RATIONALE: Drugs used in chemotherapy such as docetaxel work in different ways to stop tumor cells from dividing so they stop growing or die. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining docetaxel with imatinib mesylate may kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of combining docetaxel with imatinib mesylate in treating patients who have locally advanced or metastatic breast cancer.

Condition	Treatment or Intervention	Phase
Male Breast Cancer stage IIIB breast cancer stage IIIC breast cancer stage IV breast cancer recurrent breast cancer	Drug: docetaxel  Drug: imatinib mesylate  Procedure: chemotherapy  Procedure: enzyme inhibitor therapy  Procedure: protein tyrosine kinase inhibitor therapy	Phase I

Further Study Details: 

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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

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 2 weeks since prior 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 3 weeks since prior chemotherapy (2 weeks for weekly or oral chemotherapy and 6 weeks for nitrosoureas or mitomycin)
• No other concurrent chemotherapy

Endocrine therapy

• At least 2 weeks since prior 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 2 weeks since prior daily or weekly 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

Maryland
      Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore,  Maryland,  21231,  United States

Study chairs or principal investigators

Antonio C. Wolff, MD,  Principal Investigator,  Sidney Kimmel Cancer Center   

Study ID Numbers:  CDR0000354504; JHOC-J0214; SKCCC-J0214; NCT00080665
Record last reviewed:  February 2005
Last Updated:  February 9, 2005
Record first received:  April 7, 2004
ClinicalTrials.gov Identifier:  NCT00080665
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08