Phase 1 and 2 Molecular and Clinical Pharmacodynamic Trials ETCTN

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PROJECT SUMMARY As the California Cancer Consortium (CCC), four National Cancer Institute (NCI)-Designated Cancer Centers propose to participate in the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) to conduct early phase clinical trials of experimental therapeutics. The CCC comprises City of Hope (COH, Lead Academic Organization [LAO]), the University of Southern California (USC, Affiliated Organization [AO]), the University of California, Davis (UCD, AO), and Stanford Cancer Institute (SCI, AO), and has a 25-year history as a multidisciplinary group conducting early phase clinical trials of NCI-sponsored investigational new drugs under previous U01 and UM1 Cooperative Agreements and N01 Contracts. Our multidisciplinary group of investigators will contribute to ETCTN Project Teams by leveraging the combined expertise of COH, UCD, USC, and SCI in molecular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics, signal transduction, cell cycle regulation, non-invasive imaging, and bioinformatics to conduct innovative, laboratory-directed early phase developmental and pharmacokinetic studies. We propose to use the combined patient and scientific resources and expertise of UCD, COH, USC, and SCI to accomplish the following Specific Aims: (Aim 1) to use the existing relevant capabilities and scientific leadership of the CCC to enhance the ETCTN program; (Aim 2) to leverage the combined breadth of the clinical programs at COH, USC, UCD, and SCI NCI-Designated Comprehensive Cancer Centers to support the rapid completion of ETCTN trials; (Aim 3) to use the central Data Coordinating Center (DCC) and Biostatistics Core (BC) at COH to facilitate frequent communication within the CCC and with the NCI and ETCTN, provide rapid development and effective oversight of trials, and ensure adherence to policies and procedures; and (Aim 4) to optimize information gained from ETCTN clinical trials by including molecular characterization of patients’ malignancies and incorporating molecular pharmacodynamic endpoints and investigational imaging. These early phase studies will lead to recommended, biologically effective doses, greater understanding of the spectrum of normal tissue toxicity of agents, and initial estimates of efficacy. They will also provide mechanistic validation of the effects of the agents on critical tumor cell targets, correlate drug-related changes in tumor and host biologic markers with clinical outcome, and develop new insights into the therapeutic mechanisms of action of the compounds both in the laboratory and the clinic. As such, they will advance the ETCTN’s overall goal of accelerating the development of novel anticancer agents that capitalize on unique molecular features of individual tumors and identifying appropriate biomarkers to select patients who are most likely to respond to specific agents.