A Study of Bomedemstat (IMG-7289/MK-3543) With and Without ATRA, in Participants With Advanced Myeloid Malignancies (IMG-7289-CTP-101/MK-3543-001)

A Study of Bomedemstat (IMG-7289/MK-3543) With and Without ATRA, in Participants With Advanced Myeloid Malignancies (IMG-7289-CTP-101/MK-3543-001)

A Multi-Center, Open Label Study to Assess the Safety, Steady-State Pharmacokinetics and Pharmacodynamics of IMG-7289 With and Without ATRA (Tretinoin) in Patients With Advanced Myeloid Malignancies

This is an open label study of the dose and duration of an orally administered lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat, in patients with high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Some participants may also receive all-trans retinoic acid (ATRA; also known as tretinoin and Vesanoid®) in combination with bomedemstat. This study investigates the following: The safety and tolerability of bomedemstat with and without ATRA The pharmacodynamic effect of different doses of bomedemstat and treatment durations, as well as bomedemstat administered in combination with ATRA The pharmacokinetics of bomedemstat with and without ATRA

Participants receive bomedemstat 0.75 mg/kg/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment).

Participants receive bomedemstat 1.5 mg/kg/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment).

Participants receive bomedemstat 3 mg/kg/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment).

Participants receive bomedemstat 6 mg/kg/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment).

Participants receive bomedemstat 3 mg/kg/day orally plus tretinoin 45 mg/m^2/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment).

Participants receive bomedemstat 6 mg/kg/day orally plus tretinoin 45 mg/m^2/day orally in 14-day cycles consisting of 7 days of treatment and 7 days of rest. Participants will receive up to 4 cycles (14-day cycles) for up to a total of up 56 days (28 days on treatment).

Participants receive bomedemstat 6 mg/kg/day orally plus tretinoin 45 mg/m^2/day orally in 21-day cycles consisting of 14 days of treatment and 7 days of rest. Participants will receive up to 2 cycles (21-day cycles) for up to a total of up 42 days (28 days on treatment).

Participants receive bomedemstat 6 mg/kg/day orally for 21 days plus tretinoin 45 mg/m^2/day orally in 28-day cycles consisting of 21 days of treatment and 7 days of rest. Participants will receive at least 1 cycle (28-day cycles) and will receive subsequent cycles at the discretion of the investigator.

An AE was defined as any undesirable physical, psychological, or behavioral effect experienced by a participant during participation in an investigational study, in conjunction with the use of the drug or biologic, whether or not related to the study drug. This included any untoward signs or symptoms experienced by the participant from the time of first dose until completion of the study. The number of participants who experienced an AE is presented.

An SAE was defined as any adverse event, whether or not related to the study drug, that resulted in any of the following outcomes: Death Life-threatening experience Required or prolonged inpatient hospitalization Persistent or significant disability/incapacity Congenital anomaly Important medical events that, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above. The number of participants who experienced an SAE is presented.

An AE was defined as any undesirable physical, psychological, or behavioral effect experienced by a participant during participation in an investigational study, in conjunction with the use of the drug or biologic, whether or not related to the study drug. This included any untoward signs or symptoms experienced by the participant from the time of first dose until completion of the study. The number of participants who discontinued study treatment due to an AE is presented.

DLTs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. A DLT was defined as any of the following events that occurs during the DLT evaluation period and is considered by the Investigator possibly, probably, or definitely related to bomedemstat: A clinically significant bleeding event Any Grade 4 or 5 non-haematologic adverse event Any Grade 3 non-haematologic adverse event with failure to recover to Grade 1 within 7 days of drug cessation, with the following exceptions: ≥ Grade 3 nausea, vomiting or diarrhoea that responds to standard medical care and ≥ Grade 3 aesthenia lasting less than 14 days Any Grade 3 electrolyte abnormality unrelated to the underlying malignancy and persisting greater than 24 hours. Per protocol, DLTs were measured during the first 28-day treatment period. The number of participants who experienced a DLT is presented.

