Phase I evaluation of XL019, an oral, potent, and selective JAK2 inhibitor

Leuk Res. 2014 Mar;38(3):316-22. doi: 10.1016/j.leukres.2013.12.006. Epub 2013 Dec 11.

Abstract

This phase I study evaluated selective JAK2 inhibitor XL019 in 30 patients with myelofibrosis. The initial dose cohorts were 100, 200, and 300 mg orally on days 1-21 of a 28-day cycle. Central and/or peripheral neurotoxicity developed in all patients. Subsequently, patients were treated on lower doses; neurotoxicity was again observed, leading to study termination. Peripheral neuropathy resolved in 50%, and central neurotoxicity in all patients within months after therapy cessation. Myelosuppression was minimal. The terminal half-life of XL019 was approximately 21 h, with steady state reached by Day 8. International Working Group defined responses were seen in three (10%) patients.

Keywords: Inhibitor; JAK2; Mutation; Myelofibrosis; XL019.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacokinetics
  • Drug Administration Schedule
  • Drug Monitoring
  • Early Termination of Clinical Trials*
  • Female
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 2 / genetics
  • Male
  • Middle Aged
  • Neurotoxicity Syndromes / diagnosis
  • Neurotoxicity Syndromes / etiology*
  • Primary Myelofibrosis / drug therapy*
  • Primary Myelofibrosis / genetics
  • Primary Myelofibrosis / pathology
  • Proline / administration & dosage
  • Proline / adverse effects
  • Proline / analogs & derivatives*
  • Proline / pharmacokinetics
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects*
  • Pyrimidines / pharmacokinetics

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • XL019 compound
  • Proline
  • JAK2 protein, human
  • Janus Kinase 2