Karyopharm Therapeutics Inc. announced the initiation of a pivotal Phase 3 clinical trial (XPORT-MF-034) (NCT04562389) to assess the efficacy and safety of once-weekly selinexor 60mg in combination with ruxolitinib in JAKi-naïve patients with myelofibrosis. The randomized, double-blind, placebo-controlled study is expected to enroll 306 JAKi-naive patients with intermediate or high-risk myelofibrosis. Patients will be randomized 2:1 to ruxolitinib plus selinexor 60mg or ruxolitinib plus placebo in 28-day cycles.

Ruxolitinib dose will be determined by the investigators based on the patients' baseline platelet count per the drug's prescribing information. The co-primary endpoints of the study are spleen volume response rate of = 35% (SVR35) and symptom improvement of = 50% (TSS50) at week 24, with a key secondary endpoint of anemia response at week 24. Updated data from the Phase 1 study recently presented at American Association for Cancer Research (AACR) Annual Meeting 2023, American Society of Clinical Oncology (ASCO) 2023 and European Hematology Association (EHA) 2023 showed rapid, deep and sustained spleen responses and robust symptom improvement in patients treated with selinexor 60mg in combination with ruxolitinib as of the April 10, 2023 data cut-off date: At week 24, 91.7% (11/12) of efficacy evaluable patients demonstrated SVR35 and 77.8% (7/9) achieved TSS50.

The intent to treat population achieved a 78.6% (11/14) SVR35 and 58.3% (7/12) TSS50 respectively. SVR35 responses were observed in 100% (12/12) of evaluable patients at any time and rates were consistent regardless of subgroups, including males and patients treated with low dose ruxolitinib. Improvement in major spleen and cytokine-related symptoms were observed across all Myelofibrosis Symptom Assessment Form domains.

Selinexor was generally well tolerated with a manageable side effect profile, allowing most patients to remain on therapy, up to 74 weeks, as of the data cut-off date. The most common treatment emergent adverse events, regardless of grade, experienced with the 60mg selinexor dose, in combination with ruxolitinib were nausea (78.6%), anemia (64.3%), thrombocytopenia (64.3%) and fatigue (57.1%), and most common treatment emergent grade =3 adverse events experienced with the 60mg selinexor dose, in combination with ruxolitinib were anemia (42.9%), thrombocytopenia (28.6%) and back pain (14.3%) 75% of nausea events were grade 1, were mostly transient and did not lead to treatment-related discontinuations. Nausea rates and grades were reduced for patients who received prophylactic antiemetics.

Meaningful weight gain was observed at week 24 despite the incidence of nausea and vomiting. Karyopharm expects to present top-line data readout from this study in 2025. The company plans to expand its clinical development program in myelofibrosis by investigating selinexor in other front-line opportunities, such as novel combinations, to benefit the greatest number of myelofibrosis patients.