Summary: 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/m2 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/m2. The area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased dose dependently with increasing doses. The BAD was 5 mg/m2 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/m2 and a BAD of 5 mg/m2.
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Acknowledgements This work was supported by a Korea Science and Engineering Foundation (KOSEF) grant funded by the Ministry of Science and Technology (MOST) of Korea (R11-2000-082-02008-0) and grants from the Korean Ministry for Health, Welfare and Family Affairs (01-PJ1-PG4-01PT01-0004 and A050083). We thank Dong-Su Jang for his help with drawing the figures. Language editing was done by Sydney Sue Kim.
All Science Journal Classification (ASJC) codes
- Pharmacology (medical)