The Massachusetts General Hospital is a co-founding institution of and major contributor to the consortium New Approaches to Brain Tumor Therapy (NABTT). The MGH role has been highly productive with patient accrual second only to the NABTT center. In this application we provide for quality control of these clinical trials as well as internal audits through our protocol office. The MGH investigators perform Chair functions on three NABTT committees (Gene Therapy, Morbidity and Corporate), have sponsored two active protocols (9-AC Recurrent and High Dose MTX Therapy of Brain Lymphoma with Deferred Radiotherapy), co- authored the seminal NABTT data relating drug levels to CYP-450 induction, and established the Corporate-NABTT interaction. The MGH funded PO-1 (Gene Therapy of Brain Tumors) reflects translational clinical studies which flourished from NABTT interactions with Drs. Grossman and Colvin. The molecular classification system of Dr. D. Louis (MGH), which will serve to provide new stratifications for NABTT studies, reflects the utility of the NABTT Brain Tumor Bank. The MGH provides three resources to NABTT: (1) Genetic therapies (Drs. Breakefield and Chiocca), (2) Phase I agents (Dr. Chabner) their analysis and modeling (Dr. Supko), and (3) Assessment of morbidity and quality of life (Drs. Batchelor and Barker). (1) Dr. Hochberg heads the NABTT gene therapy committee which will provide the NABTT protocols for p53 transfection (Onyx, Introgen, Schering) to commence in 1997-8. We will make available to collaborators our herpes, adeno and amplicon vectors expressing CYP450 for the activation of prodrugs within gliomas. Most important for these NABTT studies is our template for rodent testing, primate-safety and IND application. We serve as a resource to NABTT for assessment of neuropathologic endpoints, evaluation of transgene expression and efficacy testing. (2) Dr. Chabner heads the phase I drug committee for NABTT and will make available a variety of agents including sarCNU, spicamycin and angiogenesis inhibitors. These latter compounds include TNP-470, penicillamine and VEGF MAB. TNP-470 is under evaluation at the MGH using of fMRI and fCT as surrogate markers of glioma angiogenesis. These techniques can be co-registered over FDG-PET images to provide vascular-metabolic maps of tumor, area- around-tumor and normal brain tissue. These maps will be correlated with in vitro analysis of vascular markers performed by our collaborator Dr. S. Brem. (3) Dr. Hochberg brings to NABTT the pilot study of an industry-sponsored assessment of quality of life of American patients with malignant glioma. This study will provide for validation of both physician and patient instruments for assessing outcome. The instruments are viewed as potential replacement for the KPS.
