title: Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials.
  
  
  OBJECTIVE
  To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF.
  
  
  METHODS
  Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles.
  
  
  METHODS
  The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).
  
  
  RESULTS
  The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P < .001). Symptom response rates at week 24 were 33 of 91 (36% [95% CI, 26%-46%]), 31 of 91 (34% [95% CI, 24%-44%]), and 6 of 85 (7% [95% CI, 2%-13%]) in the fedratinib 400-mg, 500-mg, and placebo groups, respectively (P < .001). Common adverse events with fedratinib treatment were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. A diagnosis of Wernicke encephalopathy was supported by magnetic resonance imaging in 3 cases and suspected clinically in 1 case.
  
  
  CONCLUSIONS
  Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued.
  
  
  BACKGROUND
  clinicaltrials.gov identifier: NCT01437787.
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.affiliation: Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, England.
authors.forename: Claire
authors.initials: C
authors.lastname: Harrison
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Hospital Clinic, IDIBAPS University of Barcelona, Barcelona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.affiliation: Division of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.affiliation: Centre for Haematology and Stem Cell Transplantation, Heartlands Hospital, Birmingham, England.
authors.forename: Donald
authors.initials: D
authors.lastname: Milligan
authors.affiliation: Department of Haematology and Stem Cell Transplantation, St István and St László Hospital, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Masszi
authors.affiliation: Hematology-Oncology Unit, Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Mishchenko
authors.affiliation: Groupe Hospitalo-Universitaire Nimes, Nimes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Jourdan
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, Scotland.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Drummond
authors.affiliation: Hematology Department, Klaipeda Seamen's Hospital, Klaipeda, Lithuania.
authors.forename: Mindaugas
authors.initials: M
authors.lastname: Jurgutis
authors.affiliation: Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Kuliczkowski
authors.affiliation: Brasov Country Hospital, Brasov, Romania.
authors.forename: Emanuil
authors.initials: E
authors.lastname: Gheorghita
authors.affiliation: University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.affiliation: Sanofi Oncology, Cambridge, Massachusetts.
authors.forename: Frank
authors.initials: F
authors.lastname: Neumann
authors.affiliation: Sanofi Oncology, Cambridge, Massachusetts.
authors.forename: Abhay
authors.initials: A
authors.lastname: Patki
authors.affiliation: Sanofi Oncology, Cambridge, Massachusetts.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D009154:Mutation; D009929:Organ Size; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects; D013154:Spleen / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D013163:Splenomegaly / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D053614:Janus Kinase 2; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human