Citations

Abstract Background: Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Methods: Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Patients 18 years or older with a diagnosis of advanced, relapsed/refractory AML (non-acute promyelocytic leukemia) and MDS were eligible and treated on study. Eligible patients had adequate hepatic, renal, and cardiac function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with uncontrolled infection, human immunodeficiency virus, cardiac and neurological disorders, or those who were pregnant were ineligible. Clinical trial information: NCT01314599. Results: Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and two patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs. 8±8% (n=16), respectively (P=0.04). Conclusions: Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients. Disclosures Rodríguez: PharmaMar: Employment. Ravandi:Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria. Daver:Sunesis: Consultancy; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Novartis: Research Funding; Otsuka: Consultancy. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Astra Zeneca: Research Funding; Servier: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maiti:Celgene Corporation: Other: Research funding to the institution. Martinez:PharmaMar: Employment. Siguero:PharmaMar: Employment. Al-Kali:Novartis: Research Funding.

Abstract Prompted by the activity of lenalidomide (Revlimid®) in pts with chronic idiopathic myelofibrosis (CIMF), we sought to evaluate the safety and efficacy of the combination of lenalidomide and prednisone in a phase II study for pts with CIMF. The rationale for this combination is that the anti-angiogenic and anti-TNFa effects of lenalidomide may be potentiated by the effects of prednisone to reduce marrow fibrosis and improve hematopoiesis in CIMF. Initial therapy consisted of lenalidomide 10 mg/d (dose level [DL] 0) on days 1–21 of a 28–day cycle for 6 cycles, in combination with prednisone 30 mg/d orally during cycle 1, 15 mg/d orally during cycle 2, and 15 mg/d every other day during cycle 3. The lenalidomide dose could be reduced to 5 mg/d (DL -1) or to 5 mg/d every other day (DL -2), or increased to 15 mg/d (DL +1) or 20 mg/d (DL +2) depending upon toxicity or lack of response, respectively. A total of 40 pts (23 male, 17 female) have been enrolled. The median age was 62 years (range, 41–86), time from CIMF diagnosis to the study treatment 10 months (range, 0–269), WBC count 87x109/L (range, 1.1–89), hemoglobin 9.8 g/dL (range, 7.8–17.3), platelets 137x109/L (range, 8–1183). Pts had received a median of 1 prior therapy (range 0–4): hydroxyurea (HU; n=14), anagrelide (AG; n=4), azacitidine (n=6), steroids (n=5), thalidomide (n=4), and interferon (n=3). Ten (25%) pts had not received any prior therapy. JAK2 V617F mutation was detected in 18 (50%) of 36 tested pts and 20 (50%) of 40 had abnormal cytogenetics. A total of 260 cycles have been administered. All 40 pts are evaluable for response and toxicity. Responses have been observed in 12 (30%) pts, including complete response (CR) in 2 (normal blood counts and <5% bone marrow blasts, off HU, AG, growth factors, and no transfusions); partial response (PR) in 7 (at least 2 of the following: Hb increase by ≥2 g/dL, 50% increase in platelets, decrease of bone marrow blasts or organomegaly by ≥50%, normalization of WBC count without blasts, or reduction in bone marrow fibrosis; off HU, AG, growth factors, and transfusion independence); and hematologic improvement (HI) in 3 (at least 2 of the following: decrease by ≥25% of pretreatment leukocytosis, splenomegaly, or marrow blasts, or increase of Hb by ≥1g/dl without growth factor or transfusion support or platelets by ≥25%; off HU, AG, growth factors). Median time to response was 12 weeks (range, 2–32). Responses have been sustained for a median of 15 wks (range, 5–36) and are ongoing in all 12 responders. Overall, 21 (53%) pts experienced grade 3–4 toxicity, being the most frequent neutropenia, anemia, musculoskeletal pain, and fatigue. Twenty-four (60%) pts have required dose reduction to DL -1, of which 5 (12.5%) further reduced to DL -2. One (2.5%) pt dose-escalated to DL +1, while 15 (25%) remained at DL 0. Twenty-one (53%) pts discontinued lenalidomide due to: lack of response (n=8), pt’s decision (n=7), grade 3–4 toxicity (n=5), and poor compliance (n=1). No deaths or transformation to acute myeloid leukemia occurred. In summary, the combination of lenalidomide and prednisone is an active and generally well-tolerated regimen for pts with CIMF. Longer follow-up is warranted to evaluate the durability of ongoing responses. Updated results will be presented at the meeting.

