Verstovšek, Srđan

Abstract Background:The Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been evaluated for patients with MF in the phase 3 COMFORT studies. In both trials, ruxolitinib prolonged OS, reduced splenomegaly, and improved MF-related symptoms and quality of life compared with controls. Here, we report the results of an exploratory pooled analysis of OS in the COMFORT studies at 5 years of follow-up. Methods: The double-blind COMFORT-I trial and the open-label COMFORT-II trial were randomized phase 3 studies that evaluated the safety and efficacy of ruxolitinib in patients with intermediate-2 (int-2) or high-risk primary MF (PMF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF). The comparator was placebo in COMFORT-I and best available therapy (BAT) in COMFORT-II. The ruxolitinib starting dose was 15 or 20 mg twice daily based on baseline platelet counts (100-200 and >200 × 109/L, respectively); dose modifications were permitted for safety and efficacy. Patients were allowed to cross over to ruxolitinib from the control arm for progressive splenomegaly, defined as a ≥25% increase in spleen volume from baseline (COMFORT-I) or study nadir (COMFORT-II), or select protocol-defined progression events; crossover was mandatory following treatment unblinding in COMFORT-I. OS was a secondary endpoint in both studies and was evaluated in an intent-to-treat (ITT) analysis using a Cox proportional hazard model that estimated the treatment effect stratified by clinical trial and International Prognostic Scoring System (IPSS) risk. The crossover-corrected treatment effect was estimated using a rank-preserving structural failure time (RPSFT) method. Results: Overall, 528 patients were randomized: 301 to ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 to placebo (n=154) or BAT (n=73). All ongoing patients in the control arms crossed over to ruxolitinib by the 3-year follow-up. Patient populations were similar between the two trials and their details were previously published. In the combined ruxolitinib group, 162 patients (53.8%) had high-risk MF and 139 (46.2%) had int-2 risk MF based on IPSS criteria. At the 5-year ITT analysis, 128 patients (42.5%) died in the ruxolitinib group compared with 117 (51.5%) in the control group. The risk of death was reduced by 30% with ruxolitinib compared with control (median OS: ruxolitinib, 63.5 mo; control, 45.9 mo; HR, 0.70; 95% CI, 0.54-0.91; P=0.0065; Figure A). After correcting for crossover using RPSFT, OS advantage was more pronounced for patients originally randomized to ruxolitinib (median OS: ruxolitinib, 63.5 mo; control, 27 mo; HR, 0.35; 95% CI, 0.23-0.59; Figure B). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged survival compared with control (median OS: ruxolitinib, 63.5 mo; control, 28.3 mo; HR, 0.53; 95% CI, 0.36−0.78; P=0.0013; Figure C). Among all patients treated with ruxolitinib, those with lower-risk disease had longer survival compared with those with high-risk disease (median OS: int-2, not reached [estimated, 102 mo]; high-risk, 50 mo; HR, 2.86; 95% CI, 1.95-4.20; P<0.0001; Figure D). In a subgroup analysis, OS favored ruxolitinib compared with placebo for patients with int-2 or high-risk MF (data not shown). At 5 years, median OS appeared to favor patients with int-2 (n=58) or high-risk (n=89) PMF who were originally randomized to ruxolitinib compared with historical (Cervantes et al; J Clin Oncol 30:2981-2987) controls (int-2 PMF, not reached [estimated, 70 mo] vs 48 mo; high-risk PMF, 34 vs 27 mo); OS was longer among patients with int-2 vs high-risk PMF (P=0.0003). Subgroup analyses showed that ruxolitinib provided an OS advantage regardless of age (>65 or ≤65 y), sex, disease type (PMF, PPV-MF, PET-MF), risk status (int-2 or high), JAK2V617F mutation status, baseline spleen volume (>10 or ≤10 cm), anemia, white blood cell count (>25 or ≤25 × 109L), or platelet count (>200 or ≤200 × 109/L). Conclusion: Long-term treatment with ruxolitinib up to 5 years prolonged survival in patients with MF compared with BAT or placebo. Corrections for patients who crossed over to ruxolitinib suggested that the separation between ruxolitinib and control OS curves was primarily caused by a delay in ruxolitinib treatment. The results suggest that earlier treatment with ruxolitinib may provide a greater survival advantage for patients with MF. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mesa:Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; CTI: Research Funding; Promedior: Research Funding; Galena: Consultancy; Gilead: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Dong:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau.

