A Phase 1, Open-Label, Dose-Escalation Study of Selinexor Plus Ruxolitinib in Patients with Treatment-Naïve Myelofibrosis

Abstract

Background: Myelofibrosis (MF) is commonly associated with acquired somatic gene mutations in JAK2, CALR, or MPL. Spleen volume reduction and improvement in symptom burden of MF are attained in 40% of patients treated with the common front-line therapy ruxolitinib (RUX), a JAK1/2 inhibitor. Selinexor (SEL) is an oral Selective Inhibitor of Nuclear Export (SINE) compound that inhibits exportin-1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins (e.g., TP53, IkB, p21), reduction in oncoprotein mRNAs (c-Myc, Bcl-2, Bcl-6, cyclin D) and selective apoptosis of cancer cells. Selinexor has received FDA approval for use in patients with multiple myeloma and diffuse large B-cell lymphoma. Preclinical studies demonstrated activity with the combination of SEL plus RUX. In patients with disease refractory to a JAK inhibitor (JAKi), SEL monotherapy had notable clinical activity and a generally manageable safety profile (NCT03627403). Methods: The ongoing multicenter, open-label, Phase 1/2 study (NCT04562389) is evaluating the safety and efficacy of SEL plus RUX in treatment-naïve MF patients. Two dose levels of SEL were evaluated, 40mg and 60mg orally once-weekly (QW) plus RUX twice daily (BID) as per label in 28-day cycles. For nausea prophylaxis, all patients received a 5-HT3 antagonist prior to each dose SEL and then as needed. Primary objectives include safety, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and preliminary efficacy. Secondary objectives include spleen, symptom, and anemia response, and overall survival. Results: As of July 2022, 19 patients have received at least one dose of oral 40mg (n=4) or 60mg (n=15) weekly SEL with RUX twice daily as per standard of care. Median age was 64 years old (range 44-77). Nine patients had primary MF, 7 had post-ET MF, and 3 had post-PV MF. At baseline, two patients had packed red blood cell (PRBC) transfusion-dependent anemia. DIPSS risk category was int-1 (n=6), int-2 (n=9), and high risk (n=4). Of patients evaluable for spleen response, 11/14 achieved spleen volume reduction of ≥35% (SVR35) at week 12 (79%, 95% CI: 49% to 95%) and 6/7 achieved SVR35 at week 24 (86%, 95% CI: 42% to 100%). Eighty-six percent (12/14) (95% CI: 57% to 98%) of patients achieved SVR35 at any time on study. Thirteen patients with available data and who received at least 12 weeks of treatment were evaluated for symptom response; 9/13 (69%, 95% CI: 39% to 91%) had a total symptom score ≥50% reduction by week 12. Eleven out of 17 PRBC transfusion-independent patients (65%) who received at least 8 weeks of therapy maintained stable hemoglobin (Hgb; ± 2g/dL) or improved Hgb levels (>2g/dL increase) at the last follow up. The most common treatment-emergent adverse events (TEAEs) were nausea (11/19, 58%), anemia (8/19, 42%) and vomiting (8/19, 42%). The most common Grade 3 TEAEs were thrombocytopenia and anemia, with only two Grade 4 TEAEs (thrombocytopenia). Conclusions: In this preliminary analysis, the combination of SEL and RUX shows promising clinical activity to date in patients with treatment-naïve myelofibrosis. The combination has been reasonably well-tolerated and with a manageable side effect profile to date.