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative disorders (MPDs) associated with activating mutations of Janus tyrosine kinase 2 (JAK2) gene. The most common mutation, JAK2 V617F, has been reported in ∼97% of patients with PV, ∼50% with ET, and ∼50% with PMF. The resultant JAK2 protein is continuously autophosporylated and therefore always active. It is believed that this mutated tyrosine kinase contributes to the existence and progression of MPDs. CEP701 is an orally available potent low nanomolar inhibitor of wild type and mutated JAK2 tyrosine kinase in enzymatic and cellular assays. Significant inhibition (growth stasis) was observed following CEP-701 subcutaneous administration to V617F-mutated JAK2-dependent HEL.92 xenografts grown in immunocompromised mice. These results indicate that CEP-701 is an attractive candidate for clinical evaluation in patients with MPD carrying a mutated, constitutively activated JAK2. CEP701 is also a potent inhibitor of FLT3 and is being evaluated as FLT3 inhibitor in Phase II/III studies in patients with acute myeloid leukemia, at the starting dose of 80mg PO BID. We designed a Phase II study of CEP701, at the dose of 80 mg PO BID, in patients with PMF and post PV/ET MF, who harbor JAK2 V617F mutation. Eleven patients have been treated so far, seven males, median age 56 years (range, 38–69), median 3 prior therapies (range 0–6); 7 with abnormal cytogenetics; 8 with enlarged spleen (2 had splenectomy); 4 with enlarged liver; 5 transfusion dependent. Five patients have been followed for at least 1 month and have had stable disease. Response will be evaluated using International Working Group for MF Consensus Response Criteria. JAK2 V617F allele burden is being measured monthly. Except for Grade 2 nausea in one patient, no toxicities have been noted so far. Updated results will be presented at the meeting.

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 Abstract 2926 Background: RAS proteins are encoded by 3 proto-oncogenes (K-RAS, N-RAS, and H-RAS) and regulate the growth and differentiation of many cellular types, including the myeloid compartment. Codons 12, 13, and 61 (in N-RAS and K-RAS) have been reported to be common targets of mutations. These mutations result in constitutive activation of the RAS pathway by increasing intracellular RAS GTP levels, which result in activation of the RAS/MEK and the RAS/PI3K pathways. Its prognostic significance in MDS is yet to be clarified. Because the potential prognostic and therapeutic implications of RAS mutations in MDS, we decided to study the impact of RAS mutations in patients (pts) with MDS. Methods: Mutation analysis of KRAS and NRAS codons 12, 13, and 61 was performed by Pyrosequencing using biotinylated reverse primers. All pts referred to MD Anderson between 2000–2009 were reviewed. In addition to standard clinical characteristics, including karyotyping, mutational status of Flt3, c-Kit and JAK2 was also analyzed. Overall survival was calculated based on Kaplan-Meier. Results: Of the 1067 pts with MDS of age above 17 evaluated for RAS mutation, 43 pts (4%) were positive. Seventy nine percent of RAS mutations were of N-RAS type (codon12 (55%), codon 13 (12%), codon 61(12%)) with K-RAS 12 comprising the rest (21%). Median age was 68 years (range, 18–94) with 66% being males (703 pts). Their median white blood cell (WBC) was 3.3×109/L (range, 0.3–72.2), hemoglobin 9.8 (range, 3–17.5), and platelets 73×109/liter (range, 1–1040). Median bone marrow blast was 5% and 77 pts (7%) had leukemic transformation. More than half of the pts had RAEB or RAEB-t (44% and 9 % respectively) which translated into fewer patients in the low IPSS category (19%). The median age was 66 years (range 26–84) in the RAS mutated (muRAS) group compared to 68 in the wild type (wtRAS). WBC was higher in the muRAS group compared to wtRAS (6.8 ×109/L vs. 3.2 ×109/L, p<0.001 by Mann-Whitney median test (M-W-T)). Percent of bone marrow blasts was higher (9%) in muRAS group compared to 5% in wtRAS (p<0.001 by M-W-T). High (Int-2 and high) risk by IPSS was more frequent in muRAS 51% compared to 40% in wtRAS group (p=0.11). Leukemic transformation was 9% and 7% (p=0.61) in both muRAS and wtRAS groups respectively. RAS mutation was detected more frequently in the CMML subgroup (12/80 (15%) pts). There were no differences in terms of response to DNA methylating inhibitors (CR in 41% in muRAS versus 40% in wtRAS). ARA-C-based regimens resulted in better CR in wtRAS than muRAS (59% vs 25%); however, the size of muRAS group was too small (1 out 4 pts).There was a trend towards shorter overall survival (OS) in the muRAS group compared to wtRAS (395 vs. 500 days, p value=0.057). MuRAS RAEB (325 vs. 450 days, p= 0.13) and RAEB-t (125 vs. 375 days, p= 0.27) subgroups showed a trend towards worse OS compared to wtRAS group. There was a significant OS decrease in RCMD (150 vs. 700 day, p= 0.015). Surprisingly, muRAS CMML group showed a trend towards better OS compared to wtRAS (728 vs. 687 days, p=0.44). Additionally we analyzed patients for presence of Flt3 mutation. These were present in only 18 of the pts (4%) but none of them had also a RAS mutation. There was no c-Kit mutations found in this cohort of pts, compared to 9/37 (24%) pts tested positive for JAK2V617F. Conclusion: MuRAS occurs in 4% of pts with MDS. In the muRAS group, pts tended to have higher risk disease and risk of transformation to acute leukemia compared with wtRAS. OS tended to be worse in some subgroups in muRAS. Although the prognostic impact of RAS mutations in MDS appears to be limited, mutations could be used to develop targeted therapeutic interventions. Disclosures: No relevant conflicts of interest to declare.