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 Inflammatory deregulation may be a major factor in cancer related symptoms (Dantzer Nature Rev Clin Oncol 2012). Improved symptoms in myelofibrosis (MF) patients treated with single arm ruxolitinib (JAK1/JAK2 inhibitor) studies has been correlated with normalization of selected cytokines increased pre-therapy (c-reactive protein, IL-1ra, MIP-1b, TNF-a, and IL-6; Verstovsek NEJM 2010). We sought to assess the impact of JAK1/JAK2 inhibitor therapy on cytokine levels and the relationship between cytokine levels and symptoms prior to and during JAK1/JAK2 inhibitor therapy in the phase III placebo controlled COMFORT-I trial (Verstovsek NEJM 2012). Methods Cytokine levels (89 cytokines measured at baseline and at weeks 4 and 24) and MF symptoms (assessed by MFSAF 2.0 – Mesa JCO 2013) were collected during the blinded phase of COMFORT-I. Patients were randomized to ruxolitinib vs. placebo. Plasma was used for the measurement of cytokines using Rules-Based Medicine, Inc. (Austin, TX) Human MAP panel. Associations between the MFSAF total symptom score (TSS) and log2-transformed cytokine data were investigated at baseline using Spearman correlations and linear regression. Mixed models were used to assess cytokine and TSS changes over time within each arm and overall. Logistic regression was used to assess the relationship between baseline cytokines and TSS response (>/=50% reduction from baseline) at week 24, and between week 4 cytokine changes and TSS response (>/=50% reduction from baseline) at week 24 within each arm and overall. Mixed and logistic regression models combining data across arms also included terms for visit, arm, and visit-by-arm interaction. All models also included age, gender, and body mass index (BMI). Given the large number of cytokines being investigated, p<0.001 was considered statistically significant. Cytokine values below the limit of detection were set at the lowest limit of detection and 25 cytokines were excluded from statistical analysis due to having more than 30% of data missing or below the limit of detection. Results Patients: 309 subjects were randomized in COMFORT-I with median age 68 (range 40-91), 46% female, 50% primary myelofibrosis, and 61% high risk. All 309 subjects had cytokines measured at one or more of the three visits included in this analysis, with 308 having cytokine values paired with a TSS score at the same visit. Cytokines at Baseline: At baseline, the highest Spearman correlations with symptomatic burden (as assessed by the TSS) were observed for APOA1 (rho=-.21) and FERRITIN (rho=-.20), followed by INTLK5, MIP1A, MMP3, INTLK2, MGB, INTLK1A, and INTLK7 with correlations between -.15 and -.17 (all p<0.01). After adjusting for age, sex, and BMI, VCAM1 and APOA1 were significantly associated with TSS at baseline. Cytokine and Symptom changes during trial: Changing levels of 5 cytokines were significantly associated with change of TSS over time beyond the change due to visit, arm, visit-by-arm interaction, age, sex and BMI including VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII. Within the placebo arm, only 5 cytokines significantly changed over time compared to 46 cytokines in the ruxolitinib arm (visit-by-arm interaction was significant for 43 in the overall models). VCAM1, B2MICG, and TNFRII were among the 5 cytokines which changed in the placebo arm, and VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII were among the 46 cytokines which changed in the ruxolitinib arm. No baseline cytokines and no changes in cytokines at week 4 univariately predicted week 24 TSS response within either arm at the p<0.001 level. Conclusions In the first serial assessment of MF symptoms and plasma cytokine levels in the conduct of a placebo controlled trial we found 5 cytokines in which improved levels correlated with decreased MF symptom burden in ruxolitinib treated patients. Development of a multivariate model for predicting symptom response, correlations with splenic response and impact on survival benefit of therapy is ongoing. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets >400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), >600 x 109/L (3.7%, 8.9%); WBC >10 and ≤15 x 109/L (16.7%, 16.1%), >15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.

