Phase 3 randomized double-blind study evaluating selinexor, an XPO1 inhibitor, plus ruxolitinib in jaki-naïve myelofibrosis: Study rationale and preliminary patient characteristics

Abstract

Abstract Background: Myelofibrosis (MF) is a myeloproliferative neoplasm driven by dysregulated JAK-STAT activity and inflammatory cytokine dysregulation. Current therapies, including JAK inhibitors (JAKi), can improve splenomegaly and symptoms but are limited by suboptimal response rates, tolerability, and disease-modifying capacity. <50% of patients (pts) achieve Week 24 SVR35 and TSS50 with ruxolitinib and probability of maintaining SVR35 decreases as early as Week 12 (Levavi 2022; Verstovsek 2017). New therapies targeting disease-relevant pathways beyond JAK-STAT are needed to provide deeper/more durable responses and disease modification. Selinexor (SEL), an oral XPO1 inhibitor, modulates multiple oncogenic pathways implicated in MF and is under investigation in this setting. In a phase 1 study, SEL (40 or 60 mg weekly) plus ruxolitinib (RUX) showed favorable preliminary safety and efficacy profiles for the 60-mg dose. Common AEs at 60 mg were nausea (79%), anemia (64%), thrombocytopenia (64%), and fatigue (57%). Nausea was predominantly Grade 1 and transient; antiemetics were not systematically used. In the 60-mg intent-to-treat group, SVR35 and TSS50 responses were observed at week 24 in 79% and 58% of pts, respectively. Absolute mean (SD) change in TSS (Abs-TSS) was −19 (14) from baseline for the 60-mg group. These data support further evaluation of SEL (60 mg) plus RUX in JAKi-naïve MF. Methods: SENTRY (XPORT-MF-034) is a global, phase 1/3, randomized, double-blind, placebo-controlled study designed to evaluate SEL+RUX in JAKi-naïve MF (NCT04562389). Pts are randomized 2:1 to receive oral SEL 60 mg or placebo once weekly (28-day cycle) plus RUX twice daily dosed per label. Randomization is stratified by DIPSS risk category (int-1 vs int-2/high-risk), spleen volume (<1800 cm3 vs >1800 cm3), and baseline platelet counts (100–200x109/L vs ≥200x109/L). Dual anti-emetics for nausea prophylaxis are required for the first two cycles. Eligibility criteria include age ≥18 years, spleen volume ≥450 cm3, active symptoms of MF (MFSAF v4.0), currently not eligible for stem cell transplantation, ECOG ≤2, and platelet count ≥100x109/L. Exclusion criteria include >10% blasts in peripheral blood or bone marrow and previous treatment with JAKi, SEL or other XPO1 inhibitors. Co-primary endpoints are SVR35 and Abs-TSS at week 24. Secondary endpoints include safety/tolerability, overall survival, progression-free survival, SVR35 and Abs-TSS at week 48, SVR duration, and SEL pharmacokinetics. Exploratory endpoints are hemoglobin stabilization, change in driver gene mutation variant-allele frequency, change in bone marrow fibrosis (BMF) grade, patient-reported outcomes, changes in cytokines and hematopoietic cell composition, and health care resource utilization. Approximately 350 pts with JAKi-naïve MF will be enrolled. Results: The study was initiated June 2023 across ~175 sites in North America, Europe, Israel, Australia, and Asia with first patient enrolled December 2023. As of 14 July 2025, 320 pts have been enrolled. Median (range) age was 66 (20–87) years, 58% of pts were male, and 51% had primary MF. Most presented with DIPSS int-1 (55%), platelet counts ≥200×109/L (68%; median 310.0), and spleen volume <1800 cm3 (64%; median 1402 cm3). Median (range) TSS (excluding fatigue) was 21.0 (2.1–58.3) with mean (SD) 21.9 (12.0). Median Hgb was 11.4 g/dL, mean (SD) peripheral blast (%) was 0.95 (1.63), and 92% of pts were transfusion independent. Driver mutations at baseline were JAK2 (69%), CALR (24%), MPL (8%), and triple negative (1%); 34% of pts had concomitant high–molecular risk mutations. Central review of BMF grade was 38% MF-3, 46% MF-2, 12% MF-1, and 4% MF-0. Conclusions: These preliminary patient characteristics demonstrate that the population enrolled to date is consistent with those enrolled in other major phase 3 studies of MF and representative of the intended population. Higher baseline TSS may lead to more robust improvements in Abs-TSS that can better assess impacts on symptom burden in heterogenous populations across disease severity than TSS50, which is less sensitive to changes and may miss clinically meaningful changes in symptoms. Results from SENTRY will provide important insights into the effects of SEL in combination with RUX and potential benefits across key subgroups in JAKi-naïve MF, a population with continued unmet need for therapies to improve splenomegaly, symptom control and address disease modification.