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| |  FDA Advisors Recommend Doxil For Refractory Ovarian Cancer SILVER SPRING, MD -- June 8, 1999 -- The United States Food and Drug Administration’s oncologic drugs advisory committee (ODAC) has recommended accelerated approval of Alza Corp.’s supplemental new drug application for Doxil(R) (doxorubicin HCl liposomal injection) in the treatment of refractory ovarian cancer. In this application, Alza seeks an expanded indication for Doxil for the treatment of women with metastatic carcinoma of the ovary who are refractory to both paclitaxel- and platinum-based chemotherapy regimens. Refractory ovarian cancer is defined as disease that progresses during treatment or within six months after completing treatment. The ODAC committee, which is made up of cancer experts from around the country, agreed that some women treated with Doxil experienced a response to therapy that was reasonably likely to predict clinical benefit. In this application, tumour shrinkage was a surrogate endpoint for clinical benefit. "The unfortunate reality is that many women with ovarian cancer will experience disease progression and very few agents are active in disease refractory to paclitaxel- and platinum-based chemotherapy," said Maurie Markman, M.D., chairman of the department of hematology and medical oncology at the Cleveland Clinic Taussig Cancer Center, who addressed the ODAC panel. "Given the limited alternatives available to these women, the need for a new agent is apparent." The FDA has agreed that there is an unmet medical need for patients addressed by the Doxil sNDA and, as such, is evaluating the supplemental application under accelerated approval regulations. Doxil has been granted orphan drug status for ovarian cancer, which provides for seven years of market exclusivity upon approval. Ovarian cancer is the second most common gynaecologic cancer and causes more deaths than any other cancer of the female reproductive system. An estimated 25,200 new cases of ovarian cancer will be diagnosed in the U.S. in 1999 and approximately 14,500 women are expected to die from the disease this year alone. Despite improvements in therapy, first-line chemotherapy fails to provide response rates in more than 20 percent of patients, and approximately 40 percent to 50 percent of women who do experience a response to initial treatment relapse within two years. ODAC members reviewed results of three phase II studies of Doxil in relapsed or refractory ovarian cancer, as well as preliminary results of a phase III randomised trial comparing the efficacy of Doxil and topotecan as second-line agents following failure of platinum-based regimens. Patients in the phase II clinical trials demonstrated a 14.4 percent response rate, defined as a reduction in tumour size of at least 50 percent. This response rate was supported by an interim analysis of phase III data. Doxil is a liposomal formulation of doxorubicin, an intravenous chemotherapy agent. Doxil uses a novel, targeted delivery system called STEALTH(R) technology to help evade recognition and uptake by the immune system. Unlike conventional liposomes, STEALTH liposomes evade detection and destruction by the immune system so they can circulate in the body longer. A long circulation time increases the likelihood that the liposomes and their pharmaceutical contents will reach their target disease sites, the tumours. Doxil was approved by the FDA in late 1995 for the treatment of AIDS-related Kaposi's sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy. In clinical trials, the most common side effects reported with Doxil therapy included reduced white blood cell count (neutropenia), reduced red blood cell count (anemia), nausea and general weakness (asthenia). Some patients experienced infusion-related reactions and skin reactions. The most common skin reaction reported was Palmar-plantar erythrodysesthesia (PPE), often referred to as hand-foot syndrome, which occurred in 17 percent of patients. Hand-foot syndrome is characterised by symptoms of swelling, pain, redness and, for some patients, peeling of the skin on the hands and feet. Heart-related side effects occurred in 9.6 percent of patients; one percent of these side effects have been severe. Due to the serious, potentially-permanent effects of some of these events, including the potential for bone marrow suppression, close monitoring is necessary.
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