title: A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis.
abstract: NS-018 is a Janus-activated kinase 2 (JAK2)-selective inhibitor, targeting the JAK-signal transducer and activator of transcription (STAT) pathway that is deregulated in myelofibrosis. In this phase I, dose-escalation portion of a phase I/II study, patients with myelofibrosis received oral NS-018 in continuous 28-day cycles. The primary study objective was to evaluate safety, tolerability and clinically active dose of NS-018. Forty-eight patients were treated; 23 (48%) had previously received a JAK inhibitor (JAKi). The most common drug-related adverse events were thrombocytopenia (27%)/anemia (15%) for hematologic events, and dizziness (23%)/nausea (19%) for non-hematologic events. Once daily NS-018 at 300 mg was chosen as the phase II study dose based on improved tolerability compared with higher doses. A ⩾50% reduction in palpable spleen size was achieved in 56% of patients (47% of patients with prior JAKi treatment), and improvements were observed in myelofibrosis-associated symptoms. Bone marrow fibrosis grade (local assessment) improved from baseline in 11/30 evaluable patients (37%) after 3 cycles of NS-018. JAK2 allele burden was largely unchanged. Changes in cytokine/protein levels were noted after 4 weeks of treatment. NS-018 reached peak plasma concentration in 1-2 h and did not accumulate with multiple dosing. NS-018 will be assessed in patients with previous JAKi exposure in the phase II portion.
authors.affiliation: Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.affiliation: Division of Hematology and Medical Oncology, Cornell University, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Ritchie
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wadleigh
authors.affiliation: University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: O
authors.initials: O
authors.lastname: Odenike
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: B
authors.initials: B
authors.lastname: Stein
authors.affiliation: NS Pharma Inc., Paramus, NJ, USA.
authors.forename: T
authors.initials: T
authors.lastname: Uno
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Mesa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D001853:Bone Marrow / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D010641:Phenotype; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2