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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (2491)	8/30/2005 9:20:35 PM
From: zeta1961	Read Replies (1) \| Respond to of 3044

<Velcade Phase 1 ovarian dose finding study> JCO, September 01, 2005..sorry if you folks already posted this.. Phase I Trial of Bortezomib and Carboplatin in Recurrent Ovarian or Primary Peritoneal Cancer C. Aghajanian, D.S. Dizon, P. Sabbatini, J.J. Raizer, J. Dupont, D.R. Spriggs From the Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, New York, NY; The Program in Women's Oncology, Women & Infants' Hospital, Brown Medical School, Providence, RI; and Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL Address reprint requests to Carol Aghajanian, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: aghajanc@mskcc.org PURPOSE: To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11. RESULTS: Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease. CONCLUSION: The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose. Supported by grant No. 5RO1 CA84009 from the National Cancer Institute (Bethesda, MD). Authors' disclosures of potential conflicts of interest are found at the end of this article.