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Establishing proof of mechanism: Assessing target modulation in early-phase clinical trials

  1. Author:
    Kummar, S.
    Do, K.
    Coyne, G. O.
    Chen, A.
    Ji, J.
    Rubinstein, L.
    Doroshow, J. H.

  2. Author Address

    National Cancer Institute, National Institutes of Health, Bethesda, MD. Electronic address: skummar@stanford.edu. National Cancer Institute, National Institutes of Health, Bethesda, MD. Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
    1. Year: 2016
    2. Date: Aug
    3. Epub Date: 9/25/2016
  2. Journal: Seminars in Oncology
    1. 43
    2. 4
    3. Pages: 446-52
  4. Type of Article: Article
  5. ISSN: 0093-7754
  1. Abstract:

    Since modulation of the putative target and the observed anti-tumor effects form the basis for the clinical development of a molecularly targeted therapy, early-phase clinical trials should be designed to demonstrate proof-of-mechanism in tissues of interest. In addition to establishing safety and the maximum tolerated dose, first-in-human clinical trials should be designed to demonstrate target modulation, define the proposed mechanism of action, and evaluate pharmacokinetic-pharmacodynamic relationships of a new anti-cancer agent. Assessing target modulation in paired tumor biopsies in patients with solid tumors presents multiple challenges, including procedural issues such as patient safety, ethical considerations, and logistics of sample handling and processing. In addition, the availability of qualified biomarker assay technologies, resources to conduct such studies, and real-time analysis of samples to detect inter-species differences that may affect the determination of optimal sampling time points must be taken into account. This article provides a discussion of the challenges that confront the practical application of pharmacodynamic studies in early-phase clinical trials of anti-cancer agents.

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External Sources

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  2. DOI: 10.1053/j.seminoncol.2016.06.002
  3. PMID: 27663476

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