Number of Participants Experiencing Any Grade 3 to 5 Adverse Events (AE) as Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03

AEs were graded for severity on a scale of 1 to 5 using CTCAE criteria. Grade 1=mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2=moderate, minimal, local, or noninvasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3=severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care. Grade 4=life-threatening consequences with urgent intervention indicated. Grade 5 =death related to AE. The number of participants who experienced any Grade 3 to 5 AE is reported.

Medical Events of Interest (MEOI) were adverse events that did not meet any criteria for a serious adverse event but were of particular interest in the context of the study. MEOIs included bleeding due to low platelets; electrocardiogram (ECG) QT corrected interval prolonged 481-500 milliseconds; and infection where, at a minimum, oral antibiotic, antifungal, or antiviral intervention is indicated. The number of participants with MEOIs is presented.

Cmax was defined as the maximum concentration of bomedemstat observed after administration of bomedemstat alone or administered with tretinoin. Plasma samples were collected at multiple time points to estimate the CMax of bomedemstat using non-compartmental methods of analysis following oral dosing of participants in Cycle 1 (Cycle 1 = 7 days of treatment and 7 days of rest for a total of 14 days). Unbound plasma concentrations of bomedemstat were estimated by assuming that protein binding was 60.57%. For the pharmacokinetic analysis, plasma concentrations below the assay limit of quantitation (LOQ) that occurred from predose to the first concentration ≥LOQ were treated as 0 and those that occured thereafter were treated as missing. The LOQ of the assay was 1 ng/mL. Per protocol, the Cmax was determined for participants in Cohort 1. The LOQ of the assay was 1 ng/mL. The Cmax of bomedemstat in unbound plasma is presented.

Cycle 1 Day 1: predose and 1, 2, 3, and 24 hours postdose; Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose

Tmax was the time required to reach the maximum concentration of bomedemstat observed after administration of bomedemstat alone or administered with tretinoin. Plasma samples were collected at multiple time points to estimate the TMax of bomedemstat using non-compartmental methods of analysis following oral dosing of participants in Cycle 1 (Cycle 1 = 7 days of treatment and 7 days of rest for a total of 14 days). For the pharmacokinetic analysis, plasma concentrations below the assay limit of quantitation (LOQ) that occurred from predose to the first concentration ≥LOQ were treated as 0 and those that occured thereafter were treated as missing. The LOQ of the assay was 1 ng/mL. Per protocol, the Tmax was determined for participants in Cohort 1. The Tmax of bomedemstat in plasma is presented.

Cycle 1 Day 1: predose and 1, 2, 3, and 24 hours postdose; Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose

Area Under the Concentration Time Curve From Time 0 to 24 Hours (AUC0-24hr) Postdose of Bomedemstat Alone or Administered With Tretinoin

AUC0-24hr was defined as the total exposure of bomedemstat over 24 hours after administration of bomedemstat alone or administered with tretinoin. Plasma samples were collected at multiple time points to estimate the AUC 0-24hr of bomedemstat using non-compartmental methods of analysis following oral dosing of participants in Cycle 1 (Cycle 1 = 7 days of treatment and 7 days of rest for a total of 14 days). Unbound plasma concentrations of bomedemstat were estimated by assuming that protein binding was 60.57%. For the pharmacokinetic analysis, plasma concentrations below the assay limit of quantitation (LOQ) that occurred from predose to the first concentration ≥LOQ were treated as 0 and those that occured thereafter were treated as missing. The LOQ of the assay was 1 ng/mL. Per protocol, the AUC 0-24hr was determined for participants in Cohort 1. The AUC 0-24hr of bomedemstat in unbound plasma is presented.

