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Phase II Study of Paclitaxel and Valspodar (PSC 833) in Refractory Ovarian Carcinoma: A Gynecologic Oncology Group Study

From the Department of Medicine, Washington University School of Medicine, St Louis, MO; Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, NY; Department of Obstetrics and Gynecology, Indiana University Medical Center, Indianapolis, IN; Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences, Oklahoma City, OK; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH; Medical Affairs-Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ; Department of Pathology, University of Arizona, Tucson, AZ; University of Mississippi School of Medicine, Jackson, MI; and Gynecologic Oncology Center, Mercy Medical Center, Baltimore, MD.

Address reprint requests to GOG Administrative Office, 1234 Market St, Ste 1945, Philadelphia, PA 19107; email: fracasso{at}im.wustl.edu

PURPOSE: A phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein–mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer.

PATIENTS AND METHODS: Patients received valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m² intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein.

RESULTS: Of 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were 1,000 ng/mL in all but two of 40 patients in the first cycle. Immunohistochemical staining for P-glycoprotein was positive for one of two responding patients.

CONCLUSION: Valspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.

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