A Study of Bomedemstat (IMG-7289/MK-3543) Compared to Best Available Therapy (BAT) in Participants With Essential Thrombocythemia and an Inadequate Response or Intolerance of Hydroxyurea (MK-3543-006)
Study Details
Study Description
Brief Summary
This is a study evaluating the safety and efficacy of bomedemstat (MK-3543) compared with the best available treatment (BAT) in participants with essential thrombocythemia (ET) who have an inadequate response to or are intolerant of hydroxyurea.
The primary study hypothesis is that bomedemstat is superior to the best available treatment with respect to durable clinicohematologic response (DCHR).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Bomedemstat Participants will begin treatment at a dose of 50 mg of bomedemstat daily. Dosage will be adjusted either up or down within specified time parameters for each participant to the dose that provides sufficient exposure to safely inhibit thrombopoiesis to decrease platelet counts to the target range. All participants will be treated daily for up to 52 weeks, and are eligible for an extended treatment phase up to 152 weeks. |
Drug: Bomedemstat
Oral Capsule
Other Names:
|
| Active Comparator: Best Available Therapy Each participant will receive either anagrelide, busulfan, interferon alfa/pegylated interferon alfa, or ruxolitinib as determined by investigator. All participants will be treated per respective approved product labels for up to 52 weeks. Participants receiving BAT who have not discontinued study treatment at Week 52 will be eligible to crossover and receive bomedemstat for up to 152 weeks at the investigator's discretion. |
Drug: Anagrelide
Oral Capsule
Drug: Busulfan
Oral Capsule
Drug: Interferon alfa/pegylated interferon alfa
Oral Capsule
Drug: Ruxolitinib
Oral Capsule
|
Outcome Measures
Primary Outcome Measures
- Durable Clinicohematologic Response (DCHR) Rate [Up to approximately 52 weeks]
DCHR rate is the percentage of participants with DCHR, defined as a confirmed reduction of platelet count to ≤400 × 109/L, absence of white blood cell (WBC) count elevation to >10 × 109/L locally assessed to be due to ET, and the absence of any thrombotic or major hemorrhagic events or disease progression to myelofibrosis (MF), myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) by Week 52.
Secondary Outcome Measures
- Change From Baseline in Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 Individual Fatigue Symptom Item Score [Baseline and pre-specified timepoints through Week 156]
The MFSAF v4.0 is a 7-item participant-reported myelofibrosis symptom assessment which asks respondents to report symptom severity at its worst for each of the 7 items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale. For this outcome measure, the change from baseline through Week 156 in scores for the individual item of fatigue severity will be presented.
- Change From Baseline in Patient-reported Outcomes Measurement Information System (PROMIS) Fatigue SF-7a Total Fatigue Score [Baseline and pre-specified timepoints through Week 156]
The PROMIS F SF-7a is a 7-item participant-reported assessment that measures both the experience of fatigue and the interference of fatigue on daily activities over the past week. Response options are on a 5-point Likert scale, ranging from 1 = never to 5 = always. Change from baseline in PROMIS Fatigue SF-7a through Week 156 will be presented.
- Change From Baseline in Total Symptom Score as Measured on the MFSAF v4.0 [Baseline and pre-specified timepoints through Week 156]
The MFSAF v4.0 is a 7-item participant-reported myelofibrosis symptom assessment which asks respondents to report symptom severity at its worst for each of the 7 items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale. MFSAF total score for all symptoms at baseline through Week 156 will be presented.
- Duration of Clinicohematologic Response (DOCHR) [Up to approximately 52 weeks]
For participants who demonstrate DCHR, duration of clinicohematologic response is defined as the time from the first documented evidence of confirmed reduction of platelet and WBC count until confirmed increase of platelet and WBC counts to above acceptable threshold, thrombotic or major hemorrhagic events or disease progression to MF, MDS or AML.
- Duration of Hematologic Remission (DOHR) [Up to approximately 52 weeks]
For participants who demonstrate hematologic remission, DOHR is defined as the time from the first documented evidence of platelet and WBC counts reduction until platelet and WBC counts increase to above acceptable threshold.
