Cortes, Jörge E.

Abstract Background: The recent discovery of JAK2V617F, as an activating mutation in the majority of patients with myeloproliferative neoplasms, has spurred development of JAK2-selective small molecule inhibitors for the treatment of these diseases. TG101348 is a potent (enzyme IC50=3 nM) and selective (35- and 334-fold selectivity over JAK1 and JAK3, respectively) orally bioavailable JAK2 inhibitor that is effective in treating a murine model of Polycythemia vera (PV) (Cancer Cell. 2008 13:311). TG101348 selectively inhibits growth of hematopoietic colonies harboring V617F, MPLW515K, or JAK2 exon 12 mutations (Leukemia. 2008 Mar 20, Epub). Methods: A Phase I dose-escalation study of TG101348 is ongoing for patients with high- or intermediate-risk (with symptomatic disease) primary myelofibrosis (PMF) and post-PV or post-essential thrombocythemia (ET) myelofibrosis (Cancer.2007109:2083). TG101348 was administered orally once daily in 28-day cycles in cohorts of at least 3 patients. Additional eligibility criteria included absolute neutrophil count of ≥1 × 109/L and platelet count of ≥50 × 109/L, but a JAK2 mutation was not required. Primary objectives were determination of safety and tolerability, as well as pharmacokinetic behavior of TG101348. The secondary objectives were evaluation of treatment response (Blood.2006108:1497), pharmacodynamic activity, and drug effect on V617F allele burden and plasma cytokine levels. The spleen response was documented as change in palpable spleen tip from the costal margin. For patients achieving less than a complete remission after 3 cycles of treatment at their initial dose, step-wise escalation was permitted at each cycle if a cohort had been shown to have tolerated that dose. Results: Fifteen patients (9 males; median age=66 years; range=53 to 79 years) have been enrolled in the study to date – 10 with PMF (8 V617F+) and 5 with post-PV MF (all V617F+). The median follow-up to date is 13 weeks (range 1–28). Treatment was discontinued in 1 patient, in cohort 1, on the 2nd day of dosing after it was discovered that the patient had baseline QTcF prolongation (Grade 1). In the remaining 14 patients, no dose-limiting toxicities or other significant non-hematological adverse events have been observed to date. The pharmacokinetic parameters of TG101348 in plasma were well characterized following single daily oral doses of 30 mg, 60 mg, 120 mg or 240 mg. Dose-proportional pharmacokinetics were observed following single and multiple doses of TG101348. Treatment response data are as follows: Cohort 1 (starting dose=30 mg; 3 patients; median follow-up=26 weeks): 2 of the 3 patients had improvement in constitutional symptoms including fatigue, night sweats and pruritus. No other benefits were noted. These patients have now been dose escalated to either 120 or 240 mg/day. Cohort 2 (starting dose=60 mg; 3 patients; median follow-up=18 weeks): 1 patient had a 40% decrease in spleen size (18 to 10 cm). All 3 patients have now been dose escalated to 120 or 240 mg/day. Cohort 3 (starting dose=120 mg; 3 patients; median follow-up=13 weeks): 2 of the 3 patients reported improvement in constitutional symptoms including fatigue, night sweats, and pruritus. 1 patient had a 25% decrease in spleen size (28 to 21 cm). 2 patients have been dose escalated to 240 mg/day. Cohort 4 (starting dose=240 mg; 3 patients; median follow-up=8 weeks): 1 patient developed Grade 3 anemia (baseline Grade 1) at the end of the first cycle. 1 patient reported decreased fatigue. All 3 patients have experienced a 20 to 53% reduction in spleen size; baseline measurements were 10, 13, and 17 cm. Cohort 5 (starting dose=360 mg; 2 patients; median follow-up=1 week). Both patients had decreased splenomegaly within 1 week of therapy, including 1 with disappearance of palpable splenomegaly from a baseline of 20 cm; this patient also reported significant improvement in constitutional symptoms. Conclusions: Preliminary findings indicate that TG101348 is well tolerated in patients with myelofibrosis. Although it is too early to make valid conclusions, a decrease in spleen size has been noted at higher dose levels. Similarly, improvement in constitutional symptoms has been reported by some patients. Updated results on current and future patients, including data on pharmacokinetics, pharmacodynamics, and changes in V617F allele burden and plasma cytokine levels will be presented at the meeting.

