Choice of starting dose for molecularly targeted agents evaluated in first-in-human phase I cancer clinical trials

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Christophe Le TourneauLillian L Siu

Abstract

One tenth of the lethal dose to 10% of mice is one of the conventional parameters used to derive a safe starting dose in phase I trials of cytotoxic agents. There is no consensus on which preclinical models and parameters should define the starting dose for molecularly targeted agents. Reports of 81 first-in-human phase I trials evaluating 60 different molecularly targeted agents administered as monotherapy were reviewed. The maximum-tolerated dose (MTD) was defined as the highest safe dose administered to patients, whereas the maximum-administered dose (MAD) was recorded if the MTD was not reached. Fifty-seven of the 81 trials specified the animal model used to determine the starting dose, with 29 (51%) of 57 based on rodent data and 28 (49%) of 57 based on non-rodent data. A wide range of toxicologic parameters was used to select the starting dose. The starting dose exceeded the human MTD in three (3.7%) of 81 trials, and in all three trials, nonhematologic toxicity was dose limiting. The median number of dose levels to reach MTD or MAD from starting dose was five (range, one to 14 dose levels), and the median ratio of MTD or MAD to starting dose was 12 (range, < 1 to 300). Hypothetical doubling of the starting dose appeared ...Continue Reading

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Citations

Apr 19, 2012·Annals of Oncology : Official Journal of the European Society for Medical Oncology·A Greystoke, M Ranson
Nov 11, 2015·Nature Reviews. Clinical Oncology·Kit Man WongS Gail Eckhardt
Aug 16, 2012·Statistics in Medicine·Alexia Iasonos, John O'Quigley
Jun 20, 2015·Annals of Oncology : Official Journal of the European Society for Medical Oncology·X PaolettiC Le Tourneau
Aug 28, 2014·Molecular Oncology·Natalie CookAlbiruni R Abdul Razak
Nov 22, 2013·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Olivier HuillardChristophe Le Tourneau
Apr 13, 2011·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Christophe Le TourneauXavier Paoletti
May 28, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Diego TosiCaroline Mollevi
Apr 29, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Hidenori MizugakiTomohide Tamura
Jul 2, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Alexia Iasonos, John O'Quigley
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Aug 1, 2012·Annals of Oncology : Official Journal of the European Society for Medical Oncology·A Greystoke, M Ranson

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