Zhang, Jenny

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 Abstract 3838 Background: SAR302503 (SAR503, formerly TG101348), a potent, oral JAK2-selective inhibitor was studied in a Phase I/II trial for the treatment of patients with high- or intermediate-risk primary, post-polycythemia vera (PV) and post-essential thrombocythemia (ET) myelofibrosis (MF). SAR503 was administered orally once daily in 28-day cycles. Eligibility criteria included platelet count of ≥50 × 109/L. Interim safety and efficacy data from this study up to April 2010 have been previously published (JCO 2011, 29(7):789–796). The aim of this presentation is to report updated safety and efficacy of ongoing patients as well as an analysis of the JAK2V617F allele burden in this cohort. Results: Overall, 59 subjects (median age 64 years) were treated. Forty four patients had PMF, 12 post-PV MF and 3 post-ET MF; 86% were JAK2 V617F-positive. Median palpable spleen size was 18 cm at study enrollment. Twenty eight patients were treated in the dose-escalation cohort (30–800 mg administered as a single daily dose); thirty one patients were treated at the MTD (680 mg) in the dose confirmation cohort. 43/59 patients (73%) completed 6 cycles of treatment and continued treatment on the extension study. Currently, 22 patients (37%) remain on treatment with a median number of 28.5 cycles (24–41 range) and a median of last dose of 440 mg/day. Safety: Treatment-emergent toxicities in cycle 1–6 have been previously reported; toxicities were dose-dependent and generally alleviated with dose-reduction. Five patients discontinued treatment beyond cycle 6 for treatment-related adverse events: thrombocytopenia, depression, mental status changes, creatinine elevation and subdural hematoma. For the subgroup of patients with a baseline platelet count between 50–100 × 109/L (n =13; median 73, range 51–94); the platelet count at defined times points during follow up was: cycle 3; median 50, range 21–138 (p=0.09) and cycle 6; median 47, range 13–85 (p=0.01). Despite 7 of the 13 patients being treated at ≥680 mg/day, only 2 instances of Grade 4 thrombocytopenia were noted in this group Spleen response: As previously reported, spleen responses were seen early, usually within first 3 cycles, with half or more patients in each dose level ≥240 mg/day showing a durable ≥50% decrease in palpable spleen size. Spleen size (mean, median, range, and proportion with ≥50% reduction) at the following time points was: Baseline (n=58; 18.33cm, 18cm, 4–38cm, NA) ; 6 months (n=57; 9.05cm, 9cm, 0–30cm, 54.4%;) 12 months (n=42; 8.55cm, 9cm, 0–28cm, 66.7%) 18 months (n=36; 8.03cm, 8.5cm, 0–33cm, 52.8%); 24 months (n=31; 8.10cm, 8cm, 0–30cm, 54.8%,) 30 months (n=18; 6cm, 7.5cm, 0–16cm, 61.1%,and) 36 months (n=9; 5.89cm, 3cm, 0–16cm, 66.7%). JAK2V617F allele burden: We previously reported a significant decrease in JAK2V617F allele burden at the end of cycles 6 and 12. A durable decrease was also demonstrable after 24 cycles of treatment (n =21; median 9%, range 0–100%) relative to baseline (n =51; median 20%, range 3–100%) (p=0.03). Similarly, for patients with JAK2 V617F allele burden >20% at baseline; there was a significant decrease after cycle 24 (n =12; median 21%, range 6–100%) relative to baseline (n =23; median 60%, range 23–100%) (p=0.03). Conclusions: SAR503 is safe and efficacious treatment with long term effect on spleen size and JAK2V617F allele burden in patients with high- and intermediate-risk myelofibrosis. Additional follow up information will be updated at the time of meeting. Disclosures: Jamieson: Wintherix: Equity Ownership; Pfizer Oncology: Research Funding; Celgene: Research Funding; Novartis: Honoraria. Gao:Sanofi-Aventis: Employment. Zhang:Sanofi-Aventis: Employment. Neumann:Sanofi-Aventis: Employment.