BMS-247550 Plus Capecitabine in Treating Patients With Metastatic Breast Cancer

A Phase I Study of BMS-247550 in Combination With Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With a Taxane and an Anthracycline

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of combining BMS-247550 with capecitabine in treating patients who have metastatic breast cancer that has not responded to previous chemotherapy with a taxane and an anthracycline.

OBJECTIVES:

• Determine the maximum tolerated dose of BMS-247550 and capecitabine, on 2 different schedules, in patients with metastatic breast cancer previously treated with a taxane and an anthracycline.
• Determine the safety profile of this regimen in these patients.
• Determine, preliminarily, any antitumor activity of this regimen in these patients.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 groups.

• Group I: Patients receive BMS-247550 IV over 3 hours on day 1 and oral capecitabine twice daily on days 1-14.
• Group II: Patients receive BMS-247550 IV over 1 hour on days 1-3 and capecitabine as in group I.

Treatment in both groups repeats every 3 weeks for 2-18 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of BMS-247550 and capecitabine until the maximum tolerated dose (MTD) is determined for each group. The MTD is defined as the dose at which no more than 1 of 6 patients experiences dose-limiting toxicity. Additional patients are treated at the MTD.

Patients are followed for at least 30 days and then every 3 months thereafter.

PROJECTED ACCRUAL: Approximately 34-60 patients will be accrued for this study within 8-12 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer

  • Metastatic disease by radiography or histology

• Must have received prior chemotherapy with a taxane and an anthracycline in the adjuvant or metastatic setting

  • No more than 2 prior chemotherapy regimens in the metastatic setting

• Measurable or evaluable disease

  • Bone lesions not measurable
  • Primary breast lesions not measurable if assessed only by physical exam

• No active brain metastasis

  • No cerebral edema by CT scan or MRI
  • No progression since prior imaging studies
  • No requirement for steroids
  • No clinical symptoms of brain metastasis

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Not specified

Menopausal status

• Not specified

Performance status

• ECOG 0-1

Life expectancy

• At least 3 months

Hematopoietic

• Absolute neutrophil count at least 2,000/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9.0 g/dL

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• ALT no greater than 2.5 times ULN

Renal

• Creatinine less than 1.5 times ULN

Cardiovascular

• No uncontrolled or significant cardiovascular disease
• No myocardial infarction within the past year
• No uncontrolled angina within the past year
• No history of congestive heart failure
• No history of atrial or ventricular arrhythmias
• No history of second- or third-degree heart block
• No uncontrolled hypertension

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No hypersensitivity to Cremophor EL or fluorouracil
• No prior intolerance to fluoropyrimidines
• No other serious uncontrolled medical disorder or active infection that would preclude study
• No dementia or altered mental status that would preclude study
• No grade 2 or greater neuropathy (neuromotor or neurosensory)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Chemotherapy
• Prior immunotherapy allowed
• No concurrent trastuzumab (Herceptin)
• No concurrent immunotherapy

Chemotherapy

• See Disease Characteristics
• At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas, mitomycin, or doxorubicin HCl liposome)
• At least 2 years since prior high-dose chemotherapy with bone marrow transplantation or peripheral blood stem cell support
• No prior epothilone, capecitabine, or continuous-infusion fluorouracil
• No other concurrent chemotherapy

Endocrine therapy

• Prior hormonal therapy allowed
• No concurrent hormonal therapy
• Concurrent hormone replacement therapy allowed

Radiotherapy

• At least 3 weeks since prior radiotherapy
• No prior radiotherapy to more than 25% of the bone marrow
• No concurrent therapeutic radiotherapy

Surgery

• Not specified

Other

• At least 3 weeks since prior investigational cytotoxic agents

• No concurrent warfarin for therapeutic anticoagulation

  • Low-dose warfarin allowed for implanted ports or indwelling catheters

• No other concurrent experimental anticancer medications

• No other concurrent antitumor therapy

• Concurrent bisphosphonates for palliation of bone metastases allowed if initiated before study