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AbstractBackgroundMagnetic Resonance Spectroscopy (MRS) is a non‐invasive technique assessing the concentration of various metabolites within the brain, both cross‐sectionally to characterize disease type and severity, and longitudinally to assess disease progression and potential treatment efficacy in the context of disease‐modifying interventions. In such context, the involvement of multiple imaging facilities inevitably introduces variability, whose amount must be known to inform on comparability between sites and sensitivity to change. Our objective is to study variability in the concentration of various brain metabolites using a dedicated MRS phantom and assess impact of field strength.Methods30 sites are being considered to participate in an on‐going clinical trial in metachromatic leukodystrophy. Site qualification mandates the scanning of a dedicated MRS phantom. 30 of these HD‐polyethylene spheres were simultaneously manufactured and filled with the same mixture of chemicals mimicking main metabolite concentrations. To date, 14 sites provided data (5 1.5T scanners and 9 3T). All sites implemented a standardized single‐voxel MRS sequence. MRS voxel was placed within the phantom and acquisition repeated 3 times. Spectra were centrally analyzed using LCModel v6.3 and quality controlled by Bioclinica. Repeat acquisitions were requested for parameter deviations, voxel positioning and/or shimming issues. Results only include passing datasets. Coefficient of Variation (CV) was calculated for NAA/Cr, Cho/Cr, mI/Cr, Glx/Cr and Lac/Cr ratios for each site and overall. LCModel quality metrics (FHWM and S/N) were also extracted to assess spectra quality. Comparison between field strengths was carried out using t‐tests.ResultsAverage CV by site was 2.0% for NAA/Cr (2.5% at 1.5T and 1.8% at 3T), 2.4% for Cho/Cr, 3.0% for mI/Cr, 4.5% for Glx/Cr and 6.1% for Lac/Cr. CVs were generally lower at 3T (except for Lac/Cr) although difference was not significant. As expected, Signal‐to‐Noise was higher at 3T (p=0.05). Overall CV by metabolite across scanners was much higher (ranging from 4.6% for Cho/Cr up to 12.1% for Lac/Cr).ConclusionMRS measures of metabolite concentrations have low variability at scanner‐level, insensitive to field strength. Nevertheless, variability across sites is much higher and would require, if possible, cross‐calibration. These phantom data make such calibration possible and will improve sensitivity of subject data analyses.

