Jourdan, Éric

SummaryFedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400‐mg daily was based on results of an updated analysis of the pivotal phase III, placebo‐controlled JAKARTA trial in patients with JAK‐inhibitor‐naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first‐line fedratinib in patients with myelofibrosis.

BACKGROUND: MF is characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib is an oral JAK2 inhibitor approved in the United States for treatment (Tx) of adult patients (pts) with intermediate (INT)-2 or high-risk MF. The randomized, placebo (PBO)-controlled, phase III JAKARTA trial evaluated clinical outcomes with fedratinib in pts with JAK-inhibitor-naïve MF. Initial findings from the JAKARTA study have been reported (Pardanani, JAMA Oncol, 2015). JAKARTA data were recently reanalyzed in preparation for regulatory review. OBJECTIVE: Evaluate the clinical efficacy and safety with fedratinib 400 mg/day in updated analyses of the JAKARTA study. METHODS: JAKARTA was an international, randomized, double-blind, PBO-controlled study that enrolled pts aged ≥ 18 years with INT-2 or high-risk primary, post-PV, or post-ET MF. Pts were randomly assigned 1:1:1 to fedratinib 400 mg, fedratinib 500 mg, or PBO, administered orally once-daily for ≥ 6 consecutive 4-week cycles ("randomized Tx period"). After completing 6 Tx cycles (or earlier in the case of disease progression), pts randomized to PBO could crossover to fedratinib. The primary endpoint was the spleen volume response rate (SVRR), the proportion of pts who achieved a ≥ 35% spleen volume reduction from baseline (BL) confirmed by MRI/CT at end of cycle 6 (EOC6), confirmed by follow-up scan 4 weeks later. Secondary endpoints included SVRR without 4-week confirmation, durability of spleen response, and symptom response rate (proportion of pts with a ≥ 50% reduction from BL in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) at EOC6. An exploratory analysis evaluated proportions of pts with ≥ 50% reductions from BL at EOC6 in individual MFSAF symptom scores: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain. These analyses are limited to pts randomized to fedratinib 400 mg (the approved starting dose of fedratinib) or to PBO. Efficacy analyses were performed for the intention-to-treat (ITT) population and safety was assessed in all pts who received ≥ 1 dose of study drug. RESULTS: 96 pts were randomized to fedratinib 400 mg and 96 pts to PBO. In the fedratinib and PBO arms, median ages at BL were 63 (range 39-86) and 66 (27-85) years, respectively, 65% and 60% of pts had primary MF, 76% and 73% had constitutional symptoms, median spleen volumes were 2652 (316-6430) and 2660 (662-7911) mL, and median TSS were 15.3 (0-57) and 12.4 (0-53). Median durations of exposure were 15.5 months in the fedratinib 400 mg arm and 6 months in the PBO arm. With a confirmation scan 4 weeks after EOC6, SVRR was significantly higher in the fedratinib arm (37% [95%CI 27%, 46%]) vs. the PBO arm (1% [0%, 3%]) (P < 0.0001). Without the confirmation scan, SVRR at EOC6 was 47% (95%CI 37%, 57%) in the fedratinib 400 mg arm and 1% (0%, 3%) in the PBO arm (P < 0.0001; Figure). Estimated median duration of spleen response with fedratinib was 18.2 months. Symptom response rate at EOC6 for evaluable pts (ie, with TSS data available at BL and EOC6) was 40% (36/89) with fedratinib and 9% (7/81) with PBO (P < 0.0001). Fedratinib was associated with higher response rates vs. PBO in all 6 MFSAF symptoms: abdominal discomfort (41% vs. 15%, respectively), night sweats (58% vs. 22%), bone or muscle pain (33% vs. 14%), early satiety (51% vs. 18%), pruritus (39% vs. 20%), and pain under the ribs on the left side (42% vs. 24%). The most common Tx-emergent adverse events (TEAEs) during the randomized Tx period were grade 1-2 gastrointestinal events (Table). New or worsening grade 3 anemia and grade ≥ 3 thrombocytopenia laboratory abnormalities were reported in 34% and 12% of fedratinib-treated pts, most (75%) occurring within 3-4 months of Tx initiation. Compared with PBO, fedratinib-treated pts more