Abstract Background SGI-110 is a second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine. The compound is delivered as a small volume, pharmaceutically stable subcutaneous (SQ) injection which allows longer half-life and more extended DAC exposure than DAC intravenous infusion. This pharmacokinetic profile offers the potential for improved biological and clinical activity and safety over currently available HMAs (Kantarjian et al. ASH, 2012). Methods A randomized Phase 1-2 first-in-human PK/PD-guided, dose-escalation study was conducted in patients with relapsed or refractory intermediate or high-risk MDS or AML. Patients were initially randomized to one of two SQ regimens - Dailyx5 or Weeklyx3, for 28-day courses. Subsequently, a Twice Weeklyx3 regimen (Monday, Thursday) was added for evaluation based on emerging LINE-1 demethylation data from the Weeklyx3 regimen. Results 93 patients (74 AML, 19 MDS) were treated in the dose escalation phase: 44, 34, and 15 patients were treated in the Dailyx5, Weeklyx3, and the Twice Weeklyx3 regimens, respectively. Across the three regimens, median age was 70 years (range, 29–86), 68% male, and 87% had ECOG PS of 0-1. The median number of prior regimens was 3 (range, 1–9) and 68% of patients had prior HMA treatment (59% AML, and 100% MDS). Of the 74 AML patients treated, 31 (42%) had secondary AML including antecedent MDS. Patients received a median of 2 courses of SGI-110 (range, 1-20). LINE-1 demethylation data at the 2 highest dose levels which were well tolerated and evaluated for all 3 regimens (60 and 90 mg/m2) are shown in the figure below. The Dailyx5 regimen demonstrated the most potent average LINE-1 demethylation, while the Twice Weeklyx3 achieved the most prolonged LINE-1 demethylation. The least potent demethylation was seen with the Weeklyx3 regimen. There was no additional demethylation at the 90 mg/m2 dose compared to 60 mg/m2in all 3 regimens. Responses were reported according to the IWG Criteria 2006 (MDS)/2003 (AML). Complete remissions were observed in 5 AML patients (2CRs, 1CRp, and 2CRi). Clinical responses (2 mCR and 3 HI-E, 1 HI-N, 1 HI-P) were observed in 6 MDS patients, all of whom had been previously treated with HMA. All AML responses and both mCR in MDS patients achieved ≥10% LINE-1 demethylation. Safety is reported based on Adverse Events (AEs) as graded by the CTCAE v4 criteria. Across regimens, the Twice Weeklyx3 demonstrated an increased number of related AEs compared to the other regimens. The most commonly reported related AEs ≥ 10% in the Dailyx5 regimen (injection site pain, thrombocytopenia, neutropenia, anemia, fatigue), Weeklyx3 regimen (injection site pain and diarrhea), and Twice Weeklyx3 regimen (injection site pain, injection site reaction, fatigue, dizziness, febrile neutropenia, neutropenia, anemia, and thrombocytopenia). Conclusions SQ SGI-110 is a potent HMA using all 3 regimens evaluated. The most potent hypomethylation was achieved with Dailyx5 dosing and the most prolonged hypomethylation was achieved using the Twice Weeklyx3 regimen. All 3 regimens were well tolerated. Clinical responses were observed in heavily pretreated patients, including those with prior HMA exposure. These results support the ongoing Phase 2 expansion study investigating the Dailyx5 dosing schedule in patients with MDS and AML who are either HMA treatment naïve or previously treated with HMAs. Disclosures: Roboz: Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Issa:Astex Pharmaceuticals Inc.: Honoraria, Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Ritchie:Astex Pharmaceuticals, Inc.: Research Funding. Rao:Astex Pharmaceuticals, Inc.: Research Funding. Larson:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Schimmer:Astex Pharmaceuticals, Inc.: Research Funding. Mesa:Astex Pharmaceuticals, Inc.: Research Funding. Blum:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment. Kantarjian:Astex Pharmaceuticals, Inc.: Research Funding.

