• Incidence of adverse events [ Time Frame: Up to 2 years ]
  Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
• Maximum-tolerated dose (MTD) [ Time Frame: Up to day 42 ]
  Will be based on the assessment of dose-limiting toxicities (DLTs) during cycle 1 and NCI CTCAE version 5.0. Standard 3+3 design rules will govern enrollment and dose de-escalation. In each arm, the dose level that produces =< 1/6 DLTs will be declared the MTD.
• Response to treatment [ Time Frame: Up to 2 years ]
  Will obtain preliminary estimates of complete remission (CR)+CR with incomplete hematologic recovery (CRi). Patients will have their response classified according to modified Cheson, 2006 criteria (myelodysplastic syndrome cohort) and Dohner et al., 2017 criteria (acute myeloid leukemia cohort). Rates and 95% Clopper-Pearson binomial confidence interval will be calculated for the complete remission rate (patients that have confirmed CR/CRi). Response rates will also be explored based on number/type of prior therapy(ies).

• Response duration [ Time Frame: From date of first documented response (CR + CRi) to documented disease relapse or death whichever occurs first, assessed up to 2 years ]
  Will be estimated using the product-limit method of Kaplan and Meier.
• Overall survival [ Time Frame: From date of first dose of study drug to date of death from any cause, assessed up to 2 years ]
  Will be estimated using the product-limit method of Kaplan and Meier.
• Progression-free survival [ Time Frame: From date of first dose of study drug to first documented disease relapse/progression or death from any cause, whichever occurs first, assessed up to 2 years ]
  Will be estimated using the product-limit method of Kaplan and Meier.
• Change in PD-1, PD-L1, and PD-L2 levels [ Time Frame: Baseline up to 2 years ]
• Change in T cell subset distribution [ Time Frame: Baseline up to 2 years ]
• Change in T cell receptor repertoire [ Time Frame: Baseline up to 2 years ]

PRIMARY OBJECTIVES:

I. Assess the safety and tolerability of pembrolizumab in combination with decitabine, by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration.

II. Determine the maximum tolerated dose(s)/schedule (MTD) and phase 2 recommended dose(s)/ schedule (RP2D) of the combination for acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

III. Obtain preliminary estimate of complete remission (CR/CR with incomplete hematologic recovery [CRi]) rate.

SECONDARY OBJECTIVES:

I. Obtain estimates of remission duration and survival probabilities (overall and progression-free) at 2 years.

II. Explore the possible association between pre-treatment PD-1, PD-L1, and PD-L2 and clinical response.

III. Evaluate change in PD-1, PD-L1, PD-L2 levels as a result of the combination therapy.

IV. Explore the possible association between specific T cell subsets (e.g. CD4 T regulatory cells, T naive, effector and memory cells), other immunological correlatives (e.g. T-cell receptor [TCR] repertoire analysis) including post-treatment changes, and clinical response to combination therapy.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT I: Patients with AML receive pembrolizumab intravenously (IV) over 30 minutes on days 1 and 22 and decitabine IV over 1 hour on days 1-10. Patients who achieve a CR receive decitabine on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.

COHORT II: Patients with MDS receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine over 1 hour on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, then every 3 and 6 months for up to 2 years.

• Acute Myeloid Leukemia
• High Risk Myelodysplastic Syndrome
• Recurrent Acute Myeloid Leukemia
• Recurrent High Risk Myelodysplastic Syndrome
• Refractory Acute Myeloid Leukemia
• Refractory High Risk Myelodysplastic Syndrome
• Secondary Acute Myeloid Leukemia
• Therapy-Related Acute Myeloid Leukemia

• Drug: Decitabine
  Given IV
  Other Names:

  • 5-Aza-2'-deoxycytidine
  • Aza-TdC
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine
• Biological: Pembrolizumab
  Given IV
  Other Names:

  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

• Experimental: Cohort I (pembrolizumab, decitabine)
  Patients with AML receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine IV over 1 hour on days 1-10. Patients who achieve a CR receive decitabine on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Decitabine
  • Biological: Pembrolizumab
• Experimental: Cohort II (pembrolizumab, decitabine)
  Patients with MDS receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine over 1 hour on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Decitabine
  • Biological: Pembrolizumab

