Sorafenib and Vinorelbine in Treating Women With Stage IV 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. Drugs used in chemotherapy, such as vinorelbine, 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 vinorelbine may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of sorafenib when given together with vinorelbine and to see how well they work in treating women with stage IV breast cancer.

Detailed Description
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OBJECTIVES: Primary To determine the safety, tolerability, and recommended phase II dose of sorafenib tosylate when administered in combination with vinorelbine ditartrate in women with stage IV adenocarcinoma of the breast. (Phase I) To evaluate the 4-month progression-free survival rate in patients treated with this regimen at the maximum tolerated dose. (Phase II) Secondary To determine time to treatment failure in these patients. To determine the response rate in these patients. To determine the overall survival and progression-free survival of these patients. To evaluate the toxicity profile of this regimen. OUTLINE: This is a phase I, dose-escalation study of sorafenib tosylate followed by a phase II study. Patients receive oral sorafenib tosylate on days 1-28 and vinorelbine ditartrate IV on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically.

Official Title
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Phase I/II Vinorelbine and Sorafenib as Salvage Therapy in Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: sorafenib tosylate
* Drug: vinorelbine ditartrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed stage IV adenocarcinoma of the breast; (unless metastatic disease is documented by computed tomography [CT] scan, magnetic resonance imaging [MRI], or bone scan; also, skin disease that has not been biopsied maybe used if in the investigators clinical opinion this represents metastatic disease) Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan Prior adjuvant therapy, and up to 2 lines of prior chemotherapy (including trastuzumab containing regimens in Her-2 positive patients) for metastatic disease are allowed; prior radiation therapy is allowed, prior hormonal therapy is allowed; the total number of patients enrolled with prior trastuzumab containing regimens will not exceed 10; no more than 50% of enrolled patients will receive the study regimen in a third line setting Life expectancy of greater than 6 months Performance status: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2 Hemoglobin >= 9.0 g/dl Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Total bilirubin =< 1.5 times ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times the upper limit of normal (ULN) (=< 5 x ULN for patients with liver involvement) Creatinine =< 1.5 times ULN International normalized ratio (INR) < 1.5 or a prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits; patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate; for patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; women of childbearing potential must have a negative serum pregnancy test performed within 7 days to the start of treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks prior; patients who had bevacizumab within 4 weeks prior to entering the study are allowed Patients may not be receiving any other investigational agents Patients with known brain metastases are excluded from this clinical trial; patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2), symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy, or psychiatric illness/social situations that would limit compliance with study requirements Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months 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 dose of study drug Serious non-healing wound, ulcer, or bone fracture Evidence or history of bleeding diathesis or coagulopathy Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug Use of St. John's Wort or rifampin (rifampicin) Known or suspected allergy to sorafenib or any agent given in the course of this trial Pregnant women Human immunodeficiency virus (HIV)-positive patients Any condition that impairs patient's ability to swallow whole pills Any malabsorption problem Patients who received prior sunitinib are excluded

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: Treatment (vinorelbine tartrate and sorafenib tosylate)<br>Patients receive sorafenib tosylate PO twice daily on days 1-28 and vinorelbine ditartrate IV on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: sorafenib tosylate<br>* Dose level 1 = 200 mg by mouth two times a day on days 1-28 of a 28 day cycle. Dose level 2 = 200 mg by mouth two times a day on days 1-28 of a 28 day cycle. Dose level 3 = 200 mg by mouth in the am and 400 mg by mouth in the pm on days 1-28 of a 28 day cycle. Dose level 4 = 400 mg by mouth two times a day on days 1-28 of a 28 day cycle.<br>Drug: vinorelbine ditartrate<br>* Dose level 1 = 20 mg/m2 IV weekly on days 1, 8, and 15 of a 28 day cycle. Dose level 2 = 25 mg/m2 IV weekly on days 1, 8, and 15 of a 28 day cycle. Dose level 3 = 25 mg/m2 IV weekly on days 1, 8, and 15 of a 28 day cycle. Dose level 4 = 25 mg/m2 IV weekly on days 1, 8, and 15 of a 28 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least One Dose Limiting Toxicity in Phase I | Dose Limiting Toxicity (DLT) defined as any treatment-related grade 3 or greater non-hematologic toxicity (excluding alopecia, controllable nausea and vomiting, and serum triglycerides < 1,500 mg/dL which recover within 1 week), grade 4 or greater thrombocytopenia, grade 4 or greater febrile neutropenia requiring hospitalization, or treatment delay of > 2 weeks as a result of unresolved toxicity during the first cycle of therapy. | 4 weeks from start of treatment, up to 2 years | 
| Recommended Phase II Dose | The maximum tolerated dose (MTD) of Vinorelbine is based on toxicities observed during the first cycle and is defined as the highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Dose escalations proceeded according to a standard 3+3 design. | 4 weeks from start of treatment, up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Rate at 4 Months | Estimated using the product-limit method of Kaplan and Meier.Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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 lesions. | 4 months following the last course of treatment | 
| Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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 lesions. | Until disease progression, up to 5 years. | 
| Objective Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response Rate defined as percentage of patients achieving a Best Response of either CR or PR. | After 2 cycles of treatment, up to 2 years. | 
| Overall Survival | Estimated using the product-limit method of Kaplan and Meier. | Until death from any cause, up to 5 years. | 
| Toxicity Profile | Number of Participants with Treatment-Related Grade 3 & 4 Toxicities for Sorafenib and Vinorelbine Combination | 28 days following the last course of treatment | 

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