Phase II Study of 5-azacytidine Maintenance After Transplant for AML or MDS

Phase II study of 5-aza maintenance after allogeneic Hematopoietic Cell Transplantation (HCT)
for high-risk Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Early studies
indicate 5-aza is a hypomethylating agent that has shown immune modulating properties that
may enhance the graft-versus-leukemia (GVL) effect, including upregulation of
tumor-associated antigen and costimulatory molecule expression. 5-aza also has properties
that suggest protection against graft-versus-host disease (GVHD). The primary objective is to
evaluate relapse rate at one year. Secondary objectives will include the incidence of both
acute and chronic GVHD as well as relapse-free survival, overall survival and toxicity.
Correlatives will be performed to evaluate the effect of 5-aza maintenance on the immune
system.

Subjects must be transplant candidates with MDS or high risk characteristics of AML. Subjects
are consented, screened, then transplanted. Those showing complete response and no active
GVHD after transplant can proceed to maintenance with 5-aza. Bone marrow biopsies are
performed for response assessment after transplant as well as every three cycles (1 cycle=28
days) while on treatment. Dosing starts at 32mg/m2 and can be increased every 2 cycles
without a serious adverse event (SAE), or reduced per toxicity for up to 12 cycles.

Inclusion Criteria:

- Age≥18 with MDS or high-risk AML, morphologically confirmed and based on World Health
Organization criteria (see below for definition of high-risk AML)*, who are transplant
candidates with an available human leukocyte antigen (HLA) -matched sibling or
unrelated donor with at least 8/8 match

*Definition of high-risk AML:

- Age≥60 years

- Age<60 years with any of the following:

- Secondary AML

- Poor risk cytogenetics, which include abnormalities of chromosome 3, 5, or 7,
trisomy 8, 11q23 abnormalities, t(6;9), 20q-, and complex karyotype

- Fms-like tyrosine kinase 3 (FLT3) mutation

- Disease status ≥ second complete remission (CR2) at time of HCT

- Detectable disease at time of HCT

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Adequate major organ function, as defined by AST and ALT < 2 x upper limit of normal,
total serum bilirubin < 2 x upper limit of normal (unless due to hemolysis or
Gilbert's syndrome, then no upper limit), creatinine < 2 x upper limit of normal,
unless there is known chronic kidney disease (creatinine must be at baseline for
subjects with chronic kidney disease)

- In agreement to use an effective barrier method of birth control to avoid pregnancy
during the study and for a minimum of 30 days after study treatment, for all male and
female patients who are fertile

Exclusion Criteria:

- Uncontrolled, life-threatening infection that is not responding to antimicrobial
therapy

- Serum creatinine > 2 x upper limit of normal, unless there is known chronic kidney
disease (creatinine must be at baseline for subjects with chronic kidney disease),
aspartate aminotransferase (AST),alanine aminotransferase (ALT), or total bilirubin >
2x upper limit of normal

- History of psychiatric disorder which may compromise compliance with the protocol or
which does not allow for appropriate informed consent

- Patient may not be receiving any other antineoplastic agents

- Pregnancy

- Concurrent use of any other investigational agents on a clinical trial

- Prior allogeneic stem cell transplant

- Known hypersensitivity to 5-azacytidine * Prior treatment with 5-azacytidine is
allowed

Post-transplant eligibility and exclusion criteria

Patients will have to meet the following post-transplant eligibility criteria to initiate
treatment:

- In complete response (including complete remission with incomplete blood count
recovery and marrow complete response) on bone marrow biopsy for response assessment
after HCT (typically day +30)

- Patient is within 30-100 days after HCT

- Absolute neutrophil count (ANC) ≥ 1000/µL, platelet count ≥ 20,000/µL

- ECOG performance status 0-2

- Adequate major organ function, as defined by AST and ALT < 2 x upper limit of normal,
total serum bilirubin < 2 x upper limit of normal (unless due to hemolysis or
Gilbert's syndrome, then no upper limit), creatinine < 2 x upper limit of normal
unless there is known chronic kidney disease (creatinine must be at baseline for
subjects with chronic kidney disease)

- In agreement to use an effective barrier method of birth control to avoid pregnancy
during the study and for a minimum of 30 days after study treatment, for all male and
female patients who are fertile

Patients may not have any of the following post-transplant exclusion criteria:

- Active grade II-IV acute GVHD, for example requiring treatment with steroids at a dose
equivalent to prednisone 1mg/kg daily or higher

- Uncontrolled, life-threatening infection that is not responding to antimicrobial
therapy

- Serum creatinine > 2 x upper limit of normal unless there is known chronic kidney
disease (creatinine must be at baseline for subjects with chronic kidney disease),
aspartate aminotransferase (AST),alanine aminotransferase (ALT), or total bilirubin >
2x upper limit of normal

- History of psychiatric disorder which may compromise compliance with the protocol or
which does not allow for appropriate informed consent

- Pregnancy

- Concurrent use of any other investigational agents on a clinical trial

- Known hypersensitivity to 5-azacytidine * Prior treatment with 5-azacytidine is
allowed