title: Phase I study of RGB-286638, a novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Diane A J
authors.initials: DA
authors.lastname: van der Biessen
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Cor H J
authors.initials: CH
authors.lastname: Lamers
authors.affiliation: Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Naus
authors.affiliation: Agennix AG, Martinsried, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Loferer
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. m.dejonge@erasmusmc.nl.
authors.forename: Maja J A
authors.initials: MJ
authors.lastname: de Jonge
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C546217:RGB 286638; D014508:Urea; D018844:Cyclin-Dependent Kinases