Abstract Background The Janus-kinase (JAK) pathway plays a critical role in normal hematopoiesis. In two phase 3 studies, the JAK1/JAK2 inhibitor ruxolitinib (RUX) demonstrated clinical benefit over placebo (COMFORT-I) or best available therapy (COMFORT-II) in patients with intermediate-2 or high-risk myelofibrosis (MF). Anemia and thrombocytopenia, the most common adverse events associated with RUX treatment, were dose-dependent and expected based on RUX's mechanism of action. These events were successfully managed and few RUX-treated patients discontinued for anemia or thrombocytopenia (<1% for each event). The ability to identify patients who would most likely benefit from a dose adjustment may contribute to improved patient management. Therefore, an analysis was conducted in patients who received RUX in COMFORT-I to identify patient characteristics that could help select patients who would potentially benefit from closer monitoring and dose titration in the early period after initiation of therapy. Methods In COMFORT-I, starting doses in the patients randomized to RUX were 15 mg twice daily (BID) for patients with baseline platelet counts of 100–200 ×109/L (n=55) and 20 mg BID for those with platelet counts >200 ×109/L (n=100). Dose reductions were required for protocol-defined decreases in platelet counts; there was no protocol-mandated dose change for anemia. The time course of dose adjustments and the most common titrated doses by starting dose were evaluated. Logistic regression analyses with baseline hemoglobin (Hgb) level, platelet count, IPSS risk category, sex, and MF type as model effects were conducted to determine predictors of: 1) titration to a RUX dose of ≤10 mg BID within 8 weeks of starting therapy (early dose titration event); or 2) development of grade ≥3 anemia or new need for RBC transfusions (≥2 units of packed RBCs) within 12 weeks of therapy initiation (anemia event). Only baseline platelet count and Hgb emerged as significant predictors (alpha=0.05). Receiver operating characteristics (ROC) analyses were also conducted for these two predictors to determine a clinically relevant cutoff of the underlying predictor variable with a positive predictive value (PPV), true positive rate (TPR), and false positive rate (FPR) obtained at all possible cutoffs and a general goal of obtaining a TPR ≥ 50%, an FPR ≤ 10%, and a high PPV. Results Approximately 70% of patients had a dose adjustment within the first 12 weeks of initiating RUX treatment. At week 24, 77% of patients with baseline platelet counts of 100–200 ×109/L and 39% of those with baseline platelet counts >200 ×109/L had titrated to a reduced RUX dose relative to their starting dose. With longer-term follow-up (median 149 weeks), the mean dose over time in patients who continued on study was ∼10 mg BID for patients starting at 15 mg BID and ∼15 mg BID for those starting at 20 mg BID (Figure). ROC analyses identified that a baseline platelet count range of less than 150–175 x109/L may predict which patients would experience an early titration event, while a baseline Hgb level of less than 10 mg/dL may predict which patients would experience an anemia event (Table). Conclusions In COMFORT-I, most patients experienced a RUX dose adjustment in the first 12 weeks of treatment and stable doses were achieved with long-term therapy. Dose titration allowed most patients to maintain adequate platelet counts. After starting therapy at 15 or 20 mg BID, the majority of patients titrated to RUX doses of 10 mg BID or higher, which have been previously been shown to produce meaningful spleen volume reductions and symptom improvements (Mesa et al. 8th Annual Hematologic Malignancies Conference. Abstract 305; Verstovsek et al. ASH 2012. Abstract 800; Talpaz et al. ASH 2012. Abstract 176). A baseline platelet count of less than 150 ×109/L and baseline Hgb level of less than 10 g/dL may be clinically useful cutoffs for predicting which patients may benefit from closer monitoring shortly after treatment initiation of RUX and appropriate dose adjustments as needed. Disclosures: Mesa: Lilly: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding. Komrokji:Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees. Sun:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Sandor:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Verstovsek:Incyte Corporation: Research Funding.

