Beyond the dose-limiting toxicity period: Dermatologic adverse events of patients on phase 1 trials of the Cancer Therapeutics Evaluation Program

Alexander Drilon, Anne A. Eaton, Katja Schindler, Mrinal M. Gounder, David R. Spriggs, Pamela Harris, S. Percy Ivy, Alexia Iasonos, Mario E. Lacouture, David M. Hyman

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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. Cancer 2016;122:1228-37.

Original languageEnglish (US)
Pages (from-to)1228-1237
Number of pages10
Issue number8
StatePublished - Apr 15 2016
Externally publishedYes

Bibliographical note

Funding Information:
This work was funded in part by the cancer center core grant P30 CA008748 from the National Institutes of Health.

Publisher Copyright:
© 2016 American Cancer Society.


  • Cancer Therapeutics Evaluation Program (CTEP)
  • dermatologic toxicity
  • dose-limiting toxicity (DLT) period
  • molecularly targeted agents
  • phase 1 trial


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