Myelodysplastic Syndrome
Conditions
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.
Interventions
DRUGEntinostat
Given PO
BIOLOGICALPembrolizumab
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Entinostat Given in Combination With Pembrolizumab | 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. Presented are the counts of participants that experienced DLT in the period up to 42 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Up to 6 months after the last dose of entinostat in combination with pembrolizumab ((treatment period: Up to 3, 21-day cycles) | 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. Upon results entry- best response to combination therapy (number of patients \[%\]; response assessment after 3 cycles) is presented as counts of the best response. |
| Median Progression-free Survival | Assessed for up to 10 months after the last dose of entinostat in combination with pembrolizumab (treatment period: Up to 3, 21-day cycles) | Median progression-free survival (PFS) is being reported as the median time with the full range. The outcome was updated at the time of results entry to include the correct presentation of the data and the updated time frame for longest PFS follow up time. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 1-year Overall Survival | From start of study to death, assessed for up to 1 year | Will be reported with a 95% confidence interval. |
| Median Response Duration for Responders | Up to 6 months after the last dose of entinostat in combination with pembrolizumab | Median response duration for responders will be determined. |
| Dynamic Quantitative Change in Proportion of Myeloid-derived Suppressor Cells (MDSCs) in Bone Marrow With Combined Therapy, Assessed by Flow Cytometry | 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. |
| 2-year Overall Survival | From start of study to death, assessed for up to 2 years | Will be reported with a 95% confidence interval. |
| Median Time of Progression to Acute Myeloid Leukemia | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 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.
Entinostat: Given PO
Pembrolizumab: Given IV | 22 |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 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.
Entinostat: Given PO | 6 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Physician Decision | 4 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Total |
|---|---|---|---|
| Age, Continuous | 74 years | 71 years | 73.5 years |
| Disease acute myeloid leukemia (AML) | 3 Participants | 0 Participants | 3 Participants |
| Disease myelodysplastic syndromes/neoplasms (MDS) | 19 Participants | 6 Participants | 25 Participants |
| ECOG performance status 0 | 4 Participants | 0 Participants | 4 Participants |
| ECOG performance status 1 | 16 Participants | 3 Participants | 19 Participants |
| ECOG performance status 2 | 2 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 6 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Number prior lines of therapy | 1 prior therapy lines | 1.5 prior therapy lines | 1 prior therapy lines |
| Prior Therapy Types ≥3 lines of therapy | 3 Participants | 2 Participants | 5 Participants |
| Prior Therapy Types ASTX727 | 1 Participants | 0 Participants | 1 Participants |
| Prior Therapy Types Azacitidine | 16 Participants | 6 Participants | 22 Participants |
| Prior Therapy Types Decitabine | 8 Participants | 1 Participants | 9 Participants |
| Prior Therapy Types HMA combination | 4 Participants | 0 Participants | 4 Participants |
| Prior Therapy Types Prior allo-HCT (%) | 0 Participants | 1 Participants | 1 Participants |
| Prior Therapy Types Prior HMA | 22 Participants | 6 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 20 Participants | 5 Participants | 25 Participants |
| Region of Enrollment United States | 22 participants | 6 participants | 28 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 17 Participants | 3 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 22 | 2 / 6 |
| other Total, other adverse events | 22 / 22 | 6 / 6 |
| serious Total, serious adverse events | 12 / 22 | 5 / 6 |
Outcome results
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. Presented are the counts of participants that experienced DLT in the period up to 42 days.
Time frame: Up to 42 days
Population: 13 participants were eligible for dose escalation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Maximum Tolerated Dose of Entinostat Given in Combination With Pembrolizumab | 1 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Maximum Tolerated Dose of Entinostat Given in Combination With Pembrolizumab | 2 Participants |
Secondary
Median Progression-free Survival
Median progression-free survival (PFS) is being reported as the median time with the full range. The outcome was updated at the time of results entry to include the correct presentation of the data and the updated time frame for longest PFS follow up time.
Time frame: Assessed for up to 10 months after the last dose of entinostat in combination with pembrolizumab (treatment period: Up to 3, 21-day cycles)
Population: All participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Median Progression-free Survival | 3.45 months |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Median Progression-free Survival | 3.68 months |
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. Upon results entry- best response to combination therapy (number of patients \[%\]; response assessment after 3 cycles) is presented as counts of the best response.
Time frame: Up to 6 months after the last dose of entinostat in combination with pembrolizumab ((treatment period: Up to 3, 21-day cycles)
Population: All those enrolled.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Stable Disease (SD) | 8 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | marrow Complete response (mCR) | 2 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Partial Response (PR) | 0 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Not evaluable | 6 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Progressive Disease (PD) | 5 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Hematologic Improvement (HI) Neutrophils | 1 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 1 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Complete Response (CR) | 0 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Hematologic Improvement (HI) Neutrophils | 0 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Complete Response (CR) | 0 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Partial Response (PR) | 0 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Stable Disease (SD) | 3 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Progressive Disease (PD) | 0 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | marrow Complete response (mCR) | 0 Participants |
| Treatment (Entinostat, Pembrolizumab) Dose Level 2 | Overall Response Rate (Complete Response [CR], Partial Response [PR], Hematologic Improvement [HI]) | Not evaluable | 3 Participants |
Other Pre-specified
1-year Overall Survival
Will be reported with a 95% confidence interval.
Time frame: From start of study to death, assessed for up to 1 year
Other Pre-specified
2-year Overall Survival
Will be reported with a 95% confidence interval.
Time frame: From start of study to death, assessed for up to 2 years
Other Pre-specified
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.
Time frame: Baseline up to 1 year
Other Pre-specified
Median Overall Survival
Will be reported with a 95% confidence interval.
Time frame: From start of study to death, assessed for up to 6 months after the last dose of entinostat in combination with pembrolizumab
Other Pre-specified
Median Response Duration for Responders
Median response duration for responders will be determined.
Time frame: Up to 6 months after the last dose of entinostat in combination with pembrolizumab
Other Pre-specified
Median Time of Progression to Acute Myeloid Leukemia
Median time of progression to acute myeloid leukemia will be determined.
Time frame: Up to 6 months after the last dose of entinostat in combination with pembrolizumab