Activity of second-line chemotherapy in docetaxel-refractory hormone-refractory prostate cancer patients : randomized phase 2 study of ixabepilone or mitoxantrone and prednisone.

BACKGROUND: This randomized, noncomparative, multicenter, clinical trial evaluated ixabepilone or mitoxantrone/prednisone (MP) as second-line chemotherapy for taxane-refractory, hormone-refractory, prostate cancer (HRPC). METHODS: Patients with HRPC that progressed during or within 60 days of cessation of taxane chemotherapy were randomly selected with equal probability to ixabepilone 35 mg/m(2) intravenously every 3 weeks, or mitoxantrone 14 mg/m(2) intravenously every 3 weeks and prednisone 5 mg orally twice daily. Treatment continued until progression or toxicity; crossover was allowed. RESULTS: Forty-one patients were accrued to each arm of the study. The median number of cycles administered for each arm was 3. Median survival from protocol entry was 10.4 months with ixabepilone and 9.8 months with MP. Prostate-specific antigen (PSA) declines of >or=50% were observed in 17% of ixabepilone (95% CI, 7-32) and 20% of second-line MP patients (95% CI, 9-35). Partial responses were observed in 1 of 24 ixabepilone and in 2 of 21 MP patients with evaluable measurable disease. Median duration of second-line ixabepilone and MP treatment was 2.2 months and 2.3 months, respectively. For third-line crossover treatment, PSA declines of >or=50% were observed in 3 of 27 ixabepilone-treated and 4 of 15 MP-treated patients. Prior taxane response was associated with an increased likelihood of second-line ixabepilone or MP response. Low baseline lactate dehydrogenase and absence of visceral metastases independently predicted improved survival. The most common grade 3/4 toxicity associated with second-line treatment was neutropenia (54% of ixabepilone patients and 63% of MP patients). CONCLUSIONS: Ixabepilone and MP had modest activity as second-line chemotherapy for docetaxel-refractory HRPC. The median survival for the entire cohort treated in this study was 9.8 months.

Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC).

To explore the pharmacokinetics and tolerability of AZD2171, an inhibitor of vascular endothelial growth factor receptors 1 and 2, in patients with hormone refractory prostate cancer. Twenty-six patients received oral daily dosing of AZD2171 at 1, 2.5, 5, 10, 20, 30 mg. The maximum tolerated dose (MTD) was defined as the dose below that at which >or=33% of patients experienced a dose-limiting toxicity (DLT) within 21 days of initiating therapy. Pharmacokinetic analysis was performed. DLTs occurred at the 30 mg dose and included grade 3 events in three patients: fatigue (n = 3) and muscle weakness (n = 2). The pharmacokinetic profile revealed an effective half-life of approximately 27 h. At steady state, the unbound drug concentration was 4.4 times above the concentration required to inhibit endothelial cell proliferation in vitro. Four patients experienced PSA reductions within 30 days following drug discontinuation (one on 2.5 mg, two on 20 mg and 1 on 30 mg). In two patients treated with 20 mg, post therapy PSA declines persisted for >17 months, despite a PSA increase on therapy. Resolution of adenopathy occurred in one patient persisting for >17 months. Plasma concentrations were maximum 2-8 h post dosing with an overall median value of 2 h. The dose of 20 mg daily was declared as the MTD. One objective response and several PSA declines following the discontinuation of therapy for toxicity suggest that evidence of clinical efficacy may be delayed. While further study is indicated, careful attention must be paid to the novel toxicities of this agent with prolonged dosing.