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Double-Blinded Randomized Study of High-Dose Calcitriol Plus Docetaxel Compared With Placebo Plus Docetaxel in Androgen-Independent Prostate Cancer: A Report From the ASCENT Investigators

Tomasz M. Beer, Christopher W. Ryan, Peter M. Venner, Daniel P. Petrylak, Gurkamal S. Chatta, J. Dean Ruether, Charles H. Redfern, Louis Fehrenbacher, Mansoor N. Saleh, David M. Waterhouse, Michael A. Carducci, Daniel Vicario, Robert Dreicer, Celestia S. Higano, Frederick R. Ahmann, Kim N. Chi, W. David Henner, Alan Arroyo, Fong W. Clow

From the Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR; Columbia Presbyterian Medical Center, New York, NY; University of Pittsburgh, Pavillion Hellman Cancer Center, Pittsburgh, PA; Sharp HealthCare; San Diego Cancer Center, Vista; Kaiser Permanente Medical Center, Vallejo; Novacea Inc, South San Francisco, CA; Georgia Cancer Specialists, Tucker, GA; Oncology Hematology Care, Cincinnati; The Cleveland Clinic Foundation, Cleveland, OH; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; Seattle Cancer Care Alliance, Seattle, WA; University of Arizona Cancer Center, Tucson, AZ; Cross Cancer Institute, Edmonton; Tom Baker Cancer Centre, Calgary, Alberta; and the University of British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia, Canada

Address reprint requests to Tomasz M. Beer, MD, Department of Medicine, Oregon Health & Science University, Mail Code CR-145, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; e-mail: beert{at}ohsu.edu

PURPOSE: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel.

PATIENTS AND METHODS: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m² intravenously for 3 weeks of a 4-week cycle combined with either 45 µg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later.

RESULTS: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%).

CONCLUSION: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

Supported by Novacea Inc and sanofi-aventis.

Presented in part at the Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; and at the European Cancer Conference (ECCO 13), October 30-November 3, 2005, Paris, France.

Oregon Health & Science University (OHSU) and Tomasz M. Beer have a significant financial interest in Novacea Inc, a company that may have a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU conflict of interest in research committee and the integrity program oversight council was implemented.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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