Abstract Background: Nilotinib, a 2nd-generation BCR-ABL inhibitor, is 20–30 times more potent than imatinib in vitro. A phase II, open-label study of safety/efficacy of nilotinib in pts with imatinib-resistant/intolerant Ph+ CML-CP or -AP was reported. Planned starting dose was 400mg BID, with escalation to 600mg BID if response was inadequate. The objective of the post-hoc analysis was to evaluate safety/efficacy of nilotinib 600mg BID in CML-CP pts who had dose escalation. Methods: Starting dose was 400mg BID. If response was inadequate (failure to achieve complete hematologic response [CHR] by 3 mos, minimal cytogenetic response [CyR] by 6 mos, or major cytogenetic response [MCyR] by 12 mos; loss of HR, CyR, or progression), nilotinib to 600mg BID dosing was permitted. Imatinib resistance was defined as treatment with imatinib ≥600 mg/d with disease progression (≥50% increase in WBC, blasts, basophils, or platelets) or no HR in peripheral blood and/or bone marrow after 4 wks. Results: Of 320 enrolled pts in CP, 269 remained on nilotinib 400mg BID; 51 pts were dose-escalated to 600mg BID for inadequate responses (mean age 57.7 yrs; 68.6% male). All pts met the study criteria for imatinib resistance. Prior imatinib dose was ≥600mg QD in 98% pts and ≥800 mg QD in 53%. 43/51 (84%) pts had no baseline CHR; 38% had no prior history of complete cytogenetic response (CCyR). 35% had prior MCyR. Median time to dose escalation was 169 (114–211) d. 14 (27.5%) pts remain on therapy; median time to discontinuation from study was 307 (235–414) d. 5 pts with disease progression and no deaths were observed among pts who received 600mg BID. CHR was achieved in 58% of evaluable pts without CHR at baseline (n=43). MCyR occurred in 29% of evaluable pts (15/51) on 600mg BID; 10% (5/51) CCyR. Disease progression was low, occurring in 10% (5/51) of pts on 600mg BID. Median time to progression for CP pts on 600mg BID was 12 mos, substantially less than for pts who stayed on 400mg BID (median not observed yet, at least 20 mo). Nonhematologic AEs in 600mg BID pts were similar to those reported for the entire CP cohort from the phase II study. Grade 3/4 hematologic lab abnormalities were: anemia 13.8%, neutropenia 7.9%, thrombocytopenia 13.7%. Hyperglycemia and elevated bilirubin occurred in 6% and 10% of pts, respectively, on 600mg BID. Conclusions: Some HR and CyR after dose escalation to 600mg BID were observed. Safety/tolerability for 600mg BID were similar to the entire CP cohort. Based on these preliminary data, nilotinib dose escalation to 600mg BID in imatinib-resistant Ph+ CML-CP pts may be effective in pts with inadequate responses to 400mg BID. As might be expected in a more resistant population, response duration was shorter than reported for the phase II CP cohort. Additional follow-up is necessary. Use of 600mg BID is not currently recommended for imatinib-resistant CML-CP pts outside clinical studies.

