Erickson‐Viitanen, Susan

Abstract Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.

7083 Background: Patients with Myelofibrosis (MF) suffer from significant fatigue, constitutional symptoms and splenomegaly (Mesa et. al. Cancer 2007) not improved by current therapy. The 6MWT measures functional status in cardio-pulmonary clinical trials. We undertook a prospective feasibility study of the 6MWT in MF patients for use in therapeutic clinical trials. Methods: MF patients (able to walk, normal vitals, not on a JAK2 inhibitor) were eligible. Baseline features and the MF symptom assessment form (MFSAF: Mesa et. al. Blood 2008) was administered. The 6MWT was administered in standardized fashion (American Thoracic Society: observed laps of a 30 - 35 meter long course, indoors, level, without encouragement), and then repeated for further validation. Results: Safety of the 6MWT: Fifty five MF patients were enrolled with only 2 patients (3%) stopping the 6MWT early secondary to fatigue. There were no adverse events attributable to undergoing the 6MWT in test subjects. Results of the 6MWT: Current results of our ongoing study demonstrate compared to age matched healthy volunteer controls, males with MF walk approximately 90 meters less and females with MF walk approximately 60 meters less (Table). Correlation of 6MWT Results to Patient Reported Symptoms (MFSAF): Results from the MFSAF demonstrated the fatigue (as assessed by the brief fatigue inventory (Medoza et. al. Cancer 1999) embedded in the MFSAF) showed patients with a higher BFI (i.e., more fatigued) had more impairment in the 6MWT than those with low BFI scores. Symptomatic burden as assessed by the MFSAF were typical for MF, correlation of individual symptom severity with 6MWT will require a larger trial for adequate power. Conclusions: The 6MWT can be safely performed in un-selected MF patients, and demonstrates a functional deficit compared to published controls. Validation of the ability of the 6MWT to measure functional improvements in MF patients as a response to novel therapy trials is planned. [Table: see text] No significant financial relationships to disclose.

Abstract BACKGROUND: MF is a progressive illness associated with cachexia and weight loss (Mesa et al, Cancer2007;109: 68). These clinical signs, resulting from both hypercatabolism (secondary to increased pro-inflammatory cytokines) and MF associated splenomegaly, are associated with decreased survival (Dupriez et al., Blood1996;88:1013). Currently, there is no therapy that decreases the progressive cachexia of MF. INCB018424 is a selective JAK1/2 inhibitor which has the potential to improve both the aberrant myeloproliferation in MF through decreasing constitutively active JAK-STAT signaling, and nutritional status by decreasing both splenomegaly and the pathologically increased cytokines. METHODS: Symptomatic patients with MF enrolled in a phase I/II trial (www.ClinicalTrials.gov, NCT00509899) with INCB018424, were analyzed for the impact of therapy on nutritional status and cachexia. Specifically, in addition to traditional endpoints of IWG-MRT response (reported elsewhere) patients were assessed for changes in body mass index (BMI), serum cholesterol values, spleen size, and patient reports of early satiety and anorexia. Additionally, leptin, an adipose-derived protein hormone that plays a key role in regulating energy balance and circulates at levels proportional to body fat in health and disease (Mantovani et al, J Mol Med2001; 79:406), was assessed serially. RESULTS: Patients: Thirty four MF patients, treated for at least 2 months with 25 mg twice daily of INCB018424, were included in this analysis. Among this group 85% demonstrated splenomegaly (median 20 cm below left costal margin, range 4 cm to 32 cm; 2 patients had prior splenectomy) and had a median BMI of 24.8 (range 17.9 to 49.7). Although the median BMI at baseline would be considered in the “normal range” (18.5–24.9), loss of lean body mass at enrollment would be underestimated by the contribution of splenomegaly or edema. Appetite: At enrollment, a clearly positive correlation between the presence of anorexia and early satiety (by patient’s report) and significant splenomegaly was observed. Treatment with INCB018424 led to resolution of the symptoms of poor appetite and early satiety, along with the reduction in splenomegaly. Weight: MF patients on therapy initially lost weight, which reflects resolution of excess extravascular water (based on investigators reported decreases in peripheral edema, ascites, or splenomegaly). As the trial progressed MF patients on INCB018424 treatment progressively gained weight (mean increase of 0.40 kg @ 1 month, 2.93 kg @ 2 mo, 3.70 @ 3 mo), and exhibited improved appetite. Importantly, weight gain was more consistent, of greater magnitude and more durable in patients who entered the study in the lowest quartile for BMI. Cholesterol: We previously reported that hypocholesterolemia (total cholesterol <150 or 100 mg/dL; HDL < 60mg/dL) is associated with decreased survival in MF patients (Mesa et al, Blood2007; 2007;110:a2548), potentially from hypercatabolism and splenic consumption of lipids. At enrollment, median total cholesterol was 95 mg/dl (range), with 94% and 55% below 150 mg/dl and 100 mg/dl, respectively. Following treatment with INCB018424, median total cholesterol increased to 145 mg/dl (range 72–289 mg/dL) with 73% increasing to an improved range above their baseline (either to the >100mg/dl or >150 mg/dl range). Leptin: At enrollment, MF patients had very low leptin levels (mean = 2.55 ng/mL with 50% below 1 ng/mL vs. a range of 6–12 ng/mL for normal volunteers). Low plasma levels are associated with shortened survival in cancer patients. The plasma leptin levels increased 176% on average after one month of treatment with INCB018424, and continued to increase to levels matching healthy volunteers with time on study (mean = 7.04 ng/mL (range 0.25 – 35 ng/mL) after 2 months on INCB018424) and correlated to weight increases. CONCLUSIONS: Therapy with INCB018424 improves the nutritional status of MF patients, including improving pathologic weight loss, hypercatabolism associated hypocholesterolemia, and pathologically decreased serum leptin. The improved nutritional status of MF patients treated with INCB018424 may reflect the ability of JAK inhibition to target the underlying pathophysiology of MF cachexia by reducing the organomegaly, levels of pro-inflammatory cytokines, and pro-inflammatory cytokine signaling.

