Over the past half century, organizational studies scholarship has increasingly drifted away from addressing broader societal and political issues, as well as an interest in developing ...policy-relevant recommendations. In this paper, we argue that the time is ripe for a systematic re-engagement with how the dynamics of economy and society are fundamentally shaped by various elites, new forms of expertise, and their command posts — centers of societal power that regulate, oversee, and aim to maintain social order. Recalling early efforts by C. Wright Mills and his contemporaries, we call for the development of an institutional approach to the study of elites and command posts that draws on contemporary theories of power and culture to inform the creation of a new body of knowledge to inform our understanding of policy making and implementation. Drawing on a diverse array of sociological literatures and examples, the institutionalist agenda we lay out requires research that goes beyond a focus on any particular nation-state; a cumulative research program that embraces cross-national comparative studies and the study of international elites and command posts that operate across nation-states is crucial.
Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised ...that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma.
In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0–1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742.
Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 23%), diarrhoea (n=5 10%), fatigue (n=5 10%), and increased alanine aminotransferase concentration (n=4 8%). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 29%), increased alanine aminotransferase concentration (n=9 17%) or aspartate aminotransferase concentration (n=7 13%), hypothyroidism (n=7 13%), and fatigue (n=6 12%). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0–84·4) patients achieved an objective response (complete or partial response).
The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331).
Pfizer Inc.
Although the fields of organization theory and social movement theory have long been viewed as belonging to different worlds, recent events have intervened, reminding us that organizations are ...becoming more movement-like - more volatile and politicized - while movements are more likely to borrow strategies from organizations. Organization theory and social movement theory are two of the most vibrant areas within the social sciences. This collection of original essays and studies both calls for a closer connection between these fields and demonstrates the value of this interchange. Three introductory, programmatic essays by leading scholars in the two fields are followed by eight empirical studies that directly illustrate the benefits of this type of cross-pollination. The studies variously examine the processes by which movements become organized and the role of movement processes within and among organizations. The topics covered range from globalization and transnational social movement organizations to community recycling programs.
We investigate information processing in randomly connected recurrent neural networks. It has been shown previously that the computational capabilities of these networks are maximized when the ...recurrent layer is close to the border between a stable and an unstable dynamics regime, the so called
edge of chaos
. The reasons, however, for this maximized performance are not completely understood. We adopt an information-theoretical framework and are for the first time able to quantify the computational capabilities between elements of these networks directly as they undergo the phase transition to chaos. Specifically, we present evidence that both information transfer and storage in the recurrent layer are maximized close to this phase transition, providing an explanation for why guiding the recurrent layer toward the edge of chaos is computationally useful. As a consequence, our study suggests self-organized ways of improving performance in recurrent neural networks, driven by input data. Moreover, the networks we study share important features with biological systems such as feedback connections and online computation on input streams. A key example is the cerebral cortex, which was shown to also operate close to the edge of chaos. Consequently, the behavior of model systems as studied here is likely to shed light on reasons why biological systems are tuned into this specific regime.
Trace elements and extant and extinct isotopic attributes in martian meteorites have been used to argue that Mars accreted quickly, differentiated into core and mantle, and established several mantle ...reservoirs, possibly within 10 Ma of T0. The partitioning of trace elements in the deep mantle has been relatively unstudied, despite the need for such knowledge in understanding magma ocean crystallization and the origin of depleted and enriched mantle reservoirs. The siderophile element composition of the martian mantle, and lithophile isotopic systems such as Sr, Hf, and Nd, are thought to record evidence for early metal-silicate equilibrium and deep magma ocean at an intermediate depth and pressure of 800 km or 14 GPa. We have carried out experiments across this pressure range to better understand the mineral/melt partitioning of a wide range of elements. These new data are used to evaluate differentiation models for Mars and to help interpret the available isotopic data. The relatively incompatible nature of Re compared to mildly compatible Os means that the crystallization of a deep magma ocean will lead to residual liquids with super chondritic Re/Os, and solids with sub-chondritic Re/Os. Such material available in the mantle could be the source of enriched isotopic reservoir that produced shergottites with + Os values. On the other hand, slightly sub-chondritic Re/Os ratios in the crystallizing solids would provide a reservoir that could produce - Os values. Melting of mixtures of these two enriched and depleted end members could explain the Nd-Os isotopic correlations and systematics of shergottites.
Summary Background Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and ...improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. Methods In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov , number NCT00835978. Findings Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22–48) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten 18% of 56 in the axitinib titration group vs five 9% of 56 in the placebo titration group vs 45 49% of 91 in the non-randomised group), diarrhoea (seven 13% vs two 4% vs eight 9%), and decreased weight (four 7% vs three 5% vs six 7%). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each 4%), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each 2%). Interpretation The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease. Funding Pfizer Inc.
The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as ...second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval.
To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC.
This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein.
Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects.
Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors RECIST, version 1.1).
A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 71.2%) and white (123 71.1%). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 95.3% postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% n = 27; 95% CI, 19.0%-37.5% and 5.1% n = 4; 95% CI, 1.4%-12.5% in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis).
Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC.
clinicaltrials.gov Identifier: NCT01693562.
Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for ...the treatment of advanced RCC after one prior antiangiogenic therapy.
To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC.
This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease.
Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily.
The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method.
The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12–45). Median PFS was 9.2 mo (95% CI 5.5–not estimable), and median OS was 15.6 mo (95% CI 9.2–not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design.
Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination.
We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects.
This trial is registered at ClinicalTrials.Gov as NCT02915783.
Lenvatinib plus everolimus showed promising anticancer activity as a potential first-line treatment for patients with advanced non–clear-cell renal cell carcinoma, with an objective response rate of 26%. The safety profile was consistent with the established profile of the study drug combination.
PDF
