Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (STELLA): Design of a confirmatory, double-blind, randomized, controlled study

Background: MB02 is a bevacizumab biosimilar developed to stringent guidelines, including non-clinical and preclinical investigations and a clinical trial as first-line treatment in metastatic colorectal cancer (Romera A et al. Lancet Gastroenterol Hepatol 2018;3 (12): 845-855). A clinical trial (STELLA) has been initiated to confirm there are no clinically meaningful differences between MB02 and reference bevacizumab (Avastin) in terms of efficacy, safety, and immunogenicity (NCT03296163). Methods: STELLA study is a multinational, double-blind, randomized, parallel-group, equivalence study comparing the efficacy and safety of MB02 vs reference bevacizumab plus chemotherapy in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC)

The influence of nitrogen pressure on the fabrication of the two-phase superhard nanocomposite (TiZrNbAlYCr)N coatings

The multicomponent nitride coatings from TiZrNbAlYCr high entropy alloy (HEA) were fabricated using the vacuum-arc method. The effect of nitrogen pressure on the crystallite size, elemental and phase composition of (TiZrNbAlYCr)N coatings was investigated. A bias voltage applied to the substrate during the deposition process was −200 V. The partial nitrogen pressure was 0.05 Pa, 0.27 Pa, and 0.5 Pa. Body-centered cubic (BCC) lattice with crystallites of 15 nm in size was formed at the lowest pressure. An increase in the pressure led to the formation of the two-phase structure: BCC phase with crystallite size of 15 nm and face-centered cubic (FCC) phase with crystallite size of about 3.5 nm. The same two-phase state was found in coatings fabricated at 0.5 Pa, while the mean crystallite size was 7 nm. The maximum hardness of the deposited coatings was about 47 GPa.Crystallite

The influence of nitrogen pressure on the fabrication of the two-phase superhard nanocomposite (TiZrNbAlYCr)N coatings

The multicomponent nitride coatings from TiZrNbAlYCr high entropy alloy (HEA) were fabricated using the vacuum-arc method. The effect of nitrogen pressure on the crystallite size, elemental and phase composition of (TiZrNbAlYCr)N coatings was investigated. A bias voltage applied to the substrate during the deposition process was −200 V. The partial nitrogen pressure was 0.05 Pa, 0.27 Pa, and 0.5 Pa. Body-centered cubic (BCC) lattice with crystallites of 15 nm in size was formed at the lowest pressure. An increase in the pressure led to the formation of the two-phase structure: BCC phase with crystallite size of 15 nm and face-centered cubic (FCC) phase with crystallite size of about 3.5 nm. The same two-phase state was found in coatings fabricated at 0.5 Pa, while the mean crystallite size was 7 nm. The maximum hardness of the deposited coatings was about 47 GPa.Crystallite

Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial

Background Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. Findings Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients

A Randomized Phase II/III Study of Naptumomab Estafenatox + IFNα versus IFNα in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis

Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) þ IFNa versus IFN in metastatic renal cell carcinoma (RCC). Experimental Design: In a randomized, open-label, multicenter, phase II/III study, 513 patients with RCC received Nap (15 mg/ kg i. v. in three cycles of four once-daily injections) + IFN (9 MU s. c. three times weekly), or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS). Results: This phase II/III study did notmeetits primary endpoint. Median OS/PFS for Nap + IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (P = 0.56; HR, 1.08/P = 0.41; HR, 0.92). Post hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of antiSEA/E-120 (anti-Nap antibodies) for drug exposure and IL6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n = 130) having concentrations below median of anti-SEA/E-120 and IL6 benefitted greatly from the addition of Nap. In SG, median OS/PFS for the patients treated with Nap þ IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (P = 0.02; HR, 0.59/P = 0.02; HR, 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile. Conclusions: The study did not meet its primary endpoint. Nap + IFN has an acceptable safety profile, and results from post hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker-defined RCC patient subgroup. The results warrant further studies with Nap in this subgroup

Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first‑line treatment of ER+/HER2− advanced breast cancer (PALOMA‑1, TRIO‑18)

Purpose Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole signifcantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748; P=0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the fnal overall survival (OS) and updated safety results. Methods Postmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety. Results A total of 165 patients were randomized. At the data cutof date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratifed hazard ratio for OS was 0.897 (95% CI 0.623–1.294; P=0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to frst subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%). Conclusions Palbociclib plus letrozole treatment led to a numerical but not statistically signifcant improvement in median OS. Pfzer Inc (NCT00721409

Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation

Aim: MERiDiAN evaluated plasma vascular endothelial growth factor-A (pVEGF-A) prospectively as a predictive biomarker for bevacizumab efficacy in metastatic breast cancer (mBC). Methods: In this double-blind placebo-controlled randomised phase III trial, eligible patients had HER2-negative mBC previously untreated with chemotherapy. pVEGF-A was measured before randomisation to paclitaxel 90 mg/m2 on days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were baseline pVEGF-A, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary endpoints were investigator-assessed progression-free survival (PFS) in the intent-to-treat and pVEGF-Ahigh populations. Results: Of 481 patients randomised (242 placeboepaclitaxel; 239 bevacizumabepaclitaxel), 471 received study treatment. The stratified PFS hazard ratio was 0.68 (99% confidence interval, 0.51e0.91; log-rank p Z 0.0007) in the intent-to-treat population (median 8.8 months with placeboepaclitaxel versus 11.0 months with bevacizumabepaclitaxel) and 0.64 (96% con-fidence interval, 0.47e0.88; log-rank p Z 0.0038) in the pVEGF-Ahigh subgroup. The PFS treatment-by-VEGF-A interaction p value (secondary end-point) was 0.4619. Bevacizumab was associated with increased incidences of bleeding (all grades: 45% versus 27% with placebo), neutropenia (all grades: 39% versus 29%; grade 3: 25% versus 13%) and hypertension (all grades: 31% versus 13%; grade 3: 11% versus 4%). Conclusion: The significant PFS improvement with bevacizumab is consistent with previous placebo-controlled first-line trials in mBC. Results do not support using baseline pVEGF-A to identify patients benefitting most from bevacizumab. Clinical trials registration: ClinicalTrials.gov NCT01663727

Особливості формування національного інформаційного простору України: від радянської системи ЗМІ до демократичної моделі

Об’єкт дослідження – національний інформаційний простір України від функціонування медійного контенту у радянські часи до демократичної преси сьогодення. Предмет дослідження – вивчення особливостей типології мас-медіа України, їх жанрової парадигми, проблемно-тематичної спрямованості, мовно-стилістично- візуального оформлення. Мета науково-дослідної роботи – розглянути головні типологічної структури засобів масової інформації України в історичному і сучасному аспектах, виявити їх жанрово-тематичний контент, мовно-стилістичні ознаки впливу на аудиторію

Особливості амінолізу ангідриду 2-(3,5-діоксо-4-азатрицикло[5.2.1.02,6-ендо]дец-8-єн-4-іл)бутандіової кислоти

The synthesis of new amide and imide derivatives of 2-(3,5-dioxo-4-azatricyclo[5.2.1.02,6‑endo]-dec-8-en-4-yl)butanedioic acid is described. The title amides were synthesized via corresponding diacid anhydride, which was treated with various amines. It has been shown that aminolysis with p-toluidine selectively delivers a single product, namely 2-(3,5-dioxo-4-azatricyclo[5.2.1.02,6-endo]dec-8-en-4-yl)-4-oxo-4-(p-tolylamino)butanedioic acid. This selectivity can be explained by the charge distribution in the starting anhydride and by larger LUMO coefficient on one of the carbonyl groups. One of the title amido acids could be converted into the corresponding cyclic imide by refluxing in pyridine. This imide is a close structural analog of thalidomide.   Описан синтез ряда новых амидных и имидных производных 2-(3,5-диоксо-4-азатрицикло[5.2.1.02,6-эндо]дец-8-ен-4-ил)бутандиовой кислоты – продукта конденсации эндикового ангидрида и аспарагиновой кислоты. Проведено квантово-химическое изучение распределения электронной плотности в ангидриде выше упомянутой кислоты, результаты которого свидетельствуют о предпочтительности атаки нуклеофильным реагентом атома углерода карбонильной группы, находящейся во втором положении ангидридного цикла. Региохимическому протеканию реакции способствуют как зарядовый, так и орбитальный факторы. Приведены спектральные параметры полученных соединений.         Описано синтез ряду нових амідних та імідних похідних 2-(3,5-діоксо-4-азатрицикло[5.2.1.02,6-ендо]дец-8-єн-4-іл)бутандіової кислоти – продукту конденсації ендикового ангидриду та аспарагінової кислоти. Проведено квантово-хімічне дослідження розподілу електронної густини у ангідриді вище згаданої кислоти, результати якого свідчать про більшу вигідність атаки нуклеофільним реагентом атому Карбона карбонільної групи, яка знаходиться в другому положенні ангідридного циклу. Регіохімічному перебігу реакції амінолізу ангідриду сприяє як зарядовий так і орбітальний фактори. Наведено спектральні параметри отриманих сполук.