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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.

Authors
 Sang Joon Shin  ;  Joong Bae Ahn  ;  Kyung Soo Park  ;  Yoon Jung Lee  ;  Yong Sang Hong  ;  Tae Won Kim  ;  Hye Ryun Kim  ;  Sun Young Rha  ;  Jae Kyung Roh  ;  Dal-Hyun Kim  ;  Chin Kim  ;  Hyun Cheol Chung 
Citation
 INVESTIGATIONAL NEW DRUGS, Vol.30(2) : 672-680, 2012 
Journal Title
INVESTIGATIONAL NEW DRUGS
ISSN
 0167-6997 
Issue Date
2012
MeSH
Adenocarcinoma/blood ; Adenocarcinoma/drug therapy* ; Adenocarcinoma/mortality ; Adenocarcinoma/secondary ; Adult ; Aged ; Angiogenesis Inhibitors/pharmacokinetics ; Antineoplastic Agents, Phytogenic/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/blood ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics* ; Camptothecin/analogs & derivatives* ; Camptothecin/therapeutic use ; Cinnamates/pharmacokinetics ; Colorectal Neoplasms/blood ; Colorectal Neoplasms/drug therapy* ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/pathology ; Cyclohexanes/pharmacokinetics ; Deoxycytidine/administration & dosage ; Deoxycytidine/adverse effects ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/blood ; Deoxycytidine/pharmacokinetics ; Disease Progression ; Disease-Free Survival ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Epoxy Compounds/pharmacokinetics ; Female ; Fluorouracil/administration & dosage ; Fluorouracil/adverse effects ; Fluorouracil/analogs & derivatives ; Fluorouracil/blood ; Fluorouracil/pharmacokinetics ; Humans ; Male ; Maximum Tolerated Dose ; Middle Aged ; Models, Biological ; Models, Statistical ; Republic of Korea ; Sesquiterpenes/pharmacokinetics ; Survival Analysis ; Treatment Failure
Keywords
Capecitabine ; CKD-732 ; Metastatic colon cancer ; Oxaliplatin ; Pharmacokinetics
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.
Full Text
http://link.springer.com/article/10.1007%2Fs10637-010-9625-x
DOI
21188464
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Roh, Jae Kyung(노재경)
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Park, Kyungsoo(박경수) ORCID logo https://orcid.org/0000-0002-6972-1143
Shin, Sang Joon(신상준) ORCID logo https://orcid.org/0000-0001-5350-7241
Ahn, Joong Bae(안중배) ORCID logo https://orcid.org/0000-0001-6787-1503
Lee, Yoon Jung(이윤정)
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/90568
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