Originally published as JCO Early Release 10.1200/JCO.2008.19.8002 on April 6 2009

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Phase I Study of Ixabepilone, Mitoxantrone, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Therapy: A Study of the Department of Defense Prostate Cancer Clinical Trials Consortium

From the Department of Medicine, University of California; Biostatistics Core, University of California San Franscisco Helen Diller Family Cancer Center, San Francisco, CA; Department of Medicine, University of Michigan, Ann Arbor, MI; Department of Medicine, OR Health and Science University, Portland, OR; and the Department of Genitourinary Medical Oncology, M. D. Anderson Cancer Center, Houston, TX.

Corresponding author: Jonathan E. Rosenberg, MD, University of California San Franscisco Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St, Box 1711, San Francisco, CA 94115; e-mail: jonathan_rosenberg{at}dfci.harvard.edu.

Purpose Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed.

Patients and Methods Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or grade 3 nonhematologic toxicity.

Results Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m² and ixabepilone 35 mg/m² every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m² plus ixabepilone 30 mg/m², nine (43%) experienced 50% PSA declines (95% CI, 22% to 66%).

Conclusion These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.

Supported in part by the DOD Physicians Research Training Grant No. W81XWH-05-1-175 from the Cancer Therapy Evaluation Program of the National Cancer Institute (J.R.), the Prostate Cancer Foundation, and the DOD Prostate Cancer Clinical Trials Consortium Grant No. W81XWH-06-01-0256.

Presented in poster format at the 2007 American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium, February 14-16 2008, San Francisco, CA; 2007 Prostate Cancer Symposium February 22-24, 2007 in Orlando, FL; and the 44th ASCO Annual Meeting, Chicago, IL, May 30 to June 3, 2008.

Written on behalf of the Department of Defense Prostate Cancer Clinical Trials Consortium.

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

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00331344 [ClinicalTrials.gov] .

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