OBJECTIVES:

• Determine the feasibility, tolerability, and toxic effects of tipifarnib and etoposide in older patients with newly diagnosed, previously untreated acute myeloid leukemia.
• Determine the maximum tolerated dose of this regimen in these patients.

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

Patients receive oral tipifarnib twice daily on days 1-14 OR 1-21 and oral etoposide once daily on days 1-3 and 8-10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) may receive up to 5 additional courses of therapy beyond documentation of CR.

Cohorts of 3-6 patients receive escalating doses of tipifarnib and etoposide 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. Up to 14 additional patients receive treatment at the MTD.

After completion of study treatment, patients are followed at 1 month and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 3-100 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed acute myeloid leukemia (AML), including the following subtypes:

  • M0
  • M1
  • M2
  • M4
  • M5
  • M6
  • M7
• Newly diagnosed de novo or secondary (myelodysplastic syndrome [MDS]-related or treatment-related) AML
• No hyperleukocytosis (i.e., ≥ 30,000 blasts/μL or rapidly rising blast count with projected doubling time of ≤ 2 days)
• No acute promyelocytic leukemia (M3)
• No active CNS leukemia

PATIENT CHARACTERISTICS:

Age

• 70 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• SGOT and SGPT ≤ 5 times upper limit of normal
• Bilirubin ≤ 2.0 mg/dL

Renal

• Creatinine ≤ 2.0 mg/dL

Other

• No active uncontrolled infection

  • Infection under active treatment and controlled with antibiotics allowed
• No other life-threatening illness
• No mental deficit and/or psychiatric history that would preclude giving informed consent or study participation
• No allergy to imidazoles (e.g., clotrimazole, ketoconazole, miconazole, or econazole)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior thalidomide, interferon, or cytokines for MDS allowed
• No concurrent immunotherapy

Chemotherapy

• Prior hydroxyurea allowed
• Prior azacytidine for MDS allowed
• No prior etoposide
• No other concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent radiotherapy

Surgery

• Not specified

Other

• Other prior noncytotoxic therapy for MDS allowed
• No prior tipifarnib
• No concurrent antacids (magnesium- or aluminum-containing formulations) within 2 hours before or after study drug administration
• No concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, or oxcarbazepine)