title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, 250 Seongsan-no, Seodaemun-gu, Seoul 120-752, South Korea.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Shin
authors.forename: Joong Bae
authors.initials: JB
authors.lastname: Ahn
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Lee
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Roh
authors.forename: Dal-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Chin
authors.initials: C
authors.lastname: Kim
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000069287:Capecitabine; D002934:Cinnamates / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003510:Cyclohexanes / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004852:Epoxy Compounds / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D010071:Oxaloacetates; D056910:Republic of Korea; D012717:Sesquiterpenes / Q000493:pharmacokinetics; D016019:Survival Analysis; D017211:Treatment Failure
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D002934:Cinnamates; D003510:Cyclohexanes; D004852:Epoxy Compounds; D010071:Oxaloacetates; D012717:Sesquiterpenes; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; C487952:CKD732; D005472:Fluorouracil; D002166:Camptothecin