BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas

B-cell lymphoma; Cancer therapy; CNS cancerLimfoma de cèl·lules B; Teràpia del càncer; Càncer del SNCLinfoma de células B; Terapia del cáncer; Cáncer del SNCBromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.This study was sponsored by Celgene, a Bristol Myers Squibb Company. The study sponsor was involved in the study design, analysis of data, and writing the manuscript. Medical writing and editorial assistance were provided by Bernard Kerr, PGDipSci, and Agata Shodeke, of Spark, funded by Bristol Myers Squibb

Round-Robin modelling of the load-bearing capacity of slender columns by using classical and advanced non-linear numerical and analytical prediction tools

Non-linear finite element analyses have intrinsic model and user factors that influence the results of the analyses. However, non-linear finite element analysis can provide a tool to assess safety using realistic descriptions of material behaviour with actual material properties. A realistic estimation of the existing safety and capacity of slender column elements can be achieved by means of "true" material properties. Nevertheless, it seems that for some structural components, such as slender columns, non-linear finite element analyses can, due to its complexity and its various setting parameters, cause the risk of overestimating the real performance of analysed components or systems. Hence, an invited expert group has carried out an investigation into the experimental testing and the prediction of the bearing capacity of slender columns by performing independent non-linear finite element analyses in order to determine the practical applicability, and its inconsistencies, with respect to the stability failure of slender columns. This work aims the characterization of modelling uncertainties, concerning the prediction of slender columns stability when forecasted by non-linear finite element analysis.This paper was partly carried out during research exchanges at TU Brno (BUT), Lehigh University (LU). The authors acknowledge also the financial support provided by the SAFEBRIDGE ATCZ190 EU Interreg project, the Scientific Grant Agency of the Ministry of Education of Slovak Republic, the Slovak Academy of Sciences VEGA No. 1/0696/14, and Slovak Research and Development Agency under the contract No. APVV-150658. The computational results presented have been achieved [in part] using the Vienna Scientific Cluster (VSC)

Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials

Immunotherapy; Phase 1 trials; Prognostic modelInmunoterapia; Ensayos de fase 1; Modelo pronósticoImmunoteràpia; Assajos de fase 1; Model pronòsticPurpose Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline. Methods Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application. Results We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3–12.7) for ICIs cohort and 7.7 m (95% CI, 6.6–8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS – ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64–0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%–90%). Conclusions PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/CE07/50610001). Cellex Foundation for providing research facilities and equipment. This work was supported by the Accelerator Award (UpSMART) from Fundacion Científica – Asociacion Espanola Contra el Cancer (FC -AECC)/ Associazione Italiana per la Ricerca sul Cancro (AIRC) /Cancer Research United Kingdom (CRUK)

Deterministic switching of the growth direction of self-catalyzed GaAs nanowires

The typical vapor–liquid–solid growth of nanowires is restricted to a vertical one-dimensional geometry, while there is a broad interest for more complex structures in the context of electronics and photonics applications. Controllable switching of the nanowire growth direction opens up new horizons in the bottom-up engineering of self-assembled nanostructures, for example, to fabricate interconnected nanowires used for quantum transport measurements. In this work, we demonstrate a robust and highly controllable method for deterministic switching of the growth direction of self-catalyzed GaAs nanowires. The method is based on the modification of the droplet–nanowire interface in the annealing stage without any fluxes and subsequent growth in the horizontal direction by a twin-mediated mechanism with indications of a novel type of interface oscillations. A 100% yield of switching the nanowire growth direction from vertical to horizontal is achieved by systematically optimizing the growth parameters. A kinetic model describing the competition of different interface structures is introduced to explain the switching mechanism and the related nanowire geometries. The model also predicts that the growth of similar structures is possible for all vapor–liquid–solid nanowires with commonly observed truncated facets at the growth interface.acceptedVersionPeer reviewe

Probabilistic and semi-probabilistic analysis of slender columns frequently used in structural engineering

The stability of slender columns is a topic that has been dealt with in research and practice for many years. The importance of this topic also increases with the possibility of using non-linear modeling approaches to determine the stability and with the increasingly complex safety formats. In order to show the complexity and the variability associated with the non-linear models, two previous contributions discussed and compared (a) the results of the Round Robin Non-Linear Modeling, and (b) the existing international associated standard specifications and safety concepts with respect to experimental results. The aim herein is to determine the reliability level (safety index) on the basis of these investigations and findings and to examine the existing safety formats of classical and extended probabilistic analyses and to derive any necessary adjustments. In addition, the method of the safety format Estimation of Coefficient of Variance of resistance (ECOV) is used for the determination of the global safety resistance factors based on the non-linear analyses' findings of the Round Robin modeling partners

Eudesmanolides and Methyl Ester Derivatives from Dimerostemma arnottii

The phytochemical investigation of Dimerostemma arnottii (Asteraceae) afforded, in addition to a known eudesmanolide, two unusual eudesmane methyl ester derivatives and a new eudesmanolide. Structural elucidation of the compounds was based on their ID and 2D NMR spectroscopic as well as HR-ESI-MS data. There is a remarkable similarity between the structures of the eudesmanes from D. arnottii and those previously encountered in other Dimerostemma species, which is in agreement with the results of a previous phylogenetic study based on molecular data. The chemotaxonomic relevance of the isolated compounds is briefly discussed.FAPESPCNPqCAPE