Abstract Background Systemic mastocytosis (SM) is characterized by abnormal proliferation and accumulation of neoplastic mast cells. Patients (pts) with SM are treated with recombinant interferon-alpha or cladribine. Responses to these agents are poor. Malignant mast cells in SM carry, in most cases, a mutation involving codon 816 of the c-KIT gene (D816V) resulting in constitutively activated c-kit receptor tyrosine kinase believed to be important for disease progression. Agents that antagonize this mutated form of c-kit may have clinical benefit in SM. Dasatinib is one such agent, proven effective in pre-clinical in vitro and in vivo models of SM. Study Design In pilot Phase II trial for SM, Dasatinib was administered at 70mg PO BID. Response was assessed after minimum of 3 months (3 cycles) of therapy. Therapy was discontinued in pts who showed no response after 6 cycles of therapy. Response was evaluated following guidelines proposed by Valent et al. (Leuk Res. 25;603–625, 2001). In addition, all symptoms related to SM were recorded and monitored. Results Thus far, a total of 30 pts have been treated; 24 are evaluable for response and toxicity, including 6 with aggressive SM (ASM), 4 with SM and associated hematologic non-mast cell disease (SM-AHNMD; 2 with chronic myelomonocytic leukemia and one each with myelofibrosis [SM-MF; JAK2 mutation positive and abnormal cytogenetics] and hypereosinophilic syndrome [SM-HES; FIP1L1-PDGFRa negative]) and 14 with indolent SM (ISM) with uncontrolled symptoms despite optimal supportive care measures. Median age is 57 years (range, 35–73); these were 10 males and 14 females; time from diagnosis to dasatinib therapy 49 months (range, 0–233), performance status 1 in 23 and 2 in 1 pt. Eleven patients were previously treated: imatinib mesylate in 6; denileukin diftitox in 4; and erythropoietin, interferon-alpha, or cladribine in 2 each. One pt, who had undergone splenectomy, had hepatomegaly prior to start of therapy. Median Hb 12.4g/dL (range, 8.5–15.4), WBC 6.7×109/L, (range, 3.5–53.3), and platelets 263×109/L (range, 60–377); no patient was transfusion dependent. Percent bone marrow mast cell varied from <10% in 9 pts, to 60% in 4 pts; blood tryptase level was ≤20ng/mL (not significant) in 7 pts and >200ng/mL (upper limit of the test) in 7 pts. A total of 94 cycles of therapy were administered. The median number of cycles was 4 (range, 1–8). Ten patients stopped therapy: 1 due to progression of AHNMD to acute leukemia, 1 lost a response (symptomatic improvement), 2 had no response after 3 months of therapy, and 6 due to toxicity. No grade 4 toxicity was observed. Twelve patients decreased the dose of dasatinib to 50mg PO BID, of which four to 40mg PO BID. Two patients (8%) achieved complete remission, one with SM-MF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). No significant response in % bone marrow mast cells (4 pts are too early in therapy) or blood tryptase levels have been observed in other patients so far. Symptoms related to SM improved significantly in 7 patients (29%). Conclusion Dasatinib is active in SM (overall response rate 37%). Updated clinical and molecular results will be presented.

