Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer

Biomarkers; Colorectal cancer; Maintenance therapyBiomarcadors; Càncer colorectal; Teràpia de mantenimentBiomarcadores; Cáncer colorrectal; Terapia de mantenimientoPurpose MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/BRAFwt or HER2‒/MSS/BRAFmut/RASmut). Methods Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). Results Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50–1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90–2.29; P = 0.128). Conclusions Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy.This work was supported by F. Hoffmann-La Roche Ltd

Design of a study assessing disease behaviour during the peri-diagnostic period in patients with interstitial lung disease: The STARLINER Study

This study will aim to characterise disease behaviour during the peri-diagnostic period in patients with suspected interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF), using daily home spirometry and accelerometry. Additionally, this study will aim to increase collaboration between secondary and tertiary centres using a digital collaboration platform

Design of a Study Assessing Disease Behaviour During the Peri-Diagnostic Period in Patients with Interstitial Lung Disease: The STARLINER Study

Background/Objectives: This study will aim to characterise disease behaviour during the peri-diagnostic period in patients with suspected interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF), using daily home spirometry and accelerometry. Additionally, this study will aim to increase collaboration between secondary and tertiary centres using a digital collaboration platform. Methods: The STARLINER study (NCT03261037) will enrol approximately 180 symptomatic patients aged 50 years or more with radiological evidence of ILD/IPF from community and tertiary centres in Canada and Europe. Approximately two-thirds of sites will be community centres. Patients will be followed during pre-diagnosis (inclusion to diagnosis; up to a maximum of 12 months) and post-diagnosis (diagnosis to treatment initiation; up to a maximum of 6 months). The study will be facilitated by a digital ecosystem consisting of the devices used for home-based assessments and a digital collaboration platform enabling communication between community and tertiary centres, and between clinicians and patients. Planned Outcomes: The primary endpoint will be time-adjusted semi-annual change in forced vital capacity (FVC; in millilitres) during the peri-diagnostic period. Physical functional capacity and patient-reported outcomes (PROs) will also be assessed. FVC and physical functional capacity will be measured using daily home spirometry and accelerometry, and at site visits using spirometry and the 6-min walk test. PROs will be assessed prior to, or during, site visits and will always be completed in the same order. Conclusions: Findings from this study may help to facilitate the early and accurate diagnosis of ILDs by increasing knowledge about disease progression, enabling collaboration between community and tertiary centres and improving communication between clinicians and patients. Trial Registration Number: NCT03261037. Funding: F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Plain Language Summary: Plain language summary available for this article

Evaluation der Maßnahmen zur Umsetzung der Vorschläge der Hartz-Kommission: Modul 1a, Neuausrichtung der Vermittlungsprozesse ; Bericht 2005 für das Bundesministerium für Wirtschaft und Arbeit

"Das Bundesministerium für Wirtschaft und Arbeit hat das Wissenschaftszentrum Berlin für Sozialforschung und das infas Institut für angewandte Sozialwissenschaft im September 2004 mit dem Evaluationsvorhaben Arbeitspaket 1, 'Modul 1a Neuausrichtung der Vermittlungsprozesse' beauftragt. Im Mittelpunkt steht die zentrale Frage, ob eine 'Verbesserung der Qualität und Schnelligkeit der Arbeitsvermittlung' nachgewiesen werden kann, die auf die Reformgesetze und -maßnahmen zurückzuführen sind. Implementationsanalysen untersuchen die Praxis der Agenturen bezüglich Bewerberdifferenzierung, Kundenmanagement, Aktivierung sowie Neuregelung von Zumutbarkeit und Sperrzeiten sowie die Vermittlungsdienstleistungen an Arbeitgeber. Auch der Einsatz vermittlungsnaher Dienstleistungen (Einschaltung Dritter nach Paragraph 37, Eingliederungsmaßnahmen durch Träger Paragraph 421i, Vermittlungsgutscheine, Personal-Service-Agenturen -PSA-) wird unter Umsetzungsgesichtspunkten untersucht. Über die Vermittlungsorganisation in Arbeitsgemeinschaften nach Paragraph 44b SGB II liegen erste Ergebnisse einer Grunderhebung vor. Die mittels Fallstudien, Dokumentenanalyse, schriftlichen und telefonischen Erhebungen gewonnenen Ergebnisse umreißen den Stand der Neuausrichtung der Vermittlungsprozesse. Die Wirkung der neu ausgerichteten Vermittlungsprozesse werden unter zwei Gesichtspunkten untersucht. Mittels multivariater Auswertungen wird zum einen die Wirkung des Kundenzentrums auf die Abgänge aus Arbeitslosigkeit geprüft. In einer instrumentenspezifisch angelegten Wirkungsanalyse wird zum anderen die Effektivität von vermittlungsnahen Dienstleistungen (Beauftragung Dritter, Beauftragung von Trägern mit Eingliederungsmaßnahmen, Personal Service Agenturen, Vermittlungsgutschein) analysiert und eine entsprechende Kosten-Nutzen-Bewertung vorgenommen. Der Bericht 2005 legt die Ergebnisse nach neun Monaten Laufzeit des Evaluationsvorhabens vor. Er ist vom Bemühen getragen, bereits belastbare Ergebnisse nach diesem vergleichsweise kurzen Zeitraum vorzulegen. Die Berichterstattung steht allerdings unter dem deutlichen Hinweis, dass die Organisation der Vermittlungsprozesse in den Agenturen und Arbeitsgemeinschaften weiterhin im Fluss ist. Die Implementationsstudien versuchen deswegen über die Momentaufnahme hinaus, grundlegende Konstruktionsfragen und -probleme aufzuzeigen. Wegen des vergleichsweise kurzen Beobachtungszeitraums seit Einführung der Kundenzentren und der vermittlungsnahen Dienstleistungen stehen auch die Wirkungsanalysen noch unter Vorbehalten." (Textauszug

