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 JAK2 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-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.

Immunological Consequences of JAK Inhibition: Friend or Foe?

“…Rates of infection were not prominent in the large phase III trial [53] however fedratinib has now been removed from the clinical arena due to reports of drug-related Wernicke's encephalopathy, secondary to inhibition of thiamine uptake [54]. To date, available data from the early phase clinical trials involving the JAKi momelotinib (Gilead Sciences) and gandotinib (Eli Lilly, Indianapolis, USA), have not, to date, demonstrated a higher rate of infectious complications but full results are awaited [55,56].…”

Ruxolitinib- but not fedratinib-induced extreme thrombocytosis: the combination therapy with hydroxyurea and ruxolitinib is effective in reducing platelet count and splenomegaly/constitutional symptoms

“…Thrombocytopenia is the main reason for drug dose reductions and discontinuations and is generically attributed to JAK2 inhibition [2]. However, other JAK2 inhibitors have shown lower rates of thrombocytopenia [3,4]. Thus, the causes of hematological toxicity may be related to other mechanisms.…”

Novel therapies for myelofibrosis

“…(43, 44) In a study of thirty-eight patients (31 with MF), a maximum tolerated dose of 120 mg was established (200-mg doses were associated with grade 3 serum creatinine level increases). (44) At a dose of 120 mg, the most frequently reported drug-related AEs (all grades) included diarrhea (44%), nausea (29%), increased creatinine levels (21%), and anemia, vomiting, and fatigue (9% each).…”