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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02842827
Registration number
NCT02842827
Ethics application status
Date submitted
12/07/2016
Date registered
25/07/2016
Date last updated
11/07/2023
Titles & IDs
Public title
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)
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Scientific title
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
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Secondary ID [1]
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IMG-7289-CTP-101
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Secondary ID [2]
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IMG-7289-CTP-101
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia
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Myelodysplastic Syndrome
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Blood
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Haematological diseases
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Blood
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Other blood disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - bomedemstat
Treatment: Drugs - tretinoin
Experimental: Cohort 1a: bomedemstat 0.75 mg/kg/day - 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).
Experimental: Cohort 1b: bomedemstat 1.5 mg/kg/day - 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).
Experimental: Cohort 1c: bomedemstat 3 mg/kg/day - 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).
Experimental: Cohort 1d: bomedemstat 6 mg/kg/day orally - 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).
Experimental: Cohort 1x3: bomedemstat 3 mg/kg/day orally plus tretinoin 45 mg/m^2 /day3 - 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).
Experimental: Cohort 1x6: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day - 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).
Experimental: Cohort 3x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day - 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).
Experimental: Cohort 4x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day - 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.
Treatment: Drugs: bomedemstat
oral administration
Treatment: Drugs: tretinoin
oral administration
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants Who Experienced an Adverse Event (AE)
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Assessment method [1]
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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.
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Timepoint [1]
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Up to approximately 24 months
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Primary outcome [2]
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Number of Participants Who Experienced a Serious Adverse Event (SAE)
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Assessment method [2]
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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.
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Timepoint [2]
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Up to approximately 24 months
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Primary outcome [3]
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Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
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Assessment method [3]
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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.
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Timepoint [3]
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Up to approximately 18 months
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Primary outcome [4]
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Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
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Assessment method [4]
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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.
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Timepoint [4]
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Up to approximately 28 Days
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Primary outcome [5]
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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
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Assessment method [5]
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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.
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Timepoint [5]
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Up to approximately 24 months
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Primary outcome [6]
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Number of Participants Who Experienced a Medical Event of Interest (MEOI)
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Assessment method [6]
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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.
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Timepoint [6]
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Up to approximately 24 months
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Primary outcome [7]
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Maximum Concentration (Cmax) of Bomedemstat Alone or Administered With Tretinoin
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Assessment method [7]
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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.
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Timepoint [7]
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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
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Primary outcome [8]
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Time to Maximum Concentration (Tmax) of Bomedemstat Alone or Administered With Tretinoin
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Assessment method [8]
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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.
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Timepoint [8]
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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
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Primary outcome [9]
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Area Under the Concentration Time Curve From Time 0 to 24 Hours (AUC0-24hr) Postdose of Bomedemstat Alone or Administered With Tretinoin
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Assessment method [9]
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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.
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Timepoint [9]
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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
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Primary outcome [10]
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Elimination Half Life (t1/2) of Bomedemstat Alone or Administered With Tretinoin
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Assessment method [10]
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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.
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Timepoint [10]
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Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
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Primary outcome [11]
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Apparent Total Body Clearance (CL/F) of Bomedemstat Alone or Administered With Tretinoin
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Assessment method [11]
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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.
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Timepoint [11]
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Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
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Primary outcome [12]
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Volume of Distribution (Vz/F) of Bomedemstat Alone or Administered With Tretinoin
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Assessment method [12]
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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.
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Timepoint [12]
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Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
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Primary outcome [13]
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Terminal Elimination Rate Constant (Kel) of Bomedemstat Alone or Administered With Tretinoin
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Assessment method [13]
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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.
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Timepoint [13]
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Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
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Primary outcome [14]
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Event-free Survival (EFS) For High-risk Acute Myeloid Leukemia (AML) Participants
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Assessment method [14]
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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.
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Timepoint [14]
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Up to approximately 24 months
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Primary outcome [15]
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Event-free Survival (EFS) For High-risk Myelodysplastic Syndromes (MDS) Participants
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Assessment method [15]
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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.
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Timepoint [15]
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Up to approximately 24 months
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Primary outcome [16]
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Overall Survival (OS) For High-risk Acute Myeloid Leukemia (AML) Participants
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Assessment method [16]
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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.
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Timepoint [16]
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Up to approximately 24 months
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Primary outcome [17]
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Overall Survival (OS) For High-risk Myelodysplastic Syndromes (MDS) Participants
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Assessment method [17]
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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.
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Timepoint [17]
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Up to approximately 24 months
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Primary outcome [18]
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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
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Assessment method [18]
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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
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Timepoint [18]
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Up to approximately 24 months
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Primary outcome [19]
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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
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Assessment method [19]
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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
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Timepoint [19]
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Up to approximately 24 months
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Primary outcome [20]
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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
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Assessment method [20]
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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
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Timepoint [20]
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Up to approximately 24 months
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Primary outcome [21]
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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
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Assessment method [21]
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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
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Timepoint [21]
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Up to approximately 24 months
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Secondary outcome [1]
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Maximum Percent Change From Baseline Up to 28 Days of Treatment in Erythrocyte Count in Whole Blood After Administration of Bomedemstat
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Assessment method [1]
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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.
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Timepoint [1]
0
0
Baseline (prior to first dose of study drug) and up to 28 days
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Secondary outcome [2]
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Maximum Percent Change From Baseline Up to 28 Days of Treatment in Neutrophil Count in Whole Blood After Administration of Bomedemstat
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Assessment method [2]
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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.
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Timepoint [2]
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0
Baseline (prior to first dose of study drug) and up to 28 days
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Secondary outcome [3]
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Maximum Percent Change From Baseline Up to 28 Days of Treatment in Platelet Count in Whole Blood After Administration of Bomedemstat
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Assessment method [3]
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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.
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Timepoint [3]
0
0
Baseline (prior to first dose of study drug) and up to 28 days
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Secondary outcome [4]
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Maximum Percent Change From Baseline Up to 28 Days of Treatment in Reticulocyte Count in Whole Blood After Administration of Bomedemstat
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Assessment method [4]
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0
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.
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Timepoint [4]
0
0
Baseline (prior to first dose of study drug) and up to 28 days
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Secondary outcome [5]
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0
Maximum Percent Change From Baseline Up to 28 Days of Treatment in The Number of Blasts in Whole Blood After Administration of Bomedemstat
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Assessment method [5]
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0
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.
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Timepoint [5]
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Baseline (prior to first dose of study drug) and up to 28 days
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Secondary outcome [6]
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Maximum Percent Change From Baseline Up to 28 Days of Treatment in Hemoglobin Level in Whole Blood After Administration of Bomedemstat
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Assessment method [6]
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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.
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Timepoint [6]
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0
Baseline (prior to first dose of study drug) and up to 28 days
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Eligibility
Key inclusion criteria
The main inclusion and exclusion criteria include but are not limited to the following:
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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
6/10/2016
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
30/10/2018
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Sample size
Target
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Accrual to date
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Final
45
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Recruitment in Australia
Recruitment state(s)
SA
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Recruitment hospital [1]
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Royal Adelaide Hospital - Adelaide
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Recruitment postcode(s) [1]
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- Adelaide
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
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
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02842827
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Medical Director
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Address
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Merck Sharp & Dohme LLC
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0
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Phone
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0
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Fax
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0
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Email
0
0
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Contact person for public queries
Name
0
0
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Address
0
0
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Country
0
0
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Phone
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0
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Fax
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0
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Email
0
0
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02842827
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