Abstract: BACKGROUND: Recurrent isocitrate dehydrogenase (IDH) 1 mutations are observed in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein, is a promising therapeutic candidate for the treatment of patients with mIDH1 AML. Through inhibition of mIDH1, ivosidenib suppresses the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from the first-in-human phase 1 study of ivosidenib in patients with mIDH1 advanced hematologic malignancies including relapsed/refractory (R/R) AML (NCT02074839). This is the first report of data from the 4 expansion cohorts, with a total of 258 patients treated on study. METHODS: The ongoing phase 1 study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mIDH1 hematologic malignancies. Enrollment was completed on May 8, 2017. During dose escalation, patients received ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the recommended dose to be tested in 4 expansion cohorts: R/R AML (Arms 1 and 4, where Arm 1 patients are those with relapse after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapse within 1 year of initial treatment, and Arm 4 patients have R/R AML but are not eligible for Arm 1); untreated AML (Arm 2); and other advanced hematologic malignancies including myelodysplastic syndrome (MDS) (Arm 3). Updated safety data will be presented for all patients. Efficacy outcomes will be presented for all R/R AML patients treated at 500 mg QD across the dose escalation and expansion cohorts who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date of May 12, 2017, as well as for the poorest prognosis Arm 1 subset. Efficacy data for all treated patients from the other expansion cohorts (untreated AML and other advanced hematologic malignancies including MDS) will also be presented. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib. As of May 12, 2017, 62 of 258 (24%) patients were continuing on treatment. The median duration of exposure to ivosidenib was 3.5 months (range 0.1-33.5). Twenty-two (8.5%) patients discontinued treatment to proceed to allogeneic stem cell transplantation. Treatment was well tolerated; the most common adverse events (AEs) (n=258) of any grade irrespective of causality occurring in ≥20% of patients were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). The majority of these AEs were grades 1-2 and reported as unrelated to treatment. Differentiation syndrome (DS) was observed in 29 of 258 (11.2%) patients, including grade ≥3 DS in 14 (5.4%); study drug was held owing to DS in 11 patients (4.3%), and no instances of DS led to permanent treatment discontinuation or death. The primary efficacy endpoint for R/R AML is the CR+CRh rate, i.e., the rate of complete remission (CR according to modified IWG 2003 criteria plus CR with partial hematologic recovery, defined as CR except absolute neutrophil count & gt;0.5 × 109/L [500/µL] and platelet count & gt;50 × 109/L [50,000/µL]). Among 125 Arm 1 R/R AML patients receiving ivosidenib 500 mg QD across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the CR+CRh rate was 30.4% (95% CI 22.5%, 39.3%), including CR in 27 (21.6%) and CRh in 11 (8.8%) patients. Median duration of CR+CRh was 8.2 months (95% CI 5.5, 12.0), and duration of CR was 9.3 months (95% CI 5.6, 18.3). The overall response rate (CR+CRi/CRp+PR+MLFS) was 41.6% (95% CI 32.9%, 50.8%) (52/125 patients). CONCLUSION: Ivosidenib monotherapy is well tolerated in patients with mIDH1 AML and other advanced hematologic malignancies. In a high-risk, molecularly defined R/R AML patient population with unmet medical need, ivosidenib induced durable remissions and improved patient outcomes. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 AML. Disclosures DiNardo: Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. De Botton: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Servier: Honoraria; Agios: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Mims: Novartis: Honoraria. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Altman: Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Collins: Celgene Corporation: Research Funding; Agios: Research Funding; Arog: Research Funding; BMS: Research Funding. Mannis: Curis: Honoraria; Juno: Research Funding; Agios: Research Funding; Amgen: Honoraria. Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Fathi: Juno: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee. Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Stuart: Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Celator/Jazz: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bayer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; MedImmune: Research Funding; Cantex: Research Funding; Astellas: Research Funding. Arellano: Cephalon Oncology: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Goldwasser: Agios: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios: Employment, Equity Ownership. Stone: Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Fuji Film: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Arog: Consultancy; Ono: Consultancy; Agios: Consultancy; Sumitomo: Consultancy. Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Abstract: Abstract 684 Background. Obesity has been associated with an increased risk of developing of lymphoma, particularly DLBCL. Genetic variation in several energy balance genes, including leptin (LEP), its receptor LEPR, ghrelin (GHRL) and neuropeptide Y (NPY) have been shown to modulate risk of lymphoma, although their impact on survival is not known. In contrast, recent studies suggest that patients either overweight (Body Mass Index (BMI), 25 to 〈 30 kg/m2) or obese (≥30 kg/m2) may have a superior prognosis in DLBCL, although its impact in FL and in the current treatment era is not known. We evaluated the association of BMI at the time of diagnosis, 2 years prior to diagnosis and at ages 18, 35 and 50 years, along with germline genetic variation in selected energy balance genes with event-free (EFS) and overall (OS) survival in DLBCL and FL. Methods. We evaluated these associations in a prospective cohort of newly diagnosed DLBCL (N=764) and FL (N=649) patients enrolled at the Mayo Clinic and University of Iowa from 2002–2009 as part of the Molecular Epidemiology Resource. Peripheral blood DNA, clinical data and self-reported historical weights were collected at enrollment. Patients received standard disease treatment strategies, and were systematically followed for disease progression, re-treatment, and death. Single nucleotide polymorphisms (SNPs) were genotyped as part of a custom Illumina iSelect panel. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled as having a log-additive effect in the regression model. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of the obesity measures and SNPs with outcome, adjusted for treatment class and subtype specific prognostic factors (IPI, FLIPI). Results. For DLBCL patients (median age 63 years, range 18–92) the median follow-up was 47 months (range 0–101); 58% had an IPI 0–1 risk disease; and 87% received immunochemotherapy. For FL patients (median age 60 years, range 25–94), the median follow-up was 60 months (range 11–110); 24% had FLIPI score 3–5; and main initial treatments were observation (32%), rituximab (R)-monotherapy (12%), CVP +/−R (19%), and anthracycline +/−R (22%). The main results for BMI and prognosis are reported in the Table. For DLBCL, obese patients at diagnosis had better EFS and OS; this association was weaker for BMI at age 50 and 35 years. In contrast, for FL, overweight and obese patients at diagnosis had a poorer EFS and OS, and this was also observed for BMIs two years before diagnosis and at ages 50 and 35 years. In FL, the LEP SNP rs2167270 was associated with inferior EFS (HR=1.25; 95%CI 1.05–1.49) and OS (HR=1.28; 95%CI 0.90–1.83). The NPYSNP rs16147 was associated with inferior FL OS (HR=1.50; 95%CI 1.03–2.17) but was not associated with EFS. None of the energy balance and metabolism SNPs were associated with DLBCL EFS or OS. Conclusions. Higher BMI prior to and at diagnosis, as well as SNPs in LEP and NPY,were significantly associated with FL prognosis, with inferior outcomes in overweight and obese patients. These novel findings in the modern treatment era suggest an important role of obesity pathways in FL prognosis. In DLBCL, we confirm the recent findings of improved survival in DLBCL in obese patients, and extend this to the modern treatment era and BMI earlier in life. Disclosures: No relevant conflicts of interest to declare.

Abstract: Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies, with an incidence rate of 3.4 cases per 100,000 in the United States. MDS affects patients predominantly over 60 years of age. As these syndromes are not well understood by many medical practitioner, patients with MDS may be underrecognized or underdiagnosed. The availability of new MDS treatment options further establishes the need to more closely assess gaps in clinical practice and underscores the necessity to develop educational activities to address those gaps. Methods A multidisciplinary panel was convened to examine current educational needs and gaps. A group consensus approach incorporating a modified nominal group technique was utilized to prioritize and review needs identified in the pre-meeting survey and to evaluate data provided by panelists prior to the meeting. Results The panel identified and prioritized seven educational areas of need: (1) MDS disease awareness, (2) diagnosis, (3) classification and risk stratification, (4) treatment issues, (5) referral to stem cell transplantation or new treatment protocols, (6) clinical monitoring and toxicity management, and (7) translation of new data into patient care. Conclusions In-depth knowledge is critical to the timely diagnosis and optimal care of MDS patients. A number of key educational needs exist. Educational programs should be practical in orientation to integrate data into practice, and they should be tailored for the intended audience. In addition, an effective educational program must be easily applied by participants.

