THERAPEUTICS STUDIES OF PRIMARY CNS MALIGNANCIES

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DESCRIPTION: The overall objective of this UOI application is to provide support for consortia of institutions to perform Phase I and 11 clinical trials of new chemotherapeutic/biologic agents in patients with primary central nervous system (CNS) tumors and to perform ancillary laboratory studies with potential clinical implications. The Harvard/Longwood Brain Tumor Center Trials Group at the Dana-Farber Cancer Institute, Brigham and Women's Hospital, The Children's Hospital, and the Beth Israel Hospital has a large and expanding patient population and commitment to clinical and laboratory research of primary brain tumors. As part of the "North American Brain Tumor Consortium" our general goals will be to perform Phase I and II trials of novel cytotoxic and biologic agents, with a special interest in anti-angiogenic agents. Although San Antonio will function as the pharmacologic center for our consortium, our center is in a position to either pilot experimental and/or extensive single institution pharmacologic/pharmacodynamic studies given our large experience in pharmacology-based Phase I trials. Since the specific agents to be studied over the next four years are unknown at this time, we have chosen to develop protocols that build on our previous work in the pre-clinical and clinical development of three agents with anti-angiogenic activity based on our long-standing interest in tumor-associated angiogenesis: a.) Thalidomide, a teratogenic sedative with anti-angiogenic activity, for which we are just completed a promising Phase 11 trial in patients with malignant gliomas: b.) A new human beta interferon with anti-angiogenic activity and significant antiglioma activity demonstrated in our recently completed Phase I trial; and, c.) Angiostatin, a recently discovered endogenous inhibitor of angiogenesis, based on work done principally in our laboratories. The specific aims of this proposal are therefore; I.) To perform a Phase II trial of combination anti-angiogenesis inhibition with thalidornide and beta interferon in patients with recurrent high grade gliomas; and 2.) To perform a Phase I trial of angiostatin, a novel inhibitor of anti-angiogenesis, in patients with recurrent high grade gliomas. Through these examples, we hope to demonstrate our experience in the preclinical development and clinical trial design of novel agents to be evaluated in primary malignant gliomas, and our capability to develop correlative laboratory studies that may ultimately yield useful biologic and clinical endpoints.