occur until all 3 patients at the previous dose level have completed the first cycle of therapy and 
four weeks have elapsed. Details of the toxicity reporting procedures are listed in the Clinical 
Protocol. 
V.C.6. Statistical and Analytical Plans 
The primary goal of Part 1 of this study is to determine the optimal dose-schedule for Ad.RSVtk 
given in combination with ganciclovir. This will be defined as the highest dose achieved with a 
tolerated schedule. Table 2 gives the probability of escalating the dose of Ad.RSVt/r given the true 
underlying toxicity rate. 
Table 2. 
Probability of Escalating Dose of Ad.RSVtk 
True Toxicity Rate 
Pr(escalating) 1 0% 20% 30% 40% 50% 60% 
0.89 0.66 0.42 0.23 0.11 0.04 
Thus, if the rate of dose limiting toxicity is 50%, there will be an 1 1 % chance of increasing the 
dose of Ad.RSVtk Virus 
* Zar JH: Statistical Analysis, 2nd edition. Englewood Cliffs NJ, Prentis- Hall, 1984 
V. C.7. Risk Assessment 
As in any clinical trial, there are certain risks that must be carefully considered. Some of 
these are briefly listed here, along with our approach to minimize these problems- a full discussion 
of each is included in the clinical protocol and consent form (See Section VI): 
7. Videothoracoscopy and Chest Tube Placement 
Several types of risks and discomfort can occur from videothoracoscopy and chest tube placement 
including risks of anesthesia, bleeding, pain, fever/infection, allergic reaction to medications. In 
Dr. Kaiser's hands this procedure has been extremely well tolerated and complications have been 
minimal (Kaiser, 1993). These risks will be minimized using regional anesthesia whenever 
possible. Other measures to minimize these risks are discussed in the protocol. 
2. Risks/Side Effects of Ganciclovir (GCV) 
The drug ganciclovir is an FDA approved drug for the treatment of cytomegalovirus retinitis in 
immunocompromised individuals. We will use the known tolerated dose (10 mg/kg) for only 14 
days. This should limit toxicity. However, GCV was not subjected to the full battery of toxicity 
studies, because of its early release for compassionate use in patients with AIDS who had severe 
viral infections with CMV or other herpes viruses. The complications listed in our Clinical Protocol 
were thus generated from populations of AIDS patients that had been treated for severe virus 
infections. It is likely that the side effects of ganciclovir will be less severe in Non-AIDS patients. 
3. Complications Caused by the Virus: 
Toxicity due to the adenovirus can be caused by several mechanisms. 
a. Ectopic or overexpression of HSVt/c : We have performed a series of studies in animals to address 
these issues. Infusion of Ad.RSVtkinto the pleural cavity of rats at very high doses followed by 
treatment with GCV was not associated with any detectable gene expression (as determined by PCR) 
in any organ system outside the chest. The normal mesothelium appears to be a good barrier to 
prevent spread of the virus. A recent study by Crystal's group showed no evidence of transgene 
expression outside the peritoneal cavity after IP infusion of an adenoviral vector containing the al- 
antitrypsin gene (Setaguchi et al., 1994). 
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