First-in-Human Phase I Study of the OX40 Agonist GSK3174998 With or Without Pembrolizumab in Patients With Selected Advanced Solid Tumors (Engage-1)

BACKGROUND: The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors. METHODS: GSK3174998 (0.003-10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity. RESULTS: 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and \u3e80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56-CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response. CONCLUSIONS: GSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers. TRIAL REGISTRATION NUMBER: NCT02528357

Tracking and Stabilization for Control Systems on Matrix Lie Groups

A wide range of dynamical systems from fields as diverse as mechanics, electrical networks and molecular chemistry can be modeled by invariant systems on matrix Lie groups. This paper introduces control systems on matrix Lie groups and studies open- loop tracking and feedback stabilization for these systems in the presence of nonholonomic constraints. Using the concept of approximate inversion, results for drift-free, left-invariant systems on specific matrix Lie groups are presented

Entwicklung und Anwendung miniaturisierter automatisierter Testverfahren zur humantoxikologischen und oekotoxikologischen Bewertung von Schadstoffen in Umweltproben Abschlussbericht

The project is financed by Deutsche Bundesstiftung Umwelt and carried out by four partners, i.e. RWTH Aachen, Ruhr-Universitaet Bochum, MERLIN Gesellschaft fuer mikrobiologische Diagnostik mbH and OPAL JENA Gesellschaft fuer optische Analytik und Labortechnik mbH. The final report contains the results of the three sub-projects: 1. Miniaturisation and automation of ecotoxicity and mutagenicity tests - definition of methodical and technical requirements - test evaluation with standard toxic substances and contaminated soils; 2. Biological Effect Monitoring; 3. Development and testing of a laser nephelometer for microtitration plate format. Part 2 got a special citation in this databaseDas von der Deutschen Bundesstiftung Umwelt gefoerderte Projekt wird von vier Kooperationspartnern, der Rheinisch-Westfaelischen Technischen Hochschule Aachen, der Ruhr-Universitaet Bochum, der MERLIN Gesellschaft fuer mikrobiologische Diagnostik mbH und der OPAL JENA Gesellschaft fuer optische Analytik und Labortechnik mbH, bearbeitet. Die Ergebnisse der Entwicklungs- und Untersuchungsergebnisse der folgenden drei Zwischenberichte sind in dem vorliegenden Abschlussbericht zusammengefasst: 1. Miniaturisierung und Automatisierung von Oekotoxizitaets- und Mutagenitaetstests - Definition der methodischen und technischen Anforderungen -Bewertung der Oekotoxizitaetstests und Mutagenitaetstests mit Standardtoxen und kontaminierten Boeden. 2. Humantoxikologische Testmethoden - Biological Effect Monitoring. 3. Entwicklung und Erprobung eines Laser-Nephelometers fuer das Mikrotitrationsplattenformat. Eine gesonderte Aufnahme wurde von Teil 2 angefertigt. (orig./MG)Available from TIB Hannover: F00B735 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDeutsche Bundesstiftung Umwelt, Osnabrueck (Germany)DEGerman

Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomised, placebo-controlled trial

Objectives: This ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE). Methods: Patients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and ’30 alternative’ definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing. Results: Ninety-three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL. Conclusion: The belimumab intravenous pharmacokinetics and benefit–risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/ kg every 4 weeks dose is appropriat