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

• Published in: Journal of clinical oncology Vol. 27; no. 17; pp. 2772 - 2778
• Main Authors: ROSENBERG, Jonathan E, RYAN, Charles J, SHARIB, Jeremy, SMALL, Eric J, WEINBERG, Vivian K, SMITH, David C, HUSSAIN, Maha, BEER, Tomasz M, RYAN, Christopher W, MATHEW, Paul, PAGLIARO, Lance C, HARZSTARK, Andrea L
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 10.06.2009
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Castration - adverse effects; Epothilones - therapeutic use; Humans; Infusions, Subcutaneous; Male; Medical sciences; Middle Aged; Military Personnel; Mitoxantrone - therapeutic use; Nephrology. Urinary tract diseases; Original Reports; Prednisone - therapeutic use; Prostate-Specific Antigen - analysis; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - mortality; Taxoids - therapeutic use; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Antineoplastic agent; Prostate disease; Metastasis; Epothilone derivatives; Cancerology; Castration; Taxane derivatives; Clinical trial; Advanced stage; Ixabepilone; Mitoxantrone; Antimitotic; Male genital diseases; Human; Corticosteroid; Anthraquinone derivatives; Urinary system disease; Docetaxel; Prednisone; Malignant tumor; Resistance; Alkylating agent; Treatment; Antimetabolic; Adrenal hormone; Phase I trial; Prostate cancer; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2008.19.8002

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. 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 > or = grade 3 nonhematologic toxicity. 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 > or = 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone > or = 30 mg/m2, nine (43%) experienced > or = 50% PSA declines (95% CI, 22% to 66%). These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.