Sirolimus, Idarubicin, and Cytarabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

1) To determine whether there is an association between baseline mammalian target of
rapamycin (mTOR) activation paired with mTOR target inhibition post-treatment in leukemic
blasts and clinical response in patients with newly diagnosed acute myeloid leukemia (AML)
treated with sirolimus idarubicin/cytarabine.

SECONDARY OBJECTIVES:

1. To estimate the response rate of sirolimus idarubicin/cytarabine in patients with newly
diagnosed AML compared to historical data using idarubicin/cytarabine alone.

2. To determine the ability of oral sirolimus to inhibit mTOR in leukemic blasts.

3. To assess if mTOR pathway inhibition correlates with clinical response.

4. To collect further information on the safety, tolerability, and efficacy of sirolimus in
combination with idarubicin/cytarabine in patients with newly diagnosed AML.

5. To describe the progression-free survival and overall survival (1 year, 2 year and 5
year) of patients treated with sirolimus idarubicin/cytarabine.

OUTLINE:

Patients receive sirolimus orally (PO) once daily (QD) on days 1-10, idarubicin intravenously
(IV) over 3-5 minutes on days 4-6, and cytarabine IV continuously over 24 hours on days 4-10.

After completion of study treatment, patients are followed up every 3 months for 5 years.

Inclusion Criteria:

1. Patients must have histologic evidence of newly diagnosed acute myeloid leukemia
(non-M3 AML) as documented by the presence of >20% myeloid blasts in the bone marrow

2. Subjects must be 18 years of age and <= 60

3. Subjects must have an ECOG performance status of 2 or less. (see attachment 1).

4. Subjects must have a life expectancy of at least 4 weeks.

5. Subjects must be able to consume oral medication.

6. Required initial laboratory values: Creatinine 2.0mg/dL; total or direct bilirubin
1.5mg/dL; SGPT(ALT) 3xULN (if not due to the leukemia itself); negative pregnancy test
for women with child-bearing potential.

7. Patients must be able to sign consent and be willing and able to comply with scheduled
visits, treatment plan and laboratory testing.

8. Subjects must have a left ventricular ejection fraction (LVEF) of >/= 45%.

Exclusion Criteria:

1. Subjects with APL - FAB M3 (t(15;17)(q22;q21)[PML-RAR] are not eligible

2. Subjects must not have received any chemotherapeutic agents for the AML (except
Hydroxyurea). Intrathecal ARA-C and intrathecal methotrexate are permissible (as they
are not systemic and only isolated to the central nervous system).

3. Subjects must not be receiving growth factors, except for erythropoietin.

4. Subjects with a "currently active" second malignancy, other than non-melanoma skin
cancers are not eligible.

5. 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.

6. Subjects taking the following are not eligible:

1. Carbamazepine (e.g., Tegretol)

2. Rifabutin (e.g., Mycobutin)

3. Rifampin (e.g., Rifadin)

4. Rifapentine (e.g., Priftin)

5. St. John's wort

6. Clarithromycin (e.g., Biaxin)

7. Cyclosporine (e.g. Neoral or Sandimmune)

8. Diltiazem (e.g., Cardizem)

9. Erythromycin (e.g., Akne-Mycin, Ery-Tab)

10. Itraconazole (e.g., Sporanox)

11. Ketoconazole (e.g., Nizoral)

12. Telithromycin (e.g., Ketek)

13. Verapamil (e.g., Calan SR, Isoptin, Verelan)

14. Voriconazole (e.g., VFEND)

15. Tacrolimus (e.g. Prograf)

7. Subjects taking fluconazole, voriconazole, itraconazole, posaconazole, and
ketoconazole within 72 hours of study entry are not eligible. Reinstitution of
fluconazole, voriconazole, itraconazole, posaconazole, ketoconazole and diltiazem is
permissible 72 hours after the last dose of sirolimus.

8. Subjects who require HIV protease inhibitors or those with AIDS-related illness

9. 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.

10. 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 due to the unknown human fetal or teratogenic toxicities of sirolimus.
Males or females of reproductive age may not participate unless they have agreed to
use an effective contraceptive method.

11. 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.

12. Subjects with bacteremia must have documented negative blood cultures prior to study
entry.