title: Defining the risk of toxicity in phase I oncology trials of novel molecularly targeted agents: a single centre experience.
abstract: BACKGROUND
  This study defined the risk of serious toxicity in phase I trials of molecularly targeted agents (MTA).
  
  
  METHODS
  A retrospective analysis of toxicity data from patients treated in phase I trials of MTAs was carried out to define the rate of treatment-related grade 3/4 toxic effects, deaths and risk factors associated with grade 3 or more toxicity.
  
  
  RESULTS
  Data from 687 patients [median age, 59.1 years (range 12.5-85.5)] treated in 36 trials were analysed. Two hundred and eleven patients were of Eastern Cooperative Oncology Group performance status (PS) zero, 432 of PS one, 38 of PS two and 6 unknown. The rate of grade 3 and 4 events was 14.1% (n=97) and 1.9% (n=13), respectively. Twenty-four percent of events were gastrointestinal, 22% constitutional and 20% metabolic. PS two was associated with a higher risk of toxicity [odds ratio (OR), 2.6; 95% confidence interval (CI) 1.1-6.1; P=0.032] as was receiving >100% of maximum tolerated dose or maximum administered dose (OR 2.5; CI 1.6-3.9; P<0.001). Mortality rate was 0.43% (n=3).
  
  
  CONCLUSIONS
  Therapy with novel MTAs in phase I trials is associated with a moderate risk of significant toxicity. This appears less than in phase I studies involving cytotoxic agents, particularly in relation to grade 4 toxicity. The risk of death is low.
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK. Electronic address: rhoda.molife@icr.ac.uk.
authors.forename: L R
authors.initials: LR
authors.lastname: Molife
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Alam
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: D
authors.initials: D
authors.lastname: Olmos
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Puglisi
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: K
authors.initials: K
authors.lastname: Shah
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: R
authors.initials: R
authors.lastname: Fehrmann
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: L
authors.initials: L
authors.lastname: Trani
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: A
authors.initials: A
authors.lastname: Tjokrowidjaja
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: U
authors.initials: U
authors.lastname: Banerji
authors.affiliation: Drug Development Unit, Royal Marsden/Institute of Cancer Research, Sutton, UK.
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002648:Child; D017321:Clinical Trials, Phase I as Topic; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000009:adverse effects* / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents