antibody, a biologically relevant assessment of antibody function that is serotype specific. Patients 
CF1 , CF2, CF3, CF4 and CF6 did not demonstrate neutralizing antibodies to Ad5 before or after gene 
transfer. However, patients CF5 and CF7 had large quantities of neutralizing antibodies before gene 
therapy (i.e., both were positive at 1:320) that remained unchanged after gene therapy. Analysis of 
sera for antibodies by complement fixation were noncontributory in that 5 patients (CF1, CF2, CF3, 
CF6, and CF7) were negative before and after gene transfer; patients CF4 and CF5 had detectable 
complement fixation assays before gene transfer that remained unchanged. Complement fixation did 
not correlate with either Westerns or neutralizing assays. 
V.C. Experimental Design 
V.C.1. Summary of Phase 1 Clinical Protocol 
The purpose of the Phase I study will be to determine the maximal tolerated dose of Ad.RSVf/c virus 
instilled into the pleural space, to evaluate the biological effects of therapy and to evaluate, in 
preliminary fashion, any response rate. To accomplish this, patients with a presumed diagnosis of 
malignant mesothelioma will recruited. Patients will be staged radiographically with a chest 
radiograph and chest CT scan and a video thoroacoscopic procedure will be performed during which 
biopsies will be taken to confirm the diagnosis of mesothelioma and disease extent assessed. A chest 
tube will be placed at the time of surgery. On the following day (post-op Day 1), virus will be 
instilled via the chest tube and the tube removed. Three days later (post-op Day 5), the patients 
will undergo a second video thoroacoscopy in which biopsies will be taken to evaluate the efficiency 
and extent of gene transfer. On the next day (post-op Day 6), intravenous ganciclovir (GCV) 
therapy will begin at a dose of 5 mg/kg BID for 14 days. The patients will be carefully evaluated for 
evidence of toxicity, viral shedding, immune responses to the virus and radiographic evidence of 
tumor response. 
V.C. 2. Patient Selection 
We will use a standard Phase I design. Four dose levels will be tested with three patients at each dose 
level. There will be a month interval between the last patient’s treatment at a dose level and the 
first patient at the next higher level. Because of the large Naval shipyard in Philadelphia, we 
routinely evaluate between 30-50 patients with mesothelioma per year at H.U.P. If additional 
patients are needed, they will be recruited from Philadelphia and the surrounding tri-state area by 
contacting physicians (Pulmonary physicians, oncologists, and surgeons) who are known to treat 
patients with mesothelioma in person, by telephone, and by letter. The list of physicians will be 
obtained from the American Thoracic Society, The American College of Chest Physicians, the 
Philadelphia Society of Pulmonary Physician, The University of Pennsylvania Cancer Center, and 
the American College of Surgeons. Announcement of the Clinical Trials will also be made in local 
trade journals and in the monthly publication sent out to local physicians by the Medical Center. 
Eligibility Criteria 
Detailed eligibility criteria are outlined in the attached Clinical Protocol. All patients must have 
histologically proven malignant mesothelioma of pleural origin, which cannot be surgically 
resected, have measurable or evaluable disease, and must be able to tolerate two surgical biopsies. 
We will exclude patients who are not able to clearly understand the consent form, who have received 
prior chemo- or radiation therapy, who have a history of malignant disease other than non- 
melanotic skin cancers, who have evidence of widespread metastases, or who have other serious 
illnesses. 
V.C. 3. Clinical Protocol 
Screening evaluation 
Evaluation will be performed within four weeks of gene therapy. Written informed consent (see 
Appendix) will be obtained prior to participation in the screening evaluation. Information obtained 
during screening will include history and physical exam, evaluation of performance status, clinical 
laboratory blood tests, pulse oximetry and arterial blood gas, electrocardiography (12-lead), PA 
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