NEW YORKIrofulven, the first of the acylfulvenes, a new class of cytotoxic agents, is being studied in a number of solid tumors, including a phase III trial in advanced pancreatic cancer, said Raymond Taetle, MD, clinical professor of medicine and pathology, University of Arizona, Arizona Cancer Center, Tucson.
Irofulven, a semisynthetic derivative of Omphalotus olearius, a toxic fungus, has demonstrated broad activity against a range of solid tumor cell lines in vitro. The agent, being developed by MGI Pharma, Minneapolis, is also known as MGI 114 or hydroxymethylacylfulvene (HMAF).
Irofulven’s mechanism of action is not completely understood, Dr. Taetle said in a presentation at the Chemotherapy Foundation Symposium XVIII. Its antitumor activity appears to be independent of cellular p53 and p21 tumor-suppressor gene status.
"It demonstrates rapid cellular uptake, binding to intracellular molecules, and potent and rapid inhibition of DNA synthesis," he said. "The absence of cross resistance to a wide variety of chemotherapy agents is promising. It is synergistic or additive in combination with many other agents, notably topoisomerase 1 and 2 inhibitors."
In vitro response rates in surgically derived primary human tumors of the colon, kidney, breast, lung, and ovary, as well as melanomas, ranged from 41% to 83%. These results were obtained with tests using short-term exposure at clinically relevant drug concentrations, Dr. Taetle said.
In vitro and in vivo studies of irofulven combined with other agents showed additive and synergistic activity with platinum-based alkylating agents, antimetabolites, tubulin binders (eg, taxanes), and gamma radiation, he said.
Phase I trials showed a partial response in one patient with refractory pancreatic cancer and stable disease in eight patients with ampullary, colon, hepatocellular, renal cell, and thymic cancers.
Irofulven is currently being studied in phase II trials in hormone-refractory prostate cancer, ovarian cancer, and hepatocellular carcinoma, and has already shown activity in prostate and ovarian cancers, Dr. Taetle said.
Side effects of irofulven include bone marrow suppression, nausea and vomiting, and fatigue.
Randomized Multicenter Trial
A pivotal phase III trial of the agent has begun in patients with advanced-stage pancreatic cancer whose disease progressed after treatment with gemcitabine(Drug information on gemcitabine) (Gemzar).
This randomized multicenter international trial compares irofulven given in an intermittent, every-other-week dosing schedule (as a 10- to 30-minute infusion) with fluorouracil(Drug information on fluorouracil) given as a continuous IV infusion. Daniel Von Hoff, MD, professor of medicine and director of the Arizona Cancer Center, is the lead investigator of the study. The trial is expected to enroll about 300 patients.
"The acylfulvenes are a highly potent new class of chemotherapy agents," Dr. Taetle commented, citing its activity against a broad range of resistant tumors and its potential synergy in combination regimens.
Patients and health care providers seeking information on the various irofulven clinical trials may call MGI Pharma’s Medical Communications Help Line at 800-562-5580.