A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia
In: Leukemia Research, Jg. 61 (2017-10-01), S. 89-95
Online
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Zugriff:
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 JAK2(V6l7F) 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 JAK2(V617F)-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. Clinicaltrials.gov identifier: NCT01134120.
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A phase 1 study of the Janus kinase 2 (JAK2)V617F inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemia
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Autor/in / Beteiligte Person: | Li, Li ; Verstovsek, Srdan ; Nunes, Fabio P. ; Mesa, Ruben A. ; Pitou, Celine ; Gregory L Price ; Jennifer L K Giles ; Prchal, Josef T. ; Walgren, Richard A. ; Salama, Mohamed E. ; D'Souza, Deborah N. |
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Zeitschrift: | Leukemia Research, Jg. 61 (2017-10-01), S. 89-95 |
Veröffentlichung: | Elsevier BV, 2017 |
Medientyp: | unknown |
ISSN: | 0145-2126 (print) |
DOI: | 10.1016/j.leukres.2017.08.010 |
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