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 SGI-110 is second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume, pharmaceutically stable SQ injection allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110 differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in the phase 1 trial (Kantarjian et al. 2012). Methods In a randomized Phase 2 study, relapsed/refractory AML, or elderly treatment naïve AML patients who were not suitable for induction chemotherapy (poor major organ function; poor cytogenetics; or secondary AML) were randomized to one of two SQ doses – the biologically effective dose (BED) of 60 mg/m2 QDx5 or 90 mg/m2 QDx5. The primary endpoint of the phase 2 study is the overall remission rate (CR, CRi, and CRp) based on the International Working Group Criteria 2003. Safety findings based on adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic data on Long Interspersed Nucleotide Element (LINE-1) DNA methylation (an index of global DNA methylation) activity were also assessed and reported. Results As of June 30, 2013, sixty-seven patients (50 relapsed/refractory AML, 17 treatment naïve elderly AML) were treated and had a minimum follow up of 3 months. Patients were randomized to either 60 mg/m2 dose (32 patients) or 90 mg/m2 dose (35 patients). The median age was 66 years (range, 22–84), 69% were male, and ECOG PS of 0/1/2 was reported in 11/47/9 patients respectively. Median number of prior regimens was 2 (range, 0–10). Patients’ characteristics were well balanced between the 2 dose groups. The primary endpoint of overall remissions (CR, CRp, or CRi) was observed in 17/67 patients (25% with 95% CI, 16–37%). There were 8 complete remissions (CR, CRp, or CRi) in 50 patients with relapsed/refractory AML (16% with 95% CI, 7-29%); and 9 complete remissions (CR, CRp, or CRi) in 17 treatment-naïve elderly AML patients (53% with 95% CI, 28-77%). Five patients (4 relapsed/refractory, and one treatment-naïve elderly AML) subsequently received a stem cell transplant. There was no difference in the complete remission rate between 60 and 90 mg/m2 doses (8 remissions in 32 patients at 60 mg/m2, and 9 remissions in 35 patients at 90 mg/m2). LINE-1 DNA methylation data before and after treatment was available in 50 (75%) patients enrolled. LINE-1 demethylation ≥ 10% post treatment was observed in 83% and 78% in the 60 mg/m2 and 90 mg/m2, respectively. The median maximum LINE-1 demethylation for responders is 25% as compared to 19% for non-responders. The most common adverse events (AEs) regardless of relationship to SGI-110 ≥ Grade 3 include febrile neutropenia, thrombocytopenia, anemia, leukopenia, neutropenia, and pneumonia. The 90 mg/m2 dose showed a greater frequency of Grade 3/4 related AEs ≥ 10% (anemia, febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia) compared to the 60 mg/m2 dose. Conclusions SQ SGI-110 is a new HMA which is well tolerated and clinically active in the treatment of AML. Complete remissions and potent demethylation of ≥10% were equally observed at the 2 dose groups of 60 and 90 mg/m2. These data support further phase 3 investigation of this agent in the treatment of AML. Preliminary overall remission rate of 53% in treatment-naïve elderly AML seems to compare favorably with previous results reported for HMA treatment but this needs to be confirmed in a larger number of patients and randomized studies. Disclosures: Kantarjian: Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Kropf:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Roboz:Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Savona:Astex Pharmaceuticals, Inc.: Research Funding. Ervin:Astex Pharmaceuticals, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals, Inc.: Research Funding. Pemmaraju:Astex Pharmaceuticals, Inc.: Research Funding. Daver:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Borthakur:Astex Pharmaceuticals, Inc.: Research Funding. Wierda:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Brandwein:Astex Pharmaceuticals, Inc.: Research Funding. Odenike:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Dimitrov:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Astex Pharmaceuticals, Inc.: Consultancy, 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 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.

