A Phase 1/2, Open-Label, Dose-Escalation, Multi-Center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered NS-018 in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (postPV MF), or Post-Essential Thrombocythemia Myelofibrosis (postET MF)
Authors: Verstovsek Srdan , Talpaz Moshe , Ritchie Ellen K. , Wadleigh Martha , Odenike Olatoyosi , Jamieson Catriona , Stein Brady L , Tomonori Uno , Mesa Ruben 
Published: October 2019

Abstract
Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2). Pre-clinically NS-018 inhibited JAK2 kinase with an IC50 value in the subnanomolar range and demonstrated splenomegaly reduction at low doses in a JAK2V617F-bearing mouse model (Blood Cancer J 2011; 1: e29.).
Methods: This multicenter, Phase 1/2, 3+3 dose-escalation study of NS-018 enrolled patients with IPSS intermediate-1, intermediate-2, or high risk PMF, postPV MF, or postET MF. Patients were ≥ 18 years, had ECOG PS ≤ 2 and required therapy but were not required to have splenomegaly in Phase 1. NS-018 was dosed orally daily (QD) or twice daily (BID) in 28-day cycles. Responses were assessed according to IWG consensus criteria, changes in spleen size by manual palpation and quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF). The Phase 1 portion of the study completed enrollment and is presented here.
Results:
Patients: 42 patients were enrolled across 10 cohorts. Patient characteristics: 33 PMF, 5 postPV MF, 4 postET MF; median age (range) 69 yrs (43-83); M/F:28/14; 31 JAK2V617F+, and 17 previously treated with a different JAK inhibitor.
Dosing and tolerability: Dose levels included 75, 125, 200, 300 and 400 mg QD and 100, 200, 250, 300 and 400 mg BID. Systemic exposures based on Cmax were approximately dose proportional across the tested range from 75 to 400 mg.
The recommended Phase 2 dose (RP2D) was 300 mg BID, based on drug-related neurological adverse events (AEs) at 400 mg BID including dizziness (Grade 2 or 3), dysphagia (Grade 2) or hypoesthesia (Grade 1) in one patient each that led to dose reduction or drug discontinuation.
Study drug-related serious AEs (SAEs) included non-cardiac chest pain (Grade 2, 200 and 300 mg BID), lower GI hemorrhage (Grade 3, 300mg BID), paresthesia (Grade 3, 300mg BID), increased lipase (Grade 2, 300mg BID), and dizziness (Grade 3, 400 mg BID) in one patient each.
For the 300 mg BID cohort (n=11), the most frequent drug-related AEs across all grades were nausea (Grade 1, 18%), decreased platelet count (≤ Grade 2, 18%), and dizziness (≤ Grade 2, 27%); Grade 3 related AEs included anemia, lower GI bleed, leukopenia, neutropenia or paresthesia (1 patient each, 9%); and no Grade 4 AEs.
Overall, 22 patients (52%) discontinued treatment due to AEs (n=7), progressive disease (PD) (n=7), or MD/patient decision (n=8). The AEs leading to discontinuation included thrombocytopenia (Grade 4), transient ischemic attack (Grade 2), muscle contraction involuntary (Grade 2), light headedness (Grade 1), insomnia (Grade 1), hemolytic anemia (Grade 3), dizziness (Grade 2), dysphagia (Grade 2), and hypoesthesia (Grade 1). Nine patients had a hemoglobin decrease ≥ 2 g/dL and 8 patients a platelet decrease ≥ 50%.
Responses: Of 33 evaluable patients with baseline splenomegaly ≥ 5 cm and treatment for ≥ 1 cycle, 16 (48%) patients showed ≥ 50% reduction in spleen size (confirmed for ≥ 8 weeks in 11 patients). In addition, 11 patients showed splenic clinical improvement (CI, for ≥ 8 weeks), 3 patients hemoglobin CI, and 2 patients platelet CI. Median (range) time to splenic response and duration of response: 1.5 cycle (1-12) and 4.5 cycles (1-29). Splenic reductions ≥50% are shown in the Table for the specified patient groups. Changes in MF-SAF and PK and PD results will be presented.
Table Splenic reduction(in evaluable patients) All doses 16/33 (48%) 300mg BID 3/6 (50%) 300mg QD 4/7 (57%) Prior different JAK inhibitor treated 8/16 (50%)
Conclusions: The dose of NS-018 determined to be the RP2D in Phase 1 was 300 mg BID. This dose provided a durable dosing schedule with an acceptable safety profile, and was associated with splenic size reduction and clinical improvements. The Phase 2 portion of the study is ongoing and includes only patients previously treated with a different JAK inhibitor.

Disclosures
Verstovsek: NS Pharma, Inc: Research Funding. Talpaz:Ariad, BMS, Sanofi, Pfizer, Incyte: Research Funding. Ritchie:Celgene, Incyte: Speakers Bureau. Odenike:Suneisis Pharmaceuticals, Incyte, Sanofi-Aventis, Algeta Pharmaceuticals, Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jamieson:Roche, Johnson&Johnson, CTI: Research Funding. Stein:Incyte Corporation: Honoraria, Speakers Bureau; Sanofi Oncology: Honoraria. Tomonori:NS Pharma, Inc.: Employment. Mesa:Incyte, CTI, NS Pharma, Inc., Gilead, Celgene: Research Funding.