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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Study Of Therapy With The Farnesyl Transferase Inhibitor R115777 (Zarnestra) Combined With Conventional Induction And Consolidation Chemotherapy For Previously Untreated Patients Over Age 55 With Acute Myeloid Leukemia (AML)

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: tipifarnib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 56 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tipifarnib with conventional induction and consolidation<br> | Drug: cytarabine<br> <br> Drug: daunorubicin hydrochloride<br> <br> Drug: tipifarnib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of tipifarnib when administered with cytarabine and daunorubicin |  | minimum of 30 days per treatment cycle | 
| Toxicity |  | All cycles | 
| Pharmacokinetics |  | Day 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myelomonocytic leukemia (M4), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), untreated adult acute myeloid leukemia