Study Title: A phase II study to evaluate the tolerability, safety, and activity of fedratinib combined with ropeginterferon alfa-2β (ROPEG-IFN-2β) in patients with myelofibrosis.
Participating Centers: 13 Trials Acceleration Programme (TAP) centers across the United Kingdom
Accrual Goal: 30 patients
Study Design: This study is a prospective, phase II, multicenter, open-label clinical trial investigating the tolerability, safety, and activity of fedratinib given in combination with ROPEG-IFN-2β in patients with myelofibrosis. The primary objective is to evaluate the tolerability of this combination in these patients. The secondary objectives are to evaluate the safety and toxicity, to establish the maximum tolerated dose of ROPEG-IFN-2β when given in combination with fedratinib, and to investigate the activity against splenomegaly and myelofibrosis-associated symptoms, quality of life, JAK2 clone size, and bone marrow fibrosis.
Rationale: Myelofibrosis is a severe myeloproliferative neoplasm (MPN) initiated by acquired mutations in hematopoietic stem cells (HSCs) affecting MPL-JAK-STAT signaling. The MPN clone stimulates abnormal deposition of extracellular matrix leading to bone marrow fibrosis, causing anemia, splenomegaly, and reduced survival. JAK2 inhibitors such as ruxolitinib, fedratinib, pacritinib, and momelotinib induce impressive reductions in spleen size, leukocytosis, and symptom burden in the majority of patients with myelofibrosis.1–4 However, despite substantial clinical activity, JAK inhibitors have not been found to selectively target the MPN clone and are not routinely associated with a reduction in mutant allele frequency, histological remissions, or a substantial improvement in life expectancy. Ruxolitinib is the current first-line standard-of-care for patients with symptomatic intermediate-2 or high-risk myelofibrosis, and fedratinib was the second JAK inhibitor recently approved in the United States, United Kingdom, and Europe.5 Fedratinib, an oral JAK2 and FLT3 inhibitor, has higher activity and a longer half-life than ruxolitinib, enabling once daily dosing. As a single agent, fedratinib has substantial efficacy in reducing spleen sizes and symptom burden in both JAK inhibitor–naïve patients as well as those resistant or intolerant to ruxolitinib.6–8
As the JAK inhibitors currently in use or in development do not induce a clonal response even in those patients who have a complete hematologic response, there is a clear logic to combining JAK inhibitors with agents that have the potential for disease-modifying activity, to increase the likelihood of a meaningful improvement in long-term survival. Interferon-α (IFN-α) has been used for several decades in the treatment of MPNs and is the only drug currently in clinical use for MPNs that has a selective effect on the MPN clone and can induce durable molecular responses in some patients. This is thought to result from restoration of immunosurveillance and induction of myeloid cell apoptosis.9 Pegylated forms of IFN are longer acting and associated with reduced adverse effects and with molecular responses and improved survival. ROPEG-IFN-2β is a next-generation, monopegylated β that has a longer half-life than “standard” PEG-IFN, enabling dosing every two weeks and improved tolerability. Early data indicate substantial clinical activity, with significant hematologic and molecular responses in patients with polycythemia vera and myelofibrosis, and improved quality of life.10 Two trials have already evaluated ruxolitinib with standard PEG-IFN, with encouraging signs of reasonable tolerability and decreased allele burden of driver and co-mutations in addition to hematologic responses.11 While both fedratinib and ROPEG-IFN have clear efficacy as single agents, their tolerability and activity in combination has not been tested.
In the FEDORA trial, patients will receive initial pretreatment with fedratinib monotherapy for up to three cycles to establish a stable tolerated dose, followed by combination therapy from cycle 2 with daily fedratinib and ROPEG-IFN every 14 days.
Comment: FEDORA is an important trial that combines two powerful agents with complementary strengths and addresses an important question in the field — whether potent inhibition of JAK2 can be combined with the immunomodulatory and anti-clonal activity of ROPEG-IFN, with acceptable toxicity. We can all hope, as a fedora-wearing Humphry Bogart once said, that “…this could be the beginning of a beautiful friendship.”
This investigator-led trial is funded by grants from BMS, AOP Orphan Pharmaceuticals and supported by Cure Leukaemia. Dr. Psaila has received research funding from Galecto, Evotec, and Alethiomics, has undertaken consultancy and paid speaker events for Novartis, Constellation Therapeutics, and Alethiomics, and is a co-founder/shareholder of Alethiomics. Dr. McMullin has undertaken consultancy and paid speaker events for Novartis, BMS, AbbVie, AOP, CTI, and Sierra Oncology.