fertility in humans. In a fertility study performed in female rats at cabazitaxel doses of 0.05, 0.1, or 0.2 mg/kg/day there was no effect of administration of the drug on mating behavior or the ability to become pregnant. There was an increase in pre-implantation loss at the 0.2 mg/kg/day dose and an increase in early resorptions at doses ≥ 0.1 mg/kg/day (approximately 0.02–0.06 times the human clinical exposure based on Cmax). In multi-cycle studies following the clinically recommended dosing schedule, atrophy of the uterus was observed at the 5 mg/kg dose level (approximately the AUC in patients with cancer at the recommended human dose) along with necrosis of the corpora lutea at doses ≥ 1 mg/kg (approximately 0.2 times the AUC at the clinically recommended human dose).
Cabazitaxel did not affect mating performances or fertility of treated male rats at doses of 0.05, 0.1, or 0.2 mg/kg/day. In multiple-cycle studies following the clinically recommended dosing schedule, however, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats treated intravenously with cabazitaxel at a dose of 1 mg/kg (approximately 0.2–0.35 times the AUC in patients with cancer at the recommended human dose), and minimal testicular degeneration (minimal epithelial single cell necrosis in epididymis) was observed in dogs treated with a dose of 0.5 mg/kg (approximately one-tenth of the AUC in patients with cancer at the recommended human dose).
14. CLINICAL STUDIES
The efficacy and safety of JEVTANA in combination with prednisone were eva luated in a randomized, open-label, international, multi-center study in patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.
A total of 755 patients were randomized to receive either JEVTANA 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles.
This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets > 100,000 cells/mm3, hemoglobin > 10 g/dL, creatinine < 1.5 × upper limit of normal (ULN), total bilirubin < 1×ULN, AST < 1.5 × ULN, and ALT < 1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.
Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 46–92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the JEVTANA group.
Efficacy results for the JEVTANA arm versus the control arm are summarized in Table 3 and Figure 1.
Table 3 - Efficacy of JEVTANA in the Treatment of Patients with Hormone Refractory Metastatic Prostate Cancer (Intent-to-Treat Analysis) JEVTANA + Prednisone
n=378 Mitoxantrone + P
