Abstract | PURPOSE: 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.
|
Authors | Diane 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 |
Journal | Clinical 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 |
PMID | 25024258
(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)
|