Safety of nintedanib added to pirfenidone treatment for idiopathic pulmonary fibrosis

We assessed safety and tolerability of treatment with pirfenidone (1602-2403 mg day-1) and nintedanib (200-300 mg day-1) in patients with idiopathic pulmonary fibrosis (IPF). This 24-week, single-arm, open-label, phase IV study (ClinicalTrials.gov identifier NCT02598193) enrolled patients with IPF with forced vital capacity % pred ≫50% and diffusing capacity of the lung for carbon monoxide % pred ≫30%. Before initiating nintedanib, patients had received pirfenidone for ≫16 weeks and tolerated a stable dose of ≫1602 mg day-1 for ≫28 days. The primary end-point was the proportion of patients who completed 24 weeks of combination treatment on pirfenidone (1602- 2403 mg day-1) and nintedanib (200-300 mg day-1). Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither. 89 patients were enrolled; 73 completed 24 weeks of treatment (69 meeting the primary end-point) and 16 discontinued treatment prematurely (13 due to TEAEs). 74 patients had 418 treatment-related TEAEs, of which diarrhoea, nausea and vomiting were the most common. Two patients had serious treatmentrelated TEAEs. Combined pirfenidone and nintedanib use for 24 weeks was tolerated by the majority of patients with IPF and associated with a similar pattern of TEAEs expected for either treatment alone. These results encourage further study of combination treatment with pirfenidone and nintedanib in patients with IPF

AUTOSAR: Achievements, roll-out, perspectives

International audienceAUTOSAR (AUTomotive Open System ARchitecture) was founded as a development partnership in 2003. AUTOSAR has been working to develop and establish an open and standardized automotive software architecture. The standard includes a set of specifications describing software architecture, application interfaces, model exchange formats, and methodology. By now, several versions of the standard have been released. The latest release 4.0 was published beginning of 2010.As AUTOSAR is currently carrying on its third development phase (2010-2012), this document gives an overview of the most important results obtained so far with a specific focus on some technologies and features introduced in the latest releases such as the support for functional safety, multi-core ar- chitectures, efficient energy management and conformance testing. The development strategy and plans developed to ensure the stability of the standard will be highlighted.Surveys show that AUTOSAR is today the global automotive software standard. A summary of the roll-out plans of the 9 Core Partners, disclosed recently will be given showing the way AUTOSAR has been introduced in series production and what is planned for the near future. In conclusion a view will be given on the perspectives after the current phase of development

Effect of pirfenidone in patients with more advanced idiopathic pulmonary fibrosis

Abstract Data from controlled clinical studies in patients with more advanced idiopathic pulmonary fibrosis (IPF) could inform clinical practice, but they are limited, since this sub-population is usually excluded from clinical trials. These exploratory post-hoc analyses of the open-label, long-term extension study RECAP (NCT00662038) aimed to assess the efficacy and safety of pirfenidone in patients with more advanced IPF. Patients were categorised according to the extent of lung function impairment at baseline: more advanced (percent predicted FVC <50% and/or DLco <35%) and less advanced (percent predicted FVC ≥50% and DLco ≥35%). Overall, 596 patients with baseline FVC and/or DLco values available were included in the analyses; 187 patients had more advanced disease, and 409 patients had less advanced disease. Mean percent predicted FVC declined throughout 180 weeks of treatment in both more and less advanced disease subgroups. Both subgroups exhibited a similar pattern of adverse events; however, adverse events related to IPF progression were experienced by a higher proportion of patients with more advanced versus less advanced disease. Discontinuation rates due to any reason, adverse events related to IPF progression, or deaths were each higher in the more advanced versus the less advanced disease subgroup. These analyses found that longer-term pirfenidone treatment resulted in a similar rate of lung function decline and safety profile in patients with more advanced versus less advanced IPF, and the data suggest that pirfenidone is efficacious, well tolerated, and a feasible treatment option in patients with more advanced IPF