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

Johns Hopkins Medicine

Status and phase

Completed

Phase 1

Conditions

Breast Cancer

Treatments

Drug: imatinib mesylate

Drug: docetaxel

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00080665

P30CA006973 (U.S. NIH Grant/Contract)

JHOC-J0214 (Other Identifier)

J0214 CDR0000354504

SKCCC-J0214 (Other Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment

12 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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 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