Idarubicin, Cytarabine, and Pravastatin Sodium in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

PRIMARY OBJECTIVES:

I. To assess the rate of achieving a "good complete response (CR)" after treating patients with newly diagnosed acute myeloid leukemia (AML) with idarubicin, cytarabine and pravastatin (pravastatin sodium) (IAP).

II. To determine the toxicity (death within 28 days of starting therapy = treatment related mortality or "TRM") with IAP in newly-diagnosed AML.

SECONDARY OBJECTIVES:

I. To determine rates of complete remission (CR), remission with incomplete blood count recovery (CRi), partial remission (PR), relapse-free survival and overall survival.

II. To identify biomarkers (ie. changes in serum cholesterol) associated with clinical responses.

OUTLINE:

Patients receive pravastatin sodium orally (PO) once daily (QD) on days 1-8, idarubicin intravenously (IV) over 10-15 minutes on days 4-6, and cytarabine IV continuously on days 4-7. Treatment repeats every 28-56 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then annually for 3 years.

• pravastatin sodium (Drug), also known as PRAV, Pravachol: Given PO
• idarubicin (Drug), also known as 4-demethoxydaunorubicin, 4-DMDR, DMDR, IDA: Given IV
• cytarabine (Drug), also known as ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside: Given IV
• laboratory biomarker analysis (Other): Correlative studies

Primary outcomes

• Number of Participants With Good Complete Remission (CR) [35 days]: A Bayesian design intended to simultaneously monitor efficacy and toxicity will be used. Definition of Good CR: Conventional criteria for CR (absolute neutrophil count > 1,000/uL, platelet count > 100,000/uL, marrow with <5% morphologic blasts) and additionally the requirements that marrow Minimal Residual Disease (MRD) - detected by 10-color flow cytometry or conventional cytogenetic evaluation - be absent and that the above blood counts be obtained.
• Number of Participants With TRM. [28 days]: A Bayesian design intended to simultaneously monitor efficacy and toxicity will be used. TRM: Treatment Related Mortality

Secondary outcomes

• Progression Free Survival (PFS) [1 year after treatment with IAP]
• Overall Survival [1 year after treatment with IAP]: Amount of time a patient lives after treatment with IAP
• Number of Biomarker-positive Participants With Clinical Responses [38 days after dosing]: Biomarkers: FLT3-ITD positive, NPM1 positive, CEBPA. A "good CR" is defined as <5% blasts in the marrow by morphologic evaluation along with the absence of any MRD by flow cytometry or cytogenetics and recovery of blood counts (platelets >100,00 and absolute neutrophil count >1,000) by day 35 after induction. Cheson AML Response Criteria is used for Morphologic Leukemia Free State, Morphologic Complete Remission, Cytogenetic Complete Remission (CRc), Molecular Complete Remission (CRm), Morphologic Complete Remission with Incomplete Blood Count Recovery (CRi), Partial Remission (PR), Treatment Failure, Recurrence (Progressive Disease).
• Rate of Complete Remission (CR), Remission With Incomplete Blood Count Recovery (CRi) and Partial Remission (PR) [35 days]: Complete remission (CR) - includes patients with good CR and CR with minimal residual disease (MRD); remission with incomplete blood count recovery (CRi), partial remission (PR)

Sex: All, ages: 18 Years to 74 Years

Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of acute myeloid leukemia by World Health Organization (WHO) 2008 criteria, including patients with >= 20% blasts in the bone marrow or peripheral blood (except acute promyelocytic leukemia), or myelodysplastic syndrome refractory anemia with excess blasts (RAEB)-2 by WHO classification or advanced myeloproliferative neoplasm with >= 10% blasts in the bone marrow or peripheral blood, including chronic myelomonocytic leukemia (CMML) CMML-2 by WHO 2008 classification
* Untreated AML or high-risk myelodysplastic syndrome (MDS) and a simplified TRM score of =< 9.2
* Bilirubin < 2.0 mg/ml
* Any creatinine value is acceptable
* Any performance status is eligible
* Life expectancy otherwise > 1 year
* Patients are not excluded based on cardiac history
* Females of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment
* Patients must use an effective contraceptive method during the study and for a minimum of 90 days after study treatment
* Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent

Participant flow

Outcome results

• Number of Participants With Good Complete Remission (CR) (Primary), Count of participants, Participants: Treatment (Pravastatin Sodium, Idarubicin, and Cytarabine) 12
• Number of Participants With TRM. (Primary), Number, participants: Treatment (Pravastatin Sodium, Idarubicin, and Cytarabine) 2 (1 to 27)
• Progression Free Survival (PFS) (Secondary), Number, percentage of patients with PFS: Treatment (Pravastatin Sodium, Idarubicin, and Cytarabine) 52.6 (28.7 to 71.9)
• Overall Survival (Secondary), Number, percentage of patients surviving: Treatment (Pravastatin Sodium, Idarubicin, and Cytarabine) 53.5 (32 to 71)
• Number of Biomarker-positive Participants With Clinical Responses (Secondary), Number, participants with clinical responses: Treatment (Pravastatin Sodium, Idarubicin, and Cytarabine) 0
• Rate of Complete Remission (CR), Remission With Incomplete Blood Count Recovery (CRi) and Partial Remission (PR) (Secondary), Count of participants, Participants: Treatment (Pravastatin Sodium, Idarubicin, and Cytarabine) 15

Adverse events

Serious adverse events by term

Other adverse events by term

• Mazyar Shadman, Principal investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

NIH grants: P30CA015704