Entinostat and Pembrolizumab in Treating Patients With Myelodysplastic Syndrome After DNMTi Therapy Failure

PRIMARY OBJECTIVES:

I. To assess safety, tolerability, and identify the maximum tolerated dose (MTD) of
entinostat given in combination with MK-3475 (pembrolizumab).

SECONDARY OBJECTIVES:

I. To obtain a preliminary estimate of efficacy of entinostat in combination with MK-3475
(pembrolizumab).

TERTIARY OBJECTIVES:

I. To assess the dynamic quantitative change in measurable immunological biomarkers
(proportions of myeloid-derived suppressor cells [MDSCs], and programmed death protein-1
[PD-1] expression in bone marrow) with the combined epigenetic-immunotherapy and correlation
with any observed clinical responses.

OUTLINE: This is a dose-escalation study of entinostat.

Patients receive lower dose entinostat orally (PO) on days 1 and 8 or higher dose entinostat
PO on days 1, 8, and 15, and pembrolizumab intravenously (IV) over 30 minutes on day 1 of
course 2 and courses thereafter. Treatment repeats every 21 days for up to 4 courses in the
absence of disease progression or unacceptable toxicity. Patients who achieve an objective
response or maintain a stable disease (SD) status after the first 4 courses may continue to
receive entinostat and pembrolizumab for up to 1 year.

After completion of study treatment, patients are followed up monthly for 6 months.

Inclusion Criteria:

- Pathologically confirmed myelodysplastic syndrome (MDS) diagnosis (regardless of
initial International Prognostic Scoring System [IPSS] risk category) or oligoblastic
acute myeloid leukemia (AML) with 21-30% bone marrow (BM) blasts in whom DNMTi have
failed; patients who have developed AML after DNMTi therapy can be enrolled as long as
they have initiated DNMTi therapy while they were in the MDS or oligoblastic AML
(20-30% BM blasts) phase and the study chair agrees; failure of DNMTis is defined as:
failure to achieve a complete response (CR), partial response (PR) or hematologic
improvement (HI) after at least 4 cycles of DNMTi or progressed after such therapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Calculated creatinine clearance by Modification of Diet in Renal Disease (MDRD) (CrCl)
>= 60 ml/min/1.73 squared meter

- Total bilirubin =< 2.0 mg/dL unless due to Gilbert's syndrome, hemolysis, or
ineffective hematopoiesis

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
upper limit of normal (ULN)

- Females of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to start of first cycle of therapy

- 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

- Women of child-bearing potential and men who are sexually active with women of
childbearing potential must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation; should a woman become pregnant or suspect she is pregnant while
she or her partner is participating in this study, she should inform her treating
physician immediately; men who are sexually active with women of childbearing
potential, treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of entinostat and MK3475 (pembrolizumab) administration

- Ability to understand and the willingness to sign a written informed consent document

- Patients, who relapsed 6 months after bone marrow transplant and have no evidence of
active graft versus host disease and are off systemic immunosuppressant medications
for at least 2 months and have received hypomethylating agents (HMA) therapy before or
after transplant and meet other eligibility criteria of progression after at least 4
months of DNMTi therapy, are eligible to be enrolled in this clinical trial

Exclusion Criteria:

- Any patients eligible for allogeneic stem cell transplantation (allo-SCT) and willing
to undergo allo-SCT as determined at time of screening for trial; patients who are
ineligible or not interested in undergoing allo-SCT will be eligible for the trial

- Any serious medical condition, uncontrolled intercurrent illness (e.g., active
infection, symptomatic congestive heart failure [CHF], unstable angina, cardiac
arrhythmias, laboratory abnormalities, or psychiatric illness and/or biopsychosocial
conditions that may limit compliance

- Patients with known active cancers who are on therapy for those cancers at time of
screening

- Patients who are human immunodeficiency virus (HIV) positive may participate IF they
meet the following eligibility requirements:

- They must be stable on their anti-retroviral regimen, and they must be healthy
from an HIV perspective

- They must have a CD4 count of greater than 250 cells/mcL

- They must not be receiving prophylactic therapy for an opportunistic infection

- Patients with a known positive test for hepatitis B virus surface antigen (HBV sAg) or
hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic
infection might be enrolled if the viral load by polymerase chain reaction (PCR) is
undetectable with/without active treatment

- Pregnant or breast feeding females (lactating females must agree not to breast feed
while taking the study drugs)

- Use of any other experimental drug or therapy within 21 days of baseline - patients
who have had chemotherapy or radiotherapy within 4 weeks of entering the study or
those who have not recovered from adverse events due to agents administered more than
4 weeks earlier

- Known hypersensitivity to MK-3475 (pembrolizumab) or history of allergic reactions to
compounds of similar chemical or biologic composition to anti-PD1 or PD-L1 antibodies
or entinostat

- Prior treatment with any anti-PD-1 blocking therapies or histone deacetylase
inhibitors (HDACi), or anti-CTLA-4 antibody, CD137 agonist or other immune activating
therapy such as anti-CD 40 antibody within the last 3 months of enrollment in the
study

- Any history of active or severe autoimmune disease: inflammatory bowel disease,
including ulcerative colitis and Crohn's disease, rheumatoid arthritis, systemic
progressive scleroderma, systemic lupus erythematosus, autoimmune vasculitis (e.g.,
Wegener's granulomatosis), CNS or motor neuropathy considered of autoimmune origin
(e.g. Guillain-Barre syndrome, myasthenia gravis, multiple sclerosis); patients with
hypothyroidism with stable hormone replacement therapy dosing are allowed on study

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis