Biomarkers in Predicting Treatment Response to Sirolimus and Combination Chemotherapy in Patients with High-Risk Acute Myeloid Leukemia

Inclusion Criteria

• Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following: * Primary refractory non-M3 AML ** Residual leukemia after a minimum of 2 prior courses of chemotherapy (same or different) ** Evidence of leukemia recurrence after a nadir bone marrow biopsy demonstrates no evidence of residual leukemia ** Evidence of leukemia after induction therapy which, in the opinion of the investigator, would be appropriate for reinduction with sirolimus/MEC therapy * Relapsed non-M3 AML * Previously untreated non-M3 AML age > 60 with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) [AML1-ETO], inversion (inv)16(p13;q22), or t(16;16)(p13;q22) [core-binding factor (CBF)beta; myosin, heavy chain (MYH)11] by cytogenetics, fluorescence in situ hybridization (FISH), or real time-polymerase chain reaction (RT-PCR) * Previously untreated secondary AML (from antecedent hematologic malignancy or following therapy with radiation or chemotherapy for another disease) with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBFbeta;MYH11] by cytogenetics, FISH, or RT-PCR
• Subjects must be >= 18 years of age
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
• Subjects must have a life expectancy of at least 4 weeks
• Subjects must be able to consume oral medication
• Subjects must have recovered from the toxic effects of any prior chemotherapy to < grade 1 (except alopecia)
• Creatinine =< 2.0 mg/dL
• Total or direct bilirubin =< 1.5 mg/dL
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN)
• Negative pregnancy test for women with child-bearing potential
• Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing
• Subjects must have a left ventricular ejection fraction (LVEF) of >= 45%

Exclusion Criteria

• Subjects with French American British (FAB) M3 (t (15; 17) (q22; q21) [promyelocytic leukemia (PML)-retinoic acid receptor (RAR) alpha]) are not eligible
• Subjects must not be receiving any chemotherapy agents (except hydroxyurea) * Intrathecal methotrexate and cytarabine are permissible
• Subjects must not be receiving growth factors, except for erythropoietin
• Subjects with a “currently active” second malignancy, other than non-melanoma skin cancers are not eligible
• Subjects with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible
• Subjects taking the following are not eligible: * Carbamazepine (e.g., Tegretol) * Rifabutin (e.g., Mycobutin) or * Rifampin (e.g., Rifadin) * Rifapentine (e.g., Priftin) * St. John's wort * Clarithromycin (e.g., Biaxin) * Cyclosporine (e.g. Neoral or Sandimmune) * Diltiazem (e.g., Cardizem) * Erythromycin (e.g., Akne-Mycin, Ery-Tab) * Itraconazole (e.g., Sporanox) * Ketoconazole (e.g., Nizoral) * Telithromycin (e.g., Ketek) * Verapamil (e.g., Calan sustained release [SR], Isoptin, Verelan) * Voriconazole (e.g., VFEND) • Tacrolimus (e.g. Prograf)
• Subjects taking fluconazole, voriconazole, itraconazole, posaconazole, and ketoconazole within 72 hours of study drug starting are not eligible; reinstitution of fluconazole, voriconazole, itraconazole, posaconazole, ketoconazole and diltiazem is permissible 72 hours after the last dose of sirolimus
• Subjects who require human immunodeficiency virus (HIV) protease inhibitors or those with acquired immune deficiency syndrome (AIDS)-related illness
• Subjects with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible
• Subjects must not have evidence of cerebellar dysfunction at baseline or during prior cytarabine therapy
• Subjects must not have received any investigational agents within 30 days of study entry
• Subjects must not be pregnant or breastfeeding; pregnancy tests must be obtained for all females of child-bearing potential; pregnant or lactating patients are ineligible for this study; males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method
• Subjects who have uncontrolled infection are not eligible; patients must have any active infections under control; fungal disease must be stable for at least 2 weeks before study entry
• Subjects with bacteremia must have documented negative blood cultures prior to study entry