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American Association for Cancer Research, Clinical Cancer Research, 18(20), p. 4776-4783, 2014

DOI: 10.1158/1078-0432.ccr-14-0325



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Phase I Study of RGB-286638, A Novel, Multitargeted Cyclin-Dependent Kinase Inhibitor in Patients with Solid Tumors

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract 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 consistent 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/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. Clin Cancer Res; 20(18); 4776–83. ©2014 AACR.