A phase I pharmacokinetic and pharmacodynamic study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer.
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).
Shin
Sang Joon
SJ
Department of Internal Medicine, Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Jeung
Hei-Cheul
HC
Ahn
Joong Bae
JB
Rha
Sun Young
SY
Roh
Jae Kyung
JK
Park
Kyung Soo
KS
Kim
Dal-Hyun
DH
Kim
Chin
C
Chung
Hyun Cheol
HC
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D002460:Cell Line; D002934:Cinnamates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D003510:Cyclohexanes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D043169:Endostatins / Q000097:blood; D004852:Epoxy Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000097:blood; D012717:Sesquiterpenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D012995:Solubility / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D020533:Angiogenesis Inhibitors; D002934:Cinnamates; D003510:Cyclohexanes; D043169:Endostatins; D004852:Epoxy Compounds; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; C487952:CKD732