CONFIRM: a double-blind, placebo controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial

Background: Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Early promising signals of activity relating to both PD-L1- and PD-1-targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint. There is a need to evaluate checkpoint inhibitors in patients with relapsed mesothelioma where treatment options are limited. Methods: The addition of 12 months of nivolumab (anti-PD1 antibody) to standard practice will be conducted in the UK using a randomised, placebo-controlled phase III trial (the Cancer Research UK CONFIRM trial). A total of 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy will be recruited from UK secondary care sites. Patients will be randomised 2:1 (nivolumab:placebo), stratified according to epithelioid/non-epithelioid, to receive either 240 mg nivolumab monotherapy or saline placebo as a 30-min intravenous infusion. Treatment will be for up to 12 months. We will determine whether the use of nivolumab increases overall survival (the primary efficacy endpoint). Secondary endpoints will include progression-free survival, objective response rate, toxicity, quality of life and cost-effectiveness. Analysis will be performed according to the intention-to-treat principle using a Cox regression analysis for the primary endpoint (and for other time-to-event endpoints). Discussion: The outcome of this trial will provide evidence of the potential benefit of the use of nivolumab in the treatment of relapsed mesothelioma. If found to be clinically effective, safe and cost-effective it is likely to become the new standard of care in the UK

Applying science to pressing conservation needs for penguins

More than half of the world's 18 penguin species are declining. We, the Steering Committee of the International Union for Conservation of Nature Species Survival Commission Penguin Specialist Group, determined that the penguin species in most critical need of conservation action are African penguin (Spheniscus demersus), Galápagos penguin (Spheniscus mendiculus), and Yellow-eyed penguin (Megadyptes antipodes). Due to small or rapidly declining populations, these species require immediate scientific collaboration and policy intervention. We also used a pairwise-ranking approach to prioritize research and conservation needs for all penguins. Among the 12 cross-taxa research areas we identified, we ranked quantifying population trends, estimating demographic rates, forecasting environmental patterns of change, and improving the knowledge of fisheries interactions as the highest priorities. The highest ranked conservation needs were to enhance marine spatial planning, improve stakeholder engagement, and develop disaster-management and species-specific action plans. We concurred that, to improve the translation of science into effective conservation for penguins, the scientific community and funding bodies must recognize the importance of and support long-term research; research on and conservation of penguins must expand its focus to include the nonbreeding season and juvenile stage; marine reserves must be designed at ecologically appropriate spatial and temporal scales; and communication between scientists and decision makers must be improved with the help of individual scientists and interdisciplinary working groups

Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer

Clinical resistance to the second-generation antiandrogen enzalutamide in castration resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights the unmet medical need for next generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide), and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR:CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm bound to heat shock proteins. Thus, we have identified third generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC