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Shin S.J.,Yonsei University | Ahn J.B.,Yonsei University | Park K.S.,Yonsei University | Lee Y.J.,Yonsei University | And 7 more authors.
Investigational New Drugs | Year: 2012

Background: We conducted a Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] in combination with capecitabine and oxaliplatin (XELOX) in nine metastatic colorectal cancer patients who had progressed on irinotecan-based chemotherapy. Methods: Using a dose-escalation schedule, CKD-732 doses of 2, 5, or 10 mg/m 2/d were administered twice weekly for 2 weeks, followed by a 1-week rest. Oxaliplatin (130 mg/m 2) was administered on day 1, and capecitabine (1,000 mg/m 2 twice a day) was orally administered for 14 days of a 3-week cycle. Results: In the group given the 10 mg/m 2/d dose, two patients experienced dose limiting toxicities (one had grade 3 nausea, insomnia, and fatigue; the other had grade 3 insomnia). The maximum tolerated dose was 10 mg/m 2/d, and the clinically recommended dose was 5 mg/m 2/d for CKD-732 in combination with XELOX. Frequently encountered non-hematological grade 3/4 adverse events included insomnia (22.2%), fatigue (11.1%), sensory neuropathy (11.1%), hyperbilirubinemia (11.1%), and dyspnea (11.1%). The area under the concentration-time curve and maximum concentration of CKD-732 increased in a dose-dependent manner. There were no notable effects of CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. Conclusion: The Phase II recommended dose of CKD-732 was determined to be 5 mg/m 2/d, and this dose was safely combined with a conventional dose of capecitabine and oxaliplatin in this patient population. Further studies on the effects of CKD-732 in combination with XELOX and other chemotherapies using a larger study population are warranted. © Springer Science+Business Media, LLC 2010.

Shin S.J.,Yonsei University | Jeung H.-C.,Yonsei University | Ahn J.B.,Yonsei University | Rha S.Y.,Yonsei University | And 4 more authors.
Investigational New Drugs | Year: 2010

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. © 2009 Springer Science+Business Media, LLC.

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