Paclitaxel for Measurable Metastatic HER2-Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: paclitaxel
* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Inclusion criteria: Histologically* confirmed breast cancer Stage IV (metastatic) disease Radiographic evidence of metastases NOTE: *Histological confirmation of the actual metastasis is not required. Measurable disease by RECIST criteria defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques (i.e., physical examination, CT scan, MRI, or x-ray) or ≥ 10 mm by spiral CT scan No prior radiotherapy unless growth has been documented following radiotherapy Primary tumor or metastatic tumor HER2-negative, defined as the following: Immunohistochemistry of 0 or 1+ OR the equivalent, if an automated quantitative assay is used HER2 fluorescent in situ hybridization (FISH) assay negative as defined by a HER2:chromosome 17 centromeric probe ratio < 1.8 (or < 2.2 if immunohistochemistry is less than 3+ or equivalent) OR equivalent values for negative FISH assays that do not normalize to chromosome 17 Hormone-receptor positive (estrogen receptor-[ER] or progesterone receptor [PgR]-positive) disease or hormone receptor-negative (ER- or PgR-negative) disease Tumor block from initial breast cancer primary or a biopsy of a metastatic site must be available for correlative studies Brain metastases allowed provided the patient is stable after completion of treatment (i.e., surgery and/or radiotherapy), asymptomatic, and off steroids with 2 consecutive stable brain scans at least 4 weeks after radiotherapy Exclusion criteria: Bone-only or other nonmeasurable-only disease Newly diagnosed brain metastases PATIENT CHARACTERISTICS: Inclusion criteria: ECOG performance status 0-1 Life expectancy > 6 months Menopausal status not specified WBC ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcL Platelets ≥ 100,000/mcL Total bilirubin < 1.5 times upper limit of normal (ULN) AST and ALT transaminases ≤ 2.5 times ULN (< 5 times ULN if liver involvement) Creatinine < 1.5 times ULN OR creatinine clearance > 60 mL/min INR < 1.5 OR PT/PTT normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception prior to and during (women and men) and for at least 3 months after (men) study therapy Able to swallow and absorb oral medications Exclusion criteria: Active or uncontrolled medical illness (e.g., active infection > CTCAE grade 2), including any of the following: HIV or chronic hepatitis B or C Uncontrolled diabetes NYHA class II-IV uncompensated congestive heart failure Unstable angina (anginal symptoms at rest) New onset angina (i.e., began within the past 3 months) Coronary artery disease Myocardial infarction within the past 6 months Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy Evidence of bleeding diathesis or coagulopathy Pulmonary hemorrhage/bleeding event > CTCAE grade 2 within 4 weeks of first dose of study drug Any other hemorrhage/bleeding event > CTCAE grade 3 within 4 weeks of first study drug Thrombotic or embolic events (i.e., cerebrovascular accident), including transient ischemic attacks within the past 6 months Hypertension that cannot be controlled with medication to ≤ 150/90 mm Hg History of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib tosylate Prior invasive cancer other than breast cancer except nonmelanoma skin cancer Chronic nonhealing wound or ulcer PRIOR CONCURRENT THERAPY: No more than 1 prior chemotherapy regimen for metastatic breast cancer (MBC) At least 3 weeks since prior hormonal therapy for MBC or adjuvant or neoadjuvant chemotherapy More than 1 year since adjuvant paclitaxel At least 4 weeks since major thoracic, abdominal, or pelvic surgery and recovered At least 3 weeks since prior and no concurrent investigational drugs Concurrent bisphosphonates allowed Concurrent anticoagulation agents (i.e., warfarin or heparin) allowed No anticipated need for or concurrent radiotherapy No concurrent Hypericum perforatum (St. John wort) or rifampin (rifampicin) No other concurrent anti-neoplastic drugs

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: Sorfenib + Paclitaxel<br>Oral sorafenib tosylate twice daily on days 1-28 and paclitaxel IV over 1 hour on days 1, 8, and 15 | Drug: paclitaxel<br>* The chemotherapy drug called paclitaxel (Taxol) treats breast cancer, lung cancer, ovarian cancer and Kaposis sarcoma<br>* Other names: Taxol, Abraxane, Onxol;Drug: sorafenib tosylate<br>* Sorafenib is a type of targeted therapy known as a kinase inhibitor used to treat advanced renal cell carcinoma and unresectable hepatocellular carcinoma<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Tumor Progression | Progression-free survival was defined as the time of treatment to the earliest date of documentation of disease progression or death due to any cause. In the case of a participant started treatment. Tenth month of progression-free rate of sorafenib and paclitaxel will be compared agains the null progression free rate of 32% using normal approximation test. | Time from first treatment to disease progression or death (up to 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT and MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. The confirmed response rate was estimated by the number of confirmed responses divided by the total number of participants randomized. | Up to 36 months | 
| Six-month Progression-free Survival | The proportion of patients with progression-free survival at 6 months. Progression-free is measured from Day-1 of study drug administration to disease progression as defined by Response Evaluation Criteria in Sole Tumors (RECIST) v1.1, or death on study. Progression is defined in RECIST v1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new leasions. | 6 months | 
| Time to Treatment Failure | Number of patients experiencing treatment failure. | Up to 36 months | 
| Clinical Benefit Rate (Tumor Response and Stable Disease) at 24 Weeks | Number of patients with either complete response (CR) or partial response (PR) as defined in Response Evaluation Criteria in Solid Tumors (for patients with measurable disease). Complete Response: Disappearance of all target lesions, disappearance of all non-target lesions for at least 4 weeks. Partial Response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameters. | 24 weeks | 
| Duration of Response | Number weeks until disease progression measured from Day-1 of study drug administration to disease progression. | Up to 36 months | 
| Tolerability of Sorafenib/Paclitaxel Regimen | Number of patients without experiencing treatment-related adverse events. | Up to 36 months | 
| Determine the Relationship of Gene Expression and Tissue/Serum Protein Markers, Where Available, Related to Response to Therapy Focusing on Growth Factor Receptor Pathways. | Median values taken for all assays at baseline and relationship to response vs. no response will be made to identify predictive markers using methods to detect differential expression between two groups samples, including variants of the two-sample t-test, analysis of variance, F-test, and the Wilcoxon rank-sum test. | Up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, male breast cancer, recurrent breast cancer, HER2-negative breast cancer