Phase 1/2 Study of NS-018, an Oral JAK2 Inhibitor, in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (postPV MF), or Post-Essential Thrombocythemia Myelofibrosis (postET MF)

Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2).In the previously-reported Phase 1 portion, patients with myelofibrosis (MF) who received NS-018 achieved steady-state plasma levels above the IC₅₀ for JAK2 at all doses (75mg QD - 400 mg BID). 300 mg QD was chosen as the recommended dose (RD) for Phase 2 portion of the study.

OBJECTIVE: The purpose of this study was to determine the safety, tolerability and efficacy of orally-administered NS-018 in patients with PMF, post-PV MF, or post-ET MF.

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, post-PV MF, or post-ET MF. NS-018 was dosed orally daily (QD) or twice daily (BID) in 28-day cycles. In Phase 1, changes in spleen size were assessed by manual palpation, quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF), and responses according to the IWG-MRT/ELN consensus criteria. Bone marrow fibrosis was evaluated by biopsy, according to standard practice at the sites. Changes from baseline in grade of BM fibrosis were categorized as improvement, stabilization, or worsening. The Phase 1 portion of the study is complete. In the ongoing Phase 2 portion, spleen size is being assessed by palpation and by centrally-read MRI, and quality of life evaluated by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).

RESULTS: 48 patients were enrolled across 10 dosing cohorts (75-400 mg QD/100-400 mg BID) in Phase 1. Patient characteristics: 37 PMF, 5 post-PV MF, 6 post-ET MF; median age (range) 69.5 yrs (38-83); M/F:29/19; 35 JAK2V617F+, and 23 previously treated with a different JAK2 inhibitor. The data cutoff for this analysis was June 30, 2016 (median follow-up time of 279.5 [range 5-1806] days from screening), at which time 10 patients remained on treatment. The median number of treatment cycles was 10 (1-65). Reasons for treatment discontinuation were disease progression (PD, n = 13), adverse events (AE, n = 8), physician consideration (n = 6), patient request (n = 4), and protocol non-compliance (n = 1).

The 300 mg QD dose was selected as the phase 2 recommended dose (P2RD) in terms of tolerability and efficacy.

For the 48 patients, reductions in MF-SAF score were observed for all symptoms after 3 cycles, including patients with priorJAK2 inhibitor treatment. Among 36 splenic-evaluable patients with baseline splenomegaly > 5 cm and treatment for > 1 cycle, 20 (56%) showed > 50% reduction in spleen size (confirmed for > 8 weeks in 16 patients), including 9/19 (47%) patients with prior JAK2 treatment. According to IWG criteria, 14/36 (39%) patients showed splenic clinical improvement for > 8 weeks, 4 with hemoglobin CI, and 1 with platelet CI.

Twenty-nine patients with prior JAK inhibitor treatment have been enrolled into the phase 2 portion of the trial. Patient characteristics: 13 PMF, 12 post-PV MF, 4 post-ET MF; median age (range) 67 yrs (48-86). The reason for discontinuation of prior JAK2 inhibitor treatment: AEs (62%) and PD (38%). To date, the median number of treatment cycles is 6 (1-20). The majority of grade 3/4 AEs were hematologic and the most common hematologic toxicities were anemia (21%) and thrombocytopenia (17%). Non-hematologic AEs were mostly grade 1/2, and the other AEs shown in > 10% of patients was nausea (14%). Updated Phase 2 efficacy and safety data will be presented at the meeting.

CONCLUSIONS: The RP2D dose of NS-018 was 300 mg QD. This dose provided a durable dosing schedule, an acceptable safety profile, splenic size reductions and clinical symptom improvement. Phase 2 is ongoing and includes patients previously treated with a different JAK2 inhibitor.