A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.
Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules.
Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma.
Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.

Maintaining legacy data: saving Belfast Harbour (UK) tide-gauge data (1902-2010)

Tide gauge data are identified as legacy data given the radical transition between observation method and required output format associated with tide gauges over the 20th-century. Observed water level variation through tide-gauge records is regarded as the only significant basis for determining recent historical variation (decade to century) in mean sea-level and storm surge. There are limited tide gauge records that cover the 20th century, such that the Belfast (UK) Harbour tide gauge would be a strategic long-term (110 years) record, if the full paper-based records (marigrams) were digitally restructured to allow for consistent data analysis. This paper presents the methodology of extracting a consistent time series of observed water levels from the 5 different Belfast Harbour tide gauges’ positions/machine types, starting late 1901. Tide-gauge data was digitally retrieved from the original analogue (daily) records by scanning the marigrams and then extracting the sequential tidal elevations with graph-line seeking software (Ungraph™). This automation of signal extraction allowed the full Belfast series to be retrieved quickly, relative to any manual x–y digitisation of the signal. Restructuring variably lengthed tidal data sets to a consistent daily, monthly and annual file format was undertaken by project-developed software: Merge&Convert and MergeHYD allow consistent water level sampling both at 60 min (past standard) and 10 min intervals, the latter enhancing surge measurement. Belfast tide-gauge data have been rectified, validated and quality controlled (IOC 2006 standards). The result is a consistent annual-based legacy data series for Belfast Harbour that includes over 2 million tidal-level data observations.