Clinical Trials /

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

NCT02936752

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia with Myelodysplasia-Related Changes
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Entinostat and Pembrolizumab in Treating Patients With Myelodysplastic Syndrome After DNMTi Therapy Failure
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01501
  • SECONDARY ID: NCI-2016-01501
  • SECONDARY ID: 10009
  • SECONDARY ID: 10009
  • SECONDARY ID: P30CA016359
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT02936752

Conditions

  • Previously Treated Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
EntinostatHDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275Treatment (entinostat, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (entinostat, pembrolizumab)

Purpose

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. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Giving entinostat together with pembrolizumab may work better in treating patients with myelodysplastic syndrome after DNMTi therapy failure.

Detailed Description

      PRIMARY OBJECTIVES:

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

      SECONDARY OBJECTIVES:

      I. To obtain a preliminary estimate of efficacy of entinostat in combination with
      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (entinostat, pembrolizumab)ExperimentalPatients 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 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 SD status after the first 4 courses may continue to receive entinostat and pembrolizumab for up to 1 year.
  • Entinostat

Eligibility Criteria

        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; 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) > 50 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 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 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 pembrolizumab
             administration

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

        Exclusion Criteria:

          -  Any patients eligible for allogeneic stem cell transplantation (allo-SCT) at time of
             screening for 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 known history of testing positive for human immunodeficiency virus
             (HIV) or known acquired immunodeficiency syndrome (AIDS) might be enrolled if the
             viral load by polymerase chain reaction (PCR) is undetectable with/without active
             treatment and absolute lymphocyte count >= 350/ul; 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 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 ipilimumab 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD of entinostat given in combination with pembrolizumab, defined as the occurrence of dose limiting toxicity among 2 dose schedules, graded according to Common Terminology Criteria for Adverse Events version 4
Time Frame:Up to 42 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Median progression-free survival
Time Frame:From start of study to progression or death, assessed for up to 6 months after the last dose of entinostat in combination with pembrolizumab
Safety Issue:
Description:Will be reported with a 95% confidence interval.
Measure:Overall response rate (CR, PR, HI) as defined by the modified International Working Group 2006
Time Frame:Up to 6 months after the last dose of entinostat in combination with pembrolizumab
Safety Issue:
Description:Rates of CR, PR and HI will be summarized separately by cohort and reported with an exact 95% confidence interval.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 18, 2017