title: 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.affiliation: Princess Margaret Cancer Centre, University of Toronto, ON, Canada vikas.gupta@uhn.on.ca.
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Phoenix, AZ, USA.
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.affiliation: Division of Hematology and Hematologic Malignancies, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Michael W N
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic Jacksonville, FL, USA.
authors.forename: Candido E
authors.initials: CE
authors.lastname: Rivera
authors.affiliation: Division of Hematology, Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Shireen
authors.initials: S
authors.lastname: Sirhan
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Carrie Baker
authors.initials: CB
authors.lastname: Brachmann
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Collins
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Kawashima
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xin
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015415:Biomarkers; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; C507924:JAK2 protein, human; D053614:Janus Kinase 2