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

University Health Network, Toronto

Status and phase: Completed; Phase 1

Conditions: Leukemia

Treatments: Drug: cytarabine; Drug: tipifarnib; Drug: daunorubicin hydrochloride

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00101153

NCI-6670

PMH-PHL-026

CDR0000405840 (Registry Identifier)

Details and patient eligibility

About

RATIONALE: Tipifarnib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and daunorubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving tipifarnib together with cytarabine and daunorubicin may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of tipifarnib when given with cytarabine and daunorubicin in treating older patients with acute myeloid leukemia.

Full description

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.

Enrollment: 24 patients

Sex: All

Ages: 56+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

24 participants in 1 patient group

Tipifarnib with conventional induction and consolidation

Experimental group

Treatment:

Drug: cytarabine

Drug: tipifarnib

Drug: daunorubicin hydrochloride