Cycle 1 Day 1: predose and 1, 2, 3, and 24 hours postdose; Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose

t1/2 was the time required to divide the bomedemstat concentration by two after reaching pseudo-equilibrium after administration of bomedemstat alone or administered with tretinoin. Plasma samples were collected at multiple time points to estimate the t1/2 of bomedemstat using non-compartmental methods of analysis following oral dosing of participants in Cycle 1 (Cycle 1 = 7 days of treatment and 7 days of rest for a total of 14 days). For the pharmacokinetic analysis, plasma concentrations below the assay limit of quantitation (LOQ) that occurred from predose to the first concentration ≥LOQ were treated as 0 and those that occured thereafter were treated as missing. The LOQ of the assay was 1 ng/mL. Per protocol, the t1/2 was determined for participants in Cohort 1. The t1/2 of bomedemstat in plasma is presented.

CL/F was the volume of plasma from which bomedemstat was eliminated per unit of time after administration of bomedemstat alone or administered with tretinoin. Plasma samples were collected at multiple time points to estimate the CL/F of bomedemstat using non-compartmental methods of analysis following oral dosing of participants in Cycle 1 (Cycle 1 = 7 days of treatment and 7 days of rest for a total of 14 days). For the pharmacokinetic analysis, plasma concentrations below the assay limit of quantitation (LOQ) that occurred from predose to the first concentration ≥LOQ were treated as 0 and those that occured thereafter were treated as missing. The LOQ of the assay was 1 ng/mL. Per protocol, the CL/F was determined for participants in Cohort 1. The CL/F of bomedemstat in plasma is presented.

Vz/F was the volume of distribution of bomedemstat during the terminal phase after administration of bomedemstat alone or administered with tretinoin. Plasma samples were collected at multiple time points to estimate the Vz/F of bomedemstat using non-compartmental methods of analysis following oral dosing of participants in Cycle 1 (Cycle 1 = 7 days of treatment and 7 days of rest for a total of 14 days). For the pharmacokinetic analysis, plasma concentrations below the assay limit of quantitation (LOQ) that occurred from predose to the first concentration ≥LOQ were treated as 0 and those that occured thereafter were treated as missing. The LOQ of the assay was 1 ng/mL. Per protocol, the Vz/F was determined for participants in Cohort 1. The Vz/F of bomedemstat in plasma is presented.

kel was the rate at which bomedemstat was removed from the body by excretion or metabolism after administration of bomedemstat alone or administered with tretinoin. Plasma samples were collected at multiple time points to estimate the kel of bomedemstat using non-compartmental methods of analysis following oral dosing of participants in Cycle 1 (Cycle 1 = 7 days of treatment and 7 days of rest for a total of 14 days). kel was obtained from the slope of the line, fitted by linear least squares regression, through the terminal points of the log (base e) concentration-time profiles. For the pharmacokinetic analysis, plasma concentrations below the assay limit of quantitation (LOQ) that occurred from predose to the first concentration ≥LOQ were treated as 0 and those that occured thereafter were treated as missing. The LOQ of the assay was 1 ng/mL. Per protocol, the kel was determined for participants in Cohort 1. The kel of bomedemstat in plasma is presented.

EFS was defined as the time from the first dose of study treatment to the date of a documented EFS event of resistance, relapse, progression, or death due to any cause as assessed by the investigator. Participants without documented events were censored at the date of the last disease assessment. The EFS, calculated using the Kaplan-Meier method, is presented.

EFS was defined as the time from the first dose of study treatment to the date of a documented EFS event of resistance, relapse, progression, or death due to any cause as assessed by the investigator. Participants without documented events were censored at the date of the last disease assessment. The EFS, calculated using the Kaplan-Meier method, is presented.

OS was defined as the time from the first dose of study treatment until death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The OS, calculated using the Kaplan-Meier method, is presented.

OS was defined as the time from the first dose of study treatment until death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. The OS, calculated using the Kaplan-Meier method, is presented.

Objective Response Rate (ORR) For High-risk Acute Myeloid Leukemia (AML) Participants Determined Using the Revised/Modified International Working Group (IWG) Response Criteria (Cheson et al., 2003) and Assessed by the Investigator

ORR was the percentage of participants with a response of complete remission (CR), CR with incomplete recovery (Cri), morphologic leukaemia-free state (MLFS), partial remission (PR), cytogenetic CR (CRc), molecular CR (CRm), or stable disease (SD): CR: <5% bone marrow (BM) blasts or blasts with Auer rods; no extramedullary disease (EMD); absolute neutrophil count ≥1000/μL; platelets ≥100,000/μL; independent of transfusion Cri: CR with residual neutropenia (<1,000/μL) or thrombocytopenia (<100,000/μL); no EMD; does not require transfusion independence (TI) MLFS: <5% blasts in BM with marrow spicules; no EMD; does not require TI PR: ≥ 50% decrease in BM blasts to a range of 5%-25%; Neutrophils ≥ 1,000/μL; Platelets ≥ 100,000/μL; independent of transfusion. ≤ 5% blasts is PR if Auer rods present CRc: CR+reversion to a normal karyotype if initially abnormal CRm: CR+no evidence of residual disease by molecular testing SD: No evidence of CR, PR, progression, new dysplastic changes

Best Overall Response (BOR) For High-risk Acute Myeloid Leukemia (AML) Participants Determined Using the Revised/Modified International Working Group (IWG) Response Criteria (Cheson et al., 2003) and Assessed by the Investigator

BOR was the percentage of participants with a best overall response of CR, Cri, MLFS, PR, CRc, CRm, or SD: CR: <5% bone marrow (BM) blasts or blasts with Auer rods; no extramedullary disease (EMD); absolute neutrophil count ≥1000/μL; platelets ≥100,000/μL; independent of transfusion Cri: CR with residual neutropenia (<1,000/μL) or thrombocytopenia (<100,000/μL); no EMD; does not require transfusion independence (TI) MLFS: <5% blasts in BM with marrow spicules; no EMD; does not require TI PR: ≥ 50% decrease in BM blasts to a range of 5%-25%; Neutrophils ≥ 1,000/μL; Platelets ≥ 100,000/μL; independent of transfusion. ≤ 5% blasts is PR if Auer rods present CRc: CR+reversion to a normal karyotype if initially abnormal CRm: CR+no evidence of residual disease by molecular testing SD: No evidence of CR, PR, progression, new dysplastic changes

Objective Response Rate (ORR) For High-risk Myelodysplastic Syndromes (MDS) Participants Determined Using the Revised/Modified International Working Group (IWG) Response Criteria (Cheson et al., 2006) and Assessed by the Investigator

ORR was the percentage of participants with a response of complete remission (CR), partial remission (PR), marrow CR (CRm), cytogenetic response (CyR), or stable disease (SD) lasting for ≥4 weeks: CR: ≤5% myeloblasts in the bone marrow (BM) with normal maturation of all cell lines; persistent dysplasia will be noted; Hgb ≥11 g/dL, Platelets ≥100 X 10^9/L, Neutrophils ≥1.0 X 10^9/L, and 0% Blasts in the peripheral blood PR: All CR criteria if abnormal before treatment except: BM blasts decreased by ≥50% over pretreatment but still >5%. Cellularity and morphology not relevant CRm: ≤ 5% myeloblasts in BM and decrease by ≥50% over pretreatment. Hematological improvement responses in the peripheral blood will be noted in addition to bone marrow CR. CyR: Complete=Disappearance of the chromosomal abnormality without appearance of new ones. Partial= ≥50% reduction of the chromosomal abnormality SD: Failure to achieve at least PR, but no evidence of progression for >8 weeks

Best Overall Response (BOR) Assessed by the Revised/Modified International Working Group (IWG) Response Criteria (Cheson et al., 2006): High-risk Myelodysplastic Syndromes (MDS) Participants

