title: Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis.
abstract: BACKGROUND
  Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor.
  
  
  METHODS
  We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis.
  
  
  RESULTS
  A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis.
  
  
  CONCLUSIONS
  INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)
authors.affiliation: M.D. Anderson Cancer Center, Houston, TX 77030, USA. sverstov@mdanderson.org
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.forename: Animesh D
authors.initials: AD
authors.lastname: Pardanani
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes-Franco
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Edward C
authors.initials: EC
authors.lastname: Bradley
authors.forename: Susan
authors.initials: S
authors.lastname: Erickson-Viitanen
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
authors.forename: Richard
authors.initials: R
authors.lastname: Levy
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000188:drug therapy / Q000209:etiology; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006529:Hepatomegaly / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009570:Nitriles; D055728:Primary Myelofibrosis / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects*; D011743:Pyrimidines; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000473:pathology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C540383:ruxolitinib; D053613:Janus Kinase 1; D053614:Janus Kinase 2