A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis

S Verstovsek, M Talpaz, E Ritchie, M Wadleigh, O Odenike, C Jamieson, B Stein, T Uno, R A Mesa, S Verstovsek, M Talpaz, E Ritchie, M Wadleigh, O Odenike, C Jamieson, B Stein, T Uno, R A Mesa

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.

Trial registration: ClinicalTrials.gov NCT01423851.

Conflict of interest statement

SV has received research support from NS Pharma, Inc. MT has received research support from Ariad, BMS, Sanofi, Pfizer and Incyte. ER is part of the speakers' bureau for Celgene and Incyte. MW has no conflicts of interest to disclose. OMO has served on the advisory committee for Incyte, CTI/Baxalta, Celgene, Spectrum and Sunesis. CJ has received research funding from J&J and CTI Biopharma. BS has served as part of the advisory committee and speakers' bureau for Incyte and on the advisory committee for Sanofi. TU is an employee of NS Pharma, Inc. RAM has received research support from Incyte, Gilead, Celgene and NS Pharma, Inc.

Figures

Figure 1
Figure 1
Patients with ⩾50% reduction in individual symptoms for (a) all evaluable patients and (b) evaluable patients who had previously received a JAK2 inhibitor. n, number of evaluable patients (⩾1 cycle treated and score >2 at baseline).
Figure 2
Figure 2
Maximum change in biomarker levels following 4 cycles of NS-018 therapy. B2M, β-2 macroglobulin; BID, twice-daily dosing; CRP, C-reactive protein; EPO, erythropoietin α IL, interleukin; MPO, myeloperoxidase; QD, once-daily dosing; TNFR2, tumor necrosis factor receptor 2.
Figure 3
Figure 3
Systemic exposure of NS-018. (a) Plot of NS-018 plasma concentration over time on Day 8; (b) AUC0–24 on Day 8. AUC0–24, area under the plasma concentration vs time curve from time 0 to 24 h (the value of AUC0–24 for BID dosing was calculated as twice the value of AUC0–12); BID, twice-daily dosing; CV, coefficient of variation; QD, once-daily dosing.

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