title: Beyond the dose-limiting toxicity period: Dermatologic adverse events of patients on phase 1 trials of the Cancer Therapeutics Evaluation Program.
abstract: BACKGROUND
  Dermatologic adverse events (AEs) can be key determinants of overall drug tolerability and of the maximum tolerated and recommended phase 2 doses in phase 1 trials. The authors present the largest dedicated analysis of dermatologic AEs on phase 1 trials to date.
  
  
  METHODS
  Data from a prospectively maintained database of patients with solid tumors who were enrolled onto Cancer Therapeutics Evaluation Program (CTEP)-sponsored phase 1 trials of cytotoxic or molecularly targeted agents (MTAs) from 2000 to 2010 were analyzed. Cumulative incidence, site, and type of drug-related dermatologic AEs were described and compared. The timing of worst drug-related dermatologic AEs was summarized.
  
  
  RESULTS
  In total, 3517 patients with solid tumors and 6165 unique, drug-related dermatologic AEs were analyzed, including 1545 patients on MTA-only trials, 671 on cytotoxic-only trials, and 1392 on combination MTA and cytotoxic trials. Of 1270 patients who had drug-related dermatologic events, the timing of the worst AE was as follows: 743 (cycle 1), 303 (cycle 2), and 224 (cycle 3 or later). Although the cumulative incidence of grade ≥3 drug-related AEs increased to 2.4% by cycle 6, it was only 1.6% at the end of cycle 1. The cumulative incidence of drug-related AEs was highest in patients who received MTA-only therapy (P < .001) and differed by dose level (P < .001). In patients who received MTA-only therapy, drug-related AEs were most common for combination kinase inhibitor-containing therapy (P < .001).
  
  
  CONCLUSIONS
  A substantial proportion of drug-related dermatologic AEs occur after the traditional dose-limiting toxicity monitoring period of phase 1 clinical trials. Future designs should account for late toxicities.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Eaton
authors.affiliation: Dermatology Department, Medical University of Vienna, Vienna, Austria.
authors.forename: Katja
authors.initials: K
authors.lastname: Schindler
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Gounder
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
authors.affiliation: Cancer Therapeutics and Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Harris
authors.affiliation: Cancer Therapeutics and Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Alexia
authors.initials: A
authors.lastname: Iasonos
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mario E
authors.initials: ME
authors.lastname: Lacouture
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions / Q000453:epidemiology* / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy / Q000009:adverse effects*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents
keywords: Cancer Therapeutics Evaluation Program (CTEP); dermatologic toxicity; dose-limiting toxicity (DLT) period; molecularly targeted agents; phase 1 trial