title: Association of creatine kinase and skin toxicity in phase I trials of anticancer agents.
abstract: BACKGROUND
  We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials.
  
  
  METHODS
  We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents.
  
  
  RESULTS
  Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249 U l(-1)) compared with G1 (median 81 U l(-1)) and no rash (median 55 U l(-1)) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK.
  
  
  CONCLUSIONS
  Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials.
authors.affiliation: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
authors.forename: V
authors.initials: V
authors.lastname: Moreno Garcia
authors.forename: P
authors.initials: P
authors.lastname: Thavasu
authors.forename: M
authors.initials: M
authors.lastname: Blanco Codesido
authors.forename: L R
authors.initials: LR
authors.lastname: Molife
authors.forename: J
authors.initials: J
authors.lastname: Vitfell Pedersen
authors.forename: M
authors.initials: M
authors.lastname: Puglisi
authors.forename: B
authors.initials: B
authors.lastname: Basu
authors.forename: K
authors.initials: K
authors.lastname: Shah
authors.forename: J
authors.initials: J
authors.lastname: Iqbal
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: U
authors.initials: U
authors.lastname: Banerji
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic; D003402:Creatine Kinase / Q000097:blood*; D005076:Exanthema / Q000097:blood / Q000139:chemically induced*; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D003402:Creatine Kinase