Results of an open-label phase 1b study of the ERK inhibitor MK-8353 plus the MEK inhibitor selumetinib in patients with advanced or metastatic solid tumors.

AIM: We evaluated MK-8353 (small molecule inhibitor of extracellular signal-regulated kinase 1/2) plus selumetinib (mitogen-activated extracellular signal-regulated kinase 1/2 inhibitor) in patients with advanced solid tumors. METHODS: This phase 1b, open-label, dose-escalation study (NCT03745989) enrolled adults with histologically/cytologically documented, locally advanced/metastatic solid tumors. MK-8353/selumetinib dose combinations were intended to be investigated in sequence: 50/25, 100/50, 150/75, 200/75, 200/100, and 250/100. Each agent was administered orally BID 4 days on/3 days off in repeating cycles every 21 days. Primary objectives were safety and tolerability and to establish preliminary recommended phase 2 doses for combination therapy. RESULTS: Thirty patients were enrolled. Median (range) age was 61.5 (26-78) years and 93% had received previous cancer therapy. Among 28 patients in the dose-limiting toxicities [DLT]-evaluable population, 8 experienced DLTs: 1/11 (9%) in the MK-8353/selumetinib 100/50-mg dose level experienced a grade 3 DLT (urticaria), and 7/14 (50%) in the 150/75-mg dose level experienced grade 2/3 DLTs (n = 2 each of blurred vision, retinal detachment, vomiting; n = 1 each of diarrhea, macular edema, nausea, retinopathy). The DLT rate in the latter dose level exceeded the prespecified target DLT rate (~30%). Twenty-six patients (87%) experienced treatment-related adverse events (grade 3, 30%; no grade 4/5), most commonly diarrhea (67%), nausea (37%), and acneiform dermatitis (33%). Three patients (10%) experienced treatment-related adverse events leading to treatment discontinuation. Best response was stable disease in 14 patients (n = 10 with MK-8353/selumetinib 150/75 mg). CONCLUSION: MK-8353/selumetinib 50/25 mg and 100/50 mg had acceptable safety and tolerability, whereas 150/75 mg was not tolerable. No responses were observed.

Measuring and Analyzing Length of Stay in Critical Care Trials.

BACKGROUND: In randomized clinical trials among critically ill patients, it is uncertain how choices regarding the measurement and analysis of nonmortal outcomes measured in terms of duration, such as intensive care unit (ICU) length of stay (LOS), affect studies' conclusions. OBJECTIVES: Assess the definitions and analytic methods used for ICU LOS analyses in published randomized clinical trials. RESEARCH DESIGN: This is a systematic review and statistical simulation study. RESULTS: Among the 80 of 150 trials providing sufficient information regarding the chosen definition of ICU LOS, 3 different start times (ICU admission, trial enrollment/randomization, receipt of intervention) and 2 end times (discharge readiness, actual discharge) were used. In roughly three quarters of these studies, ICU LOS was compared using approaches that did not explicitly account for death, either by ignoring it entirely or stratifying the analyses by survival status. The remaining studies used time-to-event (discharge) models censoring at death or applied a fixed LOS value to patients who died. In statistical simulations, we showed that each analytic approach tested a different question regarding ICU LOS, and that approaches that do not explicitly account for death often produce misleading or ambiguous conclusions when treatments produce small effects on mortality, even if those are not detected as significant in the trial. CONCLUSIONS: There is considerable variability in how ICU LOS is measured and analyzed which impairs the ability to compare results across trials and can produce spurious conclusions. Analyses of duration-based outcomes such as LOS should jointly assess the impact of the intervention on mortality to yield correct interpretations.

Statistical estimation of white matter microstructure from conventional MRI.

Diffusion tensor imaging (DTI) has become the predominant modality for studying white matter integrity in multiple sclerosis (MS) and other neurological disorders. Unfortunately, the use of DTI-based biomarkers in large multi-center studies is hindered by systematic biases that confound the study of disease-related changes. Furthermore, the site-to-site variability in multi-center studies is significantly higher for DTI than that for conventional MRI-based markers. In our study, we apply the Quantitative MR Estimation Employing Normalization (QuEEN) model to estimate the four DTI measures: MD, FA, RD, and AD. QuEEN uses a voxel-wise generalized additive regression model to relate the normalized intensities of one or more conventional MRI modalities to a quantitative modality, such as DTI. We assess the accuracy of the models by comparing the prediction error of estimated DTI images to the scan-rescan error in subjects with two sets of scans. Across the four DTI measures, the performance of the models is not consistent: Both MD and RD estimations appear to be quite accurate, while AD estimation is less accurate than MD and RD; the accuracy of FA estimation is poor. Thus, in some cases when assessing white matter integrity, it may be sufficient to acquire conventional MRI sequences alone.