A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors.

BACKGROUND: This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors. MATERIALS AND METHODS: LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity. RESULTS: Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed. CONCLUSION: The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development. CLINICALTRIALS.GOV IDENTIFIER: NCT03770494.

The CHI3L1 rs4950928 polymorphism is associated with asthma-related hospital admissions in children and young adults.

BACKGROUND: Asthma exacerbations are the commonest cause of medical admissions in childhood. These have a significant effect on quality of life and are a major financial burden on worldwide healthcare services. A range of gene-environment interactions may influence the course and severity of asthma in children and their response to medication. The Chitinase 3-like 1 (CHI3L1)-131C>G genotype (rs4950928) is associated with increased asthma susceptibility and severity in adults. OBJECTIVES: To study the interactions of the Chitinase 3-Like-1 functional promoter SNP rs4950928 and its role on asthma exacerbations in a population of children and young adults with asthma. METHODS: A cross-sectional survey was undertaken using medical records and direct interviews of 1,071 children and young adults with asthma, aged 3 to 22 years, from Scotland. Saliva samples were collected for genotyping. Binary logistic regression was used to calculate odds ratios (ORs) and P-values for measures of asthma exacerbations. RESULTS: The minor -131G allele confers protection against asthma-related hospital admissions (OR = 0.62; 95% CI 0.41-0.92; P = .018) in children and young adults with asthma. CONCLUSIONS: Our study shows that rs4950928 is significantly associated with hospital admissions in children and young adults; screening for rs4950928 may predict asthma-related hospital admissions, and through individually defined treatment management plans, potentially reduce health care costs.

A methodology to establish a database to study gene environment interactions for childhood asthma.

BACKGROUND: Gene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES--Paediatric Asthma Gene Environment Study). METHODS: Children with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR), skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database. RESULTS: To date 1045 children have been invited to participate and data collected in 501 (48%). The mean age (SD) of participants is 8.6 (3.9) years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD) FEV1 97% (15) and median (IQR) BDR is 5% (2, 9). There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024). Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part. CONCLUSIONS: It is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.

Towards Inclusive Healthcare Delivery: Potentials and Challenges of Human-Centred Design in Health Innovation Processes to Increase Healthy Aging.

National healthcare systems need to adjust services and operations to accommodate the needs of complex, aging populations living with multimorbidity and polypharmacy. This paper suggests the use of a human-centred design as a method to engage older adults and key professionals in innovation processes aiming to design person-centred healthcare services and improve quality of life in older adults. We outline three innovation phases and highlight how such processes can create engagement and new insights on how life experiences of older adult's shape preferences, beliefs, and habits. It is important to incorporate these insights into the design of successful strategies for ensuring age-friendly healthcare services. Our viewpoint is contextualised through a small-scale case study focusing on polypharmacy in older adults. From this case study, we extracted three challenges to producing co-designed health research: recruitment, time and resources, and funding. We discuss how to address these challenges. We argue for the involvement of older adults and professional stakeholders at an early stage in the design process to align expectations and to increase the likelihood of successful implementation of healthcare innovations that improve the quality of life for older adults.