BOR was the percentage of participants with a best overall response of CR, PR, CRm, CyR, or SD lasting for ≥4 weeks: CR: ≤5% myeloblasts in the bone marrow (BM) with normal maturation of all cell lines; persistent dysplasia will be noted; Hgb ≥11 g/dL, Platelets ≥100 X 10^9/L, Neutrophils ≥1.0 X 10^9/L, and 0% Blasts in the peripheral blood PR: All CR criteria if abnormal before treatment except: BM blasts decreased by ≥50% over pretreatment but still >5%. Cellularity and morphology not relevant CRm: ≤ 5% myeloblasts in BM and decrease by ≥50% over pretreatment. Hematological improvement responses in the peripheral blood will be noted in addition to bone marrow CR. CyR: Complete=Disappearance of the chromosomal abnormality without appearance of new ones. Partial= ≥50% reduction of the chromosomal abnormality SD: Failure to achieve at least PR, but no evidence of progression for >8 weeks

Maximum Percent Change From Baseline Up to 28 Days of Treatment in Erythrocyte Count in Whole Blood After Administration of Bomedemstat

Whole blood samples were collected at time intervals during the first 4 cycles (Cycle length = 7 days of treatment and 7 days of rest for a total of 14 days), which corresponds to 28 days on treatment. The percent change from baseline in erythrocyte count was measured. Baseline was the erythrocyte count at screening or the last available observation prior to the first dose of study drug. An analysis of treatment effect between the doses was determined using a Kruskal-Wallis test. This analysis was done to support the evaluation of plasma concentrations (Cmax and Cmin) and exposure (AUC) on haematopoiesis. Per protocol, the analysis was pre-specified to be done on participants that received bomedemstat alone. The maximum percent change from baseline in erythrocyte count is presented.

Maximum Percent Change From Baseline Up to 28 Days of Treatment in Neutrophil Count in Whole Blood After Administration of Bomedemstat

Whole blood samples were collected at time intervals during the first 4 cycles (Cycle length = 7 days of treatment and 7 days of rest for a total of 14 days), which corresponds to 28 days on treatment. The percent change from baseline in neutrophil count was measured. Baseline was the neutrophil count at screening or the last available observation prior to the first dose of study drug. An analysis of treatment effect between the doses was determined using a Kruskal-Wallis test. This analysis was done to support the evaluation of plasma concentrations (Cmax and Cmin) and exposure (AUC) on haematopoiesis. Per protocol, the analysis was pre-specified to be done on participants that received bomedemstat alone. The maximum percent change from baseline in neutrophil count is presented.

Maximum Percent Change From Baseline Up to 28 Days of Treatment in Platelet Count in Whole Blood After Administration of Bomedemstat

Whole blood samples were collected at time intervals during the first 4 cycles (Cycle length = 7 days of treatment and 7 days of rest for a total of 14 days), which corresponds to 28 days on treatment. The percent change from baseline in platelet count was measured. Baseline was the platelet count at screening or the last available observation prior to the first dose of study drug. An analysis of treatment effect between the doses was determined using a Kruskal-Wallis test. This analysis was done to support the evaluation of plasma concentrations (Cmax and Cmin) and exposure (AUC) on haematopoiesis. Per protocol, the analysis was pre-specified to be done on participants that received bomedemstat alone. The maximum percent change from baseline in platelet count is presented.

Maximum Percent Change From Baseline Up to 28 Days of Treatment in Reticulocyte Count in Whole Blood After Administration of Bomedemstat

Whole blood samples were collected at time intervals during the first 4 cycles (Cycle length = 7 days of treatment and 7 days of rest for a total of 14 days), which corresponds to 28 days on treatment. The percent change from baseline in reticulocyte count was measured. Baseline was the reticulocyte count at screening or the last available observation prior to the first dose of study drug. An analysis of treatment effect between the doses was determined using a Kruskal-Wallis test. This analysis was done to support the evaluation of plasma concentrations (Cmax and Cmin) and exposure (AUC) on haematopoiesis. Per protocol, the analysis was pre-specified to be done on participants that received bomedemstat alone. The maximum percent change from baseline in reticulocyte count is presented.