Abstract Abstract 3801 Purpose: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes. The aim of this study was to determine the absolute bioavailability and safety of a single oral dose of decitabine. Methods: This is an open-label, Phase 1, dose-escalation absolute bioavailability trial in which decitabine was administered orally on Cycle 1 Day 1, and followed by a 1-hour IV infusion of the currently approved regimen (20 mg/m2) on Cycle 1 Days 2–5. Serial blood samples for decitabine pharmacokinetic (PK) assessment were collected up to 6 h post-dosing during Cycle 1 on Days 1 and 2. Three subjects were recruited at each oral dose level of 30, 60, 120 and 240 mg. Subjects were evaluated for adverse events (AEs). Results: Study results are summarized in Table 1. Sixteen subjects were screened and 12 were enrolled. Nine subjects had de novo MDS and 3 had secondary MDS (IPSS score Int-2 = 6, Int-1 = 5, Low = 1). Following oral dose, Cmax was reached within 0.50 h (tmax) and after Cmax the plasma profile showed biphasic decline with terminal half-life ranging between 0.36 to 0.93 hr. Increase in oral dose did not result in proportional increase in Cmax and AUC. The PK parameters following oral doses showed very high variability. Based on comparison of dose normalized exposure, the absolute bioavailability ranged between 3.9 to 14.1% and increased proportionally with dose. The non-dose normalized bioavailabilities were calculated to find a dose at which mean oral bioavailability reaches ≥80% of the current IV regimen of 20 mg/m2. The non-dose normalized bioavailability ranged between 11.7 and 80.5% with highest oral bioavailability observed at 240 mg dose. The most common SAEs were pneumonia (n=4) and neutropenic fever (n=4). Five patients (41.7%) experienced diarrhea and nausea (all grades). Conclusion: The study demonstrates that the absolute bioavailability ranged between 3.9 and 14.1%. Oral decitabine was generally well tolerated at doses between 30–240 mg in MDS subjects and exhibited a safety profile similar to the profile following intravenous administration. The bioavailability and safety data may allow for further testing in the phase 2 setting. Disclosures: Mistry: Eisai Inc.: Employment. Jones:Eisai Inc.: Employment. Kubiak:Eisai Inc.: Employment. Garcia-Manero:Eisai Inc.: Research Funding. Litzow:Eisai Inc.: Research Funding. Mesa:Eisai Inc.: Research Funding. Tarassoff:Eisai Inc.: Employment. Cortes:Eisai Inc.: Research Funding.

Abstract Abstract 459 Background: A Phase I study of TG101348, a potent, oral JAK2-selective inhibitor in patients with high- or intermediate-risk primary, post-polycythemia vera (PV) and post-essential thrombocythemia (ET) myelofibrosis (MF) recently completed enrollment. Data from the dose escalation cohort (n=28; 30–800 mg administered as a single daily dose) showed dose-linear plasma exposure, with mean elimination T1/2 at steady state ranging from 16 to 34 hours. The dose-limiting toxicity was reversible asymptomatic grade 3 or 4 amylasemia/lipasemia; the maximum tolerated dose was 680 mg. We now present updated results from an extension study in which subjects continued treatment beyond six 28-day cycles. Result: In the entire study, 59 subjects (median age 64 years) were treated. Forty four patients had PMF, 12 post-PV MF, and 3 post-ET MF; 86% were JAK2V617F-positive. Median palpable spleen size was 18 cm and 21 (36%) patients were transfusion-dependent at study enrollment. Forty three (73%) subjects continued treatment on the extension study; the median (range) cumulative exposure to TG101348 was 380 days (170-767); the number of cycles of treatment completed ranged from 7–29, and the proportion of subjects who completed 12, 18, and 24 cycles of treatment was 72%, 28%, and 14%, respectively. The median (range) treatment dose at data cutoff was 440 mg/day (120 to 680 mg/day; n = 35). Toxicity: TG101348 was well tolerated. Non-hematologic, at least possibly related adverse events included nausea (69%; Grade 3=3%), diarrhea (64%; Grade 3=10%), and vomiting (58%; Grade 3=3%), that were dose-dependent; the symptoms were self-limited