Abstract BackgroundPacritinib, a JAK2, JAK2 V617F and FLT3 kinase inhibitor is in Phase III development in myelofibrosis. In preclinical models and in Phase 1 studies in both non-Hodgkin lymphoma and myelofibrosis, it appeared unique among this class of agents in its lack of myelosuppression at doses that inhibited the JAK2/STAT3 pathway and resulted in significant clinical efficacy. This potentially important clinical observation was verified in two Phase II studies in myelofibrosis that had no exclusion restriction for low platelets. Pacritinib was effective at reducing spleen size and symptoms regardless of starting platelet counts and there was no apparent decline in either platelet count or hemoglobin levels, or an increase in transfusion requirements. Aims and Methods: To help elucidate the mechanisms for pacritinib’s lack of myelosuppression, a kinome screening analysis against 429 recombinant kinases at 100 nM pacritinib concentration was performed, followed by titration from 1-100nM against those that were >50% inhibited at 100nM (Anastassiadis et al.; Nature Biotechnology; 2011). In humans, pacritinib achieves steady state free drug levels of approximately 200nM at the standard 400 mg daily dose. Results:All kinases with IC50 values of <50nM are included in the table. Table Kinase IC50 (nM) JAK2; JAK2(V617F) 6.0; 9.4 FLT3; FLT3-ITD; FLT3 (D835Y) 6.4; 12.0; 8.3 TYK2 27.0 JAK3 18.3 IRAK1 (IL-1 receptor kinase) 13.6 HIPK4 (PT kinase for P53 ser-9) 14.5 FMS 39.5 c-KIT and most common mutations except (V560G), (V559D/V654A) 43.8 c-Src; (c-Src (T341M)) 47.0 (55.5) Of note, pacritinib did not affect JAK1 (82% control at 100nM). As the concentrations of pacritinib achieved clinically are likely inhibit signaling the kinases listed in the table, these data suggest that the lack of myelosuppression with pacritinib may be either due to inhibition of JAK2 without affecting JAK1 or to suppression of IRAK1, an IL-1 receptor kinase, downstream from Toll-Like Receptors, and associated with the inflammatory response and suppression of normal hematopoiesis in myelodysplasia models (Rhyasen et al.; Cancer Cell; 24:90, 2013). Conclusions: The kinase profile for pacritinib is unique among agents in development for myelofibrosis combining lack of suppression of JAK1 with suppression of inflammatory signaling through IRAK1. Moreover, the kinase inhibition profile of pacritinib suggests its potential therapeutic utility in AML, MDS, and particularly in CMML due to CMML’s upregulation of JAK2, c-FMS, and IRAK1. Disclosures Singer: CTI BioPharma, Corp: Employment, Equity Ownership. Mesa:Incyte Corporation, CTI, NS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding. Verstovsek:CTI BioPharma, Corp: Research Funding.

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.

Abstract Abstract 800 Background: Ruxolitinib (RUX), an oral JAK1/JAK2 inhibitor, reduced spleen volume (SV), improved myelofibrosis (MF)-associated symptoms and quality of life (QoL), and appeared to exhibit a survival advantage over placebo (PBO) in patients (pts) with MF regardless of JAK2V617F mutation status in the phase III COMFORT-I study. We describe long-term efficacy and safety of RUX from COMFORT-I, with 1 year of additional follow up beyond previously published data. Methods: Eligible pts (N=309) were randomized (1:1) to RUX or PBO. The primary analysis occurred when all pts completed 24 weeks (wks) and when half the pts completed 36 wks of treatment. All pts receiving PBO were eligible for crossover to RUX after the primary analysis; crossover before wk 24 was permitted if pts met protocol-defined criteria for worsening splenomegaly. The proportion of pts with ≥35% SV reduction at 24 wks (primary endpoint) and durability of SV response were assessed. Although symptom burden (measured daily using the modified MF Symptom Assessment Form v2.0) was only measured up to wk 24, QoL continued to be evaluated beyond wk 24 (every 24 wks) using the EORTC QoL Questionnaire-Core 30 (QLQ-C30). Overall survival (OS) was assessed according to original randomized treatment. Results: In this updated analysis, median follow-up of pts randomized to RUX was 102 wks. All pts receiving PBO completed crossover or discontinued within 3 months of the primary analysis. Of 134 pts randomized to RUX who remained on treatment after the primary data analysis, 100 continue on study. Mean SV reduction in pts randomized to RUX was 31.6% at wk 24 and has remained stable with additional follow up through wk 96 (Table). In pts who achieved a ≥35% SV reduction, response was durable, with a median response duration of 108 wks. RUX treatment was also associated with durable improvements in the Global Health Status/QoL (Table) and the 5 functional domains of the EORTC QLQ-C30. Twenty-seven (27) pts randomized to RUX and 41 pts randomized to PBO died, representing a continued OS benefit