Purpose. Adenoviral p53 (Adp53) is a replication-deficient adenovirus contain ing human p53 cDNA. This phase I study was designed as a toxicity study of multi ple dosing of Adp53 administered by intraperitoneal (IP) d...Purpose. Adenoviral p53 (Adp53) is a replication-deficient adenovirus contain ing human p53 cDNA. This phase I study was designed as a toxicity study of multi ple dosing of Adp53 administered by intraperitoneal (IP) delivery to patients wi th ovarian cancer. Experimental Design. Eligibility criteria included patients w ith platinum-and paclitaxel-resistant metastatic epithelial ovarian cancer; a Zubrod performance status of 0, 1, or 2; and adequate bone marrow, liver, and re nal 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 ×1010, 3 ×1011, 1 ×1012, or 3 ×1012 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 doselimiting toxicities (DLT) were observed. Grade 3 toxicities included fatigue (six patient s), fever (two patients), chills (one patient), abdominal pain (three patients), nausea (two patients), and sinus congestion (one patient). One patient had Grad e 3 edema and headache. There were no hematologic toxicities. Eleven patients (6 5%) 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 do sing 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 stud y. With a negative randomized trial of ovarian cancer in front-line treatment t hat included an adenovirus p53 plus chemotherapy, we feel that further refinemen t of gene therapy is required before additional trials are undertaken. Overview summary. Ovarian cancer is the most lethal of the gynecologic malignancies. It a lso tends to recur and progress within the abdominal cavity. Because of this, regional intraperitoneal therapy for ovarian cancer is attrac tive. Mutation and/or deletion of the p53 gene are common in advanced ovarian ca ncer. In this study, we have tested the safety and practicality of using an aden ovirus-mediated delivery of the p53 gene to patients with chemo-refractory ova rian cancer via an intraperitoneal catheter. Fifteen patients were treated. Comm on toxicities were abdominal pain, fever, and chills. Several patients also had catheter infections. One patient had prolonged decrease in CA125 and stable dise ase. The best mechanism of delivery of gene therapy for patients is unclear, how ever, no severe toxicities were found using an adenovirus-mediated p53 gene in this group heavily pretreated patients with recurrent ovarian cancer.展开更多
文摘Purpose. Adenoviral p53 (Adp53) is a replication-deficient adenovirus contain ing human p53 cDNA. This phase I study was designed as a toxicity study of multi ple dosing of Adp53 administered by intraperitoneal (IP) delivery to patients wi th ovarian cancer. Experimental Design. Eligibility criteria included patients w ith platinum-and paclitaxel-resistant metastatic epithelial ovarian cancer; a Zubrod performance status of 0, 1, or 2; and adequate bone marrow, liver, and re nal 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 ×1010, 3 ×1011, 1 ×1012, or 3 ×1012 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 doselimiting toxicities (DLT) were observed. Grade 3 toxicities included fatigue (six patient s), fever (two patients), chills (one patient), abdominal pain (three patients), nausea (two patients), and sinus congestion (one patient). One patient had Grad e 3 edema and headache. There were no hematologic toxicities. Eleven patients (6 5%) 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 do sing 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 stud y. With a negative randomized trial of ovarian cancer in front-line treatment t hat included an adenovirus p53 plus chemotherapy, we feel that further refinemen t of gene therapy is required before additional trials are undertaken. Overview summary. Ovarian cancer is the most lethal of the gynecologic malignancies. It a lso tends to recur and progress within the abdominal cavity. Because of this, regional intraperitoneal therapy for ovarian cancer is attrac tive. Mutation and/or deletion of the p53 gene are common in advanced ovarian ca ncer. In this study, we have tested the safety and practicality of using an aden ovirus-mediated delivery of the p53 gene to patients with chemo-refractory ova rian cancer via an intraperitoneal catheter. Fifteen patients were treated. Comm on toxicities were abdominal pain, fever, and chills. Several patients also had catheter infections. One patient had prolonged decrease in CA125 and stable dise ase. The best mechanism of delivery of gene therapy for patients is unclear, how ever, no severe toxicities were found using an adenovirus-mediated p53 gene in this group heavily pretreated patients with recurrent ovarian cancer.
