HAMBURG, Germany - The first Phase II/III multicenter gene therapy study to treat ovarian carcinoma was started in Freiburg, Germany, earlier this month. In the randomized trial more than 200 patients will be treated with an adeno- virus vector delivering p53 tumor suppressor genes into residual cancer cells.
Among genital cancers, ovarian carcinoma is the second largest cause of death in women. Usually, the cancer is diagnosed only when it has reached proliferation into the peritoneum. The tumor then is removed surgically and patients are treated with chemotherapeutics. However, in about 60 percent of all cases some cancer cells persist in the peritoneum, so that relapses occur within a few years.
"We now try to drive those cells into apoptosis," Dirk G|nter Kieback, the coordinator of the study, told BioWorld International. "We deliver the p53 tumor suppressor gene to the cells using a modified adenovirus type V as a vector."
As DNA sequencing studies have shown, the p53 gene has deletion mutations in 60 percent of all patients with ovarian carcinoma. "This deletion prevents the p53 gene from expression so that cells do not enter apoptosis," Kieback said. "And we know from clinical studies that patients showing such a deletion usually have a bad prognosis. The adenovirus vectors deliver intact copies of the p53 gene into the cells and hopefully drive them to cell death."
A large Phase I trial with 51 patients started in August 1997. Monthly treatment of multiple doses was administered over five subsequent days. "We were able to prove that the virus entered the cells and that p53 was produced regularly. Besides, the virus was not excreted and no harmful side effects occurred," Kieback said.
The positive results encouraged the researchers to design the phase II/III study as a fast-line trial
"Patients are now treated surgically," he said. "In a randomized trial, they then receive either standard chemotherapy or chemotherapy plus gene therapy. We chose adenovirus as a vector because it infects both proliferating and non-proliferating cells and remains episomally. Transcription of the gene is only transient and the virus is degraded within days. Besides, it can be produced in a high titer so that we need to administer only a small volume to the peritoneum."
The study will include three German and two U.S. centers and is supported by Essex Pharma GmbH, of Munich, Germany, a subsidiary of Schering-Plough Corp., of Madison, N.J. Results are expected in about 36 months.
According to the German Federal Chamber of Physicians the study is one of about 25 gene therapy trials in Germany. Among them, 75 percent test vaccination or immune-stimulation strategies. Only two have reached Phase II.