Bomedemstat (IMG-7289/MK-3543) in Participants With Myelofibrosis (IMG-7289-CTP-102/MK-3543-002)

NCT03136185 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: IMG-7289-CTP-102MK-3543-0022018-003811-23
• Study Type: interventional
• Target: 90
• Locations: 5 countries
• Sites: 5

Brief Summary

This is a Phase 1/2 open-label study to evaluate the safety, tolerability, steady-state pharmacokinetic (PK) and pharmacodynamics (PD) of a lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat (IMG-7289/MK-3543), administered orally once daily in participants with myelofibrosis. The primary hypothesis is that bomedemstat is a safe and tolerable orally available agent when administered to participants with myelofibrosis including primary myelofibrosis (PMF), post-polycythaemia vera-myelofibrosis (PPVMF), and post-essential thrombocythaemia-myelofibrosis (PET-MF) (collectively referred to as 'MF'); inhibition of LSD1 by bomedemstat will reduce spleen size in those with splenomegaly, improve haematopoiesis and reduce constitutional symptoms associated with these disorders.

Conditions

Myelofibrosis; Post-polycythemia Vera Myelofibrosis (PPV-MF); Post-essential Thrombocythemia Myelofibrosis (PET-MF); Primary Myelofibrosis (PMF)

Keywords

LSD1

Outcome Measures

Primary Outcomes (10)

• Number of Participants With Dose Limiting Toxicities (DLTs)

  DLT was defined as any one of the following adverse events (AEs) that occured through Day 7 of the Initial Treatment Period (ITP) and was considered by the Investigator to be possibly, probably or definitely related to bomedemstat: * Thrombocytopenia leading to clinically significant sequelae (i.e., a clinically significant bleeding event or the need for prophylactic transfusions) * A clinically significant bleeding event in a participant with a platelet count \>50 x 10\^9/L (50 k/μL) * Any Grade 4 or 5 non-haematologic adverse event * Any Grade 3 non-haematologic adverse event with failure to recover to Grade 2 within 7 days of drug cessation, with the following exceptions: ≥ Grade 3 nausea, vomiting or diarrhea that responds to standard medical care; ≥ Grade 3 aesthenia lasting less than 14 days; any Grade 3 electrolyte abnormality unrelated to the underlying malignancy and persisting greater than 24 hours. The number of participants with a DLT were reported.

  Up to Day 7 of the ITP

• Number of Participants With Serious Adverse Events

  An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. Serious AEs (SAEs) were any AE that resulted in death, life-threatening experience, required or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly, or important medical events. The number of participants with at least one treatment-emergent (TE) SAE was reported for each arm.

  Up to approximately 30 months

• Number of Participants With Adverse Events

  An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. The number of participants with at least one TE AE was reported for each arm.

  Up to approximately 30 months

• Number of Participants That Discontinued Study Treatment Due To AEs

  An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. The number of participants that discontinued study treatment with bomedemstat due to a TE AE was reported for each arm.

  Up to approximately 29 months

• Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat

  Cmax was defined as the maximum observed concentration after administration obtained directly from the concentration time profile. Blood and plasma samples were collected at pre-specified timepoints to calculate Cmax in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis.

  Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.

• Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat

  Tmax was defined as the time to maximum concentration after administration obtained by inspection. Blood and plasma samples were collected at pre-specified timepoints to calculate Tmax in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis.

  Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.

• Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat From Time 0 to 24 Hours Post-dose (AUC0-24)

  AUC0-24 was defined as the area under the concentration versus time curve calculated using the linear trapezoidal rule from the zero time-point to the 24-hour time-point concentration. Blood and plasma samples were collected at pre-specified timepoints to calculate AUC0-24 in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis.

  Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.

• Phase 1/2a Portion: Apparent Total Clearance (CL/F) of Bomedemstat After Oral Administration

  CL/F was defined as the apparent total clearance of drug after oral administration. Blood and plasma samples were collected at pre-specified timepoints to calculate CL/F in participants of the Phase 1/2a portion of the study. As pre-specified by the protocol and Pharmacokinetic Analysis Plan (PAP), Phase 2b participants were excluded from this analysis.

  Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.

• Percentage Change From Baseline in Spleen Volume

  Change in spleen volume was assessed based on calculated spleen volume (ml) measured by magnetic resonance imaging (MRI), or computerized tomography (CT) scan (where locally permitted) if the participant was not a candidate for MRI from Day 0. Percentage change from baseline in spleen volume was reported at Initial Treatment Period (ITP) Day 84, ITP Day 168, Additional Treatment Period 1 (ATP1) Day 84 (Study Day 253), and ATP1 Day 168 (Study Day 337).

