title: A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer.
abstract: OBJECTIVE
  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 x 10(10) to 7.5 x 10(12) 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 x 10(13) particles/dose in group 2. A third group (n=15) received a 5-day regimen of SCH 58500 given at 7.5 x 10(13) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242-1009, USA. richard-buller@uiowa.edu
authors.forename: Richard E
authors.initials: RE
authors.lastname: Buller
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Runnebaum
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Horowitz
authors.forename: Mark
authors.initials: M
authors.lastname: Shahin
authors.forename: Thomas
authors.initials: T
authors.lastname: Buekers
authors.forename: Stan
authors.initials: S
authors.lastname: Petrauskas
authors.forename: Rolf
authors.initials: R
authors.lastname: Kreienberg
authors.forename: Dennis
authors.initials: D
authors.lastname: Slamon
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D018394:CA-125 Antigen / Q000096:biosynthesis; D016190:Carboplatin / Q000627:therapeutic use; D015331:Cohort Studies; D003131:Combined Modality Therapy; D004279:DNA, Viral / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005185:Fallopian Tube Neoplasms / Q000628:therapy; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D010534:Peritoneal Neoplasms / Q000628:therapy; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D019076:Transgenes / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D018394:CA-125 Antigen; D004279:DNA, Viral; D016190:Carboplatin; D017239:Paclitaxel