Récher, Christian

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 Introduction: There are few effective treatment options available for patients (pts) with myelofibrosis (MF). Pts with thrombocytopenia, a risk factor for shorter overall survival, have poorer prognosis (Gangat, J Clin Oncol 2010). Pacritinib is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFSR1 and has demonstrated minimal myelosuppression in clinical trials (Hart, Leukemia 2011; Komrokji, Blood 2015; Mesa, ASCO 2015). In the phase III open-label PERSIST-1 trial, a significantly greater proportion of pts treated with pacritinib achieved spleen volume reductions (SVR) ≥35% vs BAT (ITT: 19.1% vs 4.7%, p=0.0003; pts evaluable at baseline and Week 24: 25.0% vs 5.9%, p=0.0001; Mesa, ASCO 2015). This analysis examines pt responses across subgroups. Methods: Pts naive to treatment with JAK inhibitors were randomized 2:1 to receive oral pacritinib 400 mg once daily or BAT. Stratification factors included DIPSS risk status and baseline platelet count. Pts were eligible who had DIPSS Intermediate (Int)-1, Int-2, or High risk disease; absolute neutrophil count >500/µL; palpable splenomegaly ≥5 cm; and baseline Total Symptom Score (TSS) ≥13 using the Modified MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS and TSS 2.0). There was no restriction on baseline platelets or hemoglobin (Hgb) levels. The primary endpoint was the proportion of pts achieving SVR ≥35% at Week 24 by centrally-reviewed MRI or CT and the secondary endpoint was the proportion of pts achieving ≥50% reduction in TSS from baseline at Week 24 using 6 symptoms from the MPN-SAF TSS. Pt responses were analyzed by baseline risk factors for MF including platelet counts (<50,000/µL vs ≥ 50,000/µL and <100,000/µL vs ≥100,000/µL), sex, age (≥65 y vs <65 y), JAK2V617F mutation status (positive vs negative), baseline MF diagnosis (primary MF [PMF] vs secondary MF), reticulin and collagen fibrosis staging (> 1 vs ≤1), TSS (≥20 vs <20), white blood cell count (>25×109/L vs ≤25×109/L), peripheral blasts (≥5% vs <5%), Hgb (<10 g/dL vs ≥10 g/dL), transfusion dependency by Gale criteria (Y vs N), time from diagnosis (<12 mos vs ≥12 mos), ECOG PS (2-3 vs 0-1), and bone pain (>3 vs ≤3). In multivariate logistic regressions, the odds of SVR ≥35% and TSS reduction ≥50% at Week 24 were modeled as a function of prognostic factors for MF and adjusted for treatment (pacritinib vs BAT). Results for the 6 symptoms common to both TSS versions are reported. Results: 327 pts were enrolled and randomized (pacritinib: 220, BAT: 107). Overall, 62% of pts had PMF; 32% had baseline platelets <100,000/µL and 16% had <50,000/µL; 75% were positive for JAK2V617F. After a median follow-up of 8.4 months, treatment with pacritinib resulted in consistent rates of SVR across subgroups (Figure 1). When comparing vs BAT, the greatest differences in SVR ≥35% rates between treatment arms were observed in pts with baseline platelets <50,000/μL (+22.9% vs BAT), JAK2V617F-negative pts (+23.0% vs BAT) and those aged <65 y (+21.2% vs BAT). Improvements in TSS (TSS and TSS 2.0 reduction ≥50%) were also consistent for pts receiving pacritinib (Figure 2). By multivariate analysis, SVR ≥35% was significantly correlated only with ECOG PS ≥2 (odds ratio [OR]=2.97, p=0.030) and TSS reduction ≥50% was significantly correlated only with bone pain >3 (OR=0.35, p=0.004). Conclusions: Treatment with pacritinib resulted in consistent rates of SVR ≥35% and TSS reduction ≥50% irrespective of baseline characteristics. Comparisons vs BAT were favorable for all patient subpopulations examined for both endpoints. These results support the use of pacritinib across all intermediate- or high risk MF pt subgroups analyzed. Figure 1. Proportion of Patients Receiving PAC who Achieved ≥35% SVR from baseline to Week 24 (95% CI) Figure 1. Proportion of Patients Receiving PAC who Achieved ≥35% SVR from baseline to Week 24 (95% CI) Figure 2. Proportion of Patients Receiving PAC who Achieved ≥50% TSS reduction (6 common symptoms in MPN-SAF TSS and MPN-SAF TSS 2.0) from baseline to Week 24 (95% CI) Figure 2. Proportion of Patients Receiving PAC who Achieved ≥50% TSS reduction (6 common symptoms in MPN-SAF TSS and MPN-SAF TSS 2.0) from baseline to Week 24 (95% CI) Disclosures Vannucchi: Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This abstract discusses off-label use of pacritinib. Mesa:Gilead: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Promedior: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Prasad:BIOGEN IDEC: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Elinder:Celgene: Consultancy. Recher:Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Chugai: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dean:CTI Biopharma: Employment, Equity Ownership. Harrison:Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.