Abstract: Introduction: Activating mutations in FLT3 are present in a significant fraction of acute myeloid leukemia (AML) cases. Patients with FLT3 mutations have a significantly worse prognosis than patients with wild type FLT3, suggesting that the activated kinase is a driver of the disease. AC220 is a novel class III receptor tyrosine kinase (RTK) inhibitor. It has highly potent activity against FLT3 and is highly selective for wild type and mutant FLT3 and other class III RTKs, including KIT, CSF1R/FMS, RET and PDGFR. AC220 is currently in a phase I clinical study for relapsed or refractory AML patients. Human pharmacokinetic (PK) data from early cohorts are presented along with the preclinical profile in support of the rationale for the clinical evaluation of AC220 in AML. Methods: Cellular efficacy of AC220 was evaluated in the FLT3-dependent human leukemia cell line MV4;11. This cell line was implanted in a mouse xenograft model, which was used to assess animal efficacy. In preclinical studies, pharmacokinetics were determined in rats and dogs. The clinical study is a phase I, first-in-man, multi-center, open label, sequential dose escalation study. AC220 is administered once daily as an oral solution for 14 days with a starting dose of 12 mg. At least three centers in the U.S. enrolled AML patients into three-patient cohorts. Results: AC220 inhibits proliferation of MV4;11 cells with subnanomolar potency (IC50 = 0.3 nM). In the mouse MV4;11 xenograft model, tumor regression is observed at 3 mg/kg (9 mg/m2, p.o., qd), and tumor growth inhibition at 1 mg/kg (3 mg/m2, p.o., qd). The terminal half-life is 5.7 hours in rats and 5.9 hours in dogs. In the clinical study, one male and two female patients were enrolled into cohort 1. The weight range for these patients is 77.9 to 101.27 kg. The average plasma concentrations at the 12 mg dose are 11.2 ng/mL at day 1, 37.9 ng/mL at day 8 and 42.9 ng/mL (0.06 μM) at steady state (by day 15), with an apparent terminal half-life of at least 2.8 days. Inter-patient variability of steady state plasma concentrations within the 3-patient cohort is low. Conclusions: At the human dose of 12 mg, AC220 is well tolerated and absorbed. It has a long terminal half-life and the inter-patient pharmacokinetic variability is low. Steady state is predicted to be reached within 8 to 14 days with minor peaks and troughs. There is a strong correlation between efficacy in the mouse model and AC220 plasma levels (adjusted for plasma protein binding) relative to potency in the MV4;11 cell-based assay. At the human dose of 12 mg (average 5.2 mg/m2), the plasma level of AC220 at steady state (0.06 μM, when adjusted for plasma protein binding) is approximately twofold higher than the MV4;11 cell IC50. Continued exploration in patients is warranted to determine the role of AC220 in the treatment of AML.

