A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis
Open Access
- 7 August 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Blood Cancer Journal
- Vol. 5 (8), e335
- https://doi.org/10.1038/bcj.2015.63
Abstract
In this phase 2 open-label randomized study, 31 patients with intermediate-2 or high-risk myelofibrosis received fedratinib 300, 400 or 500 mg once daily in consecutive 4-week cycles. Mean spleen volume reductions at 12 weeks (primary end point) were 30.3% (300 mg), 33.1% (400 mg) and 43.3% (500 mg). Spleen response rates (patients achieving ⩾35% spleen reduction) at 12/24 weeks were 30%/30% (300 mg), 50%/60% (400 mg) and 64%/55% (500 mg), respectively. By 4 weeks, improvements in myelofibrosis (MF)-associated symptoms were observed. At 48 weeks, 68% of patients remained on fedratinib and 16% had discontinued because of adverse events (AEs). Common grade 3/4 AEs were anemia (58%), fatigue (13%), diarrhea (13%), vomiting (10%) and nausea (6%). Serious AEs included one case of reversible hepatic failure and one case of Wernicke’s encephalopathy (after analysis cutoff). Fedratinib treatment led to reduced STAT3 phosphorylation but no meaningful change in JAK2V617F allele burden. Significant modulation (P<0.05, adjusted for multiple comparisons) of 28 cytokines was observed, many of which correlated with spleen reduction. These data confirm the clinical activity of fedratinib in MF. After the analysis cutoff date, additional reports of Wernicke's encephalopathy in other fedratinib trials led to discontinuation of the sponsored clinical development program.Keywords
This publication has 31 references indexed in Scilit:
- Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) studyLeukemia, 2013
- The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapyArthritis Research & Therapy, 2012
- TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasmsBlood, 2011
- Infrequent occurrence of MPL exon 10 mutations in polycythemia vera and post‐polycythemia vera myelofibrosisAmerican Journal of Hematology, 2011
- Myeloproliferative disordersBlood, 2008
- Selective Inhibition of JAK2-Driven Erythroid Differentiation of Polycythemia Vera ProgenitorsCancer Cell, 2008
- Efficacy of TG101348, a Selective JAK2 Inhibitor, in Treatment of a Murine Model of JAK2V617F-Induced Polycythemia VeraCancer Cell, 2008
- Role of JAK2 in the pathogenesis and therapy of myeloproliferative disordersNature Reviews Cancer, 2007
- MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid MetaplasiaPLoS Medicine, 2006
- A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia veraNature, 2005