frequently experienced increased serum creatinine, amylase, and lipase; these were mainly grade 1-2 in severity. TEAEs led to Tx discontinuation for 14% of fedratinib pts and 8% of PBO pts. CONCLUSIONS: Fedratinib 400 mg/day significantly reduced splenomegaly and symptom burden in pts with JAK-inhibitor-naïve MF. Relatively few pts discontinued fedratinib therapy due to TEAEs, suggesting these events are manageable. These data corroborate results initially reported for the JAKARTA trial, and further support the efficacy and safety of fedratinib in this pt population. Disclosures Masszi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Drummond:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine Corporation: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jourdan:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: 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; Incyte: Membership on an entity's Board of Directors or advisory committees. Ribrag:AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; nanostring: Honoraria, Membership on an entity's Board of Directors or advisory committees; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; epizyme (EPZ): Research Funding; argenX: Research Funding; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy; gustave roussy comprehensive cancer center: Current Employment. Rambaldi:Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Omeros: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Roche: Honoraria; MSD: Honoraria. Rose:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Zhang:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Harrison:Promedior: Honoraria; Roche: Honoraria; Sierra Oncology: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; CTI Biopharma Corp: Honoraria, Speakers Bureau.

Abstract Background The JAK1/JAK2 inhibitor ruxolitinib (RUX) is approved for treatment of myelofibrosis (MF). However, some patients do not respond to RUX, while others lose responsiveness or develop intolerance to RUX over time. Preclinical data also suggest that certain JAK2 mutations (eg the gatekeeper mutation M929I) may confer resistance to RUX (Leukemia 2012;26:708). Options for these RUX resistant/intolerant patients, particularly with regard to further JAK inhibitor therapy, are unclear. Fedratinib (SAR302503) is a JAK2-selective inhibitor which has demonstrated clinically meaningful reductions in splenomegaly and symptom burden in patients with MF, with an acceptable and consistent safety profile (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Fedratinib sensitivity in vitro is unaffected by the M929I mutation. This pre-specified interim analysis of the JAKARTA-2 study (NCT01523171) investigated the efficacy and safety of fedratinib in MF patients previously treated with RUX. Methods JAKARTA-2 is a Phase II, multicenter, open-label, single-arm study of patients who previously received RUX for MF. Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles (permitted dose adjustment to 200–600 mg daily). Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib. Although there is no consensus definition of RUX resistance/intolerance, for the purpose of this study patients were classed (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX. Primary endpoint for the interim analysis: spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]) in the per-protocol (PP) population. Secondary endpoints: symptom RR (≥50% reduction in total symptom score [TSS: modified Myelofibrosis Symptom Assessment Form] from baseline to Wk 12) and safety. Results At the cut-off date for this interim analysis, 27 patients had received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4]): median age 69 yrs; 56% male; 67% primary MF; 63% high-risk MF; 67% JAK2V617F positive; 41% platelet count <100 × 109/L; baseline median spleen volume 3190 mL [1072–7815]; baseline median TSS 19.6 [4.9–46.0]. Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response; median RUX exposure 11.1 months [range 1.9–34.4]) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity; median RUX exposure 9.2 months [2.9–33.2]) to RUX. Median fedratinib exposure to cut-off date: 4 cycles (range 1–10); 19 patients remain on treatment. Spleen RRs were 40% (8/20 PP patients) and 43% (3/7) in patients with baseline platelet count <100 ×109/L. Overall, 19% (5/26 evaluable patients) had a symptom response by Wk 12 (Table). The majority of patients had a reduction in TSS at Wk 12 (Figure). The most common non-hematologic treatment-emergent adverse events (AEs) were gastrointestinal (nausea 67%; diarrhea 56%; vomiting 48%). Grade 3/4 diarrhea occurred in 2 patients; no Grade 3/4 vomiting or nausea. Anemia was the most common hematologic AE (all grades, 93%; Grade 3, 41%; Grade 4, 0%). Thrombocytopenia (all grades) occurred in 19 (70%) patients; Grade 3 in 6 patients and Grade 4 in 2 patients. One patient had Grade 3 AST elevations and 1 patient had Grade 3 hyperbilirubinemia. Seven patients (26%) discontinued treatment due to AEs. There were 2 deaths on study, both due to disease progression. Conclusions Interim results from the JAKARTA-2 study indicate that once-daily fedratinib provides clinical benefit, through reduced splenomegaly and symptom burden, in MF patients previously treated with RUX. The safety profile was acceptable and manageable, with safety results to date consistent with those reported in previous trials of fedratinib. Sponsored by Sanofi. Disclosures: Harrison: Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees. Jourdan:Sanofi: Honoraria. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Niederwieser:Novartis Pharma: Consultancy. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Reiter:Sanofi: Honoraria. Heidel:Novartis Inc.: Honoraria; Novartis Inc.: Research Funding; Novartis Inc.: Membership on an entity’s Board of Directors or advisory committees. Silver:Sanofi: Consultancy; Sanofi: Research Funding; Sanofi: Honoraria. Winton:Sanofi: Research Funding. Gupta:Incyte, Novartis: Consultancy; Incyte, Novartis: Research Funding; Novartis: Honoraria. Gisslinger:AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Zhang:Sanofi: Employment. Shi:Sanofi: Employment. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding.

Abstract Background Fedratinib (SAR302503) is a JAK2-selective inhibitor that has provided clinically meaningful reductions in MF-associated splenomegaly and symptoms in Phase I and II studies (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Here, we present efficacy and safety data from the Phase III JAKARTA study of fedratinib versus placebo in patients with MF (NCT01437787). Methods In this international double-blind, placebo-controlled, 3-arm study, patients aged ≥18 years with IPSS intermediate-2 or high-risk MF, platelet count ≥50 × 109/L, and splenomegaly were randomized (1:1:1) to receive placebo or fedratinib 400 mg or 500 mg, orally, once daily, in consecutive 4-week cycles. Patients who received placebo were eligible to cross-over to fedratinib (randomized 1:1 to 400 mg or 500 mg) following 6 cycles of treatment, or prior to Cycle 6 if the patient had disease progression. The primary endpoint was spleen response rate (RR) (≥35% reduction in spleen volume from baseline measured by MRI or CT at Week 24, and confirmed 4 weeks later). Secondary endpoints included symptom RR (≥50% reduction in total symptom score from baseline at Week 24, measured through a daily electronic eDiary using the modified Myelofibrosis Symptom Assessment Form [Cancer 2011;117:4869. Blood 2011;118:401]), and safety of fedratinib. Results A total of 289 patients were randomized: median age 65 years; 59% male; 63% primary MF; 48% high-risk MF; 67% JAK2V617F positive; 16% platelet count <100 × 109/L; median baseline spleen volume 2568 mL (range 316–8244); median baseline total symptom score 14.7 (0–57). Median (range) exposures for placebo, 400 mg and 500 mg groups were 24 (2–34), 30 (1–55) and 28 (1–60) weeks, respectively. Spleen RRs at Week 24 (placebo 1%; 400 mg 47%; 500 mg 49%), and confirmed at Week 28 (placebo 1%; 400 mg 36%; 500 mg 40%), were significantly (p<0.0001) higher in both fedratinib groups compared with placebo (Table). Nineteen