NEW YORKThe 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
"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
Virulizin, obtained from bovine bile by a process involving
solvent extraction and heat hydrolysis, is provided as a stable, injectable
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)
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 eventsincluding nausea, vomiting, fever, pain,
drowsiness, headache, and diarrheawere judged to be related to the study
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
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
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.