Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan‐Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

Abstract Lessons Learned. A phase I study of the pan‐class I phosphoinositide 3‐kinase inhibitor pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.Based on pharmacokinetic data, the recommended phase II dose of pilaralisib tablets was established as 400 mg once daily. Background. A phase I trial of pilaralisib, an oral pan‐class I phosphoinositide 3‐kinase (PI3K) inhibitor, established the maximum tolerated dose (MTD) of the capsule formulation in patients with advanced solid tumors as 600 mg once daily. This phase I study investigated pilaralisib in tablet formulation. Materials and Methods. Patients with advanced solid tumors received pilaralisib tablets (100–600 mg once daily). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics, and efficacy. Results. Twenty‐two patients were enrolled. No dose‐limiting toxicities (DLTs) were reported. The most common treatment‐related adverse events were diarrhea (40.9%), fatigue (40.9%), decreased appetite (22.7%), and hyperglycemia (22.7%). Pilaralisib plasma exposure did not appear to increase dose‐proportionally. Steady‐state exposure was higher with pilaralisib tablet formulation at 400 mg than with pilaralisib capsule formulation at 400 or 600 mg (mean area under the curve [AUC0–24] 2,820,000 ng × h/mL vs. 2,653,000 and 1,930,000 ng × h/mL, respectively). Of 18 evaluable patients, 2 (11.1%) had a partial response (PR). Conclusion. Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity. MTD was not determined. The recommended phase II dose for pilaralisib tablets, based on PK data, was 400 mg once daily

SLEEP WAVES AND RECOVERY FROM DRUG AND ALCOHOL DEPENDENCE: TOWARDS A RHYTHMANALYSIS OF SLEEP IN RESIDENTIAL TREATMENT

This paper reports on a study of sleep amongst men and women who are living in residential rehabilitation centres in the UK and who are receiving support for their recovery from addiction to alcohol and other forms of substance use. Conceptually and methodologically, the paper draws on the work of the French sociologist Lefebvre and, in particular, his rhythmanalysis. We argue that this approach offers a useful way of exploring sleep in terms of biological, experiential, temporal, spatial and social rhythms. It also has the potential to facilitate interdisciplinary dialogue. Empirical data comprising qualitative interviews with 28 individuals, sleep diaries, and actigraphy reports (which measure movement as a proxy for sleep) are examined in combination to generate insights into the challenges associated with sleep in recovery from substance misuse. We examine how sleep in recovery involves an alignment of the spatiotemporal rhythms of rehabilitation and the multiple embodied rhythms of individuals. Institutionalised routines reproduce and impose ideas of day/night sleep cycles which are presumed to accord with ‘natural’ circadian rhythms. Although study participants very much want to achieve these ‘natural hegemonies’ of sleep, alignment of individual and institutional rhythms is difficult to achieve. We develop the notion of ‘sleep waves’ as an analytic to capture the multifaceted elements of sleep and to argue that sleep waves recur but are also shaped by complex networks of rhythms, rituals and routines. Sleep waves can become relatively stabilised in rehabilitation settings, but the anticipation of moving on disturbs rhythms and generates anxieties which can affect recovery

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Abstract CT152: First in human study with EOS100850, a novel potent A2A antagonist, shows excellent tolerance and clinical benefit in immune resistant advanced cancers

Adenosine is a strong immunosuppressive mediator often found at high extracellular levels in the microenvironment of most tumors. Blocking A2A receptors, predominantly expressed on tumor-infiltrating immune cells, is aimed at reversing the immunosuppressive effect of adenosine. EOS100850 is a potent and highly selective small molecule antagonist of the A2A receptor that remains active even at the high adenosine concentration found in tumors and that does not cross the blood-brain barrier. This multicenter FIH Phase I clinical trial (NCT02740985) assessed the safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary clinical activity of EOS100850 monotherapy in subjects with refractory solid tumors. Pharmacodynamic assessments were performed in peripheral blood and tumor biopsies with simultaneous determination of plasma PK. Twenty-one adult participants with advanced malignancies were treated with EOS100850 monotherapy. Cohorts of 3 participants each were evaluated at 20 and 40 mg QD or 40 mg BID administration. Six participants were subsequently tested at doses of 80 mg BID and at the maximum administered dose of 160 mg BID. All subjects had at least 1 prior regimen (median 3). PK analysis indicated dose-proportional increase of EOS100850 plasma exposures up to 80 mg BID while PD evaluations revealed prolonged and maintained A2AR inhibition over the dosing interval. The most common adverse events (>15%) attributed to the investigational treatment included Grade 1-2 nausea, fatigue, vomiting, and liver enzyme abnormalities. No drug-related Grade 3-4 AEs and no dose-limiting toxicities were observed. As of the data cut off (15JAN20), stable disease was observed in 6 participants who remain on therapy, including head & neck cancers, endometrial cancers, and checkpoint inhibitor-refractory melanoma. Further evaluation is ongoing as monotherapy and in combination with pembrolizumab or chemotherapy in both immune checkpoint-naïve and -refractory patients