MPN-183: Preliminary Gastrointestinal Safety and Tolerability of Fedratinib from the Phase IIIb FREEDOM Trial in Patients with Intermediate- or High-Risk Myelofibrosis Previously Treated with Ruxolitinib

Context: Fedratinib is a selective JAK2/FLT3 inhibitor shown to induce spleen responses and symptom improvement in patients with myelofibrosis. Gastrointestinal (GI) events including nausea, vomiting, and diarrhea, were the most common adverse events (AEs) in fedratinib clinical trials, and were most frequent during early treatment. The JAK1/2 inhibitor, ruxolitinib, has demonstrated efficacy in patients with myelofibrosis; however, many patients discontinue ruxolitinib due to loss of response or drug-related cytopenias. The ongoing, single-arm, phase IIIb FREEDOM study evaluates fedratinib in myelofibrosis patients previously treated with ruxolitinib. FREEDOM includes prospective mitigation strategies for managing GI events. Objective: Review the frequency, severity, and mitigation of GI events during early fedratinib treatment in FREEDOM. Methods: Eligible patients are aged ≥18 years, with intermediate- or high-risk MF, ECOG-PS score 0-2, platelet count ≥50 × 109/L, and splenomegaly ≥ 450cm3 or palpable spleen > 5 cm below LCM; and had previously received ruxolitinib for ≥3 months (or ≥28 days with intolerance). Patients receive fedratinib 400 mg/day in continuous 28-day cycles. Study design includes mitigation strategies (prophylaxis, symptomatic treatment, dosing modifications, dosing with food) for managing GI toxicities. AEs are evaluated in all treated patients. Results: At data cutoff (26-Mar-2020), 22 patients had enrolled; 4 patients discontinued (none due to GI-related events). Median age was 68.5 years (range, 49-80). All patients had received ≥3 months of prior ruxolitinib treatment; the most common reason for ruxolitinib discontinuation was relapse (27%). Median fedratinib treatment duration was 18.6 weeks (1.6-48); 10 patients (46%) received >6 fedratinib cycles. Diarrhea, vomiting, and nausea occurred in 32%, 18%, and 14% of patients, respectively; none of these events were grade 3-4 or required dose modification or discontinuation. 12 patients (55%) received ondansetron and 6 (27%) received loperamide. Conclusions: Fedratinib was generally well tolerated. In similar patients receiving fedratinib 400 mg/day (starting dose) in the phase II JAKARTA2 study, which did not prespecify mitigation for GI events, rates of diarrhea, nausea, and vomiting through end-of-cycle 6, ranged from 41% to 62%. Early data from the FREEDOM study suggest frequency and severity of GI events may be reduced via mitigation strategies. Study enrollment is ongoing.