A phase I pharmacokinetic and pharmacodynamic study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer

Sang Joon Shin; Hei-Cheul Jeung; Joong Bae Ahn; Sun Young Rha; Jae Kyung Roh; Kyung Soo Park; Dal-Hyun Kim; Chin Kim; Hyun Cheol Chung

doi:10.1007/s10637-009-9287-8

A phase I pharmacokinetic and pharmacodynamic study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer

Invest New Drugs. 2010 Oct;28(5):650-8. doi: 10.1007/s10637-009-9287-8. Epub 2009 Jul 8.

Authors

Sang Joon Shin¹, Hei-Cheul Jeung, Joong Bae Ahn, Sun Young Rha, Jae Kyung Roh, Kyung Soo Park, Dal-Hyun Kim, Chin Kim, Hyun Cheol Chung

Affiliation

¹ Department of Internal Medicine, Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.

PMID: 19585083
DOI: 10.1007/s10637-009-9287-8

Abstract

We conducted a phase I trial of the antiangiogenic agent 6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate (CKD-732). Our aims were to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profiles as well as identify the biologically active dose (BAD) from ex vivo pharmacodynamics (PD) and biomarkers of CKD-732. Using a dose escalation schedule, 19 patients with refractory solid tumors were enrolled at dose levels of CKD-732 ranging from 1 to 15 mg/m(2) given twice weekly for 2 weeks followed by a 1-week rest. No treatment-related deaths occurred in this study. Confusion and insomnia were dose-limiting toxicities (DLTs), and MTD was 15 mg/m(2). The area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased dose dependently with increasing doses. The BAD was 5 mg/m(2) according to ex vivo PD. A decrement in soluble vascular endothelial growth factor receptor-3 (sVEGF-3) level was correlated with a reduction in tumor size (r = 0.54, P = 0.045). The results from this study showed an MTD of 15 mg/m(2) and a BAD of 5 mg/m(2).

Publication types

Clinical Trial, Phase I

MeSH terms

Adult
Aged
Angiogenesis Inhibitors / adverse effects
Angiogenesis Inhibitors / pharmacokinetics*
Angiogenesis Inhibitors / pharmacology
Angiogenesis Inhibitors / therapeutic use*
Area Under Curve
Cell Line
Cinnamates / adverse effects
Cinnamates / pharmacokinetics*
Cinnamates / pharmacology
Cinnamates / therapeutic use*
Cyclohexanes / adverse effects
Cyclohexanes / pharmacokinetics*
Cyclohexanes / pharmacology
Cyclohexanes / therapeutic use*
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / drug effects
Endostatins / blood
Epoxy Compounds / adverse effects
Epoxy Compounds / pharmacokinetics*
Epoxy Compounds / pharmacology
Epoxy Compounds / therapeutic use*
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms / blood
Neoplasms / drug therapy*
Receptors, Vascular Endothelial Growth Factor / blood
Sesquiterpenes / adverse effects
Sesquiterpenes / pharmacokinetics*
Sesquiterpenes / pharmacology
Sesquiterpenes / therapeutic use*
Solubility / drug effects
Vascular Endothelial Growth Factor A / blood

Substances

Angiogenesis Inhibitors
Cinnamates
Cyclohexanes
Endostatins
Epoxy Compounds
Sesquiterpenes
Vascular Endothelial Growth Factor A
Receptors, Vascular Endothelial Growth Factor
CKD732