A Global Perspective on First-in-Man Dose Selection: Oncology and Beyond

  • Peng ZouEmail author
  • Sau Lee
  • Min Li
  • Lawrence Yu
  • Duxin SunEmail author


First-in-human (FIH) studies of anticancer products differ from that of other drug products in that they are usually evaluated in cancer patients rather than healthy volunteers. The FIH dose for anticancer drugs is expected to have pharmacological effects in cancer patients and is reasonably safe to use. Therefore, it is challenging to estimate the starting dose for an anticancer drug. Furthermore, the emergence of targeted agents such as small molecule molecularly targeted agents (MTAs), monoclonal antibodies, and antibody–drug conjugates (ADCs) in oncology has posed additional challenges in FIH dose selection. Traditional FIH dose selection methods were developed in the era of cytotoxic drugs and these doses were determined by methods using preclinical toxicity data. For targeted agents, the interspecies variability in safety and efficacy, dose–efficacy curve, and dose–toxicity curve may differ from those for cytotoxic agents, and efficacy may occur at doses that do not reach the maximum tolerated dose (MTD). Therefore, traditional preclinical toxicological studies may be inadequate to support the selection of a safe and active FIH dose of targeted agents. The strategy for FIH dose determination has shifted from a primary focus on toxicity to identifying a dose that optimally inhibits the molecular target. This chapter reviews various approaches for determining FIH dose of anticancer drug products as well as preclinical studies to support the FIH dose selection.


First-in-human dose Anticancer drug Monoclonal antibody Molecularly targeted agent Antibody–drug conjugate 



This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Office of Pharmaceutical Quality, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  2. 2.Department of Pharmaceutical SciencesCollege of Pharmacy, The University of MichiganAnn ArborUSA

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