Recombinant DNA Advisory Committee - 12/1-2/94 
Dr. Erickson stated that initial concerns described in his primary review (i.e., efficacy, infection rates in 
different tumor cell lines, and inhibition of tumor cell growth) have been adequately addressed by the 
investigators. The investigators note that optimal responses to p53 transduction have been observed with 
breast cancer and osteosarcoma cell lines. Hepatocellular carcinoma and colorectal cancer cells demonstrated 
a positive response. The data derived from these preclinical studies adequately supports the protocol. 
Dr. Erickson noted that ACN53 growth suppression was observed in some nonmalignant tissue culture cells 
and tumor cell lines not containing the p53 mutation. This observation is different from the results reported 
by Dr. dayman. The correlation between ACN53 antitumor responses and p53 mutations will be easily 
obtained from this protocol. Dr. Erickson stated that the transduction efficiency obtained with hepatic artery 
delivery is acceptable. 
Dr. Erickson expressed concern about toxicity that was observed in experimental anim al studies at high doses 
of ACN53. The elevations of liver enzymes in serum corresponded to severe liver toxicity with histological 
evidence of liver cell necrosis. Such toxicity could decrease the subject’s ability to tolerate subsequent 
chemotherapy if delivered by hepatic artery infusion. Nausea, vomiting, anorexia, and alopecia should not be 
excluded as dose-limiting toxicity. Such symptoms are characteristic of hepatic damage. In their written 
response, the investigators state that these symptoms are mostly non-specific and can be easily treated or 
prevented by medications; if such symptoms are severe, dose-related toxicity will be considered. Subjects 
should be carefully monitored to ensure that any hepatic toxicity is resolved before chemotherapy is initiated. 
Most of the concerns regarding oncogenic p53 mutations raised during Dr. dayman’s review are relevant to 
this proposal. 
Review— Dr. Doi 
Dr. Doi stated this Phase I study is designed to evaluate the safety, biological efficacy, and the dosage effect of 
ACN53. ACN53 is a type 5, subgroup C recombinant adenovirus vector. The Ela, Elb, and protein IX 
coding sequences have been replaced with the wild-type p53 expression cassette. This recombinant plasmid 
will be introduced into the liver through the hepatic artery which supplies greater than 80% of the blood flow 
to liver tumors. Hepatic delivery should optimize vector delivery to the tumor and minimize the exposure to 
normal tissues outside the liver. This study is a Phase I open-label, non-randomized, dose-escalation trial. A 
maximum of 27 patients will receive the adenovirus vector with the 3 initial patients receiving a dose of 1 x 10® 
IU. If no dose-limiting toxicity is observed after 7 days, 3 patients will receive 1 x 10 9 IU; if no toxicity is 
noted after 7 days, this increasing dose-treatment will continue until the last 3 patients have received 1 x 10 13 
IU. In addition to clinical follow-up, studies will include an analysis of p53 transduction efficiency and stability, 
distribution of ACN53 to non-liver tissues, and evidence of tissue damage. 
Dr. Doi said that many of his initial concerns have been addressed in the investigators’ written response. 
Potential liver toxicity still remains a significant concern. The investigators have stated that liver toxicity was 
observed in animals at much higher doses than those that are proposed for the human study, i.e., 2,000 fold 
greater than the initial clinical dose. He asked the investigators to further elaborate on this issue. Another 
concern is the potential adverse effects on normal tissue. He asked the investigators to expand on the formal 
toxicology studies in rats and primates. Other questions have been addressed including vector targeting, 
persistence of the virus, and potential problems with over-expression in normal tissues. He inquired whether 
there is any evidence of vector outside the treated tumor mass. Transduction of peripheral normal liver cells 
was observed in the rat hepatoma model. 
Review-Ms. Meyers 
Ms. Meyers said most of her questions about the Informed Consent document have been addressed. She 
requested a rationale for selecting a total of 27 subjects to participate in this protocol. 
Ms. Meyers expressed concerns that the effects of the chemotherapy might make it difficult to determine 
Recombinant DNA Research, Volume 20 
[465] 
