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

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ClinicalTrials.gov Identifier: NCT02936752
Recruitment Status : Recruiting
First Posted : October 18, 2016
Last Update Posted : November 15, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE October 17, 2016
First Posted Date  ICMJE October 18, 2016
Last Update Posted Date November 15, 2019
Actual Study Start Date  ICMJE April 3, 2017
Estimated Primary Completion Date June 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 30, 2019)
Maximum tolerated dose of entinostat given in combination with pembrolizumab [ Time Frame: Up to 42 days ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 17, 2016)
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 ]
Change History Complete list of historical versions of study NCT02936752 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 30, 2019)
  • Overall response rate (complete response [CR], partial response [PR], hematologic improvement [HI]) [ Time Frame: Up to 6 months after the last dose of entinostat in combination with pembrolizumab ]
    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.
  • 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 ]
    Will be reported with a 95% confidence interval.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 17, 2016)
  • 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 ]
    Will be reported with a 95% confidence interval.
  • 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 ]
    Rates of CR, PR and HI will be summarized separately by cohort and reported with an exact 95% confidence interval.
Current Other Pre-specified Outcome Measures
 (submitted: March 2, 2018)
  • Median response duration for responders [ Time Frame: Up to 6 months after the last dose of entinostat in combination with pembrolizumab ]
    Median response duration for responders will be determined.
  • Median time of progression to acute myeloid leukemia [ Time Frame: Up to 6 months after the last dose of entinostat in combination with pembrolizumab ]
    Median time of progression to acute myeloid leukemia will be determined.
  • Median overall survival [ Time Frame: From start of study to death, assessed for up to 6 months after the last dose of entinostat in combination with pembrolizumab ]
    Will be reported with a 95% confidence interval.
  • 1-year overall survival [ Time Frame: From start of study to death, assessed for up to 1 year ]
    Will be reported with a 95% confidence interval.
  • 2-year overall survival [ Time Frame: From start of study to death, assessed for up to 2 years ]
    Will be reported with a 95% confidence interval.
  • Dynamic quantitative change in proportion of myeloid-derived suppressor cells (MDSCs) in bone marrow with combined therapy, assessed by flow cytometry [ Time Frame: Baseline up to 1 year ]
    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.
Original Other Pre-specified Outcome Measures
 (submitted: October 17, 2016)
  • 1-year OS [ Time Frame: From start of study to death, assessed for up to 1 year ]
    Will be reported with a 95% confidence interval.
  • 2-year OS [ Time Frame: From start of study to death, assessed for up to 2 years ]
    Will be reported with a 95% confidence interval.
  • Dynamic quantitative change in proportion of MDSCs in BM with combined therapy, assessed by flow cytometry [ Time Frame: Baseline up to 1 year ]
    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
  • Median overall survival (OS) [ Time Frame: From start of study to death, assessed for up to 6 months after the last dose of entinostat in combination with pembrolizumab ]
    Will be reported with a 95% confidence interval.
  • Median response duration for responders [ Time Frame: Up to 6 months after the last dose of entinostat in combination with pembrolizumab ]
  • Median time of progression to AML [ Time Frame: Up to 6 months after the last dose of entinostat in combination with pembrolizumab ]
 
Descriptive Information
Brief Title  ICMJE Entinostat and Pembrolizumab in Treating Patients With Myelodysplastic Syndrome After DNMTi Therapy Failure
Official Title  ICMJE 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
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Blasts 21-30 Percent of Bone Marrow Nucleated Cells
  • Myelodysplastic Syndrome
Intervention  ICMJE
  • Drug: Entinostat
    Given PO
    Other Names:
    • HDAC inhibitor SNDX-275
    • MS 27-275
    • MS-275
    • SNDX-275
  • Biological: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475
Study Arms  ICMJE 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.
Interventions:
  • Drug: Entinostat
  • Biological: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 17, 2016)
27
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2020
Estimated Primary Completion Date June 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02936752
Other Study ID Numbers  ICMJE NCI-2016-01501
NCI-2016-01501 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HIC 2000020860
10009 ( Other Identifier: Yale University Cancer Center LAO )
10009 ( Other Identifier: CTEP )
UM1CA186689 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Amer M Zeidan Yale University Cancer Center LAO
PRS Account National Cancer Institute (NCI)
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP