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3209 A Global, Phase 3, Randomized, Double-Blind Study to Evaluate Safety and Efficacy of Selinexor, an XPO-1 Inhibitor, in Combination with Ruxolitinib in JAK Inhibitor-Naïve Myelofibrosis (XPORT-MF-034)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Non-Biological therapies, Clinical Research, drug development, Diseases, Therapies, Myeloid Malignancies, Study Population, Human
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Keri Maher, DO1, Raajit K. Rampal, MD, PhD2, Prithviraj Bose, MD3, Nikolai A. Podoltsev, MD, PhD4, Claire N Harrison5, Junshik Hong, MD6, Xulong Wang7*, Kamal Chamoun7* and John Mascarenhas, MD8*

1Massey Cancer Center, Virginia Commonwealth University, Richmond, VA
2Memorial Sloan Kettering Cancer Center, New York, NY
3MD Anderson Cancer Center, The University of Texas, Houston, TX
4Associate Professor of Medicine, Department of Hematology, Yale School of Medicine, New Haven, CT
5Guy’s and St. Thomas’ NHS Foundation Trust, London, ENG, United Kingdom
6Seoul National University Hospital, Seoul National University College of Medicine, Seoul, KOR
7Karyopharm Therapeutics, Newton, MA
8Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY

Background and Significance: Myelofibrosis (MF) is a myeloproliferative neoplasm that commonly harbors somatic gene driver mutations in Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus (MPL) genes. Selinexor is an investigational oral XPO1 inhibitor that may inhibit MF-relevant pathways including STAT, extracellular signal-regulated kinase (ERK), protein kinase B (AKT) and p53. Furthermore, in vivo preclinical studies have shown potential synergy between selinexor and ruxolitinib treatment. The Phase 3 trial was initiated based on data from the Phase 1 portion of XPORT-MF-034 evaluating the combination of selinexor and ruxolitinib in JAKi-naïve patients with MF. Previously we reported that the combination of selinexor and ruxolitinib was generally tolerable and manageable and that the 60 mg selinexor dose cohort showed 71% and 79% of the intent-to-treat (ITT) population achieving a ≥35% reduction in spleen volume from baseline (SVR35) at Week 12 and Week 24, respectively; SVR35 rates were consistent across subgroups, including gender and regardless of ruxolitinib starting dose. Robust symptom improvement was also observed with 58% of the ITT achieving a ≥50% reduction in total symptom score from baseline (TSS50) at Week 24 (Ali et al., ASCO 2023; Ali et al., AACR 2023). These data provided strong support to further evaluate selinexor (60 mg) and ruxolitinib in patients with JAKi-naïve MF.

Study Design and Methods: The XPORT-MF-034 (NCT04562389) trial includes a global, Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the combination of 60 mg selinexor and ruxolitinib. Patients will be randomized 2:1 to receive oral selinexor 60 mg or placebo once weekly (28-day cycle) and twice daily ruxolitinib. Select eligibility criteria include patients ≥18 years of age, with a spleen volume of ≥450 cm3 by MRI or CT, dynamic international prognostic scoring system (DIPSS) of intermediate-1, intermediate-2, or high-risk, active symptoms of MF as determined by presence of at least 2 symptoms with a score ≥3 or total score of ≥10 at screening using the MFSAF v4.0, currently not eligible for stem cell transplantation, ECOG PS ≤2, platelet count ≥100 x 109/L, and creatinine clearance >15mL/min. Patients will be excluded if more than 10% blasts are present in peripheral blood or bone marrow; received previous treatment with JAK inhibitors for MF, or previous treatment with selinexor or other XPO1 inhibitors. The co-primary study endpoints are SVR35 at Week 24 as measured by MRI or CT scan and TSS50 at Week 24 as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) V4.0. The key secondary endpoint is anemia response as per the International Working Group Myeloproliferative Neoplasms Research and Treatment and European Leukemia Network (IWG-MRT and ELN) criteria at Week 24.

Results: The XPORT-MF-034 Phase 3 trial is currently open for enrollment; a total of 306 JAKi-naïve MF patients will be enrolled and the study was initiated on June 28, 2023.

Disclosures: Maher: Sobi (Doptelet): Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Rampal: Galecto: Consultancy; CTI BioPharma Corp: Consultancy; Celgene-BMS: Consultancy; Morphosys/Constellation: Consultancy; Sumitomo: Consultancy; Zentalis: Consultancy; Servier: Consultancy; Kartos: Consultancy; Incyte: Research Funding; Karyopharm: Consultancy; Zentalis: Research Funding; Dainippon: Consultancy; Pharmaessentia: Consultancy; Constellation: Research Funding; Ryvu: Research Funding; Stemline: Research Funding; GSK-Sierra: Consultancy; Incyte: Consultancy. Bose: Kartos, Telios, Disc, Janssen, Geron: Research Funding; GSK, Novartis, Karyopharm, AbbVie, Pharma Essentia, Jubilant, Morphic: Honoraria; Incyte, BMS, CTI, Morphosys, Blueprint, Cogent, Sumitomo, Ionis: Honoraria, Research Funding. Podoltsev: Cogent Biosciences: Other: IDMC Member; AI Therapeutics; Arog Pharmaceuticals; Astellas Pharma, Inc.; Astex Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Celgene Corporation; CTI BioPharma Corp.; Daiichi Sankyo, Inc.; Genentech, Inc.; Jazz Pharmaceuticals, Inc.; Kartos Therapeuti: Research Funding; AbbVie Inc.; Blueprint Medicines (former); Constellation Pharmaceuticals (former); CTI BioPharma Corp. (former); Incyte Corporation (former); Novartis (former); PharmaEssentia (former): Consultancy. Harrison: Galecto: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; GSK: Honoraria, Speakers Bureau; AOP: Honoraria, Speakers Bureau; Morphosys: Honoraria, Speakers Bureau; CTI: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Hong: Bridgebio Therapeutics: Consultancy; Bristol Myers Squibb Korea: Consultancy, Honoraria; Novartis Korea: Honoraria. Wang: Karyopharm: Current Employment. Chamoun: Karyopharm: Current Employment. Mascarenhas: AbbVie, Bristol Myers Squibb, Celgene, CTI BioPharma, Geron, Incyte Corporation, Novartis, Janssen, Kartos Therapeutics, Merck, PharmaEssentia, Roche: Research Funding; Bristol Myers Squibb, Celgene, Constellation Pharmaceuticals/MorphoSys, CTI BioPharma, Galecto, Geron, GSK, Incyte Corporation, Karyopharm Therapeutics, Novartis, PharmaEssentia, Prelude Therapeutics, Pfizer, Merck, Roche, AbbVie, Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte, Novartis, Roche, Geron, GSK, Celgene/BMS, Kartos, AbbVie, Karyopharm, PharmaEssentia, Galecto, Imago, Sierra Oncology, Pfizer, MorphoSys, CTI Bio: Consultancy; Bristol Myers Squibb, Celgene, CTI BioPharma, Geron, Incyte Corporation, Janssen, Kartos Therapeutics, Merck, Novartis, PharmaEssentia, Roche; Participated in consulting or advisory committees – AbbVie, Bristol Myers Squibb, Celgene, Constellation Pharmac: Research Funding; GSK: Honoraria; AbbVie, CTI BioPharma Corp, a Sobi company, Geron, GlaxoSmithKline, Imago, Incyte, Kartos, Kayropharm, MorphoSys, Novartis, Pfizer, PharmaEssentia, Sierra: Consultancy.

*signifies non-member of ASH