Purpose: RGB-286638 is a multitargeted inhibitor with targets comprising the family of cyclin-dependent kinases (CDK) and a range of other cancer-relevant tyrosine and serine/threonine kinases. The objectives of this first in human trial of RGB-286638, given i.v. on days 1 to 5 every 28 days, were to determine the maximum tolerated dose (MTD) and to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of this new drug.Experimental Design: Sequential cohorts of 3 to 6 patients were treated per dose level. Blood, urine samples, and skin biopsies for full PK and/or PD analyses were collected.Results: Twenty-six patients were enrolled in 6-dose levels from 10 to 160 mg/d. Four dose-limiting toxicities were observed in 2 of the 6 patients enrolled at the highest dose level. These toxicities were AST/ALT elevations in 1 patient, paroxysmal supraventricular tachycardias (SVTs), hypotension, and an increase in troponin T in another patient. The plasma PK of RGB-286638 was shown to be linear over the studied doses. The interpatient variability in clearance was moderate (variation coefficient 7%-36%). The PD analyses in peripheral blood mononuclear cells, serum (apoptosis induction) and skin biopsies (Rb, p-Rb, Ki-67, and p27KIP1 expression) did not demonstrate a consistentmodulation ofmechanism-related biomarkers with the exception of lowered Ki-67 levels at the MTD level. The recommendedMTD for phase II studies is 120mg/d.Conclusions: RGB-286638 is tolerated when administered at 120 mg/d for 5 days every 28 days. Prolonged disease stabilization (range, 2-14 months) was seen across different dose levels.

doi.org/10.1158/1078-0432.CCR-14-0325, hdl.handle.net/1765/86585
Clinical Cancer Research
Erasmus MC: University Medical Center Rotterdam

van der Biessen, D., Burger, H., de Bruijn, P., Lamers, C., Naus, N., Loferer, H., … de Jonge, M. (2014). Phase i study of RGB-286638, A novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors. Clinical Cancer Research, 20(18), 4776–4783. doi:10.1158/1078-0432.CCR-14-0325