FREEDOM: A phase 3b efficacy and safety study of fedratinib in intermediate- or high-risk myelofibrosis patients previously treated with ruxolitinib.

Abstract

TPS7072 Background: Myelofibrosis (MF) is a serious life-threatening condition characterized by splenomegaly, constitutional symptoms, and shortened survival. Ruxolitinib (RUX) is currently the only approved drug for treatment (Tx) of Intermediate- (Int) or High-risk MF. RUX discontinuation rates are high, mainly due to lack of response, loss of efficacy, intolerance, and drug-induced cytopenias, resulting in an important unmet medical need for a JAK2 inhibitor that is effective after RUX failure. Fedratinib (FEDR) is an oral, JAK2-selective inhibitor that produces substantial spleen volume reduction (SVR) and improves constitutional symptoms as initial therapy of MF (Pardanani, 2015) and in pts resistant to or intolerant of RUX (Harrison, 2017). Methods: This multicenter, open-label, single-arm study (NCT03755518) is enrolling adult pts with primary, post-polycythemia vera, or post-essential thrombocythemia MF; Dynamic International Prognostic Scoring System (DIPSS) Int- or High-risk disease; splenomegaly; ECOG PS ≤2; and platelet counts ≥50 × 109/L. Pts must have received prior RUX Tx for ≥3 mo or during ≥28 days of RUX therapy were RUX-intolerant (developed RBC transfusion dependence [≥2 units/mo for 2 mo] or grade ≥3 thrombocytopenia, anemia, hematoma/hemorrhage). Pts receive continuous FEDR 400 mg QD in 28-day cycles. Spleen volume is assessed by MRI/CT scan at screening, after cycles 3, 6, and 12, and at end of treatment. Primary endpoint is spleen response rate (RR; ≥35% SVR from BL by cycle 6 end). Secondary endpoints include duration of spleen RR, spleen size reduction, rate and duration of symptom response (≥50% reduction in total symptom score on the Myelofibrosis Symptom Assessment Form), and safety. Risk mitigation strategies for gastrointestinal adverse events and Wernicke encephalopathy are evaluated. Exploratory endpoints include survival, patient-reported outcomes, and biomarkers of FEDR efficacy and biochemical activity. The study will enroll ~110 pts. Assuming a spleen RR of 35%, the study will have ~90% power to detect the lower bound of the 95% CI that excludes 20%. Enrollment is ongoing. Clinical trial information: NCT03755518.