A Phase 3, Randomized, Double-Blind, Active-Comparator-Controlled Study of Bomedemstat Versus Hydroxyurea in Patients with Essential Thrombocythemia Naïve to Cytoreductive Therapy

Blood, vol. 144, pp. 4569.3

Abstract

Background and Significance: Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by thrombocytosis, increased risk of thrombosis, and the potential to develop myelofibrosis (MF) and acute myeloid leukemia (AML). ET is driven by mutations in JAK2, CALR, and MPL. Clinical management is focused on reducing the incidence of thrombotic and bleeding events. Currently available treatments can normalize platelet counts (PC) but are not effective in all patients. There remains an unmet need for novel therapies that can alter the natural history of ET. Bomedemstat (MK-3543) is an irreversible inhibitor of lysine-specific demethylase 1, an enzyme that regulates hematopoietic stem and progenitor cell proliferation and maturation, including differentiation to megakaryocytes. Bomedemstat reduced PC, white cell counts (WCC), and serum levels of inflammatory cytokines in preclinical models of myeloproliferative neoplasms. In a phase 2 clinical study of patients with ET, bomedemstat improved symptoms, durably reduced PC and WCC, and reduced mutation burden. This randomized, double-blind, active-comparator-controlled, phase 3 study (NCT06456346) will investigate the efficacy and safety of bomedemstat versus hydroxyurea in patients with high-risk ET who are naive to cytoreductive therapy. Study Design and Methods: Eligible patients are aged ≥18 years and have cytoreductive therapy naive ET with an indication for cytoreductive therapy, a bone marrow fibrosis score of 0 or 1, a PC of >450 × 109/L, and an absolute neutrophil count of ≥0.75 × 109/L. Patients with documented increased bleeding risk or an active infection requiring systemic therapy are excluded. Approximately 300 patients will be enrolled and randomly assigned 1:1 to receive either bomedemstat at a starting dose of 50 mg/day by mouth (titrated to a target PC of ≥150× 109/L to ≤350 × 109/L) or hydroxyurea at a starting dose of 500 mg/day by mouth (titration per the approved product labeling allowed). Randomization will be stratified by mutation status (JAK2 V617F vs CALR/MPL vs others) and baseline Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) fatigue score (≥4 vs <4). Clinic visits will occur every 2 weeks through week 12 and every 4 weeks thereafter. Adverse events will be monitored up to 30 days after treatment end and graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria. The primary end point is durable clinicohematologic response, defined as confirmed PC reduction to ≤400 × 109/L; absence of WCC elevation to >10 × 109/L due to ET (local assessment); WCC reduction to ≤10 × 109/L confirmed at first subsequent measurement ≥2 weeks later (starting at week 24, maintained for ≥24 weeks) in patients with WCC >10 × 109/L at screening; and absence of any thrombotic or major hemorrhagic events or disease progression to MF or myelodysplastic syndrome (MDS)/AML by week 52. Secondary end points include change in fatigue and total symptom score from baseline per the MFSAF v4.0, change in total fatigue score from baseline per the PROMIS Fatigue SF-7a scale, duration of clinicohematologic response, duration of hematologic remission, incidence of thrombotic events, incidence of major hemorrhagic events, transformation to post-ET MF or MDS/AML, event-free survival, and safety. Exploratory end points include change from baseline in patient-reported outcome scores (Patient Global Impression of Severity [PGIS]-ET, Patient Global Impression of Change [PGIC]-ET, PGI-Fatigue, PGIC-Fatigue, EORTC QLQ-30, EuroQoL-5D-5L, and Work Productivity and Activity Impairment - ET), evaluation of bomedemstat pharmacokinetics, and molecular biomarker identification. Primary analysis and secondary patient-reported outcome analyses will be conducted with the intent-to-treat population (all randomly assigned patients). Safety analyses will be conducted with all randomly assigned patients who receive at least 1 dose of study intervention. The Stratified Miettinen-Nurminen method will be used to compare the end points of durable clinicohematologic response rate and incidence of disease progression between the 2 arms. Treatment difference in event-free survival will be assessed using a stratified log-rank test. Duration of clinicohematologic response and hematologic remission and an overall safety analysis will be summarized descriptively.

Authors 20

1. Yuka Sugimoto

   Mie University

   Affiliation as printed

   1Mie University Graduate School of Medicine, Tsu, Japan

2. Eran Zimran

   Hadassah Medical Center

   Affiliation as printed

   2Hadassah Medical Center, Jerusalem, Israel

3. Yoshimitsu Shimomura

   Kobe City Medical Center General Hospital

   Affiliation as printed

   3Kobe City Medical Center General Hospital, Kobe, Japan

4. Hiroki Yamaguchi

   Nippon Medical School

   Affiliation as printed

   4Nippon Medical School, Tokyo, Japan

5. Hans Carl Hasselbach

   Zealand University Hospital

   Affiliation as printed

   5Zealand University Hospital, Roskilde, Denmark

6. Jean‐Jacques Kiladjian

   Université Paris Cité · Hôpital Saint-Louis

   Affiliation as printed

   6Hôpital Saint-Louis, Université Paris Cité, Paris, France

7. Steffen Koschmeider Aachen 7Faculty of Medicine

   RWTH Aachen University

   Affiliation as printed

   7Faculty of Medicine, RWTH Aachen University, Aachen, Germany

8. Harinder Gill

   University of Hong Kong

   Affiliation as printed

   8School of Clinical Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong

9. Kristen Marie Pettit

   University of Michigan

   Affiliation as printed

   9University of Michigan, Ann Arbor, MI

10. David M. Ross

    South Australia Pathology · Royal Adelaide Hospital

    Affiliation as printed

    10Royal Adelaide Hospital and SA Pathology, Adelaide, Australia

11. Claire Harrison

    St Thomas' Hospital · Guy's and St Thomas' NHS Foundation Trust

    Affiliation as printed

    11Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom

12. Alejandro Berkovits
    Affiliation as printed

    12Inmunocel, Santiago, Chile

13. Ahmet Muzaffer Demir

    Trakya University

    Affiliation as printed

    13Trakya University, Edirne, Turkey

14. Tsai-Yun Chen

    National Cheng Kung University Hospital · National Cheng Kung University

    Affiliation as printed

    14National Cheng Kung University Hospital Clinical Trial Center, Tainan, Taiwan

15. Stefan Scheding

    Skåne University Hospital

    Affiliation as printed

    15Skånes Universitetssjukhus Lund, Lund, Sweden

16. Claudia Barrera Carmona
    Affiliation as printed

    16Higiea Oncologia, Mexico City, Mexico

17. Alessandro Vannuchi

    University of Florence

    Affiliation as printed

    17University of Florence, Florence, Italy

18. Shiyu Zhang

    Merck & Co., Inc., Rahway, NJ, USA (United States)

    Affiliation as printed

    18Merck & Co., Inc., Rahway, NJ

19. Uzor C. Ogbu

    Merck & Co., Inc., Rahway, NJ, USA (United States)

    Affiliation as printed

    18Merck & Co., Inc., Rahway, NJ

20. Keita Kirito

    University of Yamanashi

    Affiliation as printed

    19University of Yamanashi, Chuo, Japan