1. A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis.
- Author
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Gupta V, Mesa RA, Deininger MW, Rivera CE, Sirhan S, Brachmann CB, Collins H, Kawashima J, Xin Y, and Verstovsek S
- Subjects
- Aged, Aged, 80 and over, Benzamides adverse effects, Benzamides pharmacokinetics, Biomarkers, Drug Administration Schedule, Female, Humans, Janus Kinase 2 antagonists & inhibitors, Male, Middle Aged, Phenotype, Primary Myelofibrosis diagnosis, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacokinetics, Pyrimidines adverse effects, Pyrimidines pharmacokinetics, Retreatment, Treatment Outcome, Benzamides administration & dosage, Primary Myelofibrosis drug therapy, Protein Kinase Inhibitors administration & dosage, Pyrimidines administration & dosage
- Abstract
Momelotinib, a small-molecule inhibitor of Janus kinase 1 and Janus kinase 2, has demonstrated efficacy in myelofibrosis patients with 300 mg, once-daily dosing. This open-label, non-randomized, phase 1/2 study evaluated the safety and therapeutic benefit of momelotinib with twice-daily dosing. A total of 61 subjects with primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis with intermediate- or high-risk disease received momelotinib. A phase 1 dose escalation identified 200 mg twice daily as the optimal dose to be expanded in phase 2. The most frequent adverse events were diarrhea (45.9%), peripheral neuropathy (44.3%), thrombocytopenia (39.3%), and dizziness (36.1%), the latter primarily due to a first-dose effect. The response assessment according to the 2006 International Working Group criteria (≥8 weeks duration at any time point) demonstrated spleen response by palpation of 72% (36/50) and anemia response of 45% (18/40). Spleen response by magnetic resonance imaging obtained at 24 weeks was 45.8% (27/59) for all subjects and 54.0% (27/50) for those with palpable splenomegaly at baseline. The symptoms of myelofibrosis were improved in most subjects. Cytokine analysis showed a rapid decline in interleukin-6 with momelotinib treatment, and a slower reduction in other inflammatory cytokines. In the subgroup of subjects with the JAK2V617F mutation at baseline (n=41), momelotinib significantly reduced the allele burden by 21.1% (median) at 24 weeks. These results provide evidence of tolerability and a potential therapeutic activity of momelotinib for subjects that support further evaluation in ongoing, phase 3 randomized trials. (clinicaltrials. gov identifier:01423058)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2017
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