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| |  Irofulven Holds Promise In Pancreatic Cancer In Patients Refractory to Gemzar (Gemcitabine) MINNEAPOLIS, MN -- November 9, 2000 -- Results from a Phase II clinical trial of irofulven, a novel anti-cancer agent being developed by Mgi Pharma, Inc., demonstrated anti-tumor activity in patients with advanced pancreatic cancer who were refractory to Gemzar® (gemcitabine), the current first-line chemotherapy approved for treatment of pancreatic cancer. Released this week at the 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy in Amsterdam, the results showed that ten of the 53 patients enrolled in the study achieved six-month survival, the primary endpoint for the trial. Equally important, two patients demonstrated objective responses; one patient experienced tumor shrinkage of 100 percent and another patient experienced an 84 percent decrease in tumor mass. Enrollment is expected to begin near year-end in a pivotal, Phase 3 trial with irofulven in advanced pancreatic cancer patients who are refractory to gemcitabine chemotherapy, following finalization of a protocol that will be based upon further discussion with the United States Food and Drug Administration (FDA). "This Phase 2 trial indicates that irofulven has activity in patients with advanced refractory pancreatic cancer. These findings are in agreement with the experience in the Phase 1 trial and preclinical studies," observed Dr. Daniel Von Hoff, professor of medicine and director at the Arizona Cancer Center. "The Phase II findings provide the basis for initiating a Phase 3 trial in patients with advanced pancreatic cancer whose tumors are refractory to gemcitabine. Together with the greatly improved tolerance recently reported from a dose optimization trial and encouraging discussions with the FDA, the path for conducting a pancreatic cancer registration trial with irofulven is clearly understood and patient enrollment should begin soon." Treatment is complete in the Phase II trial and final data analysis is underway. Irofulven was administered to patients with inoperable, advanced pancreatic cancer who were refractory to gemcitabine therapy using a treatment cycle of five-minute intravenous infusions each day for five days, which was repeated every 28 days. The most common side effects included nausea, vomiting, fatigue and bone marrow suppression. Patients in the planned pivotal, Phase III trial will be randomized to irofulven or 5-flourouracil, the current salvage treatment for advanced pancreatic cancer patients. They will receive irofulven using the new every other week dosing schedule. In a recent dose optimization trial, this schedule demonstrated greatly improved tolerance at equivalent dose intensity in comparison to earlier dosing schedules. Median survival will be the primary endpoint in the Phase III trial, with objective tumor response and other clinical benefit measures as secondary endpoints. When concluded, results from that trial are expected to become part of a new drug application for filing with the FDA. According to the American Cancer Society, an estimated 28,300 new cases of pancreatic cancer will be diagnosed in the United States this year, with 28,200 expected deaths. Cancer of the pancreas generally occurs without symptoms until it is in advanced stages and it has generally been considered a chemotherapy resistant disease. For all stages combined, the five-year relative survival rate is only four percent. Even modest improvements in clinical benefit are considered to be important advances because pancreatic cancer is such a devastating disease. Also being presented at the 11th NCI-EORTC-AACR Symposium is data that further expands the understanding of irofulven's mechanism of action. In earlier studies it has been shown that irofulven inhibits DNA synthesis, arrests the cell cycle in S phase and induces tumor selective apoptosis. In the studies presented at the symposium, it was demonstrated that: (a) very high levels of the anti-apoptotic protein Bcl-2 do not completely block apoptotic tumor cell death caused by irofulven, (b) pro-apoptotic effects of irofulven are likely to reflect its covalent binding to DNA (death signaling pathway) and to cellular proteins (distortion of the redox balance) and (c) irofulven produced a concentration-dependent inhibition of cell growth in certain telomerase-positive cell lines and inhibition of telomerase activity. Related Link: Mgi Pharma, Inc.
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