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Executive Summary

Phase II trials with Roche's Accutane (13-cis-retinoic acid) and Roferon-A (interferon-alfa) in advanced cases of squamous cell carcinoma of the skin and cervix indicate overall response rates of 50-68%, according to a presentation by MD Anderson Assistant Professor of Medicine Scott Lippman, MD, at the MD Anderson Fourteenth Annual Pharmacy Symposium on Oct. 11. From a 28-patient study of patients with advanced squamous cell skin cancer, Lippman reported, "the overall response rate was 68%, [with] a very high response rate (over 80%) in patients with local disease and a significantly lower response rate in patients with distant disease or with failed prior chemotherapy." The "high activity in the skin" encouraged MD Anderson researchers to examine the effect of the combo treatment on cervical cancer. Conceptually, the combination was appealing because "both agents have effects on differentiation, proliferation and modulating the immune system, and importantly for cervical cancer, have antiviral activity and have anti- angiogenic activity," Lippman observed. Results from an initial, Phase II cervical cancer study on 32 patients indicate an overall 50% response rate, Lippman said. "Four patients had a complete remission which was confirmed pathologically." The daily dosages in the cervical trials were Accutane orally 1 mg/kg and Roferon-A, subcutaneously 6 mil. units. Although the the overall response rate was low, Lippman said, "it really is...interesting that these biologic agents can actually completely eradicate this disease." MD Anderson is currently conducting a study to try to integrate comprehensive radiotherapy into the combo regimen, Lippman observed. The combination results of cis-retinoic acid and interferon are part of an expanding examination of retinoids in cancer treatment. Lippman reported that the "field has really taken off" in the last four years. Cervical cancer is one of the broadest potential cancer treatment uses currently being studied for the retinoids. There are 13,000 new cases in the U.S. each year and 4,500 deaths. The worldwide mortality figure is in excess of 100,000. The retinoid that is farthest along in development is all- trans retinoic acid (Hoffman-La Roche's tretinoin). Roche plans to file an NDA for the compound for the treatment of acute promyelocytic leukemia (APL) in 1993. The agent is currently in Phase III trials as a treatment for APL and is available on a compassionate basis through the National Cancer Institute. FDA has granted Roche orphan status for the APL indication. There are about 2,500 new cases of APL each year. Ortho Pharmaceuticals markets the topical formulation of all-trans retinoic acid -- Retin A -- for the treatment of acne. Ortho has an indication pending at FDA for photoaging. Lippman cited recent studies that reported a "nearly, if not 100%" complete remission rate in APL patients with a proven translocation of chromosomes 15 and 17, which is associated with APL. Tretinoin's activity in APL is "even more fascinating" because it decreases the risk of an associated condition, disseminated intravascular coagulation (DIC), Lippman said. In patients with APL and DIC, "if you give them [tretinoin], the DIC will go away. If they don't have DIC, you won't induce it." Although the agent shows a "very high complete response rate, [the response] is very short-lived," Lippman noted. The short duration of response indicates that the initial application for the product is likely to be for initial induction therapy. MD Anderson Clinical Practice Specialist Martha Gardner noted that the most serious reactions to tretinoin include hyperleukocytosis, seen in up to 40% of patients, and, less frequently, a "rapidly progressive pulmonary toxicity" referred to as the "retinoic acid syndrome," she noted. The mechanism of action of tretinoin is "in direct contrast with the cytodestructive effects of most chemotherapy," Gardner noted: the compound "may be the first chemotherapy agent with documented activity as a differentiating agent."

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