The overall objective of this UO1 application is to provide support for Phase I trials of new anti-cancer agents and for the conduct of pharmacokinetic, pharmacodynamic and other laboratory correlative studies. These studies will be performed by the Harvard Phase I Oncology Group consisting of investigators at Dana-Farber Partners Cancer Care (DFPCC), Beth Israel Deaconess Medical Center (BIDMC) and Children's Hospital Medical Center. The scope of the program will include Phase I and laboratory studies of: 1) investigational new cytotoxic drugs; 2) angiogenesis inhibitors; 3) signal transduction/cell cycle inhibitors; 4) differentiating agents; and 5) anti-cancer vaccines. In addition to pharmacokinetic analyses, laboratory and imaging studies, depending on the agent, will focus on inhibition of angiogenesis, alterations in signal transduction pathways, regulation of specific gene expression, induction of differentiation and activation of anti-tumor immunity. Since the agents to be studied are in part unknown at this point, we have selected the following studies as examples of our capabilities: 1) Inhibition of tumor angiogenesis with the combination of angiostatin and endostatin; 2) inhibition of signal transduction pathways with flavopiridol to increase the effectiveness of gemcitabine; 3) development of the spicamycin analog KRN5500 as a differentiating agent; and 4) induction of anti-tumor immunity with recombinant vaccinia viruses expressing the MUC1 carcinoma-associated antigen and TRICOM (LFA-3, B7.1 and ICAM-1).
The specific aims are to conduct: 1) a Phase I, pharmacokinetic and pharmacodynamic trial of the combination of angiostatin and endostatin; 2) a Phase I, pharmacokinetic and pharmacodynamic trial of gemcitabine and a novel schedule of flavopiridol; 3) a Phase I, pharmacokinetic and pharmacodynamic trial of KRN5500; and 4) a Phase I trial of recombinant vaccinia viruses that express MUC1 and TRICOM (B7.1, ICAM-1 and LFA-3). ? ? ?
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