A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis

Leukemia. 2017 Feb;31(2):393-402. doi: 10.1038/leu.2016.215. Epub 2016 Aug 1.


NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK-signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ⩾50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1-2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion.

Trial registration: ClinicalTrials.gov NCT01423851.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers
  • Bone Marrow / pathology
  • Female
  • Follow-Up Studies
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Neoplasm Grading
  • Phenotype
  • Primary Myelofibrosis / diagnosis
  • Primary Myelofibrosis / drug therapy*
  • Primary Myelofibrosis / metabolism
  • Primary Myelofibrosis / therapy
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Retreatment
  • Treatment Outcome


  • Antineoplastic Agents
  • Biomarkers
  • Protein Kinase Inhibitors
  • Janus Kinase 2

Associated data

  • ClinicalTrials.gov/NCT01423851