Weekly Vinorelbine and Oral Capecitabine as Treatment for Stage IV Breast Cancer

Weekly Vinorelbine and Oral Capecitabine as Treatment for Stage IV Breast Cancer: A Phase II Trial With Molecular Correlates

The primary purpose of the study is to examine the safety and effectiveness of combination therapy consisting of daily oral capecitabine and weekly intravenous vinorelbine in stage IV breast cancer subjects. The study is designed to assess the safety and effectiveness of this combination therapy. Safety will be assessed by analyzing the types of toxicity, the severity of toxicity and the need for dose modification or delay due to toxicity. Effectiveness will be assessed by analyzing response rates, time to treatment failure, time to progression and overall survival. Our hypothesis is that the regimen will be more effective than standard historic regimens for this type and stage of cancer.

Single-agent chemotherapy is rarely curative in advanced breast cancer. Combination regimens are the next logical step in the attempt to improve tumor response rates and prolong survival. Oral capecitabine is a convenient way to deliver drug a 5-fluorouracil analogue. In addition, vinorelbine is a newer vinca alkaloid chemotherapeutic agent with improved efficacy and probably improved toxicity over its predecessors in the treatment of breast cancer. We propose combining these two agents. As these two drugs have non-overlapping toxicities and differing mechanisms of action, we anticipate being able to deliver both drugs in near full dose.

Secondary purposes include assessing whether there is a correlation between intra-tumoral enzyme levels and prognosis.

Inclusion Criteria:

• Subject must be older than 18 and younger than 85.
• Subject must have metastatic (stage IV) breast cancer.
• Subject must have pathologic confirmation of breast cancer (at least of primary disease). Biopsy confirmation of stage IV disease is desirable but not required. Tissue blocks must be available for review.
• Subject must have measurable or non-measurable disease as defined below:

Measurable disease includes lesions that can be accurately measured in at least one dimension as greater than 2.0 cm with conventional techniques or as greater than 1.0 cm with spiral CT scan.

Non-measurable disease includes all other lesions (e.g. lesions less than 2.0 cm by conventional techniques or less than 1.0 cm by spiral CT, bone lesions, pleural effusion, etc.).

- Subject must be willing and able to provide informed consent.

Exclusion Criteria:

• Subject must not have significant co-morbid conditions such as clinically significant cardiac disease not well controlled with medication (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias), or myocardial infarction within the last 12 months or serious concurrent infection.
• Subject must not have rapidly progressing visceral involvement (e.g. liver, lymphangitic lung).
• Subject must not have evidence of CNS metastases.
• Subject must not have abnormal hematologic values (neutrophils less than 1.5 x 103/uL, platelet count less than 100 x 103/uL).
• Subject must not have impaired renal function (serum creatinine greater than 1.5 x upper normal limit) or estimated creatinine clearance below 30 mL/min by the Cockcroft and Gault equation.
• Subject must not have serum bilirubin greater than 1.5 x upper normal limit.
• Subject must not have ALT or AST greater than 2.5 x upper normal limit (or greater than 5 x upper normal limit in the case of liver metastases).
• Subject must not have alkaline phosphatase greater than 2.5 x upper normal limit (or greater than 5 x upper normal limit in the case of liver metastases or greater than 10 x upper normal limit in the case of bone disease).
• Subject must not have a lack of physical integrity of the upper gastrointestinal tract, inability to swallow or malabsorption syndrome
• Subject must not have a history of fluoropyrimidine therapy (unless given in an adjuvant setting and completed at least 12 months earlier).
• Subject must not have a life expectancy less than 3 months.
• Subject must not have a Karnofsky Performance Status less than 70%.
• Subject must not have a history of another carcinoma within the last five years except non-melanoma skin and treated in-situ cervical cancer.
• Subject must not have a history of unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity to 5-fluorouracil.
• Subject must not have organ allografts.
• Subject must not be pregnant or lactating woman. (Postmenopausal woman must have been amenorrheic for at least 12 months to be considered of non-childbearing potential).
• Subject must not be less than four weeks from completion of previous chemotherapy regimen or with related toxicities unresolved prior to the start of study treatment.
• Subject must not be less than four weeks from major surgery or without complete recovery.