in favor of RUX (HR=0.58; 95% CI: 0.36, 0.95; P = 0.028; Fig 1) similar in magnitude to that previously reported. OS favored RUX across subgroups including starting dose as well as baseline risk status and hemoglobin (Hgb). Of 34 pts randomized to RUX who discontinued after the primary analysis, 4 discontinued for an adverse event (AE). In pts who continued on RUX, anemia and thrombocytopenia remained the most frequently reported AEs. New onset of grade 3 or 4 anemia and thrombocytopenia was reported in only 12 and 5 pts, respectively. One pt discontinued for anemia. Overall, among all pts randomized to RUX, Grade 3 and 4 anemia regardless of baseline Hgb was reported in 37.4% and 14.8% of pts, respectively. Similarly, Grade 3 and 4 thrombocytopenia was reported in 11.0% and 5.2% of pts, respectively. These rates were similar to those reported in the primary analysis. By wk 36, the proportion of pts receiving red blood cell transfusions decreased to the level seen with PBO and remained stable thereafter (Fig 2). Rates of nonhematologic AEs adjusted for increased follow-up duration remain similar to those seen at the time of the primary data analysis. No additional cases of acute myeloid leukemia (AML) in pts randomized to RUX were reported. Two pts originally randomized to PBO developed AML, 21 and 178 days after crossover to RUX. There continued to be no reports of a withdrawal syndrome after RUX discontinuation. Conclusions: RUX provides durable reductions in SV and improvements in QoL. Although all pts randomized to PBO crossed over to RUX shortly after the primary analysis, with 1 year of additional follow up, RUX continues to be associated with a survival advantage over PBO. RUX continues to be well tolerated; the AE profile with long-term treatment is consistent with that previously reported. The proportion of pts receiving transfusions decreased over time to rates similar to PBO, and there were no reports of a specific withdrawal syndrome or cytokine rebound phenomenon after RUX discontinuation. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Gotlib:Incyte: Consultancy, travel to congress Other. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; YM Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofiå]Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Catalano:Incyte: Consultancy. Deininger:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau, development of educational presentations Other; Incyte: development of educational presentations, development of educational presentations Other. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; B.M.S.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Winton:Incyte: Consultancy, Honoraria. Arcasoy:Incyte: Research Funding. Lyons:Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Telik: Research Funding. Paquette:Incyte: Consultancy. Vaddi:Incyte: Employment, Equity Ownership. Erickson-Viitanen:Incyte: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: Employment, Equity Ownership. Kantarjian:Incyte: grant support Other.

Abstract Abstract 756 Background: Myelofibrosis (MF) is the most serious of chronic myeloproliferative neoplasms (MPNs) for which there is no approved therapy. Exaggerated JAK2 signaling, either by gain-of-function mutations (eg, JAK2V617F) or high circulating levels of JAK1/2 activating cytokines (eg, interleukin [IL]-6), is believed to play a key role in MPN pathogenesis. INCB018424 (424), a selective oral inhibitor of JAK1/2, has demonstrated clinical benefits including reduction of splenomegaly and improvement of symptoms in a Phase I/II trial in MF patients. Thrombocytopenia was identified as the dose limiting toxicity occurring in 30% of patients at 25mg BID. Methods: Patients with primary, post-PV or post-ET MF were enrolled in the study. Following the characterization of multiple dosing regimens, an individually optimized dose regimen strategy was developed, based on available efficacy and safety data. In a subset of patients, spleen volume change was measured by MRI at 1, 3 and 6 months of treatment in order to establish an objective measure of spleen response. The impact of 424 on MF associated symptoms was assessed using a validated instrument, MFSAF (Mesa et al., Leukemia Research 2009). As a surrogate marker of functional benefit, exercise capacity was assessed with a standardized 6-minute walk test (6MWT) at baseline, 1, 3 and 6 months of therapy. Results: 155 patients were enrolled in the study, with median duration of treatment of 1+ years and the duration of drug exposure of >150 patient years (76 patients received >1 year of therapy). Clinical responses have been maintained over the entire duration of treatment and most patients remain on therapy (115 of 155 patients; 74%). Progression to AML occurred in 3 patients, which is below the expected frequency based on published data (Barosi et al., Blood 2007). SAEs