) The overall objectives of this UO1 application are to provide support for both phase I trials of new anticancer a g ents and for pharmacokinetics, pharmacodynamic and other laboratory correlative studies in cancer patients receiving these agents. These studies will be performed by the Harvard/Boston phase I Oncology Group consisting of investigators at the Dana-Faber Partners Cancer Care (Dana-Farber Cancer Institute, Brigham and Women's Hospital, Massachusetts General Hospital), Beth I s rael-Deaconess Medical Center Boston Medical Center, and Children's Hospital. The specific goals are the following: 1) To define the toxicities of new anti-c a n c er agents in patients with advanced cancer; 2) to define the pharmacokinetics characteristics (absorption, distribution, metabolism and elimination) and pharmacodynamics (effects at the biochemical and molecular levels)of these agents; and 3) to determine a treatment regimen suitable for evaluation of anti-tumor activity in phase II trials. The scope of the program will include phase I and laboratory studies of 1) investigational new cytotoxic drugs; 2) differentiating agents; and 3) anti-angiogenesis agents. In addition to phamacokint analyses, laboratory studies, depending on the agent, will focus on regulation of specific gene expression, differentiation and inhibition of angiogenesis. Since the agents to be studied are at this point, we have selected as examples the following: 1) KRN5500 (spicamycin), an inducer of differentiation; and angiostatin, a new inhibitor of angiogenesis. Phase I pharmacokinetics trials of KRN5500 and a n g i o s tatin, as well as the appropriate laboratory correlates of p h a r macodynamics or biologic response, are included as examples of investigator-originated research to be conduct group.
The specific aims are: 1) to conduct a Phase I, pharmacokinetic and pharmacodynamic trial of the differentiating agent KRN5500; and 2) to conduct a Phase 1, pharmacokinetic and pharmacodynamic trial of the angiogenesis inhibitor angiostatin.
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