Abstract Abstract 3917 Poster Board III-853 Background Patients with Myelofibrosis (MF) suffer from significant fatigue, constitutional symptoms and splenomegaly (Mesa et. al. Cancer 2007) not improved by current therapy. The MF-SAF is a 19 item self administered instrument specific to MF associated symptoms previously validated for use at a single time point (Mesa et. al. Leukemia Research 2009). We sought to assess the performance characteristics of the MF-SAF when administered sequentially in the context of a prospective clinical trial. Methods Sequential MF patients enrolled in the prospective, uncontrolled Phase II, trial were given a 15 item modified MF-SAF to complete at enrollment, and after 15 days, 1 month, 2 months, 3 months and every 3 months thereafter. The MF-SAF was scored as previously published on a 0 (absent) to 10 (maximal) scale. Cross validation of serial change in MF-SAF scores was undertaken by comparison to objective measurements made as part of the therapeutic drug trial. Results Patients Eighty six MF patients were enrolled and had 2 or more MF-SAF instruments completed to allow for sequential analysis. Patients were of a median age (65 years), gender distribution (35 % females), and disease subtype (53 % PMF) typical for a clinical trial in MF. Baseline MF-SAF Responses: Baseline assessment of the most frequent MF abnormalities reported by patients completing the MF-SAF (see Table 1) confirmed the wide prevalence of MF associated symptoms, and their significant severity. General fatigue was the most frequent symptom cited (91%), while cough was the least frequently observed symptom (44%). 95% of patients had at least 2 symptoms present on the MF-SAF. Serial MF-SAF Changes in Response to Therapy Therapy with INCB018424 resulted in a significant and rapid reduction in MF associated symptoms with 46% to 85% of patients experiencing improvement in a given symptom. The greatest improvements in MFSAF score improvements were reported by patients experiencing abdominal discomfort, night sweats, pruritus and fever (see Table 1), and corresponded to significant improvements in the individual MF symptom scales as well as the patient's overall assessment of quality of life (QOL). Correlation of MF-SAF to Objective Changes during INCB018424 Therapy Objective measurements obtained on the INCB018424 trial included MRI measurements of splenic reduction, the six minute walk test (6MWT) for inactivity, and serial weights. Reduction in spleen size (by ≥ 35% by volume or ≥ 50% by palpable length) corresponded to improvement in MF-SAF scores of abdominal discomfort and fatigue (50% of patients, median score decrease of -1.2, and -1.8, respectively). Improvement in the 6MWT by > 50 meters was associated with a 2-fold greater improvement in inactivity score on the MF-SAF compared to subjects who improved 6MWT performance by <50 meters. Finally, improvements in weight loss and fever were corroborated by objective measurements made at physician visits on the trial. Conclusions The MF-SAF is a brief, easily self administered, MF specific instrument which was successfully administered sequentially in the conduct of a large Phase II clinical trial. The significant symptomatic improvements reported by patients in the open label trial of INCB018424 corresponded to both improvements in symptom specific scores on the MF-SAF and objective measurements. Further validation of the MF-SAF will be possible by inclusion in upcoming randomized placebo controlled trials in MF patients. Parallel trials performed in MF patients should consider use of this instrument to allow for comparisons. Disclosures: Levy: Incyte Corporation: Employment, Equity Ownership. Vaddi:Incyte Corporation: Employment, Equity Ownership. Erickson-Viitanen:Incyte Corporation: Employment, Equity Ownership. Verstovsek:Incyte: 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.

SummaryMyelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT‐I,) a double‐blind trial, where patients with intermediate‐2 or high‐risk MF were randomized to twice‐daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post‐polycythaemia vera, post‐essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100–200 × 109/l, >200 × 109/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan–Meier method according to original randomization group. In ruxolitinib‐treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT‐I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT‐I.

Purpose To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. Patients and Methods COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Results Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either “Much improved” or “Very much improved” on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Conclusion Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.