A Study of Bomedemstat (MK-3543) in Participants With Polycythemia Vera (MK-3543-004)

Study Overview
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Brief Summary
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This is a Phase 2 open label study of an orally administered lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat, in participants with polycythemia vera. The primary hypothesis is that bomedemstat is a safe and tolerable orally available agent when administered to participants with PV; and inhibition of LSD1 by bomedemstat will induce hematologic response in this population by 36 weeks, improve symptom burden and reduce spleen size in participants with enlarged spleen at baseline.

Detailed Description
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This is a Phase 2 multi-center, open-label study evaluating the safety, efficacy, pharmacokinetics and pharmacodynamics of bomedemstat administered orally once daily in participants with PV. Participants will receive 36 weeks of dosing and may qualify for additional treatment thereafter. Participants will be followed closely throughout the study for both adverse events by frequent monitoring of clinical signs and symptoms as well as safety labs. Efficacy and pharmacodynamic effects will be closely monitored by frequent hematology assessments of peripheral blood. Throughout dosing, transfusions or phlebotomy may be administered if needed in accordance with standard institutional guidelines. To ensure safety, a Safety Advisory Board will perform periodic reviews of safety parameters and pharmacodynamic markers.

Official Title
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A Phase 2 Multi-Center, Open Label Study to Assess the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Bomedemstat in Patients With Polycythemia Vera (PV)

Conditions
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Polycythemia Vera

Intervention / Treatment
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* Drug: bomedemstat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of Polycythemia Vera per World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms Has a bone marrow fibrosis score of Grade 0 or Grade 1 Has failed at least one standard cytoreductive therapy to lower hematocrit Has a life expectancy >36 weeks Has discontinued prior cytoreductive therapy for 2 weeks (4 weeks for interferon) prior to study drug initiation Exclusion Criteria: Has an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or greater Has unresolved treatment related toxicities from prior therapies (unless resolved to ≤ Grade 1) Has an uncontrolled active infection Has a known human immunodeficiency virus (HIV) infection or active Hepatitis B or Hepatitis C virus infection Has evidence of increased risk of bleeding, including known bleeding disorders Is pregnant or lactating

