Capecitabine, Vinorelbine, and Trastuzumab in Treating Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as capecitabine and vinorelbine, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor killing substances to them without harming normal cells. Giving capecitabine and vinorelbine together with trastuzumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving capecitabine and vinorelbine together with trastuzumab works in treating patients who have metastatic breast cancer.

Detailed Description
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OBJECTIVES: Primary Determine the overall response rate in patients with HER2/neu-overexpressing metastatic breast cancer treated with first- or second-line therapy comprising capecitabine, vinorelbine, and trastuzumab (Herceptin^®). Secondary Determine the time to disease progression, duration of response, and overall survival of patients treated with this regimen. Determine the safety profile of this regimen in these patients. OUTLINE: This is a multicenter study. Patients receive oral capecitabine twice daily on days 1-14, vinorelbine IV over 6-10 minutes on days 1 and 8, and trastuzumab (Herceptin^®) IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.

Official Title
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Phase II Study of Capecitabine in Combination With Vinorelbine and Trastuzumab for the First- or Second-LineTreatment of HER2+ Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Drug: capecitabine
* Drug: vinorelbine tartrate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed invasive breast cancer Metastatic disease HER2/neu-positive by immunohistochemistry (3+ by HercepTest^™ or equivalent) OR positive for amplification by fluorescent in situ hybridization Testing may be performed in the primary tumor or the metastatic site Received prior anthracycline or taxane as adjuvant therapy or for metastatic disease Measurable disease At least one measurable lesion ≥ 2.0 cm by CT scan or MRI OR ≥ 1.0 cm by spiral CT scan The following are considered non-measurable disease: Bone lesions Leptomeningeal disease Ascites Pleural/pericardial effusion Inflammatory breast disease Lymphangitis cutis/pulmonis Abdominal masses that are not confirmed and followed by imaging techniques Cystic lesions No bone metastases as the only evidence of metastasis Previously treated CNS metastases allowed provided disease has been stable for ≥ the past 3 months Hormone receptor status: Not specified PATIENT CHARACTERISTICS: Age 18 and over Sex Female or male Performance status ECOG 0-2 Life expectancy At least 12 weeks Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Hemoglobin ≥ 8.0 g/dL Platelet count ≥ 100,000/mm^3 No known uncontrolled coagulopathy Hepatic Bilirubin ≤ 3.0 times the upper limit of normal (ULN) One of the following must be true: AST or ALT ≤ 5 times ULN AND alkaline phosphatase normal Alkaline phosphatase ≤ 5 times ULN AND AST or ALT normal Alkaline phosphatase ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN INR ≤ 1.5 times ULN Renal Calcium ≤ 11.5 mg/dL Creatinine ≤ 1.5 times ULN Creatinine clearance ≥ 30 mL/min Cardiovascular LVEF ≥ 50% by MUGA or echocardiogram No clinically significant (i.e., active) cardiac disease No congestive heart failure No symptomatic coronary artery disease No myocardial infarction within the past 12 months No cardiac arrhythmia not controlled with medication Gastrointestinal Able to take oral medication No lack of physical integrity of the upper gastrointestinal tract No clinically significant malabsorption syndrome Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 30 days after study participation No history of allergy or hypersensitivity to study drugs, drug product excipients, including polysorbate 80, or chemically similar agents No prior unanticipated severe reaction to fluoropyrimidine therapy No know hypersensitivity to fluorouracil No known dihydropyrimidine dehydrogenase deficiency No history of uncontrolled seizures or CNS disorders No clinically significant psychiatric disability that would preclude giving informed consent or study compliance No other serious uncontrolled infection or disease No other malignancy within the past 5 years except cured basal cell skin cancer, carcinoma in situ of the cervix, or contralateral breast cancer PRIOR CONCURRENT THERAPY: Biologic therapy Prior adjuvant trastuzumab (Herceptin^®) allowed as adjuvant or first-line therapy for metastatic disease No concurrent immunotherapy Chemotherapy See Disease Characteristics No more than 1 prior chemotherapy regimen in the advanced or metastatic (non-adjuvant) setting No prior continuous (≥ 24 hours) fluorouracil infusion No prior capecitabine No prior oral fluoropyrimidines (e.g., eniluracil and fluorouracil, uracil and tegafur, S1, or emitefur) Endocrine therapy At least 1 day since prior hormonal therapy No concurrent hormonal therapy Radiotherapy More than 4 weeks since prior radiotherapy to the axial skeleton (i.e., skull, spinal column, sternum, or ribs) No concurrent radiotherapy Surgery More than 4 weeks since prior major surgery No prior organ allografts requiring immunosuppressive therapy Other More than 4 weeks since prior investigational drugs No concurrent sorivudine or its chemically related analogues (e.g., brivudine) No concurrent allopurinol, metronidazole, or cimetidine No other concurrent cytotoxic agents No other concurrent investigational drugs No other concurrent anticancer 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: capecitabine + vinorelbine + trastuzumab<br>Patients receive oral capecitabine twice daily on days 1-14, vinorelbine IV over 6-10 minutes on days 1 and 8, and trastuzumab (Herceptin^®) IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years. | Biological: trastuzumab<br> <br> Drug: capecitabine<br> <br> Drug: vinorelbine tartrate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate | A confirmed tumor response is defined to be either a Complete Response (CR) or Partial Response (PR) noted as the objective status on 2 consecutive evaluations at least 6 weeks apart. All patients meeting the eligibility criteria who have signed a consent form and initiated study medication will be evaluable for response. The proportion of confirmed tumor responses will be estimated by the number of tumor regressions that meet the RECIST criteria for a confirmed CR or PR divided by the total number of evaluable patients. A 95% confidence interval for the true confirmed response rate will be calculated using the properties of the binomial distribution. 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; Overall Response (OR) = CR + PR. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | Time to progression is defined as the time from registration to disease progression. Patients who died without documentation of progression will be considered to have progressed on the date of their death. If a patient starts treatment and fails to return for any evaluations, that patient will be censored for progression of disease at day one post-registration. Otherwise, for patients that do not progress, censoring will occur at the last follow up date. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least 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 or unequivocal progression of existing non-target lesions. | Up to 5 years | 
| Duration of Response as Measured by RECIST Criteria | Duration of response is defined for all eligible patients who have achieved an objective response as the date at which the patient's objective status is first noted to be either a Complete Response (CR) or Partial Response (PR) to the date progression is documented. 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. | Up to 5 years | 
| Overall Survival as Assessed by Time | Overall survival: The overall survival or survival time is defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier method. | Up to 5 years | 

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