A Trial to Evaluate Two Schedules of MS275 in Combination With 5AC in Elderly Patients With Acute Myeloid Leukemia (AML)

1. To estimate the major response rate (complete and partial responses by the International
Working Group (IWG) response criteria) in patients with AML who are >= 60 years old and
unable to tolerate or decline cytotoxic chemotherapy or patients who have relapsed
despite one prior regimen and are treated with (a) 5AC 50mg/m2
subcutaneously/intravenously for 10 days on days 1 - 10 of a 28 day cycle given in
combination with entinostat 8 mg (flat dose) administered orally on days 3 and10 of each
cycle or (b) the same regimen of 5AC with entinostat given on days 10 and 17.

2. To estimate the overall response rate (complete, partial, and hematologic improvement-
major by IWG criteria) following treatment with two different dose schedules of
5-Azacytidine and entinostat in patients with AML >= 60 years old who are unable to
tolerate or decline cytotoxic chemotherapy or those who have relapsed despite one prior
regimen.

The secondary objectives of the study are:

1. To identify changes in gene promoter methylation and gene expression in response to
combination therapy with 5AC and entinostat and compare the dynamics and kinetics of
these alterations in promoter methylation and gene re-expression in the two different
dosing schedules.

2. To evaluate the effect of entinostat on the induction of hyperacetylation of histones
from peripheral blood and/or bone marrow samples.

3. To evaluate changes in DNA damage in response to combination therapy using gammaH2AX
determination by western blotting.

4. To evaluate immune parameters after exposure to 5AC and entinostat when given at either
dosing schedule and to evaluate these in relation to clinical outcomes.

5. To evaluate duration of response.

Inclusion Criteria:

1. One of the following:

Untreated AML in (de novo or treatment related) patients in the following categories:

- Medical conditions that compromise the ability to give cytotoxic chemotherapy as
the primary modality.

- Patients who decline cytotoxic chemotherapy.

Patients with AML who have relapsed despite one prior regimen

2. ECOG performance status 0, 1, or 2

3. Patients must not have untreated active infections at the time of study entry.

4. Normal organ function as defined below:

- Creatinine < 2 mg/dl.

- Total serum bilirubin within institutional limits unless due to hemolysis,
Gilbert's syndrome, or ineffective erythropoiesis.

- AST(SGOT)/ALT(SGPT) ≤2.5 X institutional upper limit of normal.

5. Life expectancy of at least three months.

6. Patients must be informed of the investigational nature of the treatment, results that
might be expected, and potential toxicities. They must be able to understand and give
informed written consent according to federal and institutional guidelines.

7. Declined or ineligible for potentially curative options such as allogeneic stem cell
transplant.

8. No chemotherapy or study drugs for >3 weeks prior to starting study.

9. Women of childbearing potential should be advised to avoid becoming pregnant and men
should be advised to not father a child while receiving treatment. All men and women
of childbearing potential must use acceptable methods of birth control throughout the
study as described below:

- Females of childbearing potential: Recommendation is for 2 effective
contraceptive methods during the study. Adequate forms of contraception are
double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with
spermicidal jelly or foam), oral, depo provera, or injectable contraceptives,
intrauterine devices, and tubal ligation.

- Male patients with female partners who are of childbearing potential:
Recommendation is for male and partner to use at least 2 effective contraceptive
methods, as described above, during the study or to abstain.

Exclusion Criteria

1. Any of the Following:

- Treatment for acute myeloid leukemia (AML), including hematopoietic growth
factors, < 3 weeks prior to study registration. Exception: Hydroxyurea may be
administered to patients with WBC > 30,000/µL

- Diagnosis of acute promyelocytic leukemia (APL)

- Radiotherapy < 4 weeks prior to study registration

- Failure to recover (to < grade 1) from all adverse events associated with prior
therapy.

- Valproic acid < 2 weeks prior to study registration.

- Hypersensitivity to azacytidine, deoxyazacytidine, mannitol, entinostat or
components of the entinostat tablet

- Any advanced malignant hepatic tumor(s)

2. Prior therapy with demethylating agents for leukemia treatment within the last four
months.

3. Clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular
coagulation, or central nervous system leukemia.

4. Serious or uncontrolled medical conditions.

5. Concurrent use of any other investigational agents.

6. Known HIV-positive patients.

7. Pregnancy or breast feeding

8. Male and female patients who are fertile who do not agree to use an effective barrier
methods of birth control (i.e. abstinence) to avoid pregnancy during the study and for
a minimum of 30 days after study treatment.