A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia

Leuk Res. 2017 Oct;61:89-95. doi: 10.1016/j.leukres.2017.08.010. Epub 2017 Aug 31.


Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2V617F mutation. The study had a standard 3+3 dose-escalation design to define the maximum-tolerated dose. Primary objectives were to determine safety, tolerability, and recommended oral daily dose of gandotinib for patients with JAK2V617F-positive myelofibrosis, essential thrombocythemia, or polycythemia vera. Secondary objectives included estimating pharmacokinetic parameters and documenting evidence of efficacy by measuring clinical improvement. Thirty-eight patients were enrolled and treated (31 myelofibrosis, 6 polycythemia vera, 1 essential thrombocythemia). The maximum-tolerated dose of gandotinib was 120mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4h after single and multiple doses, and mean half-life on day 1 was approximately 6h. Most common treatment-emergent adverse events were diarrhea (55.3%) and nausea (42.1%), a majority of which were of grade 1 severity. Best response of clinical improvement was achieved by 29% of myelofibrosis patients. A ≥50% palpable spleen length reduction was observed at any time during therapy in 20/32 evaluable patients. Additionally, ≥50% reduction in the Total Symptom Myeloproliferative Neoplasm Symptom Assessment Form Score was seen in 11/21 (52%) and 6/14 patients (43%) receiving ≥120mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120mg supported further clinical testing. Clinicaltrials.gov identifier: NCT01134120.

Keywords: Dosage; Gandotinib; JAK-2; Myeloproliferative; Neoplasm.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Female
  • Humans
  • Imidazoles / therapeutic use*
  • Janus Kinase 2 / antagonists & inhibitors*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Polycythemia Vera / drug therapy*
  • Primary Myelofibrosis / drug therapy*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / therapeutic use*
  • Pyridazines / therapeutic use*
  • Thrombocythemia, Essential / drug therapy*


  • Antineoplastic Agents
  • Imidazoles
  • LY2784544
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridazines
  • JAK2 protein, human
  • Janus Kinase 2

Associated data

  • ClinicalTrials.gov/NCT01134120