A phase I study of Adp53 (INGN 201; ADVEXIN) for patients with platinum- and paclitaxel-resistant epithelial ovarian cancer.

Purpose: Adenoviral p53 (Adp53) is a replication-deficient adenovirus containing human p53 cDNA. This phase I study was designed as a toxicity study of multiple dosing of Adp53 administered by intraperitoneal (IP) delivery to patients with ovarian cancer.

Experimental Design: Eligibility criteria included patients with platinum- and paclitaxel-resistant metastatic epithelial ovarian cancer; a Zubrod performance status of 0, 1, or 2; and adequate bone marrow, liver, and renal function. Patients underwent laparoscopy, washings, biopsies, and placement of an IP catheter within 10 days of Adp53 administration. Adp53 was given daily for 5 days every 3 weeks at one of the following four dose levels: 3 x 10(10), 3 x 10(11), 1 x 10(12), or 3 x 10(12) viral particles (vp).

Results: Seventeen patients were enrolled in the trial. Fifteen (88%) patients are evaluable for toxicity. The mean age of the study group was 51 years (range 32-67). All but one patient received two or more chemotherapy regimens before study entry. No dose-limiting toxicities (DLT) were observed. Grade 3 toxicities included fatigue (six patients), fever (two patients), chills (one patient), abdominal pain (three patients), nausea (two patients), and sinus congestion (one patient). One patient had Grade 3 edema and headache. There were no hematologic toxicities. Eleven patients (65%) are evaluable for response. Two of 17 patients (12%) had a mixed response. Four patients (24%) had stable disease for up to four courses. Five patients (29%) had progressive disease after one to two courses.

Conclusions: Multiple dosing of IP Adp53 was well tolerated in this group of heavily pretreated patients; however, the dosing schedule and the amount cannot be concluded from this study. With a negative randomized trial of ovarian cancer in front-line treatment that included an adenovirus p53 plus chemotherapy, we feel that further refinement of gene therapy is required before additional trials are undertaken. OVERVIEW SUMMARY: Ovarian cancer is the most lethal of the gynecologic malignancies. It also tends to recur and progress within the abdominal cavity. Because of this, regional intraperitoneal therapy for ovarian cancer is attractive. Mutation and/or deletion of the p53 gene are common in advanced ovarian cancer. In this study, we have tested the safety and practicality of using an adenovirus-mediated delivery of the p53 gene to patients with chemo-refractory ovarian cancer via an intraperitoneal catheter. Fifteen patients were treated. Common toxicities were abdominal pain, fever, and chills. Several patients also had catheter infections. One patient had prolonged decrease in CA125 and stable disease. The best mechanism of delivery of gene therapy for patients is unclear, however, no severe toxicities were found using an adenovirus-mediated p53 gene in this group heavily pretreated patients with recurrent ovarian cancer.