Abstract BACKGROUND: The study of rare diseases is limited by the uncommon nature of the conditions as well as the widely dispersed patient populations. Current rare disease registries such as the National Organization of Rare Diseases utilize centralized platforms for data collection; however because of their broad nature, these do not always capture unique, disease specific elements. Hairy Cell Leukemia (HCL) is a rare leukemia globally with approximately 900 new cases diagnosed in the US each year. The HCL Foundation undertook creation of a Patient Data Registry that collects data from multiple HCL Centers of Excellence (COE) around the globe to better understand the complications, treatment outcomes, disease subtypes, comorbid conditions, epidemiology, and quality of life of patients with HCL. METHODS: Investigators at The Ohio State University Department of Biomedical Informatics and Division of Hematology in collaboration with the HCL Foundation developed a Patient Data Registry (PDR) for the longitudinal capture of high quality research data. This system differs from other registries in that it uses a federated( rather than centralized) architecture, wherein data is queried and integrated in an on-demand manner from local registry databases at each participating site. Further, the data collected for use in the registry combines both automated exports from existing electronic health records (EHRs) as well as additional data entered via a set of web-based forms. All manually entered data comes from source documents, and data provenance spanning electronic and manually entered data is maintained via multiple technical measures. Patients may be enrolled at HCL COE, or, if they do not have access to a COE they may enroll via a web-based portal (www.hairycellleukemia.org). At this time due to regulatory requirements the web-based portal is available to US patients only. All data are de-identified (see Figure 1: De-Identification Workflow) which reduces regulatory burden and increases opportunities for data access and re-use. End users have access to data via a project-specific query portal. RESULTS: The Patient Data Registry has been deployed at The Ohio State University, Royal Marsden Hospital, and MD Anderson Cancer Center, and is undergoing deployment at the University of Rochester. Up to 25 international HCL COE may participate. In addition, US patients are actively entering the registry via the web-based portal. To date, 227 patients have been consented to the registry with 119 of these being via the web-based entry point. CONCLUSION: We created an international and web-based patient data registry which will enable researchers to study outcomes in HCL in ways not previously possible given the rarity of the disease. This work was made possible by research funding from the Hairy Cell Leukemia Foundation. Figure De-Identification Workflow Figure. De-Identification Workflow Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lele:Hairy Cell Leukemia Foundation: Research Funding. Burger:Pharmacyclics: Research Funding. Delgado:Gilead: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding. Montserrat:Morphosys: Other: Expert Testimony; Vivia Biotech: Equity Ownership; Gilead: Consultancy, Other: Expert Testimony; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses. Parikh:Pharmacyclics: Honoraria, Research Funding. Park:Genentech/Roche: Research Funding; Amgen: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tam:janssen: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heckler:Hairy Cell Leukemia Foundation: Research Funding. Payne:Hairy Cell Leukemia Foundation: Research Funding.

Abstract Abstract 788 FLT3 mutations are common in AML and are associated with poor prognosis. Lestaurtinib is a multi-targeted kinase inhibitor with potent activity against FLT3. In an attempt to definitively establish whether or not there is clinical benefit for FLT3 inhibition in the relapse setting, we conducted a randomized trial of chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Patients were randomized to receive either chemotherapy alone, consisting of mitoxantrone, etoposide, and cytarabine (MEC) or high-dose cytarabine (HiDAc) depending on the duration of CR1) or chemotherapy followed by 80 mg lestaurtinib orally BID. Patients on the chemotherapy only arm were eligible for crossover if they were refractory to therapy. Patients on the lestaurtinib arm received the drug for up to 112 days on study (they could continue to receive the drug through a separate extension protocol). The primary objective was complete remission (CR/CRp). Secondary objectives included overall survival (OS), safety, and tolerability. From January 2004 through December 2008, 224 patients at 52 different centers were enrolled and randomized, with 220 patients actually receiving therapy. Blood samples from patients on the lestaurtinib arm were obtained at baseline, on Day 15, and on Day 42 for pK studies and for determination of in vivo FLT3 inhibition and measurement of plasma FLT3 ligand (FL) and alpha-1 acid glycoprotein (AGP) levels. The median age for all patients enrolled was 55 years (53.5 in the control arm, 58.5 in the lestaurtinib arm), with 88% having FLT3/ITD mutations, 8% having D835 mutations, and 4% having both. The duration of CR1 was less than 6 months