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative
• Agreement to allow the use of archival blood samples and marrow from diagnostic tumor biopsies. If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Eastern Cooperative Oncology Group (ECOG) status of 0-1
• Histologically confirmed AML or MDS with the following characteristics

• Patients diagnosed with AML by World Health Organization (WHO) classification, meeting one of following criteria:

  • Age 60 or older, newly diagnosed, untreated, who are unwilling to undergo or not candidates for conventional induction chemotherapy with cytarabine/anthracyclines
  • Age 60 or older with relapsed or refractory disease
  • Adult patients < 60 with previously untreated high-risk disease (complex karyotype, inv(3) or t(3;3), t(6;9), monosomal karyotype, therapy-related and secondary disease) that are unwilling to undergo or not candidates for conventional induction chemotherapy with cytarabine/anthracyclines and/or allogeneic stem cell transplantation
  • Adult patients < 60 with refractory/relapsed AML who are otherwise not candidates for allogeneic stem cell transplantation
  • Patients with extramedullary disease who meet one of the above criteria may be included

• Patients with a diagnosis of MDS as per WHO Classification that meets one of the following treatment history criteria

  • Newly diagnosed high-risk MDS (International Prognostic Scoring System [IPSS]: intermediate 2 and high risk)
  • Refractory to or relapsed after previous therapies
  • Human leukocyte antigen (HLA)-DR15-positive MDS that has failed immunosuppressive therapies
• Must have a life expectancy of >= 3 months
• Fully recovered (=< grade 1) from the acute toxic effects (except alopecia) of prior anti-cancer therapy
• Cannot be a candidate for allogeneic hematopoietic cell transplantation (alloHCT) within 90 days of starting treatment on the protocol and should be off pembrolizumab for at least 30 days to become eligible for alloHCT post-protocol therapy
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless has Gilbert?s disease)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN or =< 5 x ULN
• Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN
• Left ventricular ejection fraction (LVEF) >= 50%
• Corrected QT (QTc) =< 480 ms, Note: electrocardiogram (ECG) to be performed within 14 days prior to day 1 of protocol therapy

• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin [RPR]) (within 28 days prior to day 1 of protocol therapy)

  • If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

• Meets other institutional and federal requirements for infectious disease titer requirements

  • Note: Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

• Agreement by males and females of childbearing potential to use an effective birth control method of low user dependency or abstain from heterosexual activity from 4 weeks prior to first dose of treatment throughout the study treatment period and 3 (males) to 4 (females) months from the last dose of treatment

  • Childbearing potential is defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
• Also, male subjects should refrain from sperm donation from the start of treatment throughout the study treatment period and for 6 months following the last dose of treatment

Exclusion Criteria:

• Previous allogeneic cell transplantation for at least 1 year (yr) prior, have no history of graft versus host disease (GVHD) and been off all immunosuppression for at least 3 months
• Previous treatment with pembrolizumab
• Systemic steroid therapy or any other form of immunosuppressive medication
• Received a live-virus vaccination within 30 days of planned treatment start
• Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD ligand-1 (PD-L1) or PD ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms
• Prior therapy with an anti-CD137, anti-CTLA-4 antibody (including ipilimumab), denosumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Current or planned use of other investigational agents, or concurrent biological, chemotherapy, or radiation therapy during the study treatment period, or within 4 weeks prior to day 1 of protocol therapy
• Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 4 weeks prior to day 1 of protocol therapy
• Concurrent use of corticosteroids (exception: nasal or topical corticosteroids or physiologic levels for steroid replacement are allowed)
• Concurrent use of granulocyte-macrophage colony-stimulating factor (GMCSF) or granulocyte colony stimulating factor (GCSF), or within 7 days prior to start of study treatment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
• Active central nervous system (CNS) disease
• History of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed)
• Uncontrolled active infection requiring therapy

• Seronegative for HIV Ag/Ab combo, HCV, active HBV (surface antigen negative), and syphilis (RPR).

  • If positive, hepatitis C RNA quantitation must be performed
• Known history of active TB (Bacillus tuberculosis)
• History of deep venous thrombosis (DVT) or pulmonary embolism
• Symptomatic ascites or pleural effusion
• Clinically significant uncontrolled illness
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the investigator?s judgment, contraindicate the patient?s participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)