Study of Decitabine in Combination With Sequential Rapamycin or Ribavirin in High Risk AML Patients

To determine the efficacy of decitabine followed by Rapamycin in previously untreated elderly
patients not able to receive standard chemotherapy or in patients with relapsed or refractory
AML, through measurement of Complete Remission (CR), Complete Remission Incomplete Platelet
Recovery (CRp), Partial Remission (PR), and event free and overall survival (Arm A).

To determine the safety of administration of decitabine with escalating doses of Ribavirin in
elderly leukemia patients or patients with relapsed/refractory disease with M4/M5 subtypes
anticipated to express high eukaryotic translation initiation factor 4E (eIF4E) at diagnosis
(Arm B).

To establish effect of these sequential treatments on expression of phosphoinositide
3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt /mTOR) pathway proteins and
on eukaryotic translation initiation factor 4E (eIF4E) activation through Western blot and
phospho-flow methodologies.

To correlate the clinical response with baseline expression of phospho-p70S6
Kinase/phosphorylated protein kinase B (pAKT) and with the in vitro inhibitory effects of
mammalian target of rapamycin (mTOR) inhibition with rapamycin or ribavirin on the level of
downstream effectors.

To determine whether a leukemia stem cell phenotype is inhibited by the sequential
administration of decitabine/rapamycin or decitabine/ribavirin.

Inclusion Criteria:

4.1.1 Age >/= 18 4.1.2 Diagnosis of AML according to World Health Organization (WHO)
criteria except acute promyelocytic leukemia AND 4.1.3 Refractory AML defined as failure to
achieve Complete Remission (CR) after 2 cycles of induction chemotherapy or persistence of
> 40% bone marrow blasts after one cycle of chemotherapy induction OR 4.1.4 Relapsed AML
defined as any evidence of disease recurrence after achieving a documented first or greater
Complete Remission (CR) OR 4.1.5 Relapsed AML after stem cell transplantation. 90 days
(since stem cell infusion) must have elapsed between transplant and emergence of recurrent
AML OR 4.1.6 Newly diagnosed AML in a patient >65 years old not considered fit for standard
7+ 3 chemotherapy or who declines such therapy after discussion of therapeutic options
available.

4.1.7 Eastern Cooperative Oncology Group (ECOG) performance status <3

Exclusion Criteria:

4.2.1 Abnormal renal function as evidenced by a calculated creatinine clearance ≤ 30 ml/min
(Cockcroft-Gault formula (Appendix 2) 4.2.2 Abnormal liver function: Bilirubin >2.0 mg/dl,
transaminase(s) more than 2.5x the upper limits of normal 4.2.3 Active systemic infection
not responding to antibiotics 4.2.4 Known diagnosis of human immunodeficiency virus
infection (HIV) 4.2.5 Patients who are post-allogeneic transplantation should not have
active Graft vs. Host Disease (GVHD) greater than grade 1 of skin at time of enrollment.
They may have had donor lymphocyte infusion (DLI) but not within 4 weeks of beginning the
study.

4.2.6 Pregnant or breastfeeding female subjects 4.2.7 Known or suspected Central Nervous
System (CNS) leukemia involvement; past involvement is not an exclusion.