Abstract: Abstract 1507 FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib is an oral FLT3 receptor tyrosine kinase (RTK) inhibitor that inhibits both ITD-mutant and wild-type FLT3 and displays efficacy in preclinical models of AML. In this first-in-human study, quizartinib was evaluated in patients with relapsed or refractory AML who were enrolled irrespective of FLT3-ITD status. Quizartinib was administered orally on an intermittent schedule (ID, 14 days on, 14 days off) at 12–450 mg/day or continuously (CD) at 200 or 300 mg/day. A total of 76 patients (61% male; 90% white; median age 60 years [23–86]) received quizartinib; median number of prior treatments was 3 (0–12), including 16% with a prior hematopoietic stem cell transplant. FLT3-ITD status was 22% positive (+) (n=17), 49% negative (−) (n=37), and 29% indeterminate/not tested (ind) (n=22). Plasma inhibitory activity assays using plasma samples collected at trough timepoints showed a high degree of FLT3 inhibition at low dose levels (18 mg/day and higher), indicative of potent in vivo FLT3 inhibition. Marked inhibition of FLT3 phosphorylation was also demonstrated in peripheral blood following administration of quizartinib. Responses were observed in 23/76 patients (30%), with 10 patients (13%) having a best response of any type of complete remission (CR=morphologic leukemia-free state with absolute neutrophil count 〉 1×109/L and platelet count ≥100×109/L, and normal marrow differential with 〈 5% blasts with no Auer rods; CRp=CR with incomplete platelet recovery; CRi=CR with incomplete hematologic recovery). Responses included 2 CR, 3 CRp, 5 CRi, and 13 (17%) partial remissions (PR, same hematologic values as CR but with a decrease of '50% in % blasts in the bone marrow aspirate to 5% to 25%; a value of 〈 5% blasts was considered a PR if Auer rods were present). Responses were observed at doses as low as 18 mg/day ID. Nine of 17 FLT3-ITD(+) patients responded (53%; 1 CR, 1 CRp, 2 CRi, 5 PR) compared to 5/37 FLT3-ITD(−) patients (14%; 2 CRp, 3 PR) and 9/22 with FLT3-ITD(ind) status (41%; 1 CR, 3 CRi, 5 PR). Median duration of response was 13.3 weeks (95% confidence interval [CI]: 11.0, 29.0 weeks): 9.7 weeks for FLT3-ITD(+) patients (95% CI: 4.1, 29); 23.7 weeks for FLT3-ITD(−) patients (95% CI: 11, not reached); and 12.4 weeks for FLT3-ITD(ind) patients(95% CI: 8, 53). Median overall survival was 14.0 weeks (95% CI: 10.9, 18.6 weeks): 18.3 weeks for FLT3-ITD(+) patients (95% CI: 10.6, 27.1); 9.7 weeks for FLT3-ITD(−) patients (95% CI: 5.6, 14.0); and 18.7 weeks for FLT3-ITD(ind) patients (95% CI: 14.0, 21.1). Quizartinib was generally well tolerated. The most common drug-related AEs ( 〉 10% incidence) were nausea (16%), prolonged ECG QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤Grade 2. The maximum tolerated dose was 200 mg/day CD. The dose-limiting toxicity was QTcF interval prolongation, which occurred in 38% of subjects at 300 mg/day CD and in 6% at 200 mg/day CD. QTcF interval prolongation was dose dependent, and there were no associated arrhythmias. Grade 3 AEs related to quizartinib occurring in 〉 1 patient were prolonged ECG QT interval (4 patients [5%]), anemia (3 patients [4%] ), and fatigue (2 patients [3%]). Two treatment-related Grade 4 AEs (thrombocytopenia and hypoalbuminemia) were reported in 1 patient each (1%). The encouraging efficacy results in both FLT3-ITD(+) and FLT3 ITD(−) patients and an acceptable safety profile in this high-risk population support continued clinical evaluation of quizartinib with lower doses. A recent 333 patient Phase 2 study in a similar population given quizartinib at 200, 135, or 90 mg/day has been completed, and, considering the clinical activity observed at low doses, quizartinib is also being studied in patients with relapsed or refractory AML at 30 and 60 mg/day. Disclosures: Cortes: Novartis: Consultancy. Kantarjian:Ambit Biosciences: Consultancy. Foran:Ambit Biosciences: Consultancy. Ghirdaladze:Ambit Biosciences: Consultancy. Zodelava:Ambit Biosciences: Consultancy. Borthakur:Ambit Biosciences: Consultancy. Gammon:Ambit Biosciences: Employment. Trone:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment. James:Ambit Biosciences: Employment. Levis:Ambit Biosciences: Consultancy.