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

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

时间窗: Up to approximately 24 months

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.

Volume of Distribution (Vz/F) of Bomedemstat Alone or Administered With Tretinoin

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

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.

Overall Survival (OS) For High-risk Acute Myeloid Leukemia (AML) Participants

时间窗: Up to approximately 24 months

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.

Overall Survival (OS) For High-risk Myelodysplastic Syndromes (MDS) Participants

时间窗: Up to approximately 24 months

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.

Number of Participants Who Experienced a Medical Event of Interest (MEOI)

时间窗: Up to approximately 24 months

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.

Number of Participants Who Experienced an Adverse Event (AE)

时间窗: Up to approximately 24 months

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.

Elimination Half Life (t1/2) of Bomedemstat Alone or Administered With Tretinoin

时间窗: Cycle 1 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.

Number of Participants Who Experienced a Serious Adverse Event (SAE)

时间窗: Up to approximately 24 months

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.

Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)

时间窗: Up to approximately 18 months

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.

Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)

时间窗: Up to approximately 28 Days

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.

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

时间窗: 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

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.

Apparent Total Body Clearance (CL/F) of Bomedemstat Alone or Administered With Tretinoin

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

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.

Terminal Elimination Rate Constant (Kel) of Bomedemstat Alone or Administered With Tretinoin

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

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.

Maximum Concentration (Cmax) of Bomedemstat Alone or Administered With Tretinoin

时间窗: 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

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.

Event-free Survival (EFS) For High-risk Acute Myeloid Leukemia (AML) Participants

时间窗: Up to approximately 24 months

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.

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

时间窗: Up to approximately 24 months

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

时间窗: Up to approximately 24 months

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

Time to Maximum Concentration (Tmax) of Bomedemstat Alone or Administered With Tretinoin

时间窗: 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.

Event-free Survival (EFS) For High-risk Myelodysplastic Syndromes (MDS) Participants

时间窗: Up to approximately 24 months

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.

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

时间窗: Up to approximately 24 months

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

时间窗: Up to approximately 24 months

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