Clinical trial NCT02842827: 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)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Myelodysplastic Syndrome
Keywords: LSD1
High-risk Acute Myeloid Leukemia
High-risk Myelodysplastic Syndrome
Lead sponsor: Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2016-07-25
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

High-risk Acute Myeloid Leukemia (AML)

* Have a diagnosis of AML according to the World Health Organization (WHO) criteria
* Have an Eastern Cooperative Oncology Group (ECOG) performance status score ≤2
* Have AML that is classified as high risk as defined by one of the following: ≥ 60 years of age who were not candidates for or have refused standard chemotherapy; ≥18 years of age with de novo or secondary AML who were not expected to benefit from standard remission-induction chemotherapy; or had relapsed/refractory AML after no more than 3 previous lines of chemotherapy.

High-risk Myelodysplastic Syndromes (MDS)

* Have a diagnosis of myelodysplastic syndromes according to the World Health Organization (WHO) criteria
* Have either an International Prognostic Scoring System (IPSS) score equivalent to intermediate-2 risk or higher, or a Revised International Prognostic Scoring System (IPSS-R) score equivalent to intermediate risk or higher.
* Have MDS that is classified as high risk as defined by one of the following: participants who have failed first-line therapy; or treatment-related MDS, except if it is associated with favorable cytogenetics, and not a candidate for stem cell transplantation
* Prior autologous stem cell transplant is allowed if a minimum of 3 months has elapsed from the time of transplant and the patient has recovered from transplant-associated toxicities
* Prior allogeneic stem cell transplant is allowed, provided all of the following criteria are met: transplant was \>120 days prior to study enrollment; no immunosuppressive medications have been taken for at least 1 month; and no active graft versus host disease (GVHD), excluding Grade 1 skin GVHD
* Has a life expectancy \>12 weeks

Exclusion Criteria:

* Is receiving other treatments for the condition (with exceptions and time limits)
* Has had major surgery in last 4 weeks or minor surgery in the last 2 weeks
* Has a scheduled hematopoietic stem-cell transplant
* Is currently using prohibited medications
* Has clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia
* Has a concurrent second active and non-stable malignancy
* Has an uncontrolled active infection
* Has known Human Immunodeficiency Virus (HIV) infection or active Hepatitis B or Hepatitis C virus infection
* Has used an investigational agent within last 14 days
* Is a pregnant or lactating females

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 24 months
measure: Number of Participants Who Experienced a Serious Adverse Event (SAE)
timeFrame: Up to approximately 24 months
measure: Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 18 months
measure: Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
timeFrame: Up to approximately 28 Days
measure: 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
timeFrame: Up to approximately 24 months
measure: Number of Participants Who Experienced a Medical Event of Interest (MEOI)
timeFrame: Up to approximately 24 months
measure: Maximum Concentration (Cmax) of Bomedemstat Alone or Administered With Tretinoin
timeFrame: 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
measure: Time to Maximum Concentration (Tmax) of Bomedemstat Alone or Administered With Tretinoin
timeFrame: 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
measure: Area Under the Concentration Time Curve From Time 0 to 24 Hours (AUC0-24hr) Postdose of Bomedemstat Alone or Administered With Tretinoin
timeFrame: 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
measure: Elimination Half Life (t1/2) of Bomedemstat Alone or Administered With Tretinoin
timeFrame: Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
measure: Apparent Total Body Clearance (CL/F) of Bomedemstat Alone or Administered With Tretinoin
timeFrame: Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
measure: Volume of Distribution (Vz/F) of Bomedemstat Alone or Administered With Tretinoin
timeFrame: Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
measure: Terminal Elimination Rate Constant (Kel) of Bomedemstat Alone or Administered With Tretinoin
timeFrame: Cycle 1 Day 7: predose and 0.5, 1, 2, 3, 4, 8, and 24 hours postdose
measure: Event-free Survival (EFS) For High-risk Acute Myeloid Leukemia (AML) Participants
timeFrame: Up to approximately 24 months
measure: Event-free Survival (EFS) For High-risk Myelodysplastic Syndromes (MDS) Participants
timeFrame: Up to approximately 24 months
measure: Overall Survival (OS) For High-risk Acute Myeloid Leukemia (AML) Participants
timeFrame: Up to approximately 24 months
measure: Overall Survival (OS) For High-risk Myelodysplastic Syndromes (MDS) Participants
timeFrame: Up to approximately 24 months
measure: 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
timeFrame: Up to approximately 24 months
measure: 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
timeFrame: Up to approximately 24 months
measure: 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
timeFrame: Up to approximately 24 months
measure: 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
timeFrame: Up to approximately 24 months
Secondary outcomes:
measure: Maximum Percent Change From Baseline Up to 28 Days of Treatment in Erythrocyte Count in Whole Blood After Administration of Bomedemstat
timeFrame: Baseline (prior to first dose of study drug) and up to 28 days
measure: Maximum Percent Change From Baseline Up to 28 Days of Treatment in Neutrophil Count in Whole Blood After Administration of Bomedemstat
timeFrame: Baseline (prior to first dose of study drug) and up to 28 days
measure: Maximum Percent Change From Baseline Up to 28 Days of Treatment in Platelet Count in Whole Blood After Administration of Bomedemstat
timeFrame: Baseline (prior to first dose of study drug) and up to 28 days
measure: Maximum Percent Change From Baseline Up to 28 Days of Treatment in Reticulocyte Count in Whole Blood After Administration of Bomedemstat
timeFrame: Baseline (prior to first dose of study drug) and up to 28 days
measure: Maximum Percent Change From Baseline Up to 28 Days of Treatment in The Number of Blasts in Whole Blood After Administration of Bomedemstat
timeFrame: Baseline (prior to first dose of study drug) and up to 28 days
measure: Maximum Percent Change From Baseline Up to 28 Days of Treatment in Hemoglobin Level in Whole Blood After Administration of Bomedemstat
timeFrame: Baseline (prior to first dose of study drug) and up to 28 days
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: