Combination Chemotherapy and Tipifarnib in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Sponsor

Ohio State University Comprehensive Cancer Center (Other)

Overall Status

Terminated

CT.gov ID

NCT00124644

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

PURPOSE: This phase I trial is studying the side effects and best dose of tipifarnib when given together with combination chemotherapy in treating patients with newly diagnosed acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: cytarabine Drug: daunorubicin hydrochloride Drug: etoposide Drug: tipifarnib Procedure: chemotherapy Procedure: enzyme inhibitor therapy Procedure: high-dose chemotherapy	Phase 1

Detailed Description

OBJECTIVES:

Primary

Determine the maximum tolerated dose of tipifarnib when given in combination with induction therapy comprising cytarabine, daunorubicin, and etoposide followed by consolidation therapy comprising high-dose cytarabine in patients with newly diagnosed high-risk acute myeloid leukemia.

Secondary

Determine the qualitative and quantitative toxic effects of this regimen, in terms of organ specificity, time course, predictability, and reversibility, in these patients.
Determine the rate of complete remission in patients treated with this regimen.
Determine the remission duration, overall survival, and relapse-free and event-free survival of patients treated with this regimen.
Determine the pharmacokinetics of this regimen in these patients.
Correlate pharmacodynamic measurements and levels of tumor necrosis factor-alpha with clinical response in patients treated with this regimen.

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

Induction therapy: Patients receive cytarabine IV continuously on days 1-7; daunorubicin IV and etoposide IV over 2 hours on days 5-7; and oral tipifarnib twice daily on days 5-12.

Patients undergo bone marrow biopsy on day 17 OR days 17 and 24 (if day 17 bone marrow biopsy shows suspicious disease). Patients achieving a complete remission (CR) proceed to consolidation therapy. Patients with residual disease, defined as > 5% leukemic blasts in a bone marrow of ≥ 20% cellularity, receive a second course of induction therapy comprising cytarabine IV continuously on days 1-5; daunorubicin IV and etoposide IV over 2 hours on days 4 and 5; and oral tipifarnib twice daily on days 4-9. Patients achieving a CR after a second course of induction therapy proceed to consolidation therapy. Patients not achieving a CR after a second course of induction therapy are removed from the study.

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. An additional 12 patients are treated at the MTD.

Consolidation therapy: Patients receive high-dose cytarabine IV twice daily on days 1, 3, and 5. Treatment repeats approximately every 6-8 weeks for 4 courses.

After completion of study treatment, patients are followed every 3-6 months for up to 5 years.

PROJECTED ACCRUAL: A maximum of 30 patients will be accrued for this study within 10-15 months.

Study Design

Study Type:

Interventional

Primary Purpose:

Treatment

Official Title:

A Phase I Study of R115777 (Zarnestra) in Combination With Induction Chemotherapy in Patients With Newly Diagnosed, High Risk Acute Myeloid Leukemia

Study Start Date :

Mar 1, 2006

Actual Primary Completion Date :

Dec 1, 2007

Actual Study Completion Date :

Jan 1, 2008

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 59 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed acute myeloid leukemia (AML) according to the WHO classification system
High-risk disease
Newly diagnosed disease
Patients with secondary AML due to prior chemotherapy for a different malignancy are eligible
No known inv(16), t(8;21), or t(15;17) cytogenetic abnormality
No acute promyelocytic leukemia
No CNS leukemia

PATIENT CHARACTERISTICS:

Age

18 to 59

Performance status

ECOG 0-2

Life expectancy

More than 6 months

Hematopoietic

Not specified

Hepatic

AST and ALT ≤ 2.5 times upper limit of normal
Bilirubin normal

Renal

Creatinine normal OR
Creatinine clearance ≥ 60 mL/min

Cardiovascular

Ejection fraction > 50% by echocardiogram or MUGA
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia

Immunologic

No known HIV positivity
No history of allergic reactions attributed to compounds of similar chemical or biological composition to tipifarnib
No allergy to imidazoles (e.g., clotrimazole, ketoconazole, miconazole, or econazole)
No ongoing or active infection

Other