Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial.

BACKGROUND: Myelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2V617F, causing constitutive activation of the kinase and activation of downstream signalling. Fedratinib is an oral selective JAK2 inhibitor. It has shown activity in MF and is well-tolerated, but combination with other therapies is likely needed to achieve clonal remission. Combining a JAK2 inhibitor with an interferon may be synergistic, as haematopoietic cells are activated from quiescence (a typical kinase resistance mechanism) rendering them more sensitive to inhibition. Ropeginterferon alfa-2b is a next generation pegylated interferon-α-2b with high tolerability and clinical activity in patients with MF, however, evidence of tolerability and activity in combination with fedratinib is lacking in this setting. The aim of the FEDORA trial is to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b in patients with MF who require treatment to justify further investigation in a phase III trial. METHODS: FEDORA is a single arm, multicentre, open-label, Bayesian phase II trial to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b aiming to recruit 30 patients. Patients with JAK2V617F positive primary or secondary MF, who are aged ≥ 18 years, have intermediate-1 with palpable splenomegaly of > 5cm, intermediate-2, or high-risk disease according to the Dynamic International Prognostic Scoring System (DIPSS), and who require treatment are eligible. The primary outcome is tolerability, whereby the combination is deemed intolerable in a patient if drug-related toxicities in the first four months of treatment lead to: either drug being discontinued; delays in treatment exceeding 28 consecutive days; or death. FEDORA uses a within-patient dose escalation regimen to ensure each patient reaches a personalised dose combination that is acceptable. DISCUSSION: FEDORA is using a Bayesian trial design and aims to provide evidence of the tolerability, safety, and activity of combining fedratinib with ropeginterferon alfa-2b upon which the decision as to whether a phase III trial is warranted will be based. TRIAL REGISTRATION: EudraCT number: 2021-004056-42. ISRCTN: 88,102,629.