or controlled with symptomatic treatment and/or dose reduction. Also observed were asymptomatic increases in serum lipase (27%), AST/ALT (27%/25%), creatinine (24%), and alkaline phosphatase (17%). Grade 3/4 hematological adverse events possibly related to TG101348 included treatment-emergent anemia (35% of patients who were not transfusion dependent at baseline), thrombocytopenia (24%), and neutropenia (10%). Spleen: During cycles 1–6, 42% of patients achieved Clinical Improvement (CI) per the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for spleen response. The CI rate for the 43 subjects who continued treatment beyond 6 cycles was 65%, and the median time (range) to CI was 140 days (77-802). After 12 cycles, 36 (95%) of the 38 evaluable patients had some degree of spleen size reduction; 32 (85%), 26 (68%), and 10 (26%) of subjects had a minimum 25%, 50%, and 100% decrease in palpable splenomegaly. JAK2V617F allele burden: Of the 48 JAK2V617F mutation-positive subjects, 23 (48%) had a baseline mutant allele burden of >20%. Of these, 20 subjects with a baseline median allele burden (range) of 62% (23% to 100%) completed at least 6 cycles of treatment. Sixteen subjects (80%) exhibited a median 62% (range 6% to 96%) decrease in JAK2V617F burden, including 9 (45%) with a ≥50% decrease; 4 subjects (20%) had increases (range 18% to 58%). Eighteen subjects (78%) completed 12 cycles of treatment; 13 (72%) had a median 50% decrease (range 29% to 82%), including 7 (39%) subjects with a ≥50% decrease; 5 subjects (28%) had no change or increases (range 0% to 22%) in JAK2V617F. Constitutional symptoms: For patients with data at baseline and cycle 6, early satiety, fatigue, night sweats, cough, and pruritus were reported by 56%, 47%, 24%, 22%, and 19% of subjects, respectively. Improvement (complete resolution) rates observed at cycle 6 were: 75% (40%), 65% (29%), 89% (89%), 88% (75%), and 100% (57%) for the aforementioned symptoms, respectively. Leukocytosis/Thrombocytosis: Leukocytosis was present at baseline in 33 subjects; following 6 and 12 cycles of therapy, 57% (n=28) and 56% (n=25) achieved normal WBC counts. Thrombocytosis was noted at baseline for 10 (17%) subjects; following 6 and 12 cycles of therapy, 90% (n=10) and 88% (n=8) achieved normal platelet counts. Conclusion: The current study provides proof-of-concept that selective JAK2 inhibition has anti-myeloproliferative/anti-clonal activity in myelofibrosis. The majority of subjects treated with TG101348 for more than 6 cycles experienced a rapid, significant, and durable decrease in splenomegaly, normalization of leukocyte/platelet counts, and improvement of disease-related symptoms, all within the context significantly decreased JAK2V617F burden. Disclosures: Off Label Use: There is no FDA approved drug for Myelofibrosis.All the drugs discussed will be off-label. Stone:Novartis: Consultancy. Silverman:TargeGen: Consultancy. Shorr:TargeGen: Employment, Equity Ownership.

Abstract Background: Persistence of minimal residual disease (MRD) after induction, consolidation and salvage therapies is an independent poor prognostic marker in AML. The bone marrow (BM) microenvironment is a protective niche that promotes chemotherapy resistance of leukemia cells. This residual subset of chemotherapy-resistant cells present during remission eventually contributes to the leukemia relapse/persistence. Adhesion of AML cells to BM stroma is dependent on the CXCR4 receptor binding to its ligand CXCL12. High levels of CXCR4 expression correlate with poor survival in AML. It is postulated that blocking the CXCL12/CXCR4 axis will dislodge AML cells from the protective microenvironment and, when combined with chemotherapy, may improve the response to therapy. BL-8040 (BKT140) is a short peptide which inhibits the binding of CXCR4 to CXCL12, resulting in mobilization of leukemic blasts from the BM to the peripheral blood (PB). BL-8040 has strong affinity for the CXCR4 receptor with long receptor occupancy and as a single agent induces differentiation and apoptosis of leukemia cells in preclinical models. A clinical trial assessing