Pravastatin, Idarubicin, and Cytarabine in Treating Patients With Acute Myeloid Leukemia

Sponsor

Fred Hutchinson Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00107523

Collaborator

(none)

Locations

Duration (Months)

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Pravastatin may help idarubicin and cytarabine work better by making cancer cells more sensitive to the drugs. Giving pravastatin together with idarubicin and cytarabine may kill more cancer cells.

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

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: cytarabine Drug: idarubicin Drug: pravastatin	Phase 1

Detailed Description

OBJECTIVES:

Determine the biological efficacy of pravastatin in leukemia cells, in terms of measuring surrogate endpoints, including cellular cholesterol, messenger RNA encoding cholesterol synthesis, cholesterol import regulators, and specific protein farnesylation, in patients with acute myeloid leukemia.
Determine whether increasing doses of pravastatin, when administered with idarubicin and high-dose cytarabine, produce increased apoptosis in leukemia cells of these patients.
Determine the maximum tolerated dose (MTD) of pravastatin when administered with idarubicin and high-dose cytarabine in these patients.
Determine whether the MTD of pravastatin is required to achieve the maximal biological effect on cholesterol metabolism in leukemia cells of these patients.

OUTLINE: This is an open-label, multicenter, dose-escalation study of pravastatin.

Patients receive oral pravastatin once daily on days 1-8, idarubicin IV over 30 minutes on days 4-6, and high-dose cytarabine IV continuously on days 4-7. Treatment repeats every 28-42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete remission (CR) may receive additional treatment with the same doses of study drugs over fewer days. These patients receive oral pravastatin once daily on days 1-6 and idarubicin IV over 30 minutes and high-dose cytarabine IV continuously on days 4 and 5. Patients experiencing disease response with severe side effects may receive additional treatment at a lower dose of the study drug causing the side effects.

Cohorts of 3 patients receive escalating doses of pravastatin until the maximum tolerated dose (MTD)* is determined or a predetermined maximum dose is reached.

NOTE: *Patients achieving a CR with a dose of pravastatin that is subsequently determined to be above the MTD receive pravastatin at the MTD for all subsequent courses.

After completion of study treatment, patients are followed at least every 3 months for 2 years.

PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study within 2 years.

Study Design

Study Type:

Interventional

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Trial Evaluating the Effect of the Addition of HMGCoA-Reductase Inhibition With Pravastatin to Salvage Chemotherapy Idarubicin-HDAC in Patients With Relapsed or Refractory Acute Myelogenous Leukemia

Study Start Date :

Jan 1, 2005

Actual Study Completion Date :

Oct 1, 2005

Outcome Measures

Primary Outcome Measures

Biological efficacy by measuring surrogate end-points, including cellular cholesterol, messenger RNAs encoding cholesterol synthesis and cholesterol import regulators, and specific protein farnesylation []
Leukemia cell apoptosis []
Maximum tolerated dose (MTD) of pravastatin []
Maximal biological effect on cholesterol metabolism achieved with or without the MTD of pravastatin []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of acute myeloid leukemia (AML) meeting 1 of the following criteria:
Newly diagnosed disease (MDACC patients only)
In first or second relapse AND scheduled to receive first salvage therapy
Primary refractory disease after prior induction therapy for newly diagnosed disease

PATIENT CHARACTERISTICS:

Age

Over 18

Performance status

Zubrod 0-2

Life expectancy

Not specified

Hematopoietic

Not specified

Hepatic

AST or ALT ≤ 2 times normal
Alkaline phosphatase ≤ 2 times normal
Bilirubin < 2.0 mg/dL
No acute or chronic hepatic impairment

Renal

Creatinine < 1.5 times normal (unless secondary to acute myeloid leukemia)

Cardiovascular

Ejection fraction (EF) ≥ 45% by MUGA or 2-D echocardiogram
Patients who have an EF < 45% OR cardiac symptoms must be evaluated and cleared by cardiology to be eligible for study entry
No cardiac contraindication to idarubicin

Other

Not pregnant or nursing
Fertile patients must use effective contraception
HIV negative
No uncontrolled or life threatening infection
No known intolerance to study drugs
Must be able to safely tolerate the 3-day delay between the start of pravastatin and the start of chemotherapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

Not specified

Endocrine therapy

Not specified

Radiotherapy

Not specified

Surgery

Not specified

Other

No other concurrent HMG-CoAR inhibitors, including any of the following:
Atorvastatin
Fluvastatin
Lovastatin
Rosuvastatin
Simvastatin
No concurrent non-HMG-CoAR inhibitors to lower cholesterol
No concurrent use of any of the following medications:
Bezafibrate
Clofibrate
Fenofibrate
Gemfibrozil
Cholestipol
Cholestyramine resin
Colesevelam
Ezetimibe
Biphenabid
Niacin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M.D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
2	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-1024