Acute Myeloid LeukemiaPhase 1/2NCT02842827
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 Phase 1/2 study testing bomedemstat and tretinoin in people with Acute Myeloid Leukemia and Myelodysplastic Syndrome, run by Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) at 1 site in Australia.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Myeloid Leukemia, Myelodysplastic Syndrome
- What is being tested?
- bomedemstat and tretinoin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 45 participants
- Where
- 1 siteAustralia
- Study dates
- 6 Oct 2016to 30 Oct 2018
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official 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
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
- Conditions
- Acute Myeloid Leukemia, Myelodysplastic Syndrome
- Being tested
- bomedemstat, tretinoin
- Keywords
- LSD1, High-risk Acute Myeloid Leukemia, High-risk Myelodysplastic Syndrome
- Medical subject headings
- Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
bomedemstatDrug
Also called MK-3543, IMG-7289
oral administration
tretinoinDrug
Also called ATRA®, Vesanoid®, all-trans retinoic acid,
oral administration
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1a: bomedemstat 0.75 mg/kg/day | Experimental | 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). Receives: Drug: bomedemstat |
| Cohort 1b: bomedemstat 1.5 mg/kg/day | Experimental | 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). Receives: Drug: bomedemstat |
| Cohort 1c: bomedemstat 3 mg/kg/day | Experimental | 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). Receives: Drug: bomedemstat |
| Cohort 1d: bomedemstat 6 mg/kg/day orally | Experimental | 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). Receives: Drug: bomedemstat |
| Cohort 1x3: bomedemstat 3 mg/kg/day orally plus tretinoin 45 mg/m^2 /day3 | Experimental | 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). Receives: Drug: bomedemstat; Drug: tretinoin |
| Cohort 1x6: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day | Experimental | 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). Receives: Drug: bomedemstat; Drug: tretinoin |
| Cohort 3x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day | Experimental | 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). Receives: Drug: bomedemstat; Drug: tretinoin |
| Cohort 4x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day | Experimental | 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. Receives: Drug: bomedemstat; Drug: tretinoin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Who Experienced an Adverse Event (AE)
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.
Measured: Up to approximately 24 months
Number of Participants Who Experienced a Serious Adverse Event (SAE)
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.
Measured: Up to approximately 24 months
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
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.
Measured: Up to approximately 18 months
Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
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.
Measured: Up to approximately 28 Days
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.
Measured: Up to approximately 24 months
Number of Participants Who Experienced a Medical Event of Interest (MEOI)
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.
Measured: Up to approximately 24 months
Maximum Concentration (Cmax) of Bomedemstat Alone or Administered With Tretinoin
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.
Measured: 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
Time to Maximum Concentration (Tmax) of Bomedemstat Alone or Administered With Tretinoin
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.
Measured: 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.
Measured: 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
Elimination Half Life (t1/2) of Bomedemstat Alone or Administered With Tretinoin
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.
Measured: Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
Apparent Total Body Clearance (CL/F) of Bomedemstat Alone or Administered With Tretinoin
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.
Measured: Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
Volume of Distribution (Vz/F) of Bomedemstat Alone or Administered With Tretinoin
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.
Measured: Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
Terminal Elimination Rate Constant (Kel) of Bomedemstat Alone or Administered With Tretinoin
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.
Measured: Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
Event-free Survival (EFS) For High-risk Acute Myeloid Leukemia (AML) Participants
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.
Measured: Up to approximately 24 months
Event-free Survival (EFS) For High-risk Myelodysplastic Syndromes (MDS) Participants
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.
Measured: Up to approximately 24 months
Overall Survival (OS) For High-risk Acute Myeloid Leukemia (AML) Participants
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.
Measured: Up to approximately 24 months
Overall Survival (OS) For High-risk Myelodysplastic Syndromes (MDS) Participants
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.
Measured: Up to approximately 24 months
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
Measured: Up to approximately 24 months
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
Measured: Up to approximately 24 months
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
Measured: Up to approximately 24 months
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
Measured: Up to approximately 24 months
Secondary outcomes (6)
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.
Measured: Baseline (prior to first dose of study drug) and up to 28 days
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.
Measured: Baseline (prior to first dose of study drug) and up to 28 days
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.
Measured: Baseline (prior to first dose of study drug) and up to 28 days
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.
Measured: Baseline (prior to first dose of study drug) and up to 28 days
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.
Measured: Baseline (prior to first dose of study drug) and up to 28 days
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.
