Uno, Tomonori

Abstract Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2). OBJECTIVE: The purpose of this study is 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. The study drug, NS-018, was given orally either 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 were assessed according to the IWG-MRT/ELN consensus criteria. Bone marrow fibrosis (BMF) was evaluated by biopsy, according to WHO criteria. Changes in grade of BM fibrosis from baseline were categorized as improvement, stabilization, or worsening. The Phase 1 portion of the study has been completed and data are presented here. RESULTS: In this Phase 1 study, 48 patients were enrolled across 10 dosing cohorts (75-400 mg QD/100-400 mg BID). Characteristics: 37 PMF, 5 post-PV MF, 6 post-ET MF with a median age (range) 69.5 yrs (38-83); M/F:29/19; 35 JAK2V617F+, and 23 previously treated with a different JAK2 inhibitor. At 400 mg QD/BID, NS-018 dosing was associated with drug-related neurologic adverse events (AEs) including dizziness, peripheral neuropathy, headache, disturbance in attention, vertigo, dysesthesia, paresthesia, aphasia, and nervous system disorder (not otherwise specified). The 300 mg QD dose was better tolerated than 250 mg BID or 300 mg BID, with fewer neurologic AEs, and was selected as the recommended phase 2 dose (RP2D). For the 48 phase 1 patients, reductions in MF-SAF score were observed for all symptoms after 3 cycles, including for patients with prior JAK2 inhibitor treatment. In all dose cohorts, ≥ 50% patients achieved ≥ 50% score reduction from baseline in night sweats, pruritus and bone pain after 1 cycle. Moreover, ≥ 50% patients achieved ≥ 50% score reduction from baseline in abdominal pain and inactivity after 3 cycles. In patients who had received prior JAK2 inhibitor, ≥ 50% patients achieved ≥ 50% score reduction from baseline in filling up quickly, inactivity, night sweats and quality of life after 3 cycles. Among 36 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 (CI) for ≥ 8 weeks, 4 had hemoglobin CI, and 1 had platelet CI. After 3 cycles of NS-018 treatment, 11/31 (37%) evaluable patients had a reduction in bone marrow fibrosis(BMF) by ≥ 1 grade. At any time during NS-018 treatment, 17/31 (55%) evaluable patients had a reduction in BMF by ≥ 1 grade. Overall, 23% (7/31) patients maintained improvement in BMF for ≥ 12 weeks. Reduction in BMF after 3 cycles was correlated with reduction in splenomegaly and hemoglobin responses. To date, 8 patients with prior JAK inhibitor treatment have been enrolled into the phase 2 portion of the trial. Updated Phase 2 data will presented at the meeting. CONCLUSIONS: The RP2D dose of NS-018 was 300 mg QD. This dose provided an acceptable safety and tolerability profile, and reduction in symptomatic splenomegaly. Phase 2 is ongoing and includes patients previously treated with other JAK2 inhibitors. Disclosures Talpaz: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Sanofi Aventis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Odenike:Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding. Jamieson:GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding. Stein:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Research Funding; CTI Biopharma: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Genentech: Research Funding.

Abstract 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. Disclosures Talpaz: Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Ritchie:Pfizer: Honoraria; Arian: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Honoraria; Incyte: Speakers Bureau. Odenike:Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jamieson:GlaxoSmithKline: Research Funding; CTI Biopharma: Research Funding; Johnson & Johnson: Research Funding. Stein:Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

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.