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Haematologica. 2017 Jan;102(1):94-102. doi: 10.3324/haematol.2016.148924. Epub 2016 Sep 15.

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

Author information

1
Princess Margaret Cancer Centre, University of Toronto, ON, Canada vikas.gupta@uhn.on.ca.
2
Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Phoenix, AZ, USA.
3
Division of Hematology and Hematologic Malignancies, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA.
4
Division of Hematology/Oncology, Mayo Clinic Jacksonville, FL, USA.
5
Division of Hematology, Jewish General Hospital, Montreal, QC, Canada.
6
Gilead Sciences, Inc., Foster City, CA, USA.
7
University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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).

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01423058.

PMID:
27634203
PMCID:
PMC5210237
DOI:
10.3324/haematol.2016.148924
[Indexed for MEDLINE]
Free PMC Article

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