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

September 20, 2010 updated by: Fred Hutchinson Cancer Center

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 Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Houston, Texas, United States, 77030-4009
        • M.D. Anderson Cancer Center at University of Texas
    • Washington
      • Seattle, Washington, United States, 98109-1024
        • Fred Hutchinson Cancer Research Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fred Hutchinson Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2005

Study Completion (ACTUAL)

October 1, 2005

Study Registration Dates

First Submitted

April 5, 2005

First Submitted That Met QC Criteria

April 5, 2005

First Posted (ESTIMATE)

April 6, 2005

Study Record Updates

Last Update Posted (ESTIMATE)

September 21, 2010

Last Update Submitted That Met QC Criteria

September 20, 2010

Last Verified

September 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1945.00
  • FHCRC-1945.00
  • MDA-2004-0185
  • CDR0000419678 (REGISTRY: PDQ)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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