Phase I study of RGB-286638, a novel, multi-targeted cyclin-dependent kinase inhibitor in patients with solid tumors
Mené sur 26 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale d'un composé appelé RGB-286638
Purpose RGB-286638 is a multi-targeted inhibitor with targets comprising the family of cyclin dependent kinases (CDKs) and a range of other cancer relevant Tyrosine and Serine/Threonine kinases. The objectives of this first in human trial of RGB-286638, given intravenously on D1-5 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 3-6 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/day. 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 one patient, paroxysmal 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 consistent a modulation of mechanism-related biomarkers with the exception of lowered Ki-67 levels at the MTD level. The recommended MTD for phase II studies is 120 mg/day. Conclusions RGB-286638 is tolerated when administered at 120mg/day for 5 days every 28 days. Prolonged disease stabilization (range 2-14 months) was seen across different dose levels.