A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy

Sang Joon Shin, Joong Bae Ahn, Kyung Soo Park, Yoon Jung Lee, Yong Sang Hong, Tae Won Kim, Hye Ryun Kim, SunYoung Rha, Jae Kyung Roh, Dal Hyun Kim, Chin Kim, Hyuncheol Chung

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Abstract

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.

Original languageEnglish
Pages (from-to)672-680
Number of pages9
JournalInvestigational New Drugs
Volume30
Issue number2
DOIs
Publication statusPublished - 2012 Apr 1

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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