For many malignancies, the molecular aberrations that occur predominantly in cancer cells have been elucidated. Considerable interest has been generated by the discovery of agents which specifically target these aberrations, and several of these compounds have entered into clinical evaluation and are showing great promise. Many of these novel targeted agents behave in ways that are fundamentally different from cytotoxic chemotherapy. For example, new agents may be cytostatic in nature, rather than cytotoxic, or may require long-term administration. These differences call for modifications in the design of clinical trials. Indeed, in contrast to the standard paradigm for Phase I development of classic chemotherapeutic agents based predominantly on determination of maximum tolerated dose (MTD), surrogate markers and functional endpoints may be fundamental parameters for development of targeted agents. We therefore hypothesize that integration of intermediate biologic endpoints which reflect interaction with or functional impact on the target, will provide critical information for determining the optimal biologic dose (OBD) for subsequent Phase II studies. Evaluation of the ability of targeted drugs to modulate, interact with, or inhibit specific molecular and biochemical targets requires effective cooperation between clinical and laboratory investigators. In a large institution such as The University of Texas M.D. Anderson Cancer Center, a strong emphasis on clinical and translational drug development exists. Investigators across the institution have access to all of the many components critical to this endeavor, including analytic chemistry, clinical pharmacology, functional imaging, biostatistics, and numerous basic research laboratories with state-of-the-art expertise in evaluating interactions of the test agents with specific cellular and molecular endpoints and effects on tumor cell growth and apoptosis. This extensive infrastructure for clinical and translational studies will allow us to safely and efficiently evaluate clinical activity and toxicity, pharmacokinetic parameters and pharmacodynamic relationships, and develop clinically-relevant correlates and surrogate endpoints for novel targeted agents given alone or in combination, hence permitting rapid advance of these compounds through early clinical studies. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01CA062461-10
Application #
6582857
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (O1))
Program Officer
Jensen, Leeann T
Project Start
1994-03-01
Project End
2008-01-31
Budget Start
2003-03-27
Budget End
2004-01-31
Support Year
10
Fiscal Year
2003
Total Cost
$496,440
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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