in 47% of patients in each arm. On the lestaurtinib arm, 107 patients received at least 1 week of lestaurtinib (mean 60.1 days, range 8-418), with 17 of these patients receiving drug on the extension protocol. On the chemotherapy only arm, 7 patients crossed over to receive lestaurtinib, and 31 patients went on to receive lestaurtinib on the extension protocol after outcome evaluation. Lestaurtinib was generally well tolerated following chemotherapy, with 104 Grade 3/4 adverse events in the lestaurtinib arm versus 99 in the control arm. There were 61 serious adverse events in the lestaurtinib arm versus 49 in the control arm. Early death (by Day 42) occurred in 22 lestaurtinib patients (2 progressive leukemia, 14 infectious, 6 organ failure) and16 control patients (6 progressive leukemia, 5 infectious, 5 organ failure). By intention to treat analysis, there were 29 CR/CRp in the lestaurtinib arm and 23 in the control arm (26% versus 21%; p = 0.35), with no difference in OS (4.73 months versus 4.57 months) between the two arms. Blood samples from 79 of the 107 lestaurtinib-treated patients obtained on Day 15 were analyzed for FLT3 inhibitory activity (plasma inhibitory activity [PIA] assay), as well as FLT3 ligand (FL), lestaurtinib, and AGP concentrations. Mean lestaurtinib plasma concentration was 12 uM at Day 15 and fell to 7.5 uM on Day 42. Mean lestaurtinib concentration at Day 15 was 13.3 uM in patients achieving CR/CRp and 11.5uM in non-responders. A target of >85% inhibition of FLT3 maintained at trough (pre-dose) was defined from previous studies. Of the 79 patients tested, 46 (58%) achieved this degree of FLT3 inhibition on Day 15. FL concentrations rose from baseline (15.6 pg/mL) to Day 15 (1148 pg/mL), and AGP concentrations rose by an average of 52% over the same period, both of which may have reduced the degree of FLT3 inhibition. Of the 46 patients with target FLT3 inhibition on Day 15, 18 (39%) achieved CR/CRp, while only 3 (9%) of the 32 patients with below target FLT3 inhibition achieved CR/CRp. Thus, in patients with FLT3 mutant AML at first relapse, pharmacokinetic factors and possible physiologic factors (FL and AGP) limit lestaurtinib's ability to effectively inhibit FLT3. FLT3 inhibition by lestaurtinib, when achieved, correlates with better CR rates, but in this trial that benefit was negated by a poor CR rate in those patients for whom the drug did not reach the target level of FLT3 inhibition. Overall, lestaurtinib treatment following re-induction chemotherapy failed to increase response rates or prolong survival of patients with FLT3 mutant AML in first relapse. Disclosures: Levis: Cephalon: Clinical Advisory Board member. Ravandi:Cephalon: Honoraria, Member, clinical advisory board, Research Funding. Erba:Cephalon: Research Funding, Speakers Bureau. Baccarani:Novartis Pharma, Bristol Myers Squibb, Merck Sharp & Dome, Pfizer: Consultancy, Speakers Bureau. Stone:Cephalon: ad hoc consultancy; Novartis: Research Funding, ad hoc consultancy. Advani:Cephalon: Research Funding. Douer:Cephalon: Honoraria, Research Funding, Speakers Bureau. Litzow:Cephalon: Research Funding. Tremmel:Cephalon: Employment, Equity Ownership. Bensen-Kennedy:cephalon: Employment. Smith:Cephalon: Research Funding.

Abstract Abstract 414 Background: SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. Methods: A randomized Phase 1–2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment. Results: 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29–86), 65% were male, and 82% had ECOG PS of 0–1. Median number of prior regimens was 3 (range 1–9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3–4 hrs). At SGI-110 dose range of 60–125 mg/m2, observed mean decitabine AUCs (88–231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26–64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ∼2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed. Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (∼25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ∼8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved >10% LINE-1 hypomethylation. The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose. Conclusions: SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ∼25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage. Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz:Astex Pharmaceuticals: Research Funding. Rizzieri:Astex Pharmaceuticals: Research Funding. Stock:Astex Pharmaceuticals: Research Funding. O'Connell:Astex Pharmaceuticals: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding. Yee:Astex Pharmaceuticals: Research Funding. Tibes:Astex Pharmaceuticals: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Research Funding. Ravandi:Astex Pharmaceuticals: Research Funding. Walsh:Astex Pharmaceuticals: Research Funding. Feldman:Astex Pharmaceuticals: Research Funding. Ritchie:Astex Pharmaceuticals: Research Funding. Rao:Astex Pharmaceuticals: Research Funding. Decastro:Astex Pharmaceuticals: Research Funding. Schimmer:Astex Pharmaceuticals: Research Funding. Mesa:Astex Pharmaceuticals: Research Funding. Syed:Astex Pharmaceuticals: Research Funding. Choy:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals: Employment. Chung:Astex Pharmaceuticals: Research Funding. Issa:Astex Pharmaceuticals: Honoraria, Research Funding.