8.3 
The rate of regrowth of the tumor will be calculated from these measurements. 
8.4 Time to Progression and Survival Duration: The time to progression will be 
measured from the first observation with reduction in tumor bulk until there is 
evidence of progressive disease. Progressive Disease is defined as an increase 
of _> 25% in the sum of the products of the diameters of the measured lesion. 
Patients must have received at least two courses of therapy before a 
designation of progression is made. The survival of patients will be measured 
from entry into protocol. 
8.5 All toxicities encountered during the study will be evaluated according to the 
grading system (0-4) in Appendix C and recorded prior to each course of 
therapy. Duration of the toxicity and its treatment will be recorded. Life- 
threatening toxicities should be reported immediately to the Study Chairperson, 
who in turn, must notify the IRB, RAC, and FDA. 
8.6 Potential risks of retroviral gene transduction 
8.6.1 Insertional mutagenesis. The possibility of causing malignancy in normal 
cells secondary to random insertion of the retroviral vector in the genome 
exists although this risk is thought to be very low. Tests of viral 
supernate will be conducted to assure that no replication competent virus 
is present. Non-replicating bronchial epithelial cells do not take up the 
vector in the mouse studies. 
8.6.2 Risk from murine retrovirus. The retrovirus derived from the Moloney 
murine leukemia virus is modified so that it no longer contains intact viral 
genes. Thus, it cannot produce an intact infectious virus. Assays will be 
performed on the retroviral vector supernate and the packaging cell to 
insure that replication competent virus is not present (see Section 3.0). 
Extensive safety studies have been performed on related retroviral 
constructs in primates. Large infusions of infectious murine 
amphotrophic virus produce no acute pathologic effects. Primates have 
also received retroviral gene-modified autologous bone marrow cells with 
no evidence of toxicity as long as 4 years after infusion 28 . 
8.6.3 Efficacy of aminoglycoside antibiotics. The neomycin resistance gene 
product, neomycin phosphotransferase, phosphorylates the 3’ hydroxyl 
group of the aminohexose I of neomycin and its analogues. Amikacin, 
but not gentamicin and tobramycin which do not contain an hydroxyl at 
the 3" position, is inactivated. Thus, induction of the neomycin resistance 
gene would not exclude aminoglycosides or any other conventional 
antibiotic from use in these patients. 
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Recombinant DNA Research, Volume 16 
