The Gynecologic Oncology Group (GOG), a national non-profit organization with the purpose of promoting excellence in the quality and integrity of clinical and basic scientific research in the field of gynecologic malignancies, intends to conduct a randomized Phase II trial of weekly paclitaxel versus weekly paclitaxel with Reolysin® in patients with persistent or recurrent, ovarian, fallopian tube or primary peritoneal cancer (GOG186H). The study has been approved and will be sponsored by the Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, U.S. National Cancer Institute (NCI), which is part of the National Institutes of Health (NIH), under its Clinical Trials Agreement with Oncolytics, Calgary-based biotechnology company. Oncolytics will provide clinical supplies of Reolysin for this study. The Study Chair will be Dr. David E. Cohn of The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.
Reolysin is a proprietary formulation of the human reovirus and has been demonstrated to replicate specifically in tumour cells bearing an activated RAS pathway. Activating mutations of RAS and upstream elements of RAS may play a role in greater than two thirds of all human cancers. Preliminary and ongoing research shows that Reolysin may represent a novel treatment for RAS activated tumour cells and some cellular proliferative disorders.
Reovirus, an acronym for Respiratory Enteric Orphan virus, is generally believed to inhabit the respiratory and bowel systems in humans. Reovirus is found naturally in sewage and water supplies. By age 12, half of all children show evidence of reovirus exposure and by adulthood, most people have been exposed. However, the disease is non-pathogenic, meaning there are typically no symptoms from infections. The link to its cancer-killing ability was established after the reovirus was discovered to reproduce well in various cancer cell lines.
Tumours bearing an activated RAS pathway are deficient in their ability to activate the anti-viral response mediated by the host cellular protein, PKR. Since PKR is responsible for preventing reovirus replication, tumour cells lacking the activity of PKR are susceptible to reovirus replication. As normal cells do not possess RAS activations, these cells are able to stop reovirus infection through normal PKR activity. In tumour cells with an activated RAS pathway, reovirus is able to freely replicate and eventually kill the host tumour cells. As cell death occurs, progeny virus particles are then free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until there are no longer any tumour cells carrying an activated RAS pathway available.
More recently, Researchers at Oncolytics have discovered that tumour antigens generated by this viral oncolysis may educate the immune system to recognize and kill tumour cells. The activation of the RAS pathway can be mimicked in non-cancerous cells by treating these cells with the chemical 2-aminopurine (2-AP) which prevents the activation of PKR. Ovarian Cancer
The American Cancer Society estimates that 21,880 American women will be diagnosed with ovarian cancer and an estimated 13,850 will die from the disease in 2010. Ovarian cancer accounts for about 3% of all cancers among women and ranks second among gynecologic cancers. The prognosis for patients diagnosed with ovarian cancer at the localized stage is good with a five-year survival rate of 94%; however, fewer than 15% of cases are diagnosed at this stage. The relative 10-year survival rate for all stages combined is approximately 38%.
"Ovarian cancer is typically diagnosed at the later stages, because earlier stage disease usually has no obvious symptoms," said Dr. David E. Cohn. "On this basis, surgical interventions used in earlier stages are often supplemented by chemotherapy; however, there are limited treatment options for patients with recurrent disease."
The study is a randomized Phase II trial of weekly paclitaxel versus weekly paclitaxel with Reolysin in patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal cancer. Patients will be randomized to receive either paclitaxel alone or paclitaxel plus Reolysin. Patients in both arms will receive treatment with paclitaxel, with the second arm also receiving intravenous Reolysin. Patients will receive standard doses of paclitaxel on days one, eight, and 15 every 28 days. In the second arm, patients will also receive, on days one through five of each 28-day cycle, intravenous Reolysin at a dose of 3x1010 TCID50.
The primary objectives of the trial are to estimate the progression-free survival hazard ratio of the combination of weekly paclitaxel with Reolysin to weekly paclitaxel alone in patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal cancer and to determine the frequency and severity of adverse events associated with treatment with weekly paclitaxel alone and weekly paclitaxel with Reolysin as assessed by Common Terminology Criteria for Adverse Events (CTCAE). The secondary objectives are to estimate the progression-free survival and overall survival of patients treated with weekly paclitaxel alone and weekly paclitaxel with Reolysin; to estimate (and compare) the proportion of patients who respond to the regimen on each arm of the study (according to RECIST 1.1 with measurable patients and by CA-125 for those patients with detectable disease only); and to characterize and compare progression-free survival and overall survival in patients with measurable disease (RECIST 1.1 criteria) and patients with detectable (nonmeasurable) disease. The study is expected to enroll up to 150 patients.
"Oncolytics is pleased to be collaborating with the NCI and GOG as they push forward innovative research initiatives utilizing Reolysin," said Dr. Brad Thompson, President and CEO of Oncolytics. "Relationships with these groups allow us to broaden our clinical program to include additional indications and, in this case, conduct our first randomized Phase II study."