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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 : February 27, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
Blasts 21-30 Percent of Bone Marrow Nucleated Cells Myelodysplastic Syndrome Previously Treated Myelodysplastic Syndrome Drug: Entinostat Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Phase 1

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 3, 2017
Estimated Primary Completion Date : June 30, 2019
Estimated Study Completion Date : June 30, 2019

Resource links provided by the National Library of Medicine


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 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.
Drug: Entinostat
Given PO
Other Names:
  • HDAC inhibitor SNDX-275
  • MS 27-275
  • MS-275
  • SNDX-275

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Maximum tolerated dose of entinostat given in combination with pembrolizumab, defined as the occurrence of dose limiting toxicity (DLT) among 2 dose schedules, graded according to Common Terminology Criteria for Adverse Events version 5 [ Time Frame: Up to 42 days ]
    Toxicities will be tabulated and graded according to the Common Terminology Criteria for Adverse Events version 5. DLT will be assessed after the first 2 cycles of combined therapy.


Secondary Outcome Measures :
  1. Overall response rate (complete response [CR], partial response [PR], hematologic improvement [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.

  2. 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.


Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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; 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02936752


Locations
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United States, Connecticut
Smilow Cancer Center/Yale-New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu   
Principal Investigator: Amer M. Zeidan         
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu   
Principal Investigator: Amer M. Zeidan         
United States, Illinois
University of Chicago Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Site Public Contact    773-702-8222    cancerclinicaltrials@bsd.uchicago.edu   
Principal Investigator: Olatoyosi M. Odenike         
UC Comprehensive Cancer Center at Silver Cross Recruiting
New Lenox, Illinois, United States, 60451
Contact: Site Public Contact    773-702-8222    cancerclinicaltrials@bsd.uchicago.edu   
Principal Investigator: Olatoyosi M. Odenike         
University of Chicago Medicine-Orland Park Recruiting
Orland Park, Illinois, United States, 60462
Contact: Site Public Contact    773-702-8222    cancerclinicaltrials@bsd.uchicago.edu   
Principal Investigator: Olatoyosi M. Odenike         
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Site Public Contact    859-257-3379      
Principal Investigator: Reshma Ramlal         
United States, North Carolina
UNC Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Site Public Contact    877-668-0683    cancerclinicaltrials@med.unc.edu   
Principal Investigator: Joshua F. Zeidner         
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Site Public Contact    888-275-3853      
Principal Investigator: James L. Abbruzzese         
United States, Texas
UT Southwestern/Simmons Cancer Center-Dallas Recruiting
Dallas, Texas, United States, 75390
Contact: Site Public Contact    214-648-7097    canceranswerline@UTSouthwestern.edu   
Principal Investigator: Prapti Patel         
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Site Public Contact    713-798-1354    burton@bcm.edu   
Principal Investigator: Martha P. Mims         
United States, Utah
Huntsman Cancer Institute/University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Site Public Contact    888-424-2100    cancerinfo@hci.utah.edu   
Principal Investigator: Tibor J. Kovacsovics         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Amer M Zeidan Yale University Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02936752     History of Changes
Other Study ID Numbers: 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 )
First Posted: October 18, 2016    Key Record Dates
Last Update Posted: February 27, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Entinostat
Syndrome
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Pembrolizumab
Histone Deacetylase Inhibitors
Antineoplastic Agents, Immunological
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action