Maximum Percent Change From Baseline Up to 28 Days of Treatment in The Number of Blasts in Whole Blood After Administration of Bomedemstat

Whole blood samples were collected at time intervals during the first 4 cycles (Cycle length = 7 days of treatment and 7 days of rest for a total of 14 days), which corresponds to 28 days on treatment. The percent change from baseline in the number of blasts was measured. Baseline was the number of blasts at screening or the last available observation prior to the first dose of study drug. An analysis of treatment effect between the doses was determined using a Kruskal-Wallis test. This analysis was done to support the evaluation of plasma concentrations (Cmax and Cmin) and exposure (AUC) on haematopoiesis. Per protocol, the analysis was pre-specified to be done on participants that received bomedemstat alone. The maximum percent change from baseline in the number of blasts is presented.

Maximum Percent Change From Baseline Up to 28 Days of Treatment in Hemoglobin Level in Whole Blood After Administration of Bomedemstat

Whole blood samples were collected at time intervals during the first 4 cycles (Cycle length = 7 days of treatment and 7 days of rest for a total of 14 days), which corresponds to 28 days on treatment. The percent change from baseline in the hemoglobin level was measured. Baseline was the hemoglobin level at screening or the last available observation prior to the first dose of study drug. An analysis of treatment effect between the doses was determined using a Kruskal-Wallis test. This analysis was done to support the evaluation of plasma concentrations (Cmax and Cmin) and exposure (AUC) on haematopoiesis. Per protocol, the analysis was pre-specified to be done on participants that received bomedemstat alone. The maximum percent change from baseline in hemoglobin level is presented.

The main inclusion and exclusion criteria include but are not limited to the following: Inclusion Criteria: High-risk Acute Myeloid Leukemia (AML) Have a diagnosis of AML according to the World Health Organization (WHO) criteria Have an Eastern Cooperative Oncology Group (ECOG) performance status score ≤2 Have AML that is classified as high risk as defined by one of the following: ≥ 60 years of age who were not candidates for or have refused standard chemotherapy; ≥18 years of age with de novo or secondary AML who were not expected to benefit from standard remission-induction chemotherapy; or had relapsed/refractory AML after no more than 3 previous lines of chemotherapy. High-risk Myelodysplastic Syndromes (MDS) Have a diagnosis of myelodysplastic syndromes according to the World Health Organization (WHO) criteria Have either an International Prognostic Scoring System (IPSS) score equivalent to intermediate-2 risk or higher, or a Revised International Prognostic Scoring System (IPSS-R) score equivalent to intermediate risk or higher. Have MDS that is classified as high risk as defined by one of the following: participants who have failed first-line therapy; or treatment-related MDS, except if it is associated with favorable cytogenetics, and not a candidate for stem cell transplantation Prior autologous stem cell transplant is allowed if a minimum of 3 months has elapsed from the time of transplant and the patient has recovered from transplant-associated toxicities Prior allogeneic stem cell transplant is allowed, provided all of the following criteria are met: transplant was >120 days prior to study enrollment; no immunosuppressive medications have been taken for at least 1 month; and no active graft versus host disease (GVHD), excluding Grade 1 skin GVHD Has a life expectancy >12 weeks Exclusion Criteria: Is receiving other treatments for the condition (with exceptions and time limits) Has had major surgery in last 4 weeks or minor surgery in the last 2 weeks Has a scheduled hematopoietic stem-cell transplant Is currently using prohibited medications Has clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia Has a concurrent second active and non-stable malignancy Has an uncontrolled active infection Has known Human Immunodeficiency Virus (HIV) infection or active Hepatitis B or Hepatitis C virus infection Has used an investigational agent within last 14 days Is a pregnant or lactating females