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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


Phase 1
18 Years
N/A
Not Enrolling
Both
Leukemia

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Trial Information

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


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

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

Safety Issue:

No

Principal Investigator

Stephen H. Petersdorf, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center

Authority:

United States: Federal Government

Study ID:

1945.00

NCT ID:

NCT00107523

Start Date:

January 2005

Completion Date:

October 2005

Related Keywords:

  • Leukemia
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • recurrent adult acute myeloid leukemia
  • untreated adult acute myeloid leukemia
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid

Name

Location

Fred Hutchinson Cancer Research CenterSeattle, Washington  98109
M.D. Anderson Cancer Center at University of TexasHouston, Texas  77030