TY - JOUR
T1 - Establishing proof of mechanism
T2 - Assessing target modulation in early-phase clinical trials
AU - Kummar, Shivaani
AU - Do, Khanh
AU - Coyne, Geraldine O.Sullivan
AU - Chen, Alice
AU - Ji, Jiuping
AU - Rubinstein, Larry
AU - Doroshow, James H.
N1 - Funding Information:
We thank Dr Andrea Regier Voth, Leidos Biomedical Research, Inc, for medical writing support in the preparation of this manuscript. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
Publisher Copyright:
© 2016
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Biopsy surrogate tissues
KW - Drug evaluation
KW - Pharmacodynamics
KW - Phase I
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U2 - 10.1053/j.seminoncol.2016.06.002
DO - 10.1053/j.seminoncol.2016.06.002
M3 - Review article
C2 - 27663476
AN - SCOPUS:84990244669
SN - 0093-7754
VL - 43
SP - 446
EP - 452
JO - Seminars in Oncology
JF - Seminars in Oncology
IS - 4
ER -