Flavopiridol and Imatinib Mesylate in Treating Patients With Hematologic Cancer

OBJECTIVES:

• Determine the maximum tolerated dose and recommended phase II dose of flavopiridol and imatinib mesylate in patients with Bcr/Abl+ hematological malignancies.
• Determine the toxic effects of this regimen in these patients.
• Determine the disease-related effects of this regimen in these patients.
• Determine the pharmacokinetics and pharmacodynamics of this regimen in these patients.
• Correlate response to this regimen with mechanisms of imatinib mesylate resistance in patients previously treated with imatinib mesylate.

OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to percentage of blasts in the peripheral blood and bone marrow (less than 15% vs at least 15%) and recent myelosupressive treatment (no vs yes).

Patients receive oral imatinib mesylate daily and flavopiridol IV over 1 hour on days 2, 9, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of imatinib mesylate and flavopiridol 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.

PROJECTED ACCRUAL: A total of 6-80 patients will be accrued for this study within 1 year.

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

• Chronic or accelerated phase chronic myelogenous leukemia (CML) with 1 of the following:

• Hematologic progression during prior imatinib mesylate treatment
• Less than a complete hematologic response after at least 3 months of prior imatinib mesylate treatment
• Less than a major cytogenetic response after at least 6 months of imatinib mesylate treatment (cytogenetic response documented by karyotype or fluorescence in situ hybridization [FISH])
• Blastic phase CML*
• Acute lymphoblastic leukemia*
• Acute myeloid leukemia* NOTE: *Patients may be enrolled at presentation, in remission, or upon relapse
• Bcr/Abl+ in bone marrow confirmed by karyotype or FISH
• No known CNS malignancy

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST and ALT no greater than 2.5 times ULN (5 times ULN if hepatic involvement suspected [stratum 2 only])

Renal

• Creatinine no greater than 2 times ULN

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 3 months after study participation
• No prior allergic reaction attributed to compounds of similar chemical or biological composition to study agents
• No other concurrent uncontrolled medical illness
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent filgrastim (G-CSF), sargramostim (GM-CSF), or interleukin-2 during the first course of study therapy unless clinically indicated for management of febrile neutropenia or thrombocytopenia
• Concurrent epoetin alfa allowed if started before study entry and it remains clinically appropriate

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• See Disease Characteristics
• Recovered from all prior therapy
• No other concurrent investigational or anticancer agents
• No concurrent combination antiretroviral therapy for HIV-positive patients