related to 424 occurred in 12 patients, and are generally related to bone marrow suppression or return of or exacerbation of signs and symptoms of MF when therapy is discontinued. Further optimization of the dosing regimen utilized baseline platelet count to determine the starting dose (10 or 15mg BID) and allowed dose titration after 1 and 2 months of therapy; most patients were optimized to 15 or 20mg BID. This approach significantly reduced the incidence of thrombocytopenia (<5%, N=35), while providing equivalent efficacy to higher dose regimens. With an optimized dosing regimen, spleen volume reduction was evident as early as 1 month, and durable over 6 months, of therapy (33 % median decrease after 6 months, N=23). Eleven of 23 (48%) of patients achieved ≥ 35% reduction (equivalent to IWG clinical improvement criteria of 50% reduction by palpation) from baseline in spleen volume at month 6. MF patients have impaired exercise capacity at baseline (decreased 6MWT performance by 60-90 meters vs. age-matched controls). Treatment with 424 resulted in improved 6MWT performance, with median increase from baseline of 33, 58 and 70 meters after 1,3 or 6 months of therapy, respectively. Rapid and durable reduction of a total symptom score based on key symptoms (fatigue, abdominal discomfort/pain, bone/muscle pain, night sweats and pruritus) was noted (51 % and 58% of patients achieving 50% reduction in the total score following 1 and 6 months of treatment, respectively). Improvement in symptoms coincided with a rapid and sustained reduction in pro-inflammatory cytokines, including IL-1b, IL-1ra, IL-6 and TNFa, without tachyphylaxis to therapy. Finally, spleen response was associated with greater improvements in total symptom score, exercise capacity, and reduced fatigue (see Table). Conclusion: An optimized dosing regimen of INCB018424 resulted in sustained clinical, symptomatic and functional benefits in MF patients with an improved hematological safety profile compared to a 25 mg BID regimen. Safety and efficacy of 424 in MF patients is further supported by the follow-up data of >1 yr of 424 therapy. Disclosures: Verstovsek: Incyte: Research Funding. Bradley:Incyte Corporation: Employment, Equity Ownership. Erickson-Viitanen:Incyte Corporation: Employment, Equity Ownership. Vaddi:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership.

Background:Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the US FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. Moreover, CD123+ plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor‐promoting role.1,2,3 Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor, associated with rapid disease progression and shortened survival, suggesting an accelerated disease phase in MF.4 As such, tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, including patients with monocytosis.Aims:Primary objectives include assessment of safety, determining the recommended Phase 2 dose (RP2D) and schedule, and evaluating efficacy in patients with MF who were relapsed, refractory, or unable to tolerate JAKi.Methods:This multicenter, open‐label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg on days 1–3 every 21 days (cycle 1–4), 28 days (cycles 5–7), and 42 days (cycles 8+). In Stage 2 (expansion), patients are receiving the RP2D (12 mcg/kg).Results:23 patients with MF received tagraxofusp, including 12 patients who received ≥ 3 prior lines of therapy. Median age 69 years (range 55–81), 61% were female, and 30% had baseline monocytosis (≥ 1x109/L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate‐1, 12 patients (52%) with intermediate‐2, and 10 patients (44%) with high‐risk. At study entry, the median platelet count was 59 K/uL with 71% of patients had baseline platelets <100 K/uL, of which 8 patients had platelets <50 K/uL. 87% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin [LCM]). Most common treatment‐related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, alanine aminotransferase increased and thrombocytopenia. The most common ≥ grade 3 TRAE was thrombocytopenia (8%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 14 evaluable patients with baseline splenomegaly, 57% had spleen size reductions: 43% (6/14) had reductions of > 25%, of which 3 patients had reductions of ≥ 45%. In 5 patients with baseline splenomegaly and monocytosis, 80% (4/5) had reductions of > 25%, of which 2 had reductions of ≥ 45%. Six patients, including 3 patients with monocytosis and 5 patients with platelets <100 K/uL, had treatment duration of 6 months or more.Summary/Conclusion:Tagraxofusp demonstrated single agent activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor, both constituting potential areas of unmet medical need. Enrollment continues, and updated trial data will be presented. Registrational trial designs are being evaluated. Trial information: NCT02268253.