Docetaxel and Imatinib Mesylate in Treating Patients With Locally Advanced or Metastatic Breast Cancer

OBJECTIVES:

Primary

• Determine the safety profile, maximum tolerated dose, and recommended phase II dose of docetaxel when administered with imatinib mesylate in patients with locally advanced or metastatic breast cancer.

Secondary

• Determine the pharmacokinetic profile of this regimen in these patients.
• Determine the potential effects of this regimen on CYP3A4 activity and docetaxel metabolism in these patients.
• Correlate docetaxel and imatinib mesylate exposure (utilizing total and unbound docetaxel and imatinib mesylate plasma concentrations) with drug response (e.g., pharmacodynamic effects, drug toxicity, and response) in these patients.
• Determine response rate, duration of response, and time to treatment failure in patients treated with this regimen.
• Correlate proteomic profile changes in serum with tumor burden and response in patients treated with this regimen.
• Correlate pharmacokinetic parameters, tissue expression of specific receptor tyrosine kinases (e.g., c-Kit, platelet-derived growth factor receptor [PDGFR], and phosphorylated PDGFR) in paraffin blocks, and pharmacodynamic assays with antitumor activity of this regimen in these patients.

OUTLINE: This is an open-label, dose-escalation study of docetaxel.

Patients receive docetaxel IV over 1 hour on days 1, 8, and 15 and oral imatinib mesylate (STI571) on days 8-28 of course 1 and days 1-28 of all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity*. Patients with stable or responding disease after at least 2 courses of therapy may discontinue docetaxel and continue therapy with single-agent STI571 until disease progression.

NOTE: *Patients experiencing excessive docetaxel-related toxicity who have completed at least 2 full courses may continue on single-agent STI571 in the absence of disease progression or excessive STI571-related toxicity.

Cohorts of 3-6 patients receive escalating doses of docetaxel until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional cohort of 6-12 patients receives treatment at the MTD.

Patients are followed at 30 days.

PROJECTED ACCRUAL: Approximately of 18-30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast

• Stage IIIB, IIIC, or IV disease
• Measurable or evaluable disease
• Stable brain metastases allowed provided prior surgery or radiotherapy was completed more than 90 days ago
• No documented or suspected leptomeningeal disease
• Hormone receptor status:

• Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Male or female

Menopausal status

• Not specified

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Granulocyte count ≥ 1,500/mm^3
• Hemoglobin ≥ 8.0 g/dL
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ upper limit of normal (ULN)
• Meets 1 of the following criteria for AST or ALT AND alkaline phosphatase:

• AST or ALT ≤ ULN AND alkaline phosphatase ≤ 5 times ULN
• AST or ALT ≤ 2.5 times ULN AND alkaline phosphatase ≤ ULN
• AST or ALT ≤ 1.5 times ULN AND alkaline phosphatase ≤ 2.5 times ULN
• No known acute or chronic liver disease (e.g., chronic active hepatitis or cirrhosis)

Renal

• Creatinine ≤ 1.5 mg/dL

Cardiovascular

• No New York Heart Association class III or IV heart disease
• No congestive heart failure
• No myocardial infarction within the past 6 months

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after study participation
• No other primary malignancy except those malignancies that are clinically insignificant AND do not require active intervention
• No other concurrent severe and/or life-threatening medical disease
• No significant history of noncompliance to medical regimens or inability to grant reliable informed consent

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 14 days since prior systemic trastuzumab (Herceptin®)
• No concurrent trastuzumab
• No concurrent biologic therapy for the primary malignancy

Chemotherapy

• Prior taxane therapy, including docetaxel, in the adjuvant or metastatic setting allowed
• At least 21 days since prior systemic chemotherapy (14 days for weekly or oral chemotherapy and 42 days for nitrosoureas or mitomycin)
• No other concurrent chemotherapy

Endocrine therapy

• At least 14 days since prior systemic hormonal therapy
• No concurrent antiestrogen therapy
• No concurrent routine systemic corticosteroid therapy except as premedication for chemotherapy
• Concurrent megestrol allowed only as an appetite stimulant

Radiotherapy

• See Disease Characteristics
• At least 14 days since prior radiotherapy
• No prior radiotherapy to only site of measurable/evaluable disease unless there is new evidence of post-radiotherapy disease progression
• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• More than 2 weeks since prior major surgery

Other

• Recovered from all prior therapy
• At least 14 days since prior daily or weekly systemic investigational treatment
• No concurrent warfarin for full anticoagulation

• Concurrent low-dose warfarin (e.g., 1 mg/day) allowed for prophylaxis of central venous access
• No concurrent treatment with any of the following:

• Phenobarbital
• Phenytoin
• Carbamazepine
• Barbiturates
• Rifampin
• Hypericum perforatum (St. John's wort)
• No other concurrent therapies for the primary malignancy
• No other concurrent investigational drugs or systemic therapy
• No concurrent bisphosphonates unless started before study therapy
• No concurrent grapefruit juice