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Phase I study of RGB-286638, a novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors.

AbstractPURPOSE:
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 p27(KIP1) 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.
AuthorsDiane A J van der Biessen, Herman Burger, Peter de Bruijn, Cor H J Lamers, Nicole Naus, Hannes Loferer, Erik A C Wiemer, Ron H J Mathijssen, Maja J A de Jonge
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 18 Pg. 4776-83 (Sep 15 2014) ISSN: 1557-3265 [Electronic] United States
PMID25024258 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2014 American Association for Cancer Research.
Chemical References
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • RGB 286638
  • Urea
  • Cyclin-Dependent Kinases
Topics
  • Adult
  • Aged
  • Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
  • Cyclin-Dependent Kinases (antagonists & inhibitors)
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms (drug therapy)
  • Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
  • Pyrazoles (administration & dosage, adverse effects, pharmacokinetics)
  • Urea (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)

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