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

作者：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

来源：Leukemia Research, 2017, 61: 89-95.

DOI：10.1016/j.leukres.2017.08.010

• Myeloproliferative
• Neoplasm
• JAK-2
• Gandotinib
• Dosage

Mutations in Janus kinase 2 (JAK2) are implicated in the pathogenesis of Philadelphia-chromosome negative myeloproliferative neoplasms, including primary myelofibrosis, polycythemia vera, and essential thrombo-cythemia. Gandotinib (LY2784544), a potent inhibitor of JAK2 activity, shows increased potency for the JAK2(V617F) 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 120 mg daily, based on dose-limiting toxicities of blood creatinine increase or hyperuricemia at higher doses. Maximum plasma concentration was reached 4 h after single and multiple doses, and mean half-life on day 1 was approximately 6 h. 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 >= 120 mg at 12 and 24 weeks respectively. Gandotinib demonstrated an acceptable safety and tolerability profile, and findings at the maximum-tolerated dose of 120 mg supported further clinical testing.

• 出版日期2017-10