Fedora preliminary analysis of a Phase II study evaluating the tolerability, safety and activity of fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis.

Abstract

Abstract Background: In myelofibrosis (MF), JAK2 inhibitors alone are not curative. Fedratinib is a selective JAK2 inhibitor. Ropeginterferon Alfa-2b (ropeg), a next generation pegylated IFN, has been shown to induce significant responses in myeloproliferative neoplasms. Combining JAK2 inhibition with interferon may be more effective in the treatment of MF, as haematopoietic cells are activated from quiescence which may render them more sensitive to inhibition. FEDORA is a UK-based phase II trial designed to test the safety, tolerability and efficacy of a combination of fedratinib and ropeg in treatment naïve, JAK2 V617F mutated myelofibrosis. Methods: In this prospective, multicentre, open label, Bayesian, phase II clinical trial patients with JAK2V617F positive primary or secondary MF with an indication for treatment were recruited (ISRCTN:88102629). Each patient was commenced on fedratinib 400mg, as tolerated and when on a stable dose for 28 days, ropeg was introduced at a starting dose of 100micrograms (mcg) subcutaneously every 2 weeks. The dose of ropeg was increased by 50mcg each cycle to the maximum tolerated level or 250mcg. Combination treatment then continues for up to 2 years (until progression, patient choice or unacceptable side effects). Primary outcome was tolerability of the combination. Secondary endpoints included dynamic assessments of JAK2 allele burden and quality of life evaluation. Results: 34 patients from 12 UK sites were recruited. Median age was 68.8 yrs (range (r),32.8-82.9). 47% were female, 74% were White/White European and 12% Asian/Asian British. Median follow-up to date is 12.9 months. Four patients were replaced (3 did not start combination treatment, 1 withdrew within 4 months of starting combination treatment due to scheduled transplant). A total of 31 patients commenced combination treatment, with the majority doing so after receiving 1 cycle of fedratinib monotherapy. The trial met its primary outcome, defined as at least 23 of 30 patients tolerating combination treatment for at least 4 months. At the time of the data snapshot (29th May 2025), 11 patients had discontinued combination treatment. Reasons included: treatment related toxicity (n=6, 3 of which were after the 4-month primary outcome timeframe), proceeding to transplant (n=4) and both treatment-related toxicity (after 4 months) and disease progression (n=1). Symptom scores, as assessed by MPN-SAF, after 3 months of combination treatment had improved from baseline, with the average change across the 15 patients with available baseline and 3-month data showing a decrease for all symptoms. The greatest changes were observed for night sweats (mean change: -1.6 points (range: -7, 1)), abdominal discomfort (mean: -2 (range: -9, 3)), pain under the ribs (mean: -2.3 (range: -8, 1)) and satiety (mean: -2.1 (range: -9, 2)). In total,10 patients (50%) had a palpable spleen at the end of Cycle 4, compared to 25 (89%) at baseline. Across all doses, 32 patients (94%) had an adverse event (AE) related to at least 1 trial treatment, with 18 (53%) patients having a grade 3 or above related AE. The most common related grade ³3 events were anemia and uveitis (affecting 8 and 3 patients respectively). There were 18 serious AEs affecting 12 patients. This includes 9 SUSARs (Suspected Unexpected Serious Adverse Reactions) and 1 expected SAR (Serious Adverse Reaction). Of the samples that have been analysed to-date, paired data are available for 15 patients at baseline and 12 months. Seven patients achieved a relative reduction in JAK2 VAF from baseline of at least 20%, with 4 achieving at least a 50% relative reduction. Comparison of baseline to the last time point was available for 26 patients. The median relative reduction was –14.1% (range: -98.7%, 155.7%). 11 of these patients had achieved at least a 20% relative reduction, including 7 who had a 50% relative reduction or more. Conclusion: The combination of the JAK2 inhibitor fedratinib and ropeg interferon alfa-2b appears tolerable and safe. Symptom score responses and spleen reductions were observed and encouraging reductions in JAK2 allele burden seen in a proportion.