Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis

N Engl J Med. 2010 Sep 16;363(12):1117-27. doi: 10.1056/NEJMoa1002028.

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.)

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia / drug therapy
  • Anemia / etiology
  • Biomarkers / blood
  • Cytokines / blood
  • Dose-Response Relationship, Drug
  • Female
  • Hepatomegaly / drug therapy
  • Hepatomegaly / etiology
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Male
  • Middle Aged
  • Mutation
  • Primary Myelofibrosis / blood
  • Primary Myelofibrosis / complications
  • Primary Myelofibrosis / drug therapy*
  • Primary Myelofibrosis / genetics
  • Pyrazoles / administration & dosage*
  • Pyrazoles / adverse effects*
  • STAT3 Transcription Factor / drug effects
  • STAT3 Transcription Factor / metabolism
  • Spleen / drug effects
  • Spleen / pathology

Substances

  • Biomarkers
  • Cytokines
  • INCB018424
  • Pyrazoles
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Janus Kinase 1
  • Janus Kinase 2

Associated data

  • ClinicalTrials.gov/NCT00509899