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bomedemstat<br>Participants will receive bomedemstat daily for 36 weeks and may qualify for additional treatment thereafter if deriving clinical benefit. | Drug: bomedemstat<br>* Oral tablet<br>* Other names: IMG-7289;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) | An AE is defined as 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 with one or more AEs will be presented. | Up to  40 weeks | 
| Number of participants who discontinued study intervention due to AEs | An AE is defined as 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 intervention due to AEs will be presented. | Up to  36 weeks | 
| Number of participants with change from baseline of hematocrit to <45% without phlebotomy at Week 36 | Hematocrit will be analyzed by taking blood samples from participants at designated time points during the study. The number of participants who have a change from baseline of hematocrit to <45% without phlebotomy at Week 36 will be presented. | Baseline through Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of reduction of hematocrit to <45% without phlebotomy | Hematocrit will be analyzed by taking blood samples from participants at designated time points during the study. The duration of a reduction in hematocrit to <45% without phlebotomy up to Week 36 will be presented. | Baseline through Week 36 | 
| Number of participants with platelet count ≤ 450 x 10^9/L at Week 36 | Platelet count will be analyzed by taking blood samples from participants at designated time points during the study. The percentage of participants who have a platelet count ≤450 X 10^9/L will be presented. | Baseline through Week 36 | 
| Duration of platelet count ≤ 450 x 10^9/L in participants at Week 36 | Platelet count will be analyzed by taking blood samples from participants at designated time points during the study. The duration of the reduction of platelet count of ≤450 X 10^9/L in participants will be presented. | Baseline through Week 36 | 
| Number of participants with white blood cell (WBC) count of <10 x 10^9/L at Week 36 | WBC count will be analyzed by taking blood samples from participants at designated time points during the study. The percentage of participants who have a WBC count of <10 X 10^9/L will be presented. | Baseline through Week 36 | 
| Duration of white blood cell (WBC) count <10 x 10^9/L in participants at Week 36 | WBC count will be analyzed by taking blood samples from participants at designated time points during the study. The duration of the reduction of WBC count <10 X 10^9/L in participants will be presented. | Baseline through Week 36 | 
| Number of participants with thrombotic events | Thrombotic events are defined as: new or recurrent acute myocardial infarction; unstable angina; stroke; transient ischemic attack (TIA); deep venous thrombosis (DVT); pulmonary embolism (PE); thrombotic digital ischemia; other thrombotic events such as peripheral limb ischemia or Budd-Chiari syndrome that are assessed to be due to underlying PV; other vascular occlusive events such as symptoms of cardiac, abdominal or peripheral limb ischemia supported by objective evidence of vessel disease and/or ischemia. The number of participants with thrombotic events will be presented. | Baseline through Week 36 | 
| Number of participants with major hemorrhagic events | Hemorrhagic events are defined as: Major Bleeding (MB) Events such as 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 fall in hemoglobin level of 2 g/dL or more, or leading to transfusion of 2 or more units of whole blood or red cells; Clinically Relevant Non-Major Bleeding (CRNMB) Events Leading to hospitalization or increased level of care or clinically important, prompting a face-to-face medical evaluation. The number of participants with hemorrhagic events will be presented. | Baseline through Week 36 | 
| Number of participants with a reduction in splenic volume in patients with an enlarged spleen at baseline | Spleen volume will be measured by magnetic resonance imaging (MRI) (or computerized tomography [CT] if participant is not a candidate for MRI) of the abdomen according to standard procedures. The number of participants with a reduction in spleen volume by Week 36 will be presented. | Baseline through Week 36 | 
| Number of participants with progressive disease (PD) | PD is defined as the worsening of PV to post-polycythemia vera myelofibrosis, myelodysplastic syndrome or transformation to acute myeloid leukemia. The number of participants with PD will be presented. | Baseline through Week 36 | 
| Maximum plasma concentration (Cmax) of bomedemstat | Cmax is defined as the peak concentration over the dosing interval. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax of bomedemstat. | At designated time points on Day 1, Day 15 and at investigators choice of one of any regularly scheduled study visit from Week 4 (Day 29) to Week 8 (Day 57) | 
| Area under the curve 0-24 (AUC 0-24) of bomedemstat | AUC is defined as area under curve exposure. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine AUC of bomedemstat. | At designated time points on Day 1, Day 15 and at investigators choice of one of any regularly scheduled study visit from Week 4 (Day 29) to Week 8 (Day 57) | 
| Half life (t½) of bomedemstat | t½ is the time required for 50% of drug to be cleared from serum. Blood samples will be collected pre-dose and post-dose at designated timepoints to determine t½ of bomedemstat. | At designated time points on Day 1, Day 15 and at investigators choice of one of any regularly scheduled study visit from Week 4 (Day 29) to Week 8 (Day 57) | 
| Number of participants with change from baseline in The Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) 7-day recall at Week 36 | The MFSAF v4.0 is a 7-item questionnaire used for the assessment of myelofibrosis symptoms that asks participants to report symptom severity at its worst for each of the seven items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale and has a minimum score of 0 and a maximum score of 70. Participants will be evaluated with the MFSAF v4.0 at designated time points during the study. The number of participants with a change from baseline by Week 36 will be reported. | Baseline through Week 36 | 
| Number of participants with change from baseline in Patient Global Impression of Change (PGIC) | The PGIC is a one-item questionnaire based on the Clinical Global Impressions (CGI) scale and adapted to the participant. It measures change in clinical status from a scale of 1-7 with 1 being very much improved to 7 being very much worse. The number of participants with a change in PGIC score from Week 12 to Week 36 will be presented. | Week 12 through Week 36 | 
| Number of participants with a durable change in participant-reported symptom burden on the MFSAF v4.0 7-day recall | The MFSAF v4.0 is a 7-item questionnaire used for the assessment of myelofibrosis symptoms that asks participants to report symptom severity at its worst for each of the seven items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale and has a minimum score of 0 and a maximum score of 70. Participants will be evaluated with the MFSAF v4.0 at designated time points during the study. The number of participants achieving a durable change of the MFSAF Score will be presented. | Baseline through Week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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polycythemia vera, bomedemstat