Sorafenib and Vinorelbine in Treating Women With Stage IV Breast Cancer

Phase 1

Completed

Conditions: Breast Cancer

Interventions: Drug: sorafenib tosylate
Drug: vinorelbine ditartrate

Registration Number: NCT00828074

Lead Sponsor: City of Hope Medical Center

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 46

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (vinorelbine tartrate and sorafenib tosylate)	sorafenib tosylate	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.
Treatment (vinorelbine tartrate and sorafenib tosylate)	vinorelbine ditartrate	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With at Least One Dose Limiting Toxicity in Phase I	4 weeks from start of treatment, up to 2 years	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.
Recommended Phase II Dose	4 weeks from start of treatment, up to 2 years	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Until death from any cause, up to 5 years.	Estimated using the product-limit method of Kaplan and Meier.
Objective Response Rate	After 2 cycles of treatment, up to 2 years.	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.
Toxicity Profile	28 days following the last course of treatment	Number of Participants with Treatment-Related Grade 3 \& 4 Toxicities for Sorafenib and Vinorelbine Combination
Progression-free Survival Rate at 4 Months	4 months following the last course of treatment	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.
Progression-free Survival	Until disease progression, up to 5 years.	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.

Trial Locations

Locations (2): City of Hope Medical Center
🇺🇸
Duarte, California, United States
South Pasadena Cancer Center
🇺🇸
Pasadena, California, United States