XWH - 05 - 1 - 0175 TITLE : Gene expression analysis of circulating hormone refractory prostate cancer micrometastases

PurposeMitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapyin docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresis-tance was previously observed. Patients and MethodsMetastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in aphase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along withprednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 3design. 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 orfebrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or grade 3nonhematologic toxicity. ResultsThirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTsincluded grade 3 diarrhea (n 1), prolonged grade 4 neutropenia (n 4), and grade 5 neutropenicinfection (n 1). Due to prolonged neutropenia, the highest dose levels were repeated withpegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination withpegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m andixabepilone 35 mg/m every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuousprednisone 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 patientstreated with mitoxantrone 12 mg/m plus ixabepilone 30 mg/m, nine (43%) experienced50% PSA declines (95% CI, 22% to 66%). ConclusionThese results suggest that the combination of ixabepilone and mitoxantrone is feasible and activein CRPC and requires dosing with pegfilgrastim. J Clin Oncol 27:2772-2778. © 2009 by American Society of Clinical Oncology