  Baseline, ITP Day 84 (Study Day 84), ITP Day 168 (Study Day 168), ATP1 Day 84 (Study Day 253), and ATP1 Day 168 (Study Day 337)

• Percentage Change From Baseline in Spleen Size

  Change in spleen size was assessed based on spleen palpation (in cm) at each visit. Percentage change from baseline in spleen size was reported at ITP Day 84, ITP Day 168, ATP1 Day 84 (Study Day 253), ATP1 Day 168 (Study Day 337), ATP2 Day 84 (Study Day 422), ATP2 Day 168 (Study Day 506), and ATP3 Day 84 (Study Day 591). As prespecified by the Statistical Analysis Plan, assessments for the Phase 1/2 groups were summarized using visit windowing after the Day 84 visit of the ITP to allow for comparison with the Phase 2b groups at ITP Day 168.

  Baseline, ITP Day 84 (Study Day 84), ITP Day 168 (Study Day 168), ATP1 Day 84 (Study Day 253), ATP1 Day 168 (Study Day 337), ATP2 Day 84 (Study Day 422), ATP2 Day 168 (Study Day 506), and ATP3 Day 84 (Study Day 591)

Study Arms (9)

Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d

EXPERIMENTAL

In the Phase 1/2a portion of the study, PMF participants received 0.25 mg/kg/d bomedemstat orally every day (qd) for 85 days during the Initial Treatment Period (ITP). Qualifying participants could continue to receive treatment for an additional 85 days during an Additional Treatment Period (ATP) as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d

EXPERIMENTAL

In the Phase 1/2a portion of the study, PPV-MF participants received 0.25 mg/kg/d bomedemstat orally qd for 85 days during the ITP. Qualifying participants could continue to receive treatment for an additional 85 days during an ATP as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d

EXPERIMENTAL

In the Phase 1/2a portion of the study, PET-MF participants received 0.25 mg/kg/d bomedemstat orally qd for 85 days during the ITP. Qualifying participants could continue to receive treatment for an additional 85 days during an ATP as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Ph 2b PMF: Bomedemstat 0.5 mg/kg/d

EXPERIMENTAL

In the Phase 2b portion of the study, PMF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during an ATP as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d

EXPERIMENTAL

In the Phase 2b portion of the study, PPV-MF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during an ATP as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d

EXPERIMENTAL

In the Phase 2b portion of the study, PET-MF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during an ATP as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Ph 2b PMF: Bomedemstat 0.6 mg/kg/d

EXPERIMENTAL

In the Phase 2b portion of the study, PMF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during an ATP as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d

EXPERIMENTAL

In the Phase 2b portion of the study, PPV-MF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during an ATP as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d

EXPERIMENTAL

In the Phase 2b portion of the study, PET-MF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during an ATP as determined by the investigator. The ATP could repeat indefinitely in participants that continued to derive clinical benefit.

Drug: Bomedemstat

Interventions

Bomedemstat DRUG

Oral (capsule) administration according to dose allocation.

Also known as: IMG-7289, MK-3543, LSD1 inhibitor

Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d; Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d; Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d; Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d; Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d; Ph 2b PMF: Bomedemstat 0.5 mg/kg/d; Ph 2b PMF: Bomedemstat 0.6 mg/kg/d; Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d; Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \>18 years of age
• Diagnosis of either PMF per World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms, or PPV-MF or PET-MF per the International Working Group for Myelofibrosis Research and Treatment
• High or intermediate-2 risk disease

You may not qualify if:

• Receiving other treatments for the condition (with exceptions and time limits)
• Major surgery in last 4 weeks, any surgery in the last 2 weeks
• History of, or scheduled, hematopoietic stem cell transplant within 24 weeks of Screening
• History of splenectomy
• Current use of prohibited medications
• A concurrent second active and nonstable malignancy
• Known human immunodeficiency virus infection or active Hepatitis B or Hepatitis C virus infection
• Other hematologic/biochemistry requirements, as per protocol
• Use of an investigational agent within last 14 days
• Pregnant or lactating females

Sponsors & Collaborators

• Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New Jersey USA): lead

Study Sites (5)

University of Michigan

Ann Arbor, Michigan, 48105, United States

Location

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Location

Universitatsklinikum Essen

Essen, 45147, Germany

Location

Azienda Ospedaliero Universitaria Careggi

Florence, Italy

Location

Guy's and St Thomas' Hospitals

London, United Kingdom

Location

Related Links

• Merck Clinical Trials Information

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

bomedemstat

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2017
• First Posted: May 2, 2017
• Study Start: July 18, 2017
• Primary Completion: March 8, 2022
• Study Completion: March 8, 2022
• Last Updated: January 10, 2024
• Results First Posted: January 10, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share

Locations

GB (1); AU (1); US (1); DE (1); IT (1)