Recombinant DNA Advisory Committee - 12/1-2/94 
Review-Dr. Samulski 
Dr. Walters called on Dr. Samulski to present his primary review of the protocol submitted by Drs. Robert 
Grossman and Savio Woo of Baylor College of Medicine, Houston, Texas. This study is to test adenovirus 
vectors for the delivery of a cytotoxic gene to the tumors of the central nervous system (CNS). The 
investigators have provided preclinical data demonstrating the use of this vector in the reduction of brain 
tumors in a rat model as well as important preclinical data demonstrating toxicity of the vector in non-human 
primates. The investigators stated that the ultimate goal is to develop more effective and less toxic adenovirus 
vectors. This Phase I trial is designed to study the safety and efficacy of gene therapy in patients with CNS 
tumors. The investigators will use a viral dosing regimen of 1 x 10 8 pfu followed by GCV treatment for 14 
days. After monitoring the first cohort of 5 patients for one month, the dose will be escalated to 5 x 10 s , 1 x 
10 9 , and then 1.5 x 10 9 pfu. The primary objective is to monitor for any significant toxicity. The investigators 
will use MRI or CT scans in comparing survival times of viral transduced patients to the historical survival 
time. The primary objective, however, is to determine if treatment is associated with significant toxicity. 
Dr. Samulski asked why the investigator did not use the more updated adenovirus vectors which have been 
shown to have less toxicity. This new generation of vectors utilize temperature sensitive mutations of the 
adenovirus vectors and restore the often deleted E3 region. The investigators responded in writing that the 
rationale to use the vector ADV/RSV-tk is that all the preclinical data that demonstrated promising 
tumoriddal effects from this treatment used this vector construct. No data is available at the present time that 
demonstrates efficacy when using the temperature-sensitive vectors. The investigators theorize that the 
excellent efficacy in rodent tumor models and the seriousness of the brain disease justify the intent to initiate 
the present limited clinical toxicity trial. 
A major concern raised by Dr. Samulski was the toxicity observed at a high dosage in the baboon study. The 
toxicity study was suggested by FDA officials, and the investigators began the study in May 1994 to test the 
toxicity of the vector, ADV/RSV-tk, and GCV treatment in baboons. Three treatment groups were 
established: (1) Moderate dose of ADV/RSV-tk with GCV, 6 week survival. A dose of 1.5 x 10 9 pfu of the 
vector was injected into the brains of 1 male and 1 female baboon. Gross examination of the brains showed 
no abnormality. (2) High dose of ADV/RSV-tk with GCV, 3 week survival. 3 x 10 10 pfu of the vector was 
injected into the brains of 1 male and 1 female baboon. The male baboon died 5 days after virus injection. 
The female was sick and euthanized on Day 10. Both animals had 13 to 1.8 cm areas of liquefactive necrosis 
at the injection sites. (3) High dose vector, 3 x 10 10 pfu, but no GCV. One animal was necropsied at 3 weeks 
after vector injection and another at 6 weeks. Both animals had 13 cm cystic cavities. Significant toxicity 
difference in Groups 2 and 3 suggests a synergistic role of GCV in causing the toxicity. Dr. Samulski said 
either the adenovirus vector is causing the cells to divide and sensitizing them to GCV, or alternatively, the 
vector is making the cell predisposed to GCV in causing this adverse effect. Although the mechanism of this 
vector/GCV synergism is unclear, the phenomenon is alarming. 
Dr. Samulski stated that this toxicity has to be taken into account in considering the protocol approval. The 
investigators responded that the human trial will start at a lower dose and the maximum dose will not exceed 
the dose of 13 x 10 9 pfu where no toxicity was observed in the baboon experiment. Dr. Samulski noted that 
baboons are not permissive hosts for adenovirus infection while humans are, and this maximum ceiling is 
artificial. Severe toxicity might occur in the permissive human hosts at a lower dose. Dr. Samulski asked the 
investigators to elaborate on this toxicity issue. 
Review-Dr. Smith 
Dr. Smith agreed with Dr. Samulski’s review that the toxicity is a major issue, particularly when the vector is to 
be administered to the brain rather than to other organs such as the lung or the liver. Toxicity in baboons is 
very significant, and it raises even more concern in permissive humans as opposed to nonpermissive baboons 
as hosts for adenovirus infection. 
Dr. Smith noted the preclinical data of experiments with nude mice and Fisher rats showed that GCV by itself 
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