AEZS-108 Receives Special Protocol Assessment for Phase III Registration Trial in Endometrial Cancer
Posted by Peter Hofland, PhD on December 28, 2012 at 5:30pm
Preclinical and clinical studies with AEZS-108 (AN-152, zoptarelin doxorubicin; Aeterna Zentaris) a hybrid molecule composed of a targeted cytotoxic peptide conjugate analog designed for receptor-mediated targeted chemotherapy consisting of an Luteinizing Hormone Releasing Hormone carrier (LHRH; also known as gonadotropin-releasing hormone) linked to the cytotoxic agent doxorubicin (Adriamycin®/ Rubex®) shows that the uptake of trial drug is achieved by receptor-mediated endocytosis.
AEZS-108 is the first intravenous drug in clinical trials that directs a chemotherapy agent specifically to LHRH-receptor expressing tumors, resulting in more targeted treatment with less damage to healthy tissue. The study drug has successfully completed Phase I and II clinical trials for the treatment of ovarian and endometrial cancers. In this group of patients with gynecological cancers, AEZS-108 also demonstrated anticancer activity without cardiotoxicity even in highly pretreated patients.
The majority (80%) of human endometrial and ovarian cancers and about 50% of breast cancers express LHRH receptors. Since LHRH receptors are found in great number on certain cancer cells in the ovaries, endometrium, bladder and prostate but rarely on healthy cells, AEZS-108’s targeted approach could prove more efficient and cause less side effects than current treatments. Targeted chemotherapy with a cytotoxic analog of LHRH is, therefore, being considered for Phase III studies in advanced endometrial cancers positive for LHRH-receptor.
Endometrial cancer is the most common gynecologic malignancy and develops when abnormal cells amass to form a tumor in the lining of the uterus. It largely affects women over the age of 50 with a higher prevalence in Caucasians women and a higher mortality rate am
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Endometrial cancer is the most common gynecologic malignancy and develops when abnormal cells amass to form a tumor in the lining of the uterus. It largely affects women over the age of 50 with a higher prevalence in Caucasians women and a higher mortality rate among African Americans women. Approximately one in 30 women is diagnosed with endometrial cancer every year. According to the American Cancer Society, 47,130 new cases of endometrial are expected to be diagnosed in the United States in 2012, and Data Monitor expects 35,600 new cases in EU-G5 in 2013, with about 20% recurrent disease.
Mechanism of Action
AEZS-108 works like a targeting mechanism, with the compound travelling through the body and binding specifically to LHRH receptors located on the surface of certain cancer cells. Once AEZS-108 binds to these LHRH-receptors, it gains access inside the cancer cell. The targeting mechanism then separates itself from the chemotherapy which is delivered directly to the core of the cancer cell.
Earlier today, Aeterna Zentaris confirmed that it reached an agreement with the U.S. Food and Drug Administration on a Special Protocol Assessment or SPA for an upcoming Phase III registration trial in endometrial cancer with AEZS-108. The SPA of the proposed are acceptable to the FDA to support a regulatory submission.
The Special Protocol Assessment is a procedure by which the FDA provides official evaluation and written guidance on the design and size of proposed trial protocol design, clinical endpoints and planned analyses intended to form the basis for a Biologics License Application (BLA) or New Drug Application (NDA). Final marketing approval depends on the results of efficacy, the adverse event profile and an evaluation of the benefit/risk of treatment demonstrated in the Phase III trial.
Commenting on the agreement, Juergen Engel, PhD, President and CEO at Aeterna Zentaris stated "We are pleased with the agreement with the FDA which provides us with a clearly defined development and regulatory pathway for AEZS-108 in endometrial cancer. AEZS-108's innovative targeted approach could offer a new treatment option for women with endometrial cancer."
AEZS-108 has been granted orphan drug designation by the FDA and orphan medicinal product designation from the European Medicines Agency for the treatment of ovarian cancer.
The proposed trial will be an open-label, randomized, multicenter Phase III study conducted in North America and Europe, comparing AEZS-108 with doxorubicin as second line therapy for locally-advanced, recurrent or metastatic endometrial cancer. The trial will involve approximately 500 patients and the primary efficacy endpoint is improvement in median Overall Survival.
LHRH receptors are also present in other cancers including human colon cancers, melanomas, lymphomas, and sarcomas. Clinical trials for some of these cancers with AEZS-108 is currently considered. Before such treatment with AEZS-108 is begun, the status of tumoral LHRH receptors of patients must be determined.