Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To estimate the overall response rate (complete, partial, and hematologic
improvement-major by International Working Group [IWG] criteria) in response to azacitidine
and entinostat.

II. To estimate the major response rate (complete and partial responses by the IWG response
criteria) to a 10-day regimen of azacitidine and to the same regimen of azacitidine in
combination with entinostat administered orally on days 3 and 10 of each cycle in patients
with de novo myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMMoL)
(dysplastic) and acute myeloid leukemia with trilineage dysplasia (AML-TLD), as well as in
patients with treatment-induced MDS, CMMoL (dysplastic) and AML-TLD.

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of azacitidine and entinostat in this patient population.

II. To identify changes in gene promoter methylation and gene expression which may be
associated with response to azacitidine and entinostat.

III. To identify other molecular mechanisms (such as deoxyribonucleic acid [DNA] damage)
which may be associated with response to azacitidine and entinostat.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive azacitidine subcutaneously (SC) once daily (QD) on days 1-10.

ARM B: Patients receive azacitidine as in Arm A and entinostat orally (PO) on days 3 and 10.

In both arms, treatment repeats every 28 days for 6-24 courses in the absence of disease
progression or unacceptable toxicity.

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

Inclusion Criteria:

- The following diagnoses will be eligible for this study:

- Myelodysplastic syndromes: the diagnosis of MDS must be confirmed by a bone marrow
aspirate and/or biopsy within two weeks prior to registration; NOTE: blast count must
be < 20%; patients with any International Prognostic Score (IPSS) are eligible;
patients with low or intermediate (INT)-1 IPSS must have a platelet count <
50,000/mm^3 and/or absolute neutrophil count (ANC) < 500/mm^3 within seven days prior
to registration

- Chronic myelomonocytic leukemia (dysplastic subtype): the diagnosis of CMMoL must be
confirmed by a bone marrow aspirate and/or biopsy within two weeks prior to
registration; patients with CMMoL must have a WBC < 12,000/mm^3, documented within 4
weeks prior to study entry (two sets of counts that are 2 weeks apart will be taken)

- Acute myeloid leukemia with multilineage dysplasia: the diagnosis of AML-TLD must be
confirmed by a bone marrow aspirate and/or biopsy within two weeks prior to
registration; NOTE: there must be evidence of >= 20% blasts on the review of the bone
marrow aspirate and/or biopsy; AML-TLD will be interpreted to include patients
formerly diagnosed by French-American-British (FAB) criteria as refractory anemia
with excess blasts in transformation (RAEB-t), as well as patients with no history of
antecedent hematologic disorder who have AML which meets criteria for AML-TLD by
World Health Organization (WHO) criteria; patients with AML-TLD must have a white
blood cell (WBC) =< 30,000/mm^3 documented within 4 weeks prior to study entry (two
sets of counts that are 2 weeks apart will be taken); patients whose WBC has doubled
within this period of time and is greater than 20,000/mm^3 at the time of screening
will not be eligible

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood test or urine study within two weeks prior to registration to rule
out pregnancy

- Women of childbearing potential and sexually active males must be strongly advised to
use an accepted and effective method of contraception

- Patient must have Eastern Cooperative Oncology Group (ECOG) performance status
between 0-2

- Patient must have no prior treatment with azacitidine, decitabine or entinostat

- Patients must not have active infections at the time of registration

- Serum creatinine < 2.0 mg/dL; test must be done within seven days prior to
registration

- Total serum bilirubin within institutional limits unless due to intra- or
extramedullary hemolysis or Gilbert's syndrome; test must be done within seven days
prior to registration

- Aspartate transaminase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional upper limit of normal (ULN); tests must be done within seven days prior
to registration

- Patients must not have received any AML induction chemotherapy or stem cell
transplantation; any other treatment for their disease, including hematopoietic
growth factors may not be given, within three weeks prior to registration, and should
have recovered from all toxicities of prior therapy (to grade 0 or 1)

- Patients must have no clinical evidence of central nervous system (CNS) or pulmonary
leukostasis, disseminated intravascular coagulation, or CNS leukemia

- Patients must have no serious or uncontrolled medical conditions

- Patients who have therapy-induced MDS, CMMoL (dysplastic) and AML-TLD are eligible
and will be treated as separate cohorts from the patients with de novo MDS, CMMoL
(dysplastic) and AML-TLD

- Patients should have a life expectancy of at least six months

- Patients must not have advanced malignant hepatic tumors

- Patients must not have a known hypersensitivity to azacitidine or mannitol

- Southwest Oncology Group (SWOG) ONLY: all SWOG patients must be registered on
SWOG-9007 ("Cytogenetic Studies in Leukemia Patients"); collection of the
pretreatment bone marrow specimen (or of peripheral blood if the marrow is not
aspirable) must be completed within 28 days before registration; the pretreatment
specimen must be submitted to a SWOG-approved cytogenetics laboratory as described in
protocol SWOG-9007; note that submission of bone marrow cytogenetic studies are
required to calculate the IPSS score (stratification issue); in addition, cytogenetic
response will be measured at follow-up requiring a second cytogenetic study at the
end of protocol treatment; NOTE: In addition to SWOG-9007, SWOG patients must be
offered participation in S9910, the leukemia centralized reference laboratories and
tissue repositories ancillary study; If consent is given, collection of pretreatment
blood and/or marrow specimens must be completed within 14 days prior to registration.
If the patient consents to participate in S9910, pretreatment specimens of marrow
and/or peripheral blood must be submitted to the Southwest Oncology Group Myeloid
Repository at the University of New Mexico for cellular and molecular studies; S9910
also requests submission of remission and relapse specimens