BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis

Author:

Verstovsek Srdan1ORCID,Al-Ali Haifa Kathrin2ORCID,Mascarenhas John3ORCID,Perkins Andrew4ORCID,Vannucchi Alessandro Maria5ORCID,Mohan Sanjay R6,Scott Bart L7ORCID,Woszczyk Dariusz8ORCID,Koschmieder Steffen9ORCID,García-Delgado Regina10,László Rejtő11,McGreivy Jesse S12,Rothbaum Wayne P12,Kiladjian Jean-Jacques13ORCID

Affiliation:

1. The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2. Krukenberg Cancer Center, University Hospital, Halle, 33790, Germany

3. Icahn School of Medicine at Mount Sinai, NY 10029, USA

4. Australian Centre for Blood Diseases, Monash University, Victoria, 3294, Australia

5. University of Florence, Florence, 50121, Italy

6. Vanderbilt University Medical Center, Nashville, TN 37232, USA

7. Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA

8. Hematology Department, University of Opole, Opole, 45-040, Poland

9. Department of Hematology, Oncology, Haemostaseology & Stem Cell Transplantation (Department of Medicine IV), Faculty of Medicine, RWTH University Aachen, Aachen, 52062, Germany

10. Virgen de la Victoria University Hospital, Málaga, 29010, Spain

11. Josa András Teaching Hospital, Nyíregyháza, 4400, Hungary

12. Kartos Therapeutics, Inc., Redwood City, CA 94065, USA

13. Saint-Louis Hospital & Université Paris Cité, Paris, 75010, France

Abstract

Patients with myelofibrosis (MF) who discontinue ruxolitinib due to progression/resistance have poor prognoses. JAK inhibitors control symptoms and reduce spleen volumes with limited impact on underlying disease pathophysiology. Murine double minute 2 (MDM2), a negative regulator of p53, is overexpressed in circulating malignant CD34+ MF cells. The oral MDM2 inhibitor navtemadlin (KRT-232) restores p53 activity to drive apoptosis of wild-type TP53 tumor cells by inducing expression of pro-apoptotic Bcl-2 family proteins. Navtemadlin demonstrated promising clinical and disease-modifying activity and acceptable safety in a phase II study in patients with relapsed/refractory MF. The randomized phase III BOREAS study compares the efficacy and safety of navtemadlin to best available therapy in patients with MF that is relapsed/refractory to JAK inhibitor treatment. Clinical Trial Registration: NCT03662126 ( ClinicalTrials.gov ).

Funder

Kartos Therapeutics

Publisher

Future Medicine Ltd

Subject

Cancer Research,Oncology,General Medicine

Reference42 articles.

1. KRT-232 versus best available therapy for the treatment of subjects with myelofibrosis who are relapsed or refractory to JAK inhibitor treatment (BOREAS). (2021). (Accessed 12 Aug) https://clinicaltrials.gov/ct2/show/NCT03662126

2. Epidemiology of myeloproliferative neoplasms in the United States

3. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment

4. Primary myelofibrosis: 2021 update on diagnosis, risk‐stratification and management

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