Tipifarnib, Cytarabine, and Daunorubicin in Treating Older Patients With Acute Myeloid Leukemia

OBJECTIVES:

• Determine the maximum tolerated dose of tipifarnib when administered with cytarabine and daunorubicin in older patients with previously untreated acute myeloid leukemia.
• Determine the toxicity of this regimen in these patients.
• Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a multicenter, dose-escalation study of tipifarnib.

Induction therapy (1 course): Patients receive cytarabine IV continuously on days 1-7, daunorubicin IV on days 6-8, and oral tipifarnib twice daily on days 6-15 in the absence of unacceptable toxicity. Patients achieving complete remission proceed to consolidation therapy.

Consolidation therapy (1 course): After hematologic recovery, patients begin consolidation therapy 35-60 days after the start of induction therapy. Patients receive cytarabine, daunorubicin, and tipifarnib as in induction therapy.

Cohorts of 3-6 patients receive escalating doses of tipifarnib 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. A total of 10 patients are treated at the recommended phase II dose.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 3-28 patients will be accrued for this study within 1.5-22 months.

DISEASE CHARACTERISTICS:

• Diagnosis of acute myeloid leukemia (AML)

• All subtypes, except acute promyelocytic leukemia, are allowed
• At least 20% bone marrow or peripheral blood blasts OR biopsy-confirmed extramedullary disease
• No cerebrospinal fluid involvement

PATIENT CHARACTERISTICS:

Age

• 56 and over

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics
• WBC < 100,000/mm^3 (treatment with hydroxyurea allowed)

Hepatic

• Bilirubin ≤ 1.25 times upper limit of normal (ULN)
• AST and ALT ≤ 2.0 times ULN

Renal

• Creatinine < 1.7 mg/dL OR
• Creatinine clearance ≥ 60 mL/min

Cardiovascular

• LVEF ≥ 50%
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Immunologic

• HIV negative
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to tipifarnib or imidazole drugs (e.g., ketoconazole, clotrimazole, or miconazole)
• No ongoing or active infection

Other

• Not pregnant
• Fertile patients must use effective contraception
• Able to swallow oral medications
• No other uncontrolled illness
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for AML except hydroxyurea for cytoreduction
• More than 4 weeks since prior chemotherapy except hydroxyurea (6 weeks for nitrosoureas or mitomycin) and recovered

• At least 24 hours since prior hydroxyurea

Endocrine therapy

• No concurrent dexamethasone

Radiotherapy

• More than 4 weeks since prior radiotherapy and recovered
• No prior radiotherapy > 3,000 cGy to marrow-producing areas

Surgery

• Not specified

Other

• No other concurrent investigational agents
• No other concurrent antileukemic agents
• No concurrent treatment with any of the following:

• Ketoconazole
• Itraconazole
• Voriconazole
• Clarithromycin
• Erythromycin
• Phenytoin
• Carbamazepine
• Barbiturates
• Cyclosporine
• Pimozide
• Warfarin
• Grapefruit juice
• Simvastatin
• Lovastatin
• Atorvastatin
• No concurrent magnesium- or aluminum-containing antacids within 2 hours before or after tipifarnib administration