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”

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.

Study Type: Interventional

Study Design: Treatment, Open Label

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.

Intervention(s) in this Clinical Trial

• Drug: cytarabine
• Drug: idarubicin
• Drug: pravastatin

Primary Measures

• Biological efficacy by measuring surrogate end-points, including cellular cholesterol, messenger RNAs encoding cholesterol synthesis and cholesterol import regulators, and specific protein farnesylation
  • Safety Issue?: No
• Leukemia cell apoptosis
  • Safety Issue?: No
• Maximum tolerated dose (MTD) of pravastatin
  • Safety Issue?: Yes
• Maximal biological effect on cholesterol metabolism achieved with or without the MTD of pravastatin
  • Safety Issue?: Yes

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Fred Hutchinson Cancer Research Center

Overall Clinical Trial Officials and Contacts

Stephen H. Petersdorf, MD Principal Investigator Fred Hutchinson Cancer Research Center  

Information obtained from ClinicalTrials.gov on October 06, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00107523

Study ID Number: CDR0000419678

ClinicalTrials.gov Identifier: NCT00107523

Health Authority: United States: Federal Government

Clinical trial summary from the National Cancer Institute's PDQ® database