BACKGROUND: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based CD3 x CD20 bispecific antibody (bsAb) that has demonstrated encouraging safety, tolerability and preliminary efficacy in a first-in-human study of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). We report updated safety and efficacy data from the dose escalation and early dose expansion phase of the ongoing Phase (P)1 study (NCT02290951). METHODS: Odronextamab was administered using a step-up dose schedule consisting of an initial dose at Week (W)1, an intermediate dose at W2, and thereafter, a fixed weekly dose until W12 followed by maintenance Q2W dosing. Dexamethasone premedication was used to mitigate the risk for cytokine release syndrome (CRS). Key primary objectives were to assess safety and dose-limiting toxicities (DLTs), and to establish a maximum tolerated dose (MTD) and recommended P2 dosing regimen (RP2DR). Secondary objectives included a preliminary assessment of anti-tumor activity. RESULTS: As of Jun 25, 2020, 127 pts with R/R B-NHL have been treated at doses ranging from 0.03-320 mg. The study included pts with diffuse large B-cell lymphoma (DLBCL; n=71), follicular lymphoma (FL) Grade (Gr) 1-3a (n=37), mantle cell lymphoma (MCL; n=11), marginal zone lymphoma (n=6), and other B-NHLs (n=2). Pts were highly refractory (80.3%) and had received a median of 3 (range: 1‒11) prior lines of therapy; 29 pts (22.8%) received prior CAR T therapy (FL: 2; DLBCL: 25; MCL: 2) and 85 pts (66.9%) were double refractory to alkylator and anti-CD20 antibody, in any line of therapy. Median follow-up was 3.9 (0.4‒37.6) months (mo). No DLTs were reported during dose escalation and MTD was not reached with odronextamab doses up to 320 mg weekly. The most frequent treatment-related adverse events (AEs) of any grade were pyrexia (76.4%), CRS (62.2%), and chills (48.0%). Gr 3 CRS occurred in 8 pts (6.3%) and a Gr 4 CRS occurred in 1 pt (0.8%). Most of the CRS events occurred during the first 2 weeks of step-up dosing and resolved within a median of 2 days (range 1-41) with supportive care measures. No pts discontinued odronextamab treatment due to CRS. Gr 3 neurologic AEs were noted in 5 pts, of which only 3 (2.3%) were considered treatment-related: somnolence, syncope, and encephalopathy. None of these events required treatment discontinuation. There were no Gr 4 or higher neurologic AEs. Overall, 7 pts (5.5%) discontinued treatment due to treatment-related AEs. In pts with R/R FL Gr 1-3a, odronextamab demonstrated a broad window of therapeutic activity. In pts treated at doses of ≥5 mg (n=28), objective response rate (ORR) was 92.9%, and complete response (CR) rate was 75.0%; median duration of response (DoR) was 7.7 mo (range 0+-20.9+), with 13 of 21 CRs ongoing at last tumor assessment. The median duration of complete response (DoCR) was 8.1 mo (range 0+-19.9+) and follow-up is ongoing (Table). In pts with R/R DLBCL, encouraging activity was observed at higher odronextamab dose levels. In DLBCL pts who had not received prior CAR T therapy, treated at doses ≥80 mg (n=10), ORR and CR rate were 60%; median observed DoR was 10.3 mo (range 2.9-18.6+), with 4 of 6 CRs ongoing at last tumor assessment. The median DoCR was 9.5 mo (range 2.9-18.6+) and follow-up is ongoing. In DLBCL pts who were refractory to prior CAR T therapy, treated at doses ≥80 mg (n=21), ORR was 33.3%, and CR rate was 23.8%; median observed DoR was 2.8 mo (range 0+-18.9+), with 5 of 5 CRs ongoing at last tumor assessment. The median DoCR was 4.4 mo (range 0+-18.9+) and follow-up is ongoing. Based on an evaluation of preliminary antitumor activity and PK, RP2DR was identified for dose expansion cohorts. CONCLUSIONS: Odronextamab has demonstrated encouraging single agent antitumor activity in highly refractory pts with B-NHLs. Durable CRs have been observed in both indolent and aggressive B-NHL pts, including in pts refractory to CAR T therapy. Most CRs are ongoing at time of data cutoff, and updated data will be presented. Odronextamab has an acceptable safety and tolerability profile. Dexamethasone premedication and step-up dosing mitigates the risk for CRS and allows odronextamab administration up to 320 mg weekly without DLTs. A global P2 trial investigating odronextamab in R/R B-NHL is ongoing. Disclosures Bannerji: Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Brown:Catapult: Consultancy; Sun: Research Funding; Loxo: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novartis: Consultancy; Nextcea: Consultancy; MEI Pharma: Consultancy; Kite: Consultancy; Juno/Celgene: Consultancy; Eli Lilly and Company: Consultancy; Dynamo Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding. O'Brien:Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy. Duell:Morphosys: Research Funding. Martin:Sandoz: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy; Teneobio: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Janssen: Consultancy. Li:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Flink:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Zhu:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Weinreich:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sirulnik:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chaudhry:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Ambati:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. OffLabel Disclosure: The data described in the abstract will report on use of odronextamab in a Phase 1 clinical trial of patients with B-NHL

AbstractIntroductionWe conducted an open‐label study to examine the effects of the flavonoid (−)‐epicatechin in seven ambulatory adult patients with Becker muscular dystrophy (BMD).MethodsSeven participants received (−)‐epicatechin 50 mg twice per day for 8 weeks. Pre‐ and postprocedures included biceps brachii biopsy to assess muscle structure and growth‐relevant endpoints by western blotting, mitochondria volume measurement, and cristae abundance by electron microscopy, graded exercise testing, and muscle strength and function tests.ResultsWestern blotting showed significantly increased levels of enzymes modulating cellular bioenergetics (liver kinase B1 and 5′‐adenosine monophosphate–activated protein kinase). Peroxisome proliferator‐activated receptor gamma coactivator‐1alpha, a transcriptional coactivator of genes involved in mitochondrial biogenesis and cristae‐associated mitofilin levels, increased as did cristae abundance. Muscle and plasma follistatin increased significantly while myostatin decreased. Markers of skeletal muscle regeneration myogenin, myogenic regulatory factor‐5, myoblast determination protein 1, myocyte enhancer factor‐2, and structure‐associated proteins, including dysferlin, utrophin, and intracellular creatine kinase, also increased. Exercise testing demonstrated decreased heart rate, maximal oxygen consumption per kilogram, and plasma lactate levels at defined workloads. Tissue saturation index improved in resting and postexercise states.Discussion(−)‐Epicatechin, an exercise mimetic, appears to have short‐term positive effects on tissue biomarkers indicative of mitochondrial biogenesis and muscle regeneration, and produced improvements in graded exercise testing parameters in patients with BMD.

