title: A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis.
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.
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
authors.affiliation: Department of Medicine, UCSD Moores Cancer Centre, University of California San Diego, La Jolla, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: Gabrail Cancer Center, Canton, OH, USA.
authors.forename: N Y
authors.initials: NY
authors.lastname: Gabrail
authors.affiliation: Sanofi Oncology, Sanofi, Cambridge, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lebedinsky
authors.affiliation: Sanofi Oncology, Sanofi, Cambridge, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gao
authors.affiliation: Sanofi Oncology, Sanofi, Cambridge, MA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: Sanofi Oncology, Sanofi, Cambridge, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Xu
authors.affiliation: Sanofi Oncology, Sanofi, Cambridge, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Cao
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The University of Michigan Hospital and Health Systems, Ann Arbor, MI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D055728:Primary Myelofibrosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D011759:Pyrrolidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D053614:Janus Kinase 2; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human