Recombinant DMA Advisory Committee - 12/1-2/94 
Dr. Straus stated that a total of 40 patients have been entered on 5 gene therapy/HIV studies. The major 
problem with these studies is that the investigators have failed to provide timely data reporting. M inim al data 
have been provided regarding biological efficacy. 
The RAC approved Dr. Wong-Staal’s protocol (#9309-057) in September 1993, but it is still waiting for final 
NIH and FDA approvals. Mr. Capron inquired if there is any particular reason for the long delay. Ms. 
Wilson noted that the protocol has been approved by NIH after the deadline of the data reporting. Dr. Wong- 
Staal’s protocol was recommended for approval contingent on the submission of additional preclinical data 
involving primary human CD34{ + ) cells. These data were only recently submitted for approval. Dr. Noguchi 
could not comment on the question of FDA approval 
Dr. Samulski suggested that the information contained in the Data Management Report should be published in 
a scientific journal to benefit others who are interested in gene transfer studies. 
V-B. UPDATE ON ADVERSE EVENT REPORTS-PROTOCOLS INVOLVING PA317/GlTklSvNa VECTOR 
PRODUCER CELLS/DRS. BERGER AND MARCUS 
Dr. Walters called on Dr. Steven Marcus, Director of Regulatory Affairs of Genetic Therapy, Inc. (GTI), 
Gaithersburg, Maryland, to provide an update of adverse events regarding the use of vector producer cells 
(VPC), PA317/GlTklSvNa, in the treatment of brain tumors. These VPC have been used in Protocols 
#9206-019, 9303-037, 9306-050, and 9312-059. Before discussing the adverse events, Dr. Marcus provided an 
update of patient accrual on these studies. The initial clinical trial was conducted at NIH on 15 patients with 
malignant brain tumors (13 of them had recurrent glioblastoma (Dr. Oldfield’s Protocol #9206-019)). Subjects 
received intratumoral stereotactic administration of VPC. Based on the encouraging results from this first 
trial additional clinical trials were initiated with a new generation of VPC which produced higher retrovirus 
vector titers. One subject was treated on Drs. Oldfield and Ram’s leptomeningeal carcinomatosis protocol 
#9312-059 which resulted in a very serious adverse event. Nine subjects have been treated on Dr. Culver’s 
protocol #9303-037 involving monthly VPC injections through an Ommaya catheter into the tumor cavity of 
brain tumor patients, followed by systemic GCV administration. 
Dr. Marcus described the adverse events that have been observed on these studies to date. Two patients 
developed hemorrhage after stereotactic injection of VPC; both have recovered. Two patients had serious 
hypertension, fever, and headache, which were believed to be related to intraventricular injection of VPC. 
Four patients developed seizures while on study, a common event occurring in patients with recurrent 
glioblastoma. Two patients developed serious infections associated with catheter insertion; most patients were 
on high dose steroid medication and were susceptible to infection. Autopsy results from one of these patients 
revealed multiple abscesses throughout the body. The cause of death was staphylococcal bacteremia caused by 
infection from the Hickman catheter. Autopsy of another patient revealed the cause of death by a pulmonary 
embolus. There were additional 2 deaths in the ongoing study. A patient developed pancytopenia; studies of 
the antiplatelet antibodies in the patient’s serum ruled out VPC reaction as a cause of death. One patient had 
ischemic infarct in the opposite cerebral hemisphere believed to be unrelated to the injection. There have 
been a total of 11 deaths in the 15 patients entered on Protocol #9206-019; and 2 deaths for the 9 subjects 
entered on Protocol #9309-037. Dr. Marcus concluded that it is always possible that the causes of death are 
related to VPC; however, data indicates that this relationship is improbable. Mr. Capron remarked that the 
word "possible" means that the association cannot be ruled out. 
Dr. Marcus stated that the average survival rate for patients entered on Protocol #9206-019 was longer than 
the 3 months; this survival rate is greater than expected. Four patients have survived for periods of 21, 13, 11, 
and 7 months respectively. 
Dr. Haselkorn asked if any of these "extended survival" patients are off the study at present. Dr. Marcus said 
that these patients received a single injection of VPC. Dr. Secundy asked if the quality of life has improved 
for these patients. Dr. Marcus said their quality of life is quite good considering that these patients have 
received prior craniotomy and radiation therapy. Dr. Chase commented that this study is uncontrolled; 
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