P1048: MYF3001: A RANDOMIZED OPEN LABEL, PHASE 3 STUDY TO EVALUATE IMETELSTAT VERSUS BEST AVAILABLE THERAPY IN PATIENTS WITH INTERMEDIATE-2 OR HIGH-RISK MYELOFIBROSIS REFRACTORY TO JANUS KINASE INHIBITOR

HemaSphere, vol. 6, pp. 938–939

Abstract

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm. The Janus Kinase inhibitors (JAKi) ruxolitinib and fedratinib are the only FDA approved treatment options for MF. Despite benefits reported with ruxolitinib in the front-line setting, a high proportion of patients discontinue treatment (Abdelrahman 2015), and the median overall survival (OS) is 11-16 months (Kuykendall 2018; Newberry 2017; Schain 2019; Palandri 2019; Mascarenhas 2020), highlighting a great unmet need for pts non-responsive to a JAKi treatment. Imetelstat, a first-in-class telomerase inhibitor, has shown meaningful clinical improvement in IMbark, a Phase 2 study in patients with intermediate-2 or high-risk MF who have relapsed after or are refractory to JAKi (Mascarenhas JCO 2021). Treatment with 9.4 mg/kg imetelstat resulted in 32.2% symptom response (total symptom score [TSS] reduction ≥50%) at Week 24 and median overall survival (OS) of 29.9 months with overall study follow up of 27.4 months. Dose-dependent inhibition of telomerase with imetelstat resulted in on-target activity that correlated with clinical benefits; dose-dependent reduction in variant allele frequency of MF driver mutations indicated targeting of the underlying malignant clone. Aims: The Phase 2 results support continued study of imetelstat 9.4 mg/kg in a Phase 3 randomized controlled study, for which the study design is described here. Methods: Study MYF3001 (IMpactMF; NCT04576156) is an open label, randomized (2:1), multicenter, Phase 3 study of imetelstat compared with best available therapy (BAT) in ~320 patients with intermediate 2 or high-risk MF refractory to JAKi treatment. Patients will be randomized to receive imetelstat 9.4 mg/kg IV every 21 days or investigator selected BAT including hydroxyurea, thalidomide, interferon, danazol, hypomethylating agents, chemotherapy, or other non-JAKi containing therapy as appropriate). Eligible patients will be stratified based on a) Intermediate 2 or high-risk per Dynamic International Prognostic Scoring System; b) platelet count at entry (platelets ≥ 75 and < 150 x 109/L vs ≥ 150 x 109/L). Patients who meet progressive disease criteria and discontinue BAT may be eligible to crossover to imetelstat. Results: The primary endpoint is OS and one interim analysis is planned when approximately >71% of death events have occurred. Secondary endpoints include symptom and spleen response rates at week 24, progression-free survival, clinical response assessment per modified 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria, time to and duration of response, reduction in degree of bone marrow fibrosis, safety, pharmacokinetics and patient-reported outcomes. Biomarkers and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones. (Figure 1) Image:Summary/Conclusion: Approximately 180 sites are planned in North and South America, Europe, Middle East, Australia and Asia. The study is open for enrollment.

Authors 17

1. John O Mascarenhas corresponding

   Tisch Cancer Institute · Icahn School of Medicine at Mount Sinai

   Affiliation as printed

   Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America

2. Claire N. Harrison

   Guy's Hospital · St Thomas' Hospital

   Affiliation as printed

   Guy’s and St Thomas’ Hospital, London, United Kingdom

   Guy's and St Thomas' Hospital, London, United Kingdom

3. Jean‐Jacques Kiladjian

   Hôpital Saint-Louis

   Affiliation as printed

   Hôpital Saint-Louis, Université Paris, Paris, France

4. Rami S. Komrokji

   Moffitt Cancer Center

   Affiliation as printed

   H Lee Moffitt Cancer Center, Tampa, FL, United States of America

5. Steffen Koschmieder Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University, Aachen, Germany

6. Alessandro Maria Vannucchi

   University of Florence

   Affiliation as printed

   AOU Careggi, University of Florence, Florence, Italy

7. T. Berry

   Geron (United States)

   Affiliation as printed

   Geron Corporation, Parsippany, NJ

8. Denise Redding

   Geron (United States)

   Affiliation as printed

   Geron Corporation, Parsippany, NJ

9. Laurie Jill Sherman

   Geron (United States)

   Affiliation as printed

   Geron Corporation, Parsippany, NJ

10. Souria Dougherty

    Geron (United States)

    Affiliation as printed

    Geron Corporation, Parsippany, NJ

11. Lixian Peng

    Geron (United States)

    Affiliation as printed

    Geron Corporation, Parsippany, NJ

12. Louise Y. Sun

    Geron (United States)

    Affiliation as printed

    Geron Corporation, Parsippany, NJ

13. Fei Huang

    Geron (United States)

    Affiliation as printed

    Geron Corporation, Parsippany, NJ

14. Ying Wan

    Geron (United States)

    Affiliation as printed

    Geron Corporation, Parsippany, NJ

15. Faye M. Feller

    Geron (United States)

    Affiliation as printed

    Geron Corporation, Parsippany, NJ

16. Aleksandra Rizo

    Geron (United States)

    Affiliation as printed

    Geron Corporation, Parsippany, NJ

17. Srđan Verstovšek

    The University of Texas MD Anderson Cancer Center

    Affiliation as printed

    The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America