the safety and efficacy of BL-8040 in combination with cytarabine (Ara-C) for the treatment of relapsed/refractory AML patients was recently completed (NCT01838395). Here we report results from correlative studies done on samples from patients who participated in this trial. Objective: To assess BL-8040 single agent anti leukemia effects in relapsed/refractory AML. Method: Patients received a once daily SC dose of BL-8040 monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5g/m2 for patients ≥60; 3g/m2 for patients <60) per day on days 3-7. Six dose levels of BL-8040 (0.5 - 2.0 mg/kg) were tested. PD parameters such as mobilization of leukemic blasts and induction of differentiation and apoptosis were assessed after monotherapy with BL-8040 using frequent PB sampling and BM aspirates at baseline and on day 3 prior to Ara-C administration. Results: 45 patients (including 3 receiving compassionate use BL-8040) with a median age of 61 yrs were treated. The majority of patients had poor risk disease with 24% secondary AML and 17% with prior allogeneic stem-cell transplantation. Most patients were heavily pretreated with 19% relapsing after a short first remission (CR1 ≤12 months), 17% had ≥2 relapses and 45% refractory to 1-2 inductions. The CR+CRi rate was 38% in subjects receiving BL-8040 dose ≥1.0 mg/kg (n=39). Ongoing follow-up (FU) of responding patients (expansion phase; N=19) shows median EFS of 9.3 months (range 4.3-12.8 months). At the time of this analysis 10/19 patients are alive with a FU range of 0.96 - 12.8 months. FACS analysis revealed that BL-8040 monotherapy triggered an average 4.3-fold increase of immature AML blasts (CD45+Low/CD34+/CD117+/HLA-DR+) in PB (i.e., mobilization). Response to treatment was associated with more robust mobilization of AML blasts following BL-8040 monotherapy (responders 9.5 vs non-responders 1.7 fold median). Preferential mobilization of AML blasts over normal cells (4.7 fold vs. 1.4 fold, respectively) was confirmed by FISH analysis in a subset of patients with informative cytogenetic abnormalities. Induction of granulocytic differentiation of immature leukemia progenitors (2.5 fold) in the BM following BL-8040 monotherapy was noted. Finally, induction of AML blasts apoptosis (40% increase) by BL-8040 alone was evident by FACS in day 3 (pre-araC) bone marrow biopsies. Conclusions: The data demonstrate that sustained blockade of the CXCR4-CXCL12 axis with BL-8040 is safe and well tolerated and when given in combination with Ara-C improves the response rate achieved historically with Ara-C alone. In addition, treatment with BL-8040 as a single agent rapidly and efficiently induces mobilization, differentiation and cell death of AML blasts. This selective effect on chemotherapy-resistant cells may be translated into reduction of residual disease arguing for incorporation into front-line trials and such studies are ongoing. Disclosures Foran: Millennium Pharmaceuticals, Inc.: Research Funding; medscape: Honoraria; karyopharm: Honoraria; pfizer: Honoraria; novartis: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. DiPersio:Incyte Corporation: Research Funding. Peled:Biokine Therapeutics: Employment. Abraham:Biokine Therapeutics Ltd: Employment. Pereg:BioLineRx Ltd: Employment. Vainstein:BioLineRx Ltd.: Employment. Oberkovitz:BioLineRx Ltd.: Employment. Aharon:BioLineRx Ltd.: Employment. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Abstract Background: The bone marrow (BM) niche protects acute myeloid leukemia (AML) cells from chemotherapy. BM homing of AML cells is dependent on CXCR4 and its ligand CXCL12; high levels of CXCR4 expression correlate with poor survival in AML. It is postulated that blocking the CXCL12/CXCR4 axis with a potent CXCR4 antagonist will disrupt the interaction of the leukemic blasts with the BM and augment the anti-leukemic effect of chemotherapy. BL-8040 (BKT140) is a short synthetic peptide which inhibits the binding of CXCR4 to CXCL12, resulting in the mobilization of leukemic blasts from the bone marrow to the peripheral blood. BL-8040 also inhibits CXCR4/CXCL12 mediated pro-survival