Abstract CT261: A Phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis
Authors: Ali Haris , Kishtagari Ashwin , Maher Keri , Mohan Sanjay , Ansaldo Karen , Wang Xulong , Chamoun Kamal , Prchal Josef T. , Tantravahi Srinivas K. 
Published: April 2023

Abstract
Background Myelofibrosis (MF) is a myeloproliferative neoplasm that commonly harbors acquired somatic gene mutations in JAK2, CALR, or MPL. In the Phase 3 COMFORT-1 trial, which enrolled 309 patients (pts) with JAK inhibitor-naïve MF, ruxolitinib (RUX) showed spleen volume reduction of ≥35% (SVR35) and an improvement of 50% or more in the total symptom score (TSS50) in 42% and 46%, respectively compared to placebo. Activity has been shown with the combination of selinexor (SEL) plus RUX in preclinical studies.
Methods XPORT-MF-034 is an open-label, Phase 1/2 study (NCT04562389) to evaluate the safety and efficacy of SEL plus RUX in treatment-naïve MF pts. SEL is evaluated at 2 dose levels, 40mg and 60mg once-weekly plus twice daily RUX in 28-day cycles. For nausea, all pts receive prophylaxis with a 5-HT3 antagonist prior to each SEL dose and as needed. Primary endpoints are to determine maximum tolerated dose, recommended Phase 2 dose (RP2D), and safety. Secondary endpoints include spleen and symptom response, and hemoglobin stabilization and improvement. The efficacy population for spleen and symptom evaluable pts included those who had a spleen assessment or at least one symptom score available, respectively, at baseline and the W12 or W24 timepoint.
Results As of Oct 21, 2022, 24 pts have received at least one dose of 40mg or 60mg weekly SEL with RUX twice daily as per standard of care. Median age was 64 years old (range 44-77) and 11 pts had primary MF, 6 had post-ET MF, and 7 had post-PV MF. DIPSS risk category was int-1, int-2, and high risk for 7, 11, and 6, respectively. The median daily dose of ruxolitinib received was 20 mg. In efficacy evaluable pts, 63% (12/19) and 92% (11/12) achieved SVR35 at W12 and W24, and 83% (10/12) and 67% (4/6) achieved TSS50 at W12 and W24. Among the 11 pts who had a baseline hemoglobin level &lt;10 g/dL, the median hemoglobin level decreased by 0.6 g/dL from baseline to W12 and increased by 0.8 g/dL from baseline to W24. The most common adverse events (AEs) were nausea (75%), anemia (63%), fatigue (58%), and thrombocytopenia (54%). The most common Grade ≥3 AEs were anemia (38%), thrombocytopenia (21%), neutropenia (17%), and atrial fibrillation (13%). Two pts discontinued treatment due to treatment-related AEs (G3 thrombocytopenia, G3 peripheral neuropathy) and no treatment-related deaths were reported.
Conclusions To date, in pts with treatment-naïve MF, the novel combination of SEL and RUX has been reasonably well-tolerated with a generally manageable safety profile and has shown encouraging activity in spleen and symptom responses, in addition to hemoglobin stabilization. Updated safety and efficacy, including symptom data amongst those pts non evaluable for TSS50 at the time of the Oct data cutoff, as well as RP2D, will be available for presentation at AACR 2023.
Citation Format: Haris Ali, Ashwin Kishtagari, Keri Maher, Sanjay Mohan, Karen Ansaldo, Xulong Wang, Kamal Chamoun, Josef T. Prchal, Srinivas K. Tantravahi. A Phase 1, open-label, dose-escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT261.