Recombinant DNA Advisory Committee - 12/1-2/94 
distribution of vector sequences in these animals was examined; there was no virus spread except for a positive 
finding of the blood samples from the first 2 days of a high dosage group. Dr. Woo said the cotton rat 
experiment indicates no fatality in all test animals. Dr. Chase explained that a formal toxicity study for drugs 
would involve escalating dose series to determine the half maximum dose for toxicity. Dr. Miller said the 
investigators have performed the cotton rat experiment with a very high dose and have observed no toxicity. 
Dr. Samulski said the protocol could be approved contingent on providing the data from the cotton rat 
experiments. He was uncomfortable with using the baboon data alone as a basis for approval since the 
baboon is a nonpermissive host. 
Committee Motion 
Dr. Samulski made a motion to approve the protocol with contingencies. Dr. Smith seconded the motion. Dr. 
Samulski said the cotton rat experiments should test the ADV/RSV-tk vector on nonimmunized and 
immunized animals with and without GCV at an escalating dose regimen above the lethal dose for the baboon. 
Dr. Parkman said the data from the ongoing cotton rat experiment of nasal inoculation followed by 
intracerebral vector administration is acceptable. In addition, the data from a dose escalation study with and 
without GCV is needed. Dr. DeLeon said the histological data regarding inflammatory responses should be 
included. Dr. Samulski said the preclinical study has demonstrated the efficacy of the adenoviral HSV- 
TK/GCV approach in treating brain tumors, and the present study is to define the treatment window that is 
not associated with toxicity. 
Dr. Samulski suggested that a plan for autopsy should be included in the Informed Consent document. Ms. 
Meyers said a description of serious side effects observed in the retroviral HSV-TK/GCV studies should be 
included in the section of the Informed Consent document discussing side effects. Dr. Grossman accepted Ms. 
Meyers’ suggestion. 
Dr. Chase commented that the design of the present protocol is not to evaluate the efficacy of the treatment 
strategy since it would involve many factors that need to be evaluated. Dr. Grossman agreed completely with 
Dr. Chase’s statement; this protocol is the first step to develop a new brain tumor treatment, and it is a Phase 
I toxicity study. 
The RAC approved a motion by Dr. Samulski and seconded by Dr. Smith to accept the protocol submitted by 
Drs. Robert Grossman and Savio Woo by a vote of 16 in favor, 0 opposed, and 1 abstention. Approval of the 
protocol is contingent on the review and approval of the following by the primary RAC reviewers: (1) Data 
(including histological analysis) derived from the ongoing preclinical cotton rat study in which animals undergo 
intranasal preimmunization with the adenovirus followed by direct injection of the adenovirus vector into the 
brain (to determine the effect on the CNS). (2) Data derived from dose-escalation toxicology studies in non- 
immunized cotton rats (with and without the administration of GCV) up to a dose that is greater than the 
dose that was lethal for baboons. (3) The Informed Consent document will be revised to include a statement 
that informs potential participants that adverse events (toxicity) have been reported for a similar Phase I 
human gene therapy protocol involving a HSV-TK/retrovirus gene delivery system. 
Summary 
Drs. Robert G. Grossman and Savio L. C. Woo of Baylor College of Medicine, Houston, Texas, may conduct 
gene transfer experiments on 20 subjects (£18 years of age) with malignant tumors of the CNS. Patients with 
malignant brain tumors refractory to all potentially curative therapy will be treated with stereotactic intra- 
tumoral injections of a replication-defective adenovirus vector delivering the HSV-TK gene. The vector, 
ADV/RSV-tk, is constructed from adenovirus type 5 with El and E3 deletions; the expression of the HSV-TK 
gene is driven by a Rous sarcoma virus long terminal repeat. GCV will then be administered intravenously at 
10 mg/kg/day for 14 days. Only one course of therapy will be administered. Five patients will be tested at an 
initial dose of 1 x 10* pfu, and they will be closely monitored for 1 month for evidence of toxicity before other 
groups of patients are to be treated at higher doses of 5 x 10* and 1.5 x 10 9 pfu. Effectiveness of the treatment 
will be monitored by MRI and/or CT scans and by comparing survival times to the historical survival times for 
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Recombinant DNA Research, Volume 20 
