Virulizin, Novel Biologic Agent, Is Promising in Pancreatic Cancer

NEW YORK—The biologic response modifier virulizin, which has in vitro and preclinical activity in a variety of cancers, has exhibited possible activity in pancreatic cancer in phase I and II clinical trials, said Michael P. Thirlwell, MD, director, Department of Oncology, McGill University, Montreal.

"If the efficacy of virulizin is proven, then it may be useful to combine it with other agents in the treatment of advanced pancreatic carcinoma," Dr. Thirlwell said at the Chemotherapy Foundation Symposium XVIII.

Virulizin, obtained from bovine bile by a process involving solvent extraction and heat hydrolysis, is provided as a stable, injectable solution.

Peripheral blood cell monocytes, when stimulated with virulizin, demonstrate significantly enhanced killing capacity. It is thought that the cytocidal function may be associated with expression of tumor necrosis factor (TNF)-alpha, Dr. Thirlwell said.

Dr. Thirlwell described three clinical studies of virulizin including a total of 156 patients with pancreatic and other cancers. Dr. Thirlwell’s group conducted the first such study, involving 108 patients with a variety of tumors and lymphomas no longer responding to standard chemotherapy. They were treated with virulizin injections three times weekly for approximately 3 months.

This preliminary study, presented in abstract form at the American Society of Clinical Oncology (ASCO) annual meeting in 1991, included 13 patients with pancreatic cancer. Median survival in the pancreatic cancer patients was 5.5 months, and 1-year survival was nearly 31%. No serious adverse events were observed, Dr. Thirlwell said.

Based on this suggestion of activity, a phase II study led by a Toronto investigator was started in 1990. This study included 22 chemotherapy-naïve patients with unresectable or metastatic pancreatic adenocarcinoma. Of the 17 patients treated for at least 3 months, and therefore evaluable, median survival was 4.8 months and 1-year survival was 17.6%, according to results published in 1993.

Phase I-II US Study

Three years later, a US phase I-II trial was started in patients with advanced pancreatic cancer failing previous chemotherapy. A variety of doses (1.5, 3.0, and 6.0 mL) and schedules (3 or 5 times weekly) were used.

For the 19 patients evaluable for efficacy, median survival was 6.7 months, and 1-year survival was 21%.

One patient, who had several liver metastases documented on CT scan, had a complete response. Six had stabilization of disease based on imaging studies and CA 19-9 evaluations. Patients with tumor response generally had improvement in secondary efficacy variables, including pain assessment, quality of life, natural killer cell function, and performance status.

Safety analysis shows that, for 445 patients with a variety of cancers (including melanoma and lung and colon cancer) who have been treated with virulizin, adverse events have been seen in 65 patients (15%). Fifteen percent of adverse events—including nausea, vomiting, fever, pain, drowsiness, headache, and diarrhea—were judged to be related to the study drug.

Meta-Analysis

In a meta-analysis of 61 pancreatic cancer patients treated with virulizin (46% with prior chemotherapy), median survival was 4.6 months overall and 5.7 months for the 49 evaluable patients, with no deterioration in secondary parameters such as quality of life and pain, Dr. Thirlwell said. The average number of injections was 29 per patient, or about 3 months’ worth of treatment.

The 9-month survival rate was 25% for all patients and 31% for evaluable patients. One-year survival was 18% for all patients and 22.5% for evaluable patients.

These results compare favorably with results from trials of gemcitabine (Gemzar). In the pivotal phase II study of gemcitabine in fluorouracil (5-FU)-refractory pancreatic cancer, 9-month survival was 15%. In the phase III study of gemcitabine vs 5-FU in chemotherapy-naïve patients, 9-month survival was 24% for the gemcitabine group vs 6% for 5-FU.

Phase III Study Planned

Dr. Thirlwell and his colleagues plan to initiate a phase III study in pancreatic adenocarcinoma patients who failed standard chemotherapy to determine whether virulizin improves survival vs best supportive care. Secondarily, the study will evaluate progression-free survival, pain, and quality of life, among other parameters, he said.

Dr. Thirlwell acknowledged co-authors from the National Cancer Institute of Canada Clinical Trials Group and Lorus Therapeutics, Inc. (Toronto), which is developing virulizin.