Measured: Baseline (prior to first dose of study drug) and up to 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jul 2016 (estimated)
- Study start6 Oct 2016
- Primary completion30 Oct 2018
- Study completion30 Oct 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Merck Sharp & Dohme LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02842827
- Sponsor's protocol ID
- IMG-7289-CTP-101
- Other IDs
- IMG-7289-CTP-101, MK-3543-001
- Status last verified
- Jul 2023
- First submitted
- 12 Jul 2016
- Last updated
- 11 Jul 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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
- ClinicalTrials.gov ID
- NCT02842827
- Acronym / sponsor ID
- IMG-7289-CTP-101
- Conditions
- Acute Myeloid Leukemia, Myelodysplastic Syndrome
- Keywords
- LSD1, High-risk Acute Myeloid Leukemia, High-risk Myelodysplastic Syndrome
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)Industry (pharma, biotech, devices)
- Study start
- 6 Oct 2016 (actual)
- Primary completion
- 30 Oct 2018 (actual)
- Study completion
- 30 Oct 2018 (actual)
- First posted
- 25 Jul 2016 (estimated)
- Results
- Posted 11 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 8
| Arm | Type | Receives |
|---|---|---|
| Cohort 1a: bomedemstat 0.75 mg/kg/day | Experimental | Drug: bomedemstatParticipants 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). |
| Cohort 1b: bomedemstat 1.5 mg/kg/day | Experimental | Drug: bomedemstatParticipants 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). |
| Cohort 1c: bomedemstat 3 mg/kg/day | Experimental | Drug: bomedemstatParticipants 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). |
| Cohort 1d: bomedemstat 6 mg/kg/day orally | Experimental | Drug: bomedemstatParticipants 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). |
| Cohort 1x3: bomedemstat 3 mg/kg/day orally plus tretinoin 45 mg/m^2 /day3 | Experimental | Drug: bomedemstat, Drug: tretinoinParticipants 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). |
| Cohort 1x6: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day | Experimental | Drug: bomedemstat, Drug: tretinoinParticipants 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). |
| Cohort 3x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day | Experimental | Drug: bomedemstat, Drug: tretinoinParticipants 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). |
| Cohort 4x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day | Experimental | Drug: bomedemstat, Drug: tretinoinParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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)
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| bomedemstatAlso: MK-3543, IMG-7289oral administration | Drug | Cohort 1a: bomedemstat 0.75 mg/kg/day, Cohort 1b: bomedemstat 1.5 mg/kg/day, Cohort 1c: bomedemstat 3 mg/kg/day, Cohort 1d: bomedemstat 6 mg/kg/day orally, Cohort 1x3: bomedemstat 3 mg/kg/day orally plus tretinoin 45 mg/m^2 /day3, Cohort 1x6: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day, Cohort 3x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day, Cohort 4x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day |
| tretinoinAlso: ATRA®, Vesanoid®, all-trans retinoic acid,oral administration | Drug | Cohort 1x3: bomedemstat 3 mg/kg/day orally plus tretinoin 45 mg/m^2 /day3, Cohort 1x6: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day, Cohort 3x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day, Cohort 4x: bomedemstat 6 mg/kg/day plus tretinoin 45 mg/m^2/day |
Primary outcome
Number of Participants Who Experienced an Adverse Event (AE)
Time frame: 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.
Number of Participants Who Experienced a Serious Adverse Event (SAE)
Time frame: 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)
Time frame: 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)
Time frame: 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.
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
Time frame: 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.
Number of Participants Who Experienced a Medical Event of Interest (MEOI)
Time frame: 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.
Maximum Concentration (Cmax) of Bomedemstat Alone or Administered With Tretinoin
Time frame: 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.
Time to Maximum Concentration (Tmax) of Bomedemstat Alone or Administered With Tretinoin
Time frame: 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.
Area Under the Concentration Time Curve From Time 0 to 24 Hours (AUC0-24hr) Postdose of Bomedemstat Alone or Administered With Tretinoin
Time frame: 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.
Elimination Half Life (t1/2) of Bomedemstat Alone or Administered With Tretinoin
Time frame: 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.
Apparent Total Body Clearance (CL/F) of Bomedemstat Alone or Administered With Tretinoin
Time frame: 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.
Volume of Distribution (Vz/F) of Bomedemstat Alone or Administered With Tretinoin
Time frame: 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.
Terminal Elimination Rate Constant (Kel) of Bomedemstat Alone or Administered With Tretinoin
Time frame: 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.
Event-free Survival (EFS) For High-risk Acute Myeloid Leukemia (AML) Participants
Time frame: 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.
Event-free Survival (EFS) For High-risk Myelodysplastic Syndromes (MDS) Participants
Time frame: 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.
Overall Survival (OS) For High-risk Acute Myeloid Leukemia (AML) Participants
Time frame: 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
Time frame: 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.
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
Time frame: 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) 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
Time frame: 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
Time frame: 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
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
Time frame: 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
6 secondary outcomes
Maximum Percent Change From Baseline Up to 28 Days of Treatment in Erythrocyte Count in Whole Blood After Administration of Bomedemstat
Time frame: Baseline (prior to first dose of study drug) and up to 28 days
Maximum Percent Change From Baseline Up to 28 Days of Treatment in Neutrophil Count in Whole Blood After Administration of Bomedemstat
Time frame: Baseline (prior to first dose of study drug) and up to 28 days
Maximum Percent Change From Baseline Up to 28 Days of Treatment in Platelet Count in Whole Blood After Administration of Bomedemstat
Time frame: Baseline (prior to first dose of study drug) and up to 28 days
Maximum Percent Change From Baseline Up to 28 Days of Treatment in Reticulocyte Count in Whole Blood After Administration of Bomedemstat
Time frame: Baseline (prior to first dose of study drug) and up to 28 days
Maximum Percent Change From Baseline Up to 28 Days of Treatment in The Number of Blasts in Whole Blood After Administration of Bomedemstat
Time frame: Baseline (prior to first dose of study drug) and up to 28 days
Maximum Percent Change From Baseline Up to 28 Days of Treatment in Hemoglobin Level in Whole Blood After Administration of Bomedemstat
Time frame: Baseline (prior to first dose of study drug) and up to 28 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jul 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Merck Sharp & Dohme LLC
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing bomedemstat and tretinoin in people with Acute Myeloid Leukemia and Myelodysplastic Syndrome, run by Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA) at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Who Experienced an Adverse Event (AE) (time frame: Up to approximately 24 months). The study lists 21 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jul 2023.