TY - JOUR
T1 - A phase 1/2, open-label study evaluating twice-daily administration of momelotinib in myelofibrosis
AU - Gupta, Vikas
AU - Mesa, Ruben A.
AU - Deininger, Michael W.N.
AU - Rivera, Candido E.
AU - Sirhan, Shireen
AU - Brachmann, Carrie Baker
AU - Collins, Helen
AU - Kawashima, Jun
AU - Xin, Yan
AU - Verstovsek, Srdan
N1 - Funding Information:
This study was supported by Gilead Sciences, Inc. Previously presented in part at the European Hematology Association Meeting, Milan, Italy, June 2014. Cytokine data were presented at the American Society of Hematology Meeting, Orlando, FL, USA, December 2015.
Publisher Copyright:
© 2017 Ferrata Storti Foundation.
PY - 2017
Y1 - 2017
N2 - 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, nonrandomized, 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.
AB - 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, nonrandomized, 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.
UR - http://www.scopus.com/inward/record.url?scp=85008414144&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85008414144&partnerID=8YFLogxK
U2 - 10.3324/haematol.2016.148924
DO - 10.3324/haematol.2016.148924
M3 - Article
C2 - 27634203
AN - SCOPUS:85008414144
VL - 102
SP - 94
EP - 102
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 1
ER -