A combination of selinexor (Xpovio) and ruxolitinib (Jakafi) induced rapid splenic responses at week 12 and demonstrated a manageable toxicity profile in patients with treatment-naïve myelofibrosis.
A combination of selinexor (Xpovio) and ruxolitinib (Jakafi) induced rapid splenic responses at week 12 and demonstrated a manageable toxicity profile in patients with treatment-naïve myelofibrosis, according to data from a phase 1 study (NCT04562389) presented during the EHA 2022 Congress .
Results showed that 75% of evaluable patients (n=8) with the doublet achieved at least a 35% (SVR35) reduction in spleen volume by week 12. The combination was also found to induce a rapid reduction in Total Symptom Score (TSS). at this time.
“The combination of selinexor and ruxolitinib was well tolerated and manageable [adverse] Effect [AE] profile,” wrote the study’s lead author, Haris Ali, MD, an associate professor in the Department of Hematology and Hematopoietic Cell Transplantation, Division of Leukemia, at the City of Hope Comprehensive Cancer Center, and colleagues in a poster accompanying the data. “No dose-limiting toxicities [DLTs] were observed in patients with treatment-naïve myelofibrosis receiving oral selinexor 40 mg or 60 mg once weekly in combination with standard-dose ruxolitinib.”
In a mouse model from JAK2V617F-induced myeloproliferative neoplasm, the combination was previously found to result in a significant reduction in the number of white blood cells, granulocytes, green fluorescent spleen protein-positive cells and spleen weight at day 28 (P < 0.05).
In addition, it was found that treatment with single-agent selinexor resulted in 40% of patients with myelofibrosis whose disease was refractory to JAK inhibitors achieving SVR35 at 24 weeks or more; The agent was also found to have an acceptable toxicity profile.
The phase 1 study will enroll patients with treatment-naïve myelofibrosis who have a spleen volume of ≥ 450 cm3 by MRI or CT and Dynamic International Prognostic Scoring System Intermediate 1, Intermediate 2, or high-risk disease. In addition, to be eligible for inclusion, patients must have an ECOG performance status of 0 to 2 and a platelet count ≥ 100 x 109/L
In the dose escalation phase 1a of the study, the researchers evaluated 2 dose levels of the combination. Those receiving the regimen at dose level 1 (n=3) received selinexor at a weekly dose of 40 mg plus ruxolitinib at a standard twice daily dose of 15/20 mg. Those receiving the combination at dose level 2 (n=3) received selinexor at a weekly dose of 60 mg with standard ruxolitinib.
The dose expansion phase of the research will include approximately 15 patients who will receive weekly selinexor at the recommended dose in combination with standard ruxolitinib.
The primary endpoints of the study include determination of the maximum tolerated dose and the recommended phase 2 dose of the regimen and assessment of adverse events. Secondary endpoints included SVR35, SVR25, TSS50, overall survival, anemia response, AEs, overall response rate, and pharmacokinetics. Digital monitoring via a smartwatch was used to examine quality of life, which serves as the exploratory endpoint of the research.
As of May 1, 2022, the regimen has been administered to a total of 15 patients; 3 patients received 40 mg selinexor and 12 received 60 mg selinexor. The mean age of study participants was 64 (range 45-76). Most patients (n = 10) were male. Four patients had postessential thrombocytopenia, 8 patients primary disease, and 3 patients postpolycythemia vera disease.
In terms of DIPSS risk, 5 patients had intermediate 1-risk disease, 7 had intermediate 2-risk disease, and 3 had high-risk disease. In addition, 3 patients had a driver mutation of CALand the remaining patients had JAK2. Only 2 of the 15 patients were transfusion dependent.
All 15 patients who received at least 1 dose of selinexor were included in the safety population. Eight patients were determined to be evaluable for the spleen; these patients underwent at least one post-baseline splenic examination. In addition, 7 patients were symptom evaluable as they had available data and were treated for at least 12 weeks. Finally, 10 anemia patients were evaluable; these patients were transfusion independent at baseline and had received at least 8 weeks of treatment.
Additional data showed that 5 of the 10 transfusion independent patients who received at least 8 weeks of treatment had maintained stable hemoglobin levels or had improved hemoglobin levels.
In terms of safety, the most common treatment-emergent adverse reactions of the regimen included nausea (Grade 1, 27%; Grade 2, 7%; Grades 3/4, 7%), dysgeusia (Grade 1, 20%; Grade 2, 7%), Hyponatraemia (Grade 1, 20%), dizziness (Grade 1, 20%), vomiting (Grade 1, 13%; Grade 2, 7%), headache (Grade 1, 7%; Grade 2, 13%), anorexia ( Grade 1, 7%, Grade 3/4, 7%), atrial fibrillation (Grade 3/4, 20%), failure to thrive (Grade 3/4, 7%), pulmonary hypertension (Grade 3/4, 7%), tumor lysis syndrome (Grade 3/4, 7%), Neutropenia (Grade 1, 13%; Grade 3/4, 20%), Anemia (Grade 1, 7%, Grade 2, 13%, Grade 3/4, 20%), and Thrombocytopenia (Grade 1, 7%; Grade 2, 7%; Grade 3/4, 27%).
Haematological toxicities were found to be reversible with dose interruptions and reductions. At the time of last follow-up, 53% of patients had a ruxolitinib dose reduction and 20% had a selinexor dose reduction.
One patient discontinued treatment after 5 months due to unrelated adverse events of dizziness, atrial fibrillation and pulmonary hypertension. Another patient discontinued the regimen after 8 weeks of treatment because his disease progressed to acute myeloid leukemia.
According to Ali, patients are currently being enrolled in the study.
Ali H, Kishtagari A, Maher K, et al. A phase 1 open-label dose escalation study of selinexor plus ruxolitinib in patients with treatment-naïve myelofibrosis. Presented at: EHA Congress 2022; 9th-12th June 2022; Vienna, Austria. Summary P1005.