ABSTRACT
BACKGROUND: Xentuzumab is a humanised monoclonal antibody that binds to IGF-1 and IGF-2, neutralising their proliferative activity and restoring inhibition of AKT by everolimus. This study evaluated the addition of xentuzumab to everolimus and exemestane in patients with advanced breast cancer with non-visceral disease. METHODS: This double-blind, randomised, Phase II study was undertaken in female patients with hormone-receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative advanced breast cancer with non-visceral disease who had received prior endocrine therapy with or without CDK4/6 inhibitors. Patients received a weekly intravenous infusion of xentuzumab (1000 mg) or placebo in combination with everolimus (10 mg/day orally) and exemestane (25 mg/day orally). The primary endpoint was progression-free survival (PFS) per independent review. RESULTS: A total of 103 patients were randomised and 101 were treated (n = 50 in the xentuzumab arm and n = 51 in the placebo arm). The trial was unblinded early due to high rates of discordance between independent and investigator assessment of PFS. Per independent assessment, median PFS was 12.7 (95% CI 6.8-29.3) months with xentuzumab and 11.0 (7.7-19.5) months with placebo (hazard ratio 1.19; 95% CI 0.55-2.59; p = 0.6534). Per investigator assessment, median PFS was 7.4 (6.8-9.7) months with xentuzumab and 9.2 (5.6-14.4) months with placebo (hazard ratio 1.23; 95% CI 0.69-2.20; p = 0.4800). Tolerability was similar between the arms, with diarrhoea (33.3-56.0%), fatigue (33.3-44.0%) and headache (21.6-40.0%) being the most common treatment-emergent adverse events. The incidence of grade ≥ 3 hyperglycaemia was similar between the xentuzumab (2.0%) and placebo (5.9%) arms. CONCLUSIONS: While this study demonstrated that xentuzumab could be safely combined with everolimus and exemestane in patients with HR-positive/HER2-negative advanced breast cancer with non-visceral disease, there was no PFS benefit with the addition of xentuzumab. Trial registration ClinicalTrials.gov, NCT03659136. Prospectively registered, September 6, 2018.
Subject(s)
Breast Neoplasms , Humans , Female , Everolimus , AndrostadienesABSTRACT
A variety of clinical scales are available to assess dyskinesia severity in Parkinson's disease patients; however, such assessments are subjective, do not provide long term monitoring, and their use is subject to inter- and intra-rater variability. In this paper, an objective dyskinesia score was developed using an IMU -based motion capture system. Deep brain stimulation (DBS) surgery is currently the only acute intervention that results in the rapidly progressive reduction of dyskinesia's severity; hence, this form of therapy was selected as a model to validate the proposed method. Thirteen Parkinson's disease participants undergoing DBS surgery and 12 age-matched healthy control participants were assessed using the motion capture system. Concurrent Unified Dyskinesia Rating Scale (UDysRS) ratings were also performed. Parkinson's disease participants were assessed pre-operatively and for five visits post-operatively while seated at rest, during arms outstretched and while performing an action task. The kinematic data were used to develop an objective measure defined as the dyskinesia severity score. Generally, a strong correlation was observed between the UDysRS ratings and the full-body dyskinesia severity scores. The results suggest that it is feasible and clinically meaningful to utilize an objective full-body dyskinesia score for the assessment of dyskinesia. The portable motion capture system along with the developed software can be used remotely to monitor the full-body severity of dyskinesia, necessary for therapeutic optimization, especially in the patients home environment.