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
- 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
- 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
PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study within 2 years.
Masking: Open Label, Primary Purpose: Treatment
Biological efficacy by measuring surrogate end-points, including cellular cholesterol, messenger RNAs encoding cholesterol synthesis and cholesterol import regulators, and specific protein farnesylation
Stephen H. Petersdorf, MD
Fred Hutchinson Cancer Research Center
United States: Federal Government
|Fred Hutchinson Cancer Research Center||Seattle, Washington 98109|
|M.D. Anderson Cancer Center at University of Texas||Houston, Texas 77030|