Testing the Safety and Efficacy of the Combination of the Antibody Pembrolizumab and Entinostat in Patients With Myelodysplastic Syndrome Who Are Not Responding to Hypomethylating Agents

A Phase 1b Study of the Anti-PD1 Antibody Pembrolizumab in Combination With the Histone Deacetylase Inhibitor, Entinostat for Treatment of Patients With Myelodysplastic Syndromes After DNA Methyltransferase Inhibitor Therapy Failure

This phase Ib trial studies the side effects and best dose of entinostat when given together with pembrolizumab in treating patients with myelodysplastic syndrome after deoxyribonucleic acid (DNA) methyltransferase inhibitor (DNMTi) therapy failure. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving entinostat together with pembrolizumab may work better in treating patients with myelodysplastic syndrome after DNMTi therapy failure.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Entinostat; Biological: Pembrolizumab

Detailed Description

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVE:

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

EXPLORATORY OBJECTIVE:

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 cycle 2 and cycles thereafter. Treatment repeats every 21 days for up to 4 cycles 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 cycles 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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
    • New Haven, Connecticut, United States, 06510
      • Smilow Cancer Center/Yale-New Haven Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • New Lenox, Illinois, United States, 60451
      • UC Comprehensive Cancer Center at Silver Cross
    • Orland Park, Illinois, United States, 60462
      • University of Chicago Medicine-Orland Park
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas Clinical Research Center
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Cancer Center
    • Westwood, Kansas, United States, 66205
      • University of Kansas Hospital-Westwood Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky/Markey Cancer Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68118
      • Nebraska Medicine-Village Pointe
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
• The effects of entinostat and MK-3475 (pembrolizumab) on the developing human fetus are unknown; for this reason, 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

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

  • Must be on an effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • They must have a CD4 count of greater than 250 cells/mcL
  • They must not be receiving prophylactic therapy for an opportunistic infection

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Drug: Entinostat; Given PO; Other Names: HDAC inhibitor SNDX-275; MS 27-275; MS-275; SNDX-275; MS275; MS 275; SNDX 275; SNDX275; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; MK3475; SCH-900475; BCD-201; Pembrolizumab Biosimilar BCD-201; Pembrolizumab Biosimilar QL2107; QL2107; GME 751; GME751; Pembrolizumab Biosimilar GME751; MK 3475; SCH900475; Pembrolizumab Biosimilar RPH-075; RPH 075; RPH-075; RPH075

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose of Entinostat Given in Combination With Pembrolizumab	Toxicities will be tabulated and graded according to the Common Terminology Criteria for Adverse Events version 5. Dose-limiting toxicities will be assessed after the first 2 cycles of combined therapy. Presented are the counts of participants that experienced DLT in the period up to 42 days.	Up to 42 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI])	Will be defined by the modified International Working Group 2006. Rates of CR, PR and HI will be summarized separately by cohort and reported with an exact 95% confidence interval. Upon results entry- best response to combination therapy (number of patients [%]; response assessment after 3 cycles) is presented as counts of the best response.	Up to 6 months after the last dose of entinostat in combination with pembrolizumab ((treatment period: Up to 3, 21-day cycles)
Median Progression-free Survival	Median progression-free survival (PFS) is being reported as the median time with the full range. The outcome was updated at the time of results entry to include the correct presentation of the data and the updated time frame for longest PFS follow up time.	Assessed for up to 10 months after the last dose of entinostat in combination with pembrolizumab (treatment period: Up to 3, 21-day cycles)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Response Duration for Responders	Median response duration for responders will be determined.	Up to 6 months after the last dose of entinostat in combination with pembrolizumab
Median Time of Progression to Acute Myeloid Leukemia	Median time of progression to acute myeloid leukemia will be determined.	Up to 6 months after the last dose of entinostat in combination with pembrolizumab
Median Overall Survival	Will be reported with a 95% confidence interval.	From start of study to death, assessed for up to 6 months after the last dose of entinostat in combination with pembrolizumab
1-year Overall Survival	Will be reported with a 95% confidence interval.	From start of study to death, assessed for up to 1 year
2-year Overall Survival	Will be reported with a 95% confidence interval.	From start of study to death, assessed for up to 2 years
Dynamic Quantitative Change in Proportion of Myeloid-derived Suppressor Cells (MDSCs) in Bone Marrow With Combined Therapy, Assessed by Flow Cytometry	Will correlate with any observed clinical responses. Will be estimated using mixed effects models to take into account the within-patient correlation. Likelihood ratio tests will be performed to confirm if random intercepts and slopes are necessary in the model. The fixed effect for change in MDSCs over time will be evaluated for significance. The variability in the rate of change in MDSCs across patients will also be examined. The association between the clinical outcome and a meaningful reduction in MDSCs, which will be defined after a review of the data, will be assessed with the chi-square test. The quantity of MDSCs at baseline and during treatment as continuous variables can also be compared between responding and non-responding patients using a t-test or Mann-Whitney U-Test, if more appropriate.	Baseline up to 1 year

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Amer M Zeidan, Yale University Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2017
• Primary Completion (Actual): November 4, 2022
• Study Completion (Actual): February 12, 2025

Study Registration Dates

• First Submitted: October 17, 2016
• First Submitted That Met QC Criteria: October 17, 2016
• First Posted (Estimated): October 18, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 11, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Hematologic Diseases; Precancerous Conditions; Bone Marrow Diseases; Syndrome; Preleukemia; Myelodysplastic Syndromes; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Pembrolizumab; Entinostat; Histone Deacetylase Inhibitors
• Other Study ID Numbers: NCI-2016-01501 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186689 (U.S. NIH Grant/Contract); HIC 2000020860; 10009 (CTEP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No