Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Anne A EatonDavid M Hyman

Abstract

Phase I studies rely on investigators to accurately attribute adverse events as related or unrelated to study drug. This information is ultimately used to help establish a safe dose. Attribution in the phase I setting has not been widely studied and assessing the accuracy of attribution is complicated by the lack of a gold standard. We examined dose-toxicity relationships as a function of attribution and toxicity category to evaluate for evidence of toxicity misattribution. Individual patient records from 38 phase I studies activated between 2000 and 2010 were used. Dose was defined as a percentage of maximum dose administered on each study. Relationships between dose and patient-level toxicity were explored graphically and with logistic regression. All P values were two-sided. 11,909 toxicities from 1,156 patients were analyzed. Unrelated toxicity was not associated with dose (P = 0.0920 for grade ≥ 3, P = 0.4194 for grade ≥ 1), whereas related toxicity increased with dose (P < 0.0001, both grade ≥ 3 and ≥ 1). Similar results were observed across toxicity categories. In the five-tier system, toxicities attributed as "possibly," "probably," or "definitely" related were associated with dose (all P < 0.0001), whereas toxicities a...Continue Reading

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Citations

Apr 12, 2017·Clinical Pharmacology and Therapeutics·P H O'DonnellM J Ratain
Jul 14, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Berna C ÖzdemirAnna Dorothea Wagner
Jul 13, 2019·The Journal of Law, Medicine & Ethics : a Journal of the American Society of Law, Medicine & Ethics·Karolina Strzebonska, Marcin Waligora
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Apr 10, 2019·Experimental Biology and Medicine·Ajaikumar B KunnumakkaraBharat B Aggarwal
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