ERK/Akt signaling and alters balance of pro/anti-apoptotic Bcl-2 proteins. BL-8040 has strong affinity for the CXCR4 receptor with long receptor occupancy, and, in contrast to other CXCR4 inhibitors, as a single agent induces apoptosis of leukemia cells ex-vivo in clinical samples. A clinical trial assessing the safety and efficacy of BL-8040 in combination with cytarabine (Ara-C) for the treatment of adult relapsed/refractory AML patients is currently ongoing (NCT01838395). Objective: To assess the safety, efficacy and pharmacodynamics/pharmacokinetic parameters of BL-8040 in combination with Ara-C in first or second relapse and refractory AML patients. Method: The study includes a dose escalation phase (3+3 design) followed by an expansion phase. Each patient receives a once daily SC dose of BL-8040 monotherapy on days 1-2 followed by the same dose of BL-8040 plus Ara-C (1.5 g/m2 for patients ≥60; 3 g/m2 for patients <60) on days 3-7. Five dose levels of BL-8040 (0.5, 0.75, 1, 1.25 and 1.5 mg/kg) have been tested. Extensive pharmacodynamic parameters such as CXCR4 expression on the leukemic cells, receptor occupancy, mobilization of leukemic cells and induction of apoptosis are being assessed after monotherapy with BL-8040 using peripheral blood sampling (PB) and BM aspirates at baseline and on day 3 prior to Ara-C administration. Clinical response to treatment is evaluated by BM biopsy on day 30 (-/+ 2). Results: Twenty two patients (median age, 61 y; range, 43-74 y) with relapsed/refractory AML were treated during the escalation phase. BL-8040 was escalated up to 1.5 mg/kg (recommended phase 2 dose) without reaching the MTD. Combination of BL-8040 with Ara-C was safe and well tolerated at all doses tested. Only one SAE (Sweet Syndrome) was reported as possibly related to study drug. The primary treatment related AEs were transient injection site and systemic reactions. The composite complete remission including complete remission (CR) and complete remission with incomplete blood count recovery (CRi) rate was 38% in subjects receiving BL-8040 doses of 1 mg/kg and higher (n=16). Two days of BL-8040 monotherapy triggered an average 40.2-fold (range 1.0-350.9) mobilization of immature AML progenitors (CD45+Low/CD34+/CD117+/HLA-DR+) from the BM to the PB. Moreover, a significant apoptotic effect on the immature leukemia progenitors in the BM following 2 days of BL-8040 monotherapy was noted. Flow cytometric evidence of apoptosis by BL-8040 was corroborated by an increase in cleaved caspase 3 positive blasts in day 3 bone marrow biopsies. In addition, BL-8040 treatment resulted in a median decrease of 57.7% (range, -10.4% to -96.2%) in the number of BM Leukemia progenitor cells (CD45+Low/CD34+/CD117+/HLA-DR+ out of total CD45+/CD34+ normal/progenitor cells) compared with the baseline biopsy. This decrease was accompanied with a 3.1 fold increase in granulocytes in the day 3 BM biopsy supporting differentiation effect. Finally, long receptor occupancy (up to 24 hours post dosing) was confirmed by FACS analysis measuring surface CXCR4 staining. Pharmacokinetics analysis confirmed dose incremental BL-8040 exposure with a short plasma half-life. Conclusions: The current data demonstrate that sustained blockade of the CXCR4-CXCL12 axis with BL-8040 has potent anti leukemic activity and in combination with Ara-C may improve the response typically achieved in this advanced AML population. Mechanistically, BL-8040 was able to induce apoptosis of leukemic progenitor cells, overcoming the stroma protection, inducing mobilization and differentiation. Disclosures Rowe: BioLineRx Ltd.: Consultancy; Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:Novartis: Research Funding. Altman:Seattle Genetics: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; BMS: Consultancy. Peled:Biokine Ltd.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BiolineRX: Consultancy, Research Funding. Pereg:BioLineRx: Employment. Vainstein:BioLineRx: Employment. Aharon:BioLineRx: Employment. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Teva: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.