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

Myelodysplastic Syndrome Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02936752
• Other study ID #: NCI-2016-01501
• Secondary ID: NCI-2016-01501HI
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: June 23, 2017
• Est. completion date: March 21, 2025

Study information

• Verified date: March 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 28
• Est. completion date: March 21, 2025
• Est. primary completion date: October 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Entinostat
Given PO

Biological:
• Pembrolizumab
Given IV

Locations

Country	Name	City	State
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Kansas Clinical Research Center	Fairway	Kansas
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Smilow Cancer Center/Yale-New Haven Hospital	New Haven	Connecticut
United States	Yale University	New Haven	Connecticut
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Nebraska Medicine-Village Pointe	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	1-year overall survival	Will be reported with a 95% confidence interval.	From start of study to death, assessed for up to 1 year
Other	2-year overall survival	Will be reported with a 95% confidence interval.	From start of study to death, assessed for up to 2 years
Other	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
Primary	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.	Up to 42 days
Secondary	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.	Up to 6 months after the last dose of entinostat in combination with pembrolizumab
Secondary	Median progression-free survival	Will be reported with a 95% confidence interval.	From start of study to progression or death, assessed for up to 6 months after the last dose of entinostat in combination with pembrolizumab