Recombinant DNA Advisory Committee - 12/1-2/94 
Dr. Parkman said it is unfair to the investigators to fault them for bringing in the toxicity data; the 
investigators have been very responsive to the reviewers’ questions. The prolonged discussion is due to 
complexity of the novel scientific issue: This protocol is the first systemic administration of an adenovirus 
vector, and the deliberation will set a precedent for review of future protocols. The significant new issues 
should be resolved by the full RAC rather than by a subcommittee. 
Dr. Secundy commented that if it is an important issue, the contingency of the present protocol should be 
reviewed not just by a subcommittee. Dr. Miller indicated his interest in reviewing such data. Dr. Parkman 
clarified that the present contingency is very specific, and it should be resolved by a subcommittee. Dr. 
DeLeon appreciated the learning curve for the RAC in dealing with a new issue, concluding that the discussion 
was very worthwhile. Dr. Smith said the subcommittee for this protocol should include all RAC members who 
share concerns about the safety data. 
Ms. Meyers expressed her concern regarding approval of this protocol with contingency; it will set a precedent 
for investigators to hastily submit a protocol for a provisional approval even with the knowledge of serious 
toxicity problems. Dr. Erickson said that such a statement is very unfair to the investigators; the responses 
from the investigators are very thoughtful. Dr. Miller said that the lack of toxicity data, particularly in regard 
to the preimmunized animals, is too serious to warrant an approval; he preferred to review the new data with 
an opportunity to discuss it at the full RAC meeting. Dr. Secundy agreed with Dr. Miller’s statement. Dr. 
Walters suggested a large subcommittee for this protocol, and Dr. Zallen asked that the subcommittee report 
their decision to the RAC. 
The motion was made by Mr. Capron and seconded by Dr. Erickson to accept the protocol submitted by Drs. 
Alan Venook and Robert Warren, contingent on the review and approval of the following by the scientific 
members of the RAC: (1) Data derived from preclinical studies (toxicology and transduction efficiency) in 
both an immunized and non-immunized permissive host (Le., cotton rats). (2) Data demonstrating that the 
adenovirus vector does not integrate into the germ line of a permissive host. (3) Development of a sensitive 
screening assay (preferably biologic, e.g., the HPV assay) to detect the presence of p53 mutations in the 
adenovirus vector stocks. In the event that a mutation is identified, that stock will be discarded. (4) 
Submission of a detailed description of the analyses that will be conducted on available post-mortem tissue. 
The motion to approve the protocol (with contingencies) passed by a vote of 10 in favor, 7 opposed, and no 
abstentions. 
Summary 
Drs. Alan P. Venook and Robert S. Warren of the University of California at San Francisco, San Francisco, 
California, may conduct gene transfer experiments on 27 subjects (£18 and s75 years of age) with 
hepatocellular carcinoma or liver metastasis of colorectal cancer. The adenovirus vector, ACN53, to transduce 
the human p53 tumor suppressor gene is derived from adenovirus type 5 by replacing the El region including 
Ela, Elb, and protein IX coding region with a p53 expression cassette driven by the CMV promoter. The 
vector is additionally deleted for 1.9 kb DNA sequences in the E3 region. ACN53 will be administered as a 
single bolus infusion via a hepatic artery catheter. This Phase I dose-escalation trial is designed primarily to 
assess the safety of ACN53 and secondarily its biological efficacy. Biological efficacy including efficiency and 
stability of gene transfer will be studied by analysis of tumor tissues obtained 7 days following gene transfer. 
Clinical evidence of anti-tumor efficacy will also be collected. The effect of ACN53 dosage on patient 
tolerance and toxicity will be evaluated in the dose escalation cohorts. As an important part of this objective, 
the pharmacokinetics of ACN53 will be studied. 
XIII. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN GENE TRANSFER 
PROTOCOL ENTITLED: PHASE I STUDY OF ADENOVIRAL VECTOR DELIVERY OF THE HSV-TK 
GENE AND THE INTRAVENOUS ADMINISTRATION OF GANCICLOVIR IN ADULTS WITH 
MALIGNANT TUMORS OF THE CENTRAL NERVOUS SYSTEM /DRS. GROSSMAN AND WOO 
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Recombinant DNA Research, Volume 20 