Abstract Background and study aims Lumen-apposing metal stents (LAMS) are increasingly used for drainage of walled-off pancreatic necrosis (WON). Recent studies suggested greater adverse event (AE) rates with LAMS for WON. We conducted a systematic review and meta-analysis to compare the safety and efficacy of LAMS with double-pigtail plastic stents (DPPS) for endoscopic drainage of WON. The primary aim was to evaluate stent-related AEs. Methods In October 2019, we searched the Ovid (Embase, MEDLINE, Cochrane) and Scopus databases for studies assessing a specific LAMS or DPPS for WON drainage conducted under EUS guidance. Safety outcomes were AE rates of bleeding, stent migration, perforation, and stent occlusion. Efficacy outcomes were WON resolution and number of procedures needed to achieve resolution. A subanalysis including non-EUS-guided cases was performed. Results Thirty studies including one randomized controlled trial (total 1,524 patients) were analyzed. LAMS were associated with similar bleeding (2.5 % vs. 4.6 %, P = 0.39) and perforation risk (0.5 % vs. 1.1 %, P = 0.35) compared to DPPS. WON resolution (87.4 % vs. 87.5 %, P = 0.99), number of procedures to achieve resolution (2.09 vs. 1.88, P = 0.72), stent migration (5.9 % vs. 6.8 %, P = 0.79), and stent occlusion (3.8 % vs. 5.2 %, P = 0.78) were similar for both groups. Inclusion of non-EUS-guided cases led to significantly higher DPPS bleeding and perforation rates. Conclusions LAMS and DPPS were associated with similar rates of AEs and WON resolution when limiting analysis to EUS-guided cases. Higher bleeding rates were seen in historical studies of DPPS without EUS guidance. Additional high-quality studies of WON treatment using consistent outcome definitions are needed.

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.

1087 Background: OlympiAD (NCT02000622) demonstrated the benefit of olaparib over standard of care in patients (pts) with HER2-negative (HER2-) metastatic breast cancer (MBC) and germline BRCA mutations (gBRCAm). LUCY (NCT03286842) aimed to provide additional data on the real-world effectiveness and safety of olaparib monotherapy in this setting. Methods: This Phase IIIb, open-label, single-arm study of olaparib 300 mg twice-daily, enrolled pts with HER2- gBRCAm MBC who had received a taxane and/or anthracycline in the (neo)adjuvant/metastatic setting, and ≤2 lines of chemotherapy for MBC. Hormone receptor-positive (HR+) pts had progressed on prior endocrine therapy (ET), and further ET was considered unsuitable. Primary endpoint: investigator-defined progression-free survival (PFS). Secondary endpoints: overall survival, time to first subsequent therapy or death (TFST), and investigator-assessed clinical response rate (CRR). The interim analysis was planned after 160 PFS events. Results: From Oct 2018-Sept 2019, 252 pts were enrolled (160 sites, 15 countries; mean age 46.2 [range 22-75] years; 73.4% ECOG PS 0). Median total treatment duration: 7.9 months (mo; range 0.2-20.0). Median PFS: 8.1 mo (95% confidence interval [CI] 6.9, 8.7; 166 events [65.9%]). Clinical trial information: NCT03286842 . Median TFST: 9.7 mo (95% CI 8.7, 11.1). CRR: 48.6% (95% CI 42.2, 55.0). Adverse events (AEs) in >20% of pts (all grades): nausea, anemia, asthenia, vomiting, and fatigue. 24.6% of pts reported a grade ≥3 AE, including anemia (n=33 [13.1%]). 4.4% of pts had an AE leading to treatment discontinuation. Conclusions: Interim results in this real-world population of pts with HER2- gBRCAm MBC were consistent with the OlympiAD study, and support olaparib as a chemotherapy-free alternative treatment for pts with gBRCAm advanced BC. [Table: see text]

Abstract Older patients often have multiple medical issues which predisposes them to complications of polypharmacy and medication interactions. We present a case of an 89-year-old female who presented to the emergency department after a fall. An electrocardiogram (ECG) showed a junctional bradycardia with a ventricular rate of 50 beats per minute (BPM). Her magnesium was 3.5 mg/dl (1.7–2.3 mg/dl). She had recently increased her milk of magnesia use for constipation. Pertinent other medications included verapamil 280 mg daily. On admission 2 grams of calcium gluconate IV were administered and the verapamil was held. An ECG the next morning showed sinus rhythm with a ventricular rate of 76 BPM.