Establishing proof of mechanism: Assessing target modulation in early-phase clinical trials.
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.
National Cancer Institute, National Institutes of Health, Bethesda, MD. Electronic address: skummar@stanford.edu.
Shivaani
S
Kummar
National Cancer Institute, National Institutes of Health, Bethesda, MD.
Khanh
K
Do
National Cancer Institute, National Institutes of Health, Bethesda, MD.
Geraldine O'Sullivan
GO
Coyne
National Cancer Institute, National Institutes of Health, Bethesda, MD.
Alice
A
Chen
Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
Jiuping
J
Ji
National Cancer Institute, National Institutes of Health, Bethesda, MD.
Larry
L
Rubinstein
National Cancer Institute, National Institutes of Health, Bethesda, MD.
James H
JH
Doroshow
D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001706:Biopsy / Q000941:ethics; D002986:Clinical Trials as Topic; D006801:Humans; D057054:Molecular Imaging; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*
D000970:Antineoplastic Agents
Biomarkers; Biopsy surrogate tissues; Drug evaluation; Pharmacodynamics; Phase I