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

Sponsor

University Health Network, Toronto (Other)

Overall Status

Completed

CT.gov ID

NCT00101153

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

Patients Per Site

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: cytarabine Drug: daunorubicin hydrochloride Drug: tipifarnib	Phase 1

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Study Start Date :

Apr 1, 2007

Actual Primary Completion Date :

Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tipifarnib with conventional induction and consolidation	Drug: cytarabine Drug: daunorubicin hydrochloride Drug: tipifarnib

Arm

Intervention/Treatment

Experimental: Tipifarnib with conventional induction and consolidation

Drug: cytarabine

Drug: daunorubicin hydrochloride

Drug: tipifarnib

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of tipifarnib when administered with cytarabine and daunorubicin [minimum of 30 days per treatment cycle]
Toxicity [All cycles]
Pharmacokinetics [Day 6]

Eligibility Criteria

Criteria

Ages Eligible for Study:

56 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
2	London Regional Cancer Program at London Health Sciences Centre	London	Ontario	Canada	N6A 465