Recombinant DNA Advisory Committee- 9/12-13/94 
transduction, patients will be treated with GCV intravenously at a dose of 5 mg twice a 
day for 14 days. TK-expressing cells will become subject to GCV-mediated toxicity and 
death. It is hoped that there will be extensive killing of transduced mesothelioma cells 
and that some collateral killing of tumor cells will occur as well. 
The preclinical data suggested that the present approach might work, and the protocol was 
sound. Dr. Straus raised several questions regarding timing of vector administration after 
biopsy diagnosis, issues in the Informed Consent document, issues about dealing with 
GCV toxicity, and several points about preclinical studies. Most of these questions have 
been answered satisfactorily by the investigators in writing. 
One remaining question is about the potential management of GCV toxicity. Dr. Straus 
said that GCV is a toxic drug that causes bone marrow suppression and has been fatal on 
rare occasions. The revised protocol stated that if Grade 4 bone marrow toxicity persists 
for more than 5 days, the drug dose will be reduced to 75% of full dose. If toxicity 
persists for another 5 days, it will be reduced to 50%; and if it still persists, the treatment 
will be stopped. Dr. Straus said that he is uncomfortable with this prolonged exposure to 
drug toxicity. He said the toxicity management in the previous protocol is more agreeable. 
If toxicity is seen, the dose will be reduced to 75% without waiting for 5 days. If absolute 
granulocyte counts drops to less than 500/mm 3 , the GCV administration will discontinue, 
and resume to a 50% level when the count comes back. He asked the investigators to 
explain the toxicity management schedule. 
Review-Dr. Saha 
Dr. Saha noted a discrepancy of the adenovirus vector nomenclature stated in the title of 
the protocol which is different from Dr. Eck’s protocol. Dr. Straus clarified that it 
appears to be the same vector and is a typographical error in the present protocol title. 
Dr. Saha said the investigators have performed excellent preclinical studies in both cell 
culture and in animal models. In the latter category, rats with the rat mesothelioma and 
severe combined immunodeficiency (SCID) mice with the human mesothelioma were 
utilized. Dr. Saha was concerned about the rat data demonstrating presence of vector 
DNA in the pleural cavity following intraperitoneal injection of the vector. In the human 
study, the vector will be injected into the pleural cavity rather than the peritoneal cavity. 
He was concerned about the spread of vector sequences from the peritoneum to liver and 
kidney in the rat experiments. The complete nucleotide sequence of the vector is not 
provided. Dr. Saha made a general comment regarding the use of GCV as opposed to 
acyclovir (ACV) for killing the HSV-TK transduced cells. There is known toxicity for 
GCV. If other nucleoside analogues are available and if HSV-TK gene is going to 
become a routine strategy for cell killing, it is worth exploring other alternative drugs for 
killing the HSV-TK transduced cells. 
Review-Dr. Zallen 
Dr. Zallen said that the investigators have responded to each of the questions she raised 
in her original review. She anticipated seeing the data concerning the presence of vector 
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Recombinant DNA Research, Volume 20 
