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 Overview
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Brief Summary
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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).

Official Title
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A Phase 3, Randomized, Open-label, Active-Comparator-Controlled Clinical Study to Evaluate the Safety and Efficacy of Bomedemstat (MK-3543/IMG-7289) Versus Best Available Therapy (BAT) in Participants With Essential Thrombocythemia Who Have an Inadequate Response to or Are Intolerant of Hydroxyurea

Conditions
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Essential Thrombocythemia

Intervention / Treatment
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* Drug: Bomedemstat
* Drug: Anagrelide
* Drug: Busulfan
* Drug: Interferon alfa/pegylated interferon alfa
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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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 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 Has an inadequate or loss of response to their most recent prior ET therapy, requiring a change of cytoreductive therapy Has a platelet count > 450 × 109/L (450k /μL) assessed up to 72 hours before first dose of study intervention Has an absolute neutrophil count (ANC) ≥0.75 × 109/L assessed up to 72 hours before first dose of study intervention 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 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 Evidence at the time of Screening of increased risk of bleeding 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 Human immunodeficiency virus (HIV)-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bomedemstat<br>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<br>* Oral Capsule<br>* Other names: IMG-7289;|
| Active Comparator: Best Available Therapy<br>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<br>* Oral Capsule<br>Drug: Busulfan<br>* Oral Capsule<br>Drug: Interferon alfa/pegylated interferon alfa<br>* Oral Capsule<br>Drug: Ruxolitinib<br>* Oral Capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durable Clinicohematologic Response (DCHR) Rate | 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. | Up to approximately 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 Individual Fatigue Symptom Item Score | 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. | Baseline and pre-specified timepoints through Week 156 | 
| Change From Baseline in Patient-reported Outcomes Measurement Information System (PROMIS) Fatigue SF-7a Total Fatigue Score | 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. | Baseline and pre-specified timepoints through Week 156 | 
| Change From Baseline in Total Symptom Score as Measured on the MFSAF v4.0 | 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. | Baseline and pre-specified timepoints through Week 156 | 
| Duration of Clinicohematologic Response (DOCHR) | 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. | Up to approximately 52 weeks | 
| Duration of Hematologic Remission (DOHR) | 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. | Up to approximately 52 weeks | 
| Percentage of Participants with Thrombotic Events | 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. | Up to 156 weeks | 
| Percentage of Participants with Major Hemorrhagic Events | 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. | Up to 156 weeks | 
| Disease Progression Rate | 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. | Up to approximately 52 weeks | 
| Event Free Survival (EFS) | 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. | Up to approximately 52 weeks | 
| Number of Participants with An Adverse Event (AE) | 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. | Up to 180 weeks | 
| Number of Participants Discontinuing From Study Therapy Due to an AE | 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. | Up to 152 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ET, essential thrombocythemia, bomedemstat, IMG-7289