patients had a spleen response at Week 24 not confirmed 4 weeks later (spleen reduction 25–35% [n=10]; image not available/evaluable [n=8]; image taken outside time window [n=1]). Spleen RRs by baseline platelet level are shown in the table. Patients treated with fedratinib had significantly (p<0.0001) greater improvements in MF symptoms compared with placebo (Table). The most common all grade non-hematologic treatment-emergent adverse event (TEAE) was diarrhea (16%, 66% and 56% of patients in the placebo, 400 mg and 500 mg groups, respectively). Grade 3/4 diarrhea was reported in 5% of patients in both the 400 mg and 500 mg dose groups. The most common hematologic TEAE was anemia (any grade 91%, 99% and 98%; Grade 3/4 25%, 43% and 60% in the placebo, 400 mg and 500 mg groups, respectively). Rates of Grade 3/4 thrombocytopenia were 9% (placebo), 17% (400 mg), and 27% (500 mg). Incidences of Grade 3/4 liver function tests (placebo/400 mg/500 mg) were: bilirubin, 2%/2%/1%; ALT, 0%/3%/3%; and AST, 1%/2%/2%. Overall treatment discontinuation rates up to 24 weeks of treatment were 25% (placebo), 22% (400 mg) and 32% (500 mg). Twenty-five patients died during the study (10, 5 and 10 in the placebo, 400 mg and 500 mg groups, respectively); the most common causes of death: disease progression (placebo [n=5]; 400 mg [n=3]; 500 mg [n=4]) and adverse events (placebo [n=4]; 400 mg [n=1]; 500 mg [n=4]). Conclusions In this Phase III, randomized, placebo-controlled, 3-arm study of 289 MF patients, treatment with fedratinib 400 mg or 500 mg once-daily demonstrated clinically meaningful and statistically significant reductions in splenic volume and MF-associated symptom burden versus placebo. Fedratinib had an acceptable safety profile, with the adverse events reported consistent with those observed in previous studies. This study was sponsored by Sanofi. Disclosures: Pardanani: Sanofi, Bristol Myers Squibb, PharmaMar and JW Pharma: Clinical trial support Other. Harrison:Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding. Jourdan:Sanofi: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Drummond:Sanofi, Novartis, Celgene: Honoraria; TargeGen, Novartis: Speakers Bureau; Sanofi, Novartis, Celgene: Consultancy. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Neumann:Sanofi: Employment. Gao:Sanofi: Employment.

Abstract Introduction Fedratinib (SAR302503), a JAK2-selective inhibitor, has demonstrated clinical improvements in splenomegaly and constitutional symptoms in patients with MF in Phase I/II trials (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). The aim of this primary analysis was to determine the effect of fedratinib on key MF symptom burden and global assessment of HRQoL in the JAKARTA trial (NCT01437787). Methods JAKARTA is a double-blind, placebo-controlled, international, 3-arm, Phase III study, in which patients ≥18 years of age with intermediate- or high-risk MF, platelet count ≥50 × 109/L, and splenomegaly were randomized (1:1:1) to receive placebo or fedratinib at a dose of 400 or 500 mg, orally, once daily, in consecutive 4-week cycles. Total symptom score (TSS), a key efficacy end point (TSS: averaged daily total score of 6 item measures over 1 week: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain), was assessed through a daily electronic eDiary using the modified Myelofibrosis Symptom Assessment Form (MFSAF; Cancer 2011;117:4869. Blood 2011;118:401), with symptom response defined as a ≥50% reduction in TSS at the end of Cycle 6 (EOC6). HRQoL was assessed using the EuroQOL (EQ)-5D instrument that was completed at baseline and EOC6. Patient performance was assessed using the Eastern Cooperative Oncology Group Performance Scale (ECOG PS). Spleen volume was measured by MRI or CT at baseline and EOC6. Results In JAKARTA, a total of 289 patients were randomized: median age 65 years; 59% male; 63% primary MF; 48% high-risk MF; 67% JAK2V617F positive; 16% platelet count <100 × 109/L. The symptom evaluable population comprised 261 patients (placebo [n=82]; 400 mg [n=89]; 500 mg [n=90]). The mean (SD) baseline TSS was 14.6 (11.9), 17.6, (13.5), and 16.9 (11.9) in the placebo, 400 mg, and 500 mg groups, respectively. At Week 24 (EOC6), the proportion of patients with a symptom response was significantly higher (p<0.0001) in the 400 and 500 mg groups versus placebo (Table). Symptom responses with fedratinib were also higher than placebo in the subgroup of patients with baseline platelets <100 × 109/L (Table). For individual symptoms, the greatest improvements were seen for night sweats and early satiety (Table). Baseline HRQoL (EQ-5D, mean [SD]) was similar in the three groups (placebo: 62.5 [21.2]; 400 mg: 61.3 [22.2]; 500 mg: 60.1 [20.1]). Fedratinib treatment led to improvements in HRQoL from baseline to Week 24, whereas placebo treatment led to slight worsening of HRQoL (Table). At Week 24, the degree of improvement in TSS was greatest in patients with ≥35% reduction in spleen volume from baseline (Figure). Mean TSS improvement was correlated with improvement in HRQoL (TSS reductions were greater in EQ-5D improvers versus non-improvers), and ECOG PS (TSS reductions were greater in patients with ECOG PS 1 or 2 score improvement versus those with ECOG PS worsening). Conclusions Fedratinib treatment over 24 weeks led to significant improvements in MF symptoms versus placebo. Patients treated with fedratinib also experienced substantial improvements in HRQoL versus placebo. Symptom improvements were associated with spleen responses. This study was sponsored by Sanofi. Disclosures: Mesa: Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Jourdan:Sanofi: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Drummond:TargeGen, Novartis: Speakers Bureau; Sanofi, Novartis, Celgene: Honoraria; Sanofi, Novartis, Celgene: Consultancy. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Neumann:Sanofi: Employment. Joulain:Sanofi: Employment. Iqbal:Sanofi: Employment. Harrison:Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees.

LBA7006 Background: PAC is a potent JAK2 inhibitor without significant JAK1 inhibition with minimal myelosuppression in early-phase studies in MF. Methods: The efficacy and safety of daily oral PAC was compared to BAT (2:1 randomization stratified for risk and platelet count). The 10 endpoint was the proportion of ITT patients (pts) achieving ≥ 35% spleen volume reduction (SVR) at week (wk) 24 by centrally reviewed MRI or CT. Secondary endpoints included the proportion achieving ≥ 50% reduction in total symptom score (TSS) at wk 24 using the MPN Symptom Assessment Form. Results: Patients:327 were enrolled (PAC:220, BAT:107), 62% with 10 MF. Median time from diagnosis was 1.12 years (PAC 0.99, BAT 1.60): 32% and 15% had a platelet counts < 100,000/µL or <50,000/ µL; 75% were JAK2V617F positive. Efficacy: The median duration of treatment was 16.2 months PAC and 5.9 months BAT. Sixty-two percent of BAT patients received active disease directed therapy. The SVR rates at week 24 were 19.1% for PAC vs. 4.7% for BAT (p=0.0003) in ITT and 25% vs. 5.9% (p=0.0001) in the evaluable population. 79% of BAT patients crossed over to PAC; 21% had achieved a >35% reduction in spleen volume at data cutoff. TSS composite V1 + V2 response rates were 24.5%for PAC vs. 6.5% for BAT (p<0.0001) by ITT, and were 40.9% vs. 9.9% in evaluable pts (p<0.0001). Efficacy with baseline cytopenias: In pts with <100,000 and <50,000 platelets/μ/L, the SVR rates were 16.7% for PAC vs. 0% for BAT (p=0.009), and 22.9% vs. 0% (p=0.045) by ITT and 23.5% vs. 0% (p=0.007) and 33.3% vs. 0% (p=0.037) in evaluable pts. In RBC transfusion dependent pts, 25.7% of PAC pts became RBC independent vs. 0% of BAT pts (p=0.043). Safety: The most common adverse events (AE) for PAC were diarrhea, nausea, and vomiting; (grade 3 were <5%, <1%, <1% respectively). Hematologic AEs were similar between PAC and BAT. Conclusions: This study demonstrated PAC was well tolerated and induced significant and sustained SVR and symptom control even in patients with severe thrombocytopenia. PAC therapy resulted in RBC transfusion independence in a significant proportion of pts. Clinical trial information: NCT01773187.