The antibody-drug conjugate DMUC5754A, a novel member of a relatively new class of drugs, showed activity in women with ovarian cancer, even those with hard-to-treat, platinum-resistant disease, in a phase I trial presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10. Those women with the highest expression of the drug's target, MUC16, gained the most benefit from treatment, which may help researchers predict which patients will benefit from treatment.
"If the activity of this drug is confirmed in additional trials, this will represent a novel type of therapy for ovarian cancer, with effectiveness in platinum-resistant ovarian cancer, which is the hardest type of ovarian cancer to treat," said Joyce F. Liu, M.D., M.P.H., an instructor in medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, Mass. "This would represent a real step forward in finding new, effective treatments for advanced ovarian cancer."
According to Liu, ovarian cancer is the leading cause of death from gynecologic cancers in the United States. It affects more than 22,000 women per year and results in about 16,000 deaths per year. One of the biggest challenges in treating ovarian cancer is the development of platinum resistance, where the cancer cells stop responding to platinum chemotherapy, one of the most effective drugs in treating this cancer. Standard chemotherapies have limited effect against these platinum-resistant ovarian cancers, and women whose cancers have become platinum-resistant inevitably have disease progression.
"The drug we tested in this clinical trial, DMUC5754A, is from a new class of drugs called antibody-drug conjugates," Liu said. "This drug consists of an antibody and a potent toxin joined by a cleavable linker. The antibody identifies a protein, MUC16, which is highly expressed in ovarian cancers, and targets the toxin to kill the cancer cells."
Unlike other cancer treatments, the antibody-drug conjugate releases the toxin with relative selectivity to the MUC16-positive cancer cells. This allows delivery of drugs that would otherwise be too toxic for treatment, according to Liu.
She and her colleagues evaluated the safety, pharmacokinetics and pharmacodynamic activity of DMUC5754A in 44 patients with advanced, recurrent, platinum-resistant ovarian cancer. Researchers reported one complete response and four partial responses. All five of these confirmed responses occurred at the 2.4-mg/kg dose and in patients with high expression levels of MUC16 in their cancer cells.
During the study, two dose-limiting toxicities occurred: one grade 4 neutropenia and one grade 4 uric acid increase, which occurred at the maximum administered dose of 3.2 mg/kg. Grade 3 adverse events included fatigue in 9 percent of patients and neutropenia in 9 percent of patients. Fatigue was the most common adverse event at all dose levels and occurred in 57 percent of patients. Other commonly reported adverse events were nausea, vomiting, decreased appetite, diarrhea and peripheral neuropathy.
Liu and her colleagues next plan to evaluate this drug in comparison with standard chemotherapy.
DMUC5754A is being developed by Genentech, a member of the Roche Group.
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