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

• Published in: Leukemia research Vol. 61; pp. 89 - 95
• Main Authors: Verstovsek, Srdan, Mesa, Ruben A., Salama, Mohamed E., Li, Li, Pitou, Celine, Nunes, Fabio P., Price, Gregory L., Giles, Jennifer L., D’Souza, Deborah N., Walgren, Richard A., Prchal, Josef T.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2017
• Subjects: Adult; Aged; Antineoplastic Agents - therapeutic use; Dosage; Female; Gandotinib; Humans; Imidazoles - therapeutic use; JAK-2; Janus Kinase 2 - antagonists & inhibitors; Male; Maximum Tolerated Dose; Middle Aged; Myeloproliferative; Neoplasm; Polycythemia Vera - drug therapy; Primary Myelofibrosis - drug therapy; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - therapeutic use; Pyridazines - therapeutic use; Thrombocythemia, Essential - drug therapy; Neoplasm; JAK-2; Gandotinib; Myeloproliferative; Dosage
• ISSN: 0145-2126; 1873-5835; 1873-5835
• DOI: 10.1016/j.leukres.2017.08.010

•Gandotinib shows increased potency for the JAK2V617F mutation.•The recommended phase 2 dose of 120mg was associated with clinical improvement.•Findings at the maximum-tolerated dose of 120mg supported further clinical testing.•Gandotinib demonstrated an acceptable safety and tolerability profile. 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.