¹Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA

²Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany

³University of California, Los Angeles, California, USA

⁴Schering-Plough Research Institute, Kenilworth, New Jersey, USA

⁵University of Ulm, Ulm, Germany

Correspondence to: Dr Richard E Buller, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 200 Hawkins Drive ¾ #4630 JCP, Iowa City, IA 52242-1009, USA. E-mail: richard-buller@uiowa.edu

^†Presented in part at the 7th International Conference on Gene Therapy of Cancer, San Diego, CA, November 19-21, 1998 and the 30th Annual Meeting of the Society of Gynecologic Oncologists, San Francisco, CA March 20-24, 1999.

Purpose: To determine the safety, gene transfer, host immune response, and pharmacokinetics of a replication-deficient adenovirus encoding human, recombinant, wild-type p53 (SCH 58500) delivered into the peritoneal cavity (i.p.) alone and sequentially in combination with platinum-based chemotherapy, of patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer containing aberrant or mutant p53. Methods: SCH 58500 was administered i.p. to three groups of patients with heavily pretreated recurrent disease. Group 1 (n=17) received a single dose of SCH 58500 escalated from 7.5´10¹⁰ to 7.5´10¹² particles. Group 2 (n=9) received two or three doses of SCH 58500 given alone for one cycle, and then with chemotherapy for two cycles. The SCH 58500 dose was further escalated to 2.5´10¹³ particles/dose in group 2. A third group (n=15) received a 5-day regimen of SCH 58500 given at 7.5´10¹³ particles/dose per day i.p. alone for cycle 1 and then with intravenous carboplatin/paclitaxel chemotherapy for cycles 2 and 3. Results: No dose-limiting toxicity resulted from the delivery of 236/287 (82.2%) planned doses of SCH 58500. Fever, hypotension abdominal complaints, nausea, and vomiting were the most common adverse events. Vector-specific transgene expression in tumor was documented by RT-PCR in cells from both ascitic fluid and tissue biopsies. Despite marked increases in serum adenoviral antibody titers, transgene expression was measurable in 17 of 20 samples obtained after two or three cycles of SCH 58500. Vector was detectable in peritoneal fluid by 24 hours and persisted for as long as 7 days whereas none was detected in urine or stool. There was poor correlation between CT scans and CA125 responses. CA125 responses, defined as a greater than 50% decrement in serum CA125 from baseline, were documented in 8 of 16 women who completed three cycles of the multidose regimen. Conclusion: CT scans are not a valid measure of response to i.p. SCH 58500 due to extensive adenoviral-induced inflammatory changes. Intraperitoneal SCH 58500 is safe, well tolerated, and combined with platinum-based chemotherapy can be associated with a significant reduction of serum CA125 in heavily pretreated patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. Cancer Gene Therapy (2002) 9, 553-566 doi:10.1038/sj.cgt.7700472

p53; gene therapy; ovarian cancer; CA125