A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis.

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).

• Authors: Vikas Gupta, Ruben A Mesa, Michael W N Deininger, Candido E Rivera, Shireen Sirhan, Carrie Baker Brachmann, Helen Collins, Jun Kawashima, Yan Xin, Srdan Verstovsek
• Journal: Haematologica (Haematologica) Vol. 102 Issue 1 Pg. 94-102 (01 2017) ISSN: 1592-8721 [Electronic] Italy
• PMID: 27634203 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Ferrata Storti Foundation.

Chemical References

• Benzamides
• Biomarkers
• Protein Kinase Inhibitors
• Pyrimidines
• N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
• JAK2 protein, human
• Janus Kinase 2

Topics

• Aged
• Aged, 80 and over
• Benzamides (administration & dosage, adverse effects, pharmacokinetics)
• Biomarkers
• Drug Administration Schedule
• Female
• Humans
• Janus Kinase 2 (antagonists & inhibitors)
• Male
• Middle Aged
• Phenotype
• Primary Myelofibrosis (diagnosis, drug therapy)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Retreatment
• Treatment Outcome