- Percentage of Participants with Thrombotic Events [Up to 156 weeks]
Thrombotic events include but are not limited to new or recurrent acute myocardial infarction, unstable angina, stroke, transient ischemic attack, deep venous thrombosis, pulmonary embolism, thrombotic digital ischemia, or other thrombotic events.
- Percentage of Participants with Major Hemorrhagic Events [Up to 156 weeks]
Major hemorrhagic events include but are not limited to fatal bleeding, and/or symptomatic bleeding in a critical area or organ such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a decrease in hemoglobin level of 2 g/dL or more, or leading to transfusion of 2 or more units of whole blood or red cells.
- Disease Progression Rate [Up to approximately 52 weeks]
Disease progression rate is the percentage of participants with disease progression, defined as the transformation to post-essential thrombocythemia myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia as assessed by the adjudication committee. The disease progression rate of participants in each arm will be presented.
- Event Free Survival (EFS) [Up to approximately 52 weeks]
Event free survival (EFS) is defined as the time from randomization to the first documented thrombotic or major hemorrhagic event or disease progression as assessed by the adjudication committee, or death due to any cause, whichever occurs first.
- Number of Participants with An Adverse Event (AE) [Up to 180 weeks]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
- Number of Participants Discontinuing From Study Therapy Due to an AE [Up to 152 weeks]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinue study treatment due to an adverse event will be presented.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Has a diagnosis of ET per WHO 2016 diagnostic criteria for myeloproliferative neoplasms
-
Has a bone marrow fibrosis score of Grade 0 or Grade 1, as per a modified version of the European Consensus Criteria for Grading Myelofibrosis
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Has a history of inadequate response to or intolerance of hydroxyurea per at least 1 of the following criteria, based on modified European LeukemiaNet (ELN) criteria for hydroxyurea resistance or intolerance: hydroxyurea resistance (or inadequate response) or hydroxyurea Intolerance
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Has an inadequate or loss of response to their most recent prior ET therapy, requiring a change of cytoreductive therapy
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Has a platelet count > 450 × 109/L (450k /μL) assessed up to 72 hours before first dose of study intervention
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Has an absolute neutrophil count (ANC) ≥0.75 × 109/L assessed up to 72 hours before first dose of study intervention
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Has a life expectancy of >52 weeks
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If capable of producing sperm, the participant agrees to not donate sperm and to either abstain from heterosexual intercourse or use a highly effective method of contraception for the duration of the study period and for at least the time needed to eliminate each study intervention after the final dose
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Participants assigned female sex at birth are eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies: is not a participant of childbearing potential (POCBP) or is POCBP and uses a highly effective method of contraception or is abstinent from penile-vaginal intercourse during the study period and for at least the time needed to eliminate each study intervention after the last dose
Exclusion Criteria:
-
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to bomedemstat or lysine demethylase or monoamine oxidase inhibitor (LSDi or MAOi) that contraindicates participation
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History of any illness/impairment of GI function that might interfere with drug absorption (eg, chronic diarrhea or history of gastric bypass surgical procedure), confound the study results or pose an additional risk to the individual by participation in the study
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Evidence at the time of Screening of increased risk of bleeding
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History of a malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Note: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder
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Human immunodeficiency virus (HIV)-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
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Use of prohibited medication within 14 days of first dose of study intervention (eg, all hematopoietic growth factors, MAOIs, strong inhibitors and inducers of CYP3A4 or CYP2D6, drugs such as chloroquine whose metabolites are known to inhibit CYP3A4 or CYP2D6, Class 1c antiarrhythmics such as propafenone that are known to cause thrombocytopenias, etc.) or expected to require any of these medications during study treatment
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Has received prior treatment for their ET within 1 week (4 weeks for interferon) before first dose of study intervention
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Has received prior treatment with bomedemstat
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Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
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Has an active infection requiring systemic therapy
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Has had major surgical procedure ≤4 weeks before first dose of study intervention or has not recovered from side effects of major surgical procedure >4 weeks before first dose
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharpe & Dohme LLC
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 3543-006
- 2023-504865-21
- IMG-7289-CTP-301
- MK-3543-006