Source – Karyopharm Therapeutics
Karyopharm Therapeutics has initiated a Phase III clinical trial (NCT04562389) to evaluate the effectiveness and safety of combining selinexor and ruxolitinib in patients with myelofibrosis who have not received JAK inhibitor (JAKi) treatment before.
The decision to launch this Phase III trial is supported by positive results from a Phase I study. The Phase I findings showed rapid, profound, and sustained reductions in spleen size and significant improvement in symptoms after 24 weeks of treatment with selinexor at a dosage of 60 mg per week.
The intent-to-treat analysis revealed that 78.6% of patients achieved a spleen volume reduction of 35% or more (SVR35), and 58.3% experienced a 50% or greater improvement in symptoms (TSS50). All 12 evaluable patients achieved SVR35 at some point during the study, and consistent response rates were observed across various patient subgroups, including those treated with a low dose of ruxolitinib.
The combination treatment resulted in improved major spleen and cytokine-related symptoms, and selinexor was generally well-tolerated with manageable adverse events (AEs). Most patients were able to continue the therapy for up to 74 weeks. The most common treatment-related AEs reported with the 60 mg dose of selinexor in combination with ruxolitinib included nausea (78.6%), anemia (64.3%), thrombocytopenia (64.3%), and fatigue (57.1%).
Grade 3 or higher AEs that emerged as a result of the combination with ruxolitinib were primarily anemia (42.9%), thrombocytopenia (28.6%), and back pain (14.3%). Notably, 75% of nausea events were classified as grade I and did not lead to discontinuation of treatment.
The Phase III study will be a randomized, double-blind, placebo-controlled trial involving approximately 306 JAKi-naive patients with intermediate or high-risk myelofibrosis. Participants will be enrolled in a 2:1 ratio to receive either ruxolitinib plus selinexor at a dosage of 60 mg or ruxolitinib plus placebo, with treatment cycles lasting 28 days.
“Selinexor and ruxolitinib appear to work synergistically, resulting in meaningful improvements in spleen response and total symptom score for patients with myelofibrosis. We believe that an opportunity exists to expand upon the initial response, depth, and duration of JAK inhibitors to ultimately improve patient outcomes. This combination has the potential to become a cornerstone treatment in front-line myelofibrosis and we are excited to start this pivotal trial to deliver on our goal of bringing forward an innovative new approach for the treatment of myelofibrosis that can benefit MF patients.”
– Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm
Eligible patients for enrollment must be 18 years or older and have a diagnosis of primary myelofibrosis, post-essential thrombocythemia, or post-polycythemia vera myelofibrosis. During the screening period, patients must exhibit measurable splenomegaly, fall into the intermediate-1, intermediate-2, or high-risk category according to the international prognostic scoring system, have an ECOG performance status of 2 or less, and a life expectancy greater than 6 months. Additionally, patients must experience active symptoms of myelofibrosis and provide bone marrow biopsy samples at screening and during the study.
“The substantial degree of spleen volume reduction observed across all subgroups with selinexor 60mg in combination with ruxolitinib is very encouraging. There is a significant unmet need in the treatment of patients with myelofibrosis, and these data demonstrate that the addition of XPO1 inhibition with selinexor with standard-of-care ruxolitinib has the potential to significantly improve outcomes for first-line myelofibrosis patients. As the principal investigator for the Phase III study, I look forward to defining a potential new standard of care for Jak naïve MF patients.”
– Dr. John Mascarenhas, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders
