III.C.5 
Evaluation for dissemination of virus 
Evidence of dissemination of the adenovirus vector will be systematically sought, although we believe 
that this is an unlikely event In the cystic fibrosis gene therapy trial currently in progress, up to 10 8 
pfu of adenovirus has been instilled into the lungs of patients. No dissemination has been detected. Since 
installation into the brain represents a more contained administration of the virus, we feel that 
dissemination is less likely. If it doses occur, the probable routes of initial spread will be via the 
cerebrospinal fluid (CSF) and via the blood stream. Entry into the CSF can occur via direct contact with 
the virally infected tumor, and entry into blood vessels can occur through damaged tumor capillaries. 
CSF, blood, urine, stool and respiratory samples will all be analyses for the presence of the viral 
vector. If detected, the findings will be reported to the FDA and to the RAC. 
III.C.6 Dose limiting toxicity: Definition 
Dose limiting toxicity (DLT) will be defined as (1) neurologic toxicity of grade 3 or 4 by the 
classification in Appendix VI. H, page 44. (2) clinical or MRI manifestations of generalized encephalitis 
or meningitis. (3) increase in edema or mass effect by MRI scan, associated with development of 
herniation, or decrease in level of consciousness to Glasgow Coma Scale of 10, despite appropriate 
measures (e.g. mannitol, corticosteroids.) However, if these changes occur more than 2 weeks post- 
operatively and are associated with an MRI appearance consistent with tumor growth, this will not be 
considered dose limiting toxicity. (4) any other grade 3 or 4 toxicity in other organ systems which is 
not attributable to Ganciclovir and which persists despite discontinuation of Ganciclovir. Any patient 
experiencing DLT will be removed from the study. 
In the operating room, universal precautions will be observed. All instruments will be soaked in bleach 
after the procedure, and disposable instruments and linens will sealed in autoclave bags and removed 
from the operating room. No pregnant medical personnel will be permitted to participate in the surgical 
procedure. 
III.D Evaluation for Biological Efficacy 
The primary end points will be radiographic and histologic evidence for tumor regression. MRI and PET 
studies will be used to evaluate tumor response. In those patients undergoing palliative resection, tissue 
from the tumor bed will be removed for histological examination for evidence of tumor, as well as 
possible adverse effects of therapy such as edema, demyelinization, inflammatory reaction. These 
findings will be correlated with the MRI and PET scans. 
III.D.1 Radiological evaluation. 
We will adopt a comprehensive approach to magnetic resonance imaging of these brain tumors. Our 
evaluation can be divided into two broad goals, the first will be "classical" anatomic issues, the second 
will be attempts to improve characterization of tissue changes associated with primary tumors and 
therapy. The major anatomic goals will be to define the extent of the tumor and associated 
abnormalities. These are: (l)Volume of enhancing tissue as measured on "Tl-weighted" volumetric 
gradient-echo image sets obtained before and after administration of gadopentetate dimeglumine contrast 
material. (2) Volume of "edema" detected on Fast Spin-Echo "T2-weighted“ images, recognizing that 
this will include portions of the neoplasm, white matter infiltrated by neoplastic cells and vasogenic 
edema located beyond the confines of the tumor. (3) presence and severity of mass effect will be 
evaluated using linear measurements on the T1- and T2- weighted images. For obvious reasons, these 
results will be expected to be highly correlated with 1 and 2, above. (4) Local cerebral blood volume 
measurements will be determined using dynamic susceptibility-contrast imaging following a bolus 
injection of contrast material. MR-determined blood volume has been reported to correlate with tumor 
vascularity, mitotic activity and histologic grade [43]. Thus, these measurements may be helpful in 
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