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

Study Overview
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Brief Summary
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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. Giving docetaxel with imatinib mesylate may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of docetaxel when given together with imatinib mesylate in treating patients with locally advanced or metastatic breast cancer.

Detailed Description
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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.

Official Title
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A Phase I Study Of Weekly Taxotere (Docetaxel) And Gleevec (STI571, Imatinib Mesylate, CGP 57148B) In Locally Advanced Or Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: docetaxel
* Drug: imatinib mesylate


Participation Criteria
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Eligibility Criteria
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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

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: Imatinib mesylate and docetaxel<br>Imatinib mesylate (400-600 mg, oral, once daily) and docetaxel (15-30 mg/m2, IV, weekly on days 1, 8, and 15) each 28 day cycle | Drug: docetaxel<br>* Docetaxel (15-30 mg/m2, IV, weekly on days 1, 8, and 15) each 28 day cycle<br>* Other names: Taxotere;Drug: imatinib mesylate<br>* Imatinib mesylate (400-600 mg, oral, once daily) each 28 day cycle<br>* Other names: Gleevec, STI571;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2.1.1 To determine the safety profile, maximum tolerated dose, and recommended dose for subsequent phase II studies of a combination regimen of daily STI571 with weekly docetaxel on days 1, 8, and 15 in a 28-day cycle. |  | 4 weeks | 

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