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

NCT ID: NCT02936752

Last Updated: 2025-03-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-23
• Study Completion Date: 2025-02-12

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.

Conditions

Myelodysplastic Syndrome

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Entinostat

Intervention Type: DRUG

Given PO

Pembrolizumab

Intervention Type: BIOLOGICAL

Given IV

Interventions

Entinostat

Given PO

Intervention Type: DRUG

Pembrolizumab

Given IV

Intervention Type: BIOLOGICAL

Other Intervention Names

HDAC inhibitor SNDX-275; MS 27-275; MS 275; MS-275; MS275; SNDX 275; SNDX-275; SNDX275; BCD-201; GME 751; GME751; Keytruda; Lambrolizumab; MK 3475; MK-3475; MK3475; Pembrolizumab Biosimilar BCD-201; Pembrolizumab Biosimilar GME751; Pembrolizumab Biosimilar QL2107; Pembrolizumab Biosimilar RPH-075; QL2107; RPH 075; RPH-075; RPH075; SCH 900475; SCH-900475; SCH900475

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; 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Amer M Zeidan

Role: PRINCIPAL_INVESTIGATOR

Yale University Cancer Center LAO

Locations

Smilow Cancer Center/Yale-New Haven Hospital

New Haven, Connecticut, United States

Yale University

New Haven, Connecticut, United States

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, United States

Northwestern University

Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States

UC Comprehensive Cancer Center at Silver Cross

New Lenox, Illinois, United States

University of Chicago Medicine-Orland Park

Orland Park, Illinois, United States

University of Kansas Clinical Research Center

Fairway, Kansas, United States

University of Kansas Cancer Center

Kansas City, Kansas, United States

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas, United States

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, United States

Nebraska Medicine-Village Pointe

Omaha, Nebraska, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center

Lebanon, New Hampshire, United States

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, United States

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, United States

Countries

United States

References

Bewersdorf JP, Shallis RM, Sharon E, Park S, Ramaswamy R, Roe CE, Irish JM, Caldwell A, Wei W, Yacoub A, Madanat YF, Zeidner JF, Altman JK, Odenike O, Yerrabothala S, Kovacsovics T, Podoltsev NA, Halene S, Little RF, Piekarz R, Gore SD, Kim TK, Zeidan AM. A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents. Ann Hematol. 2024 Jan;103(1):105-116. doi: 10.1007/s00277-023-05552-4. Epub 2023 Dec 1.

Reference Type: DERIVED

PMID: 38036712 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2016-01501

Identifier Type: REGISTRY

Identifier Source: secondary_id

HIC 2000020860

Identifier Type: -

Identifier Source: secondary_id

10009

Identifier Type: OTHER

Identifier Source: secondary_id

10009

Identifier Type: OTHER

Identifier Source: secondary_id

UM1CA186689

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2016-01501

Identifier Type: -

Identifier Source: org_study_id