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

Abstract

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.

Conflict of interest statement

Conflict of interest

Li Li, Celine Pitou, Fabio P. Nunes, Gregory L. Price, Jennifer L. Giles, and Richard Walgren are employees of Eli Lilly and Company. Deborah D’Souza is an employee of inVentiv Health Clinical, LLC. Srdan Verstovsek received research support for conduct of this clinical study. Mohamed Salama received research support for pathology studies. Josef T. Prchal received research support for conduct of this clinical study. Ruben Mesa receives research support from Incyte, Gilead, CTI, Genentech, Lilly, Promedior, NS Pharma and is a consultant for Novartis and Shire.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Fig. 1.

Study design. Part A1. Dose-escalation without lead-in period. Part A2. Dose-escalation with lead-in period. Starting dose for lead-in was 120 mg. After the lead-in period doses of 200 and 300 mg were tested. Part B. Dose-confirmation portion of the study; For Part B, a dose of 120 mg was used. Abbreviations: DLT = dose-limiting toxicity; ET = essential thrombocythemia; MTD = maximum tolerated dose; PMF = primary myelofibrosis; pts = patients; PV = polycythemia vera; TD = therapeutic day.

Fig. 2.

Number of patients with a ≥50% reduction in MPN-SAF scores among patients receiving starting dose ≥ 120 mg. References: 1Mesa RA, et al. Leuk Res 2009;33:1199–1203; 2Mesa RA, et al. Cancer 2007;109:68–76; 3Mesa RA, Cortes J. J Hematol Oncol 2013;6:79; 4Mendoza TR, et al. Cancer 1999;85:1186–1196; 5Scherber R, et al. Blood 2011;118:401–408. Abbreviations: MPN-SAF = Myeloproliferative Neoplasm-Symptom Assessment Form; wks = weeks.