Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer.

BACKGROUND: We previously reported the pharmacokinetic profile and preliminary tolerability of cabazitaxel in a phase I study in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report the final safety profile and anti-tumor activity of cabazitaxel in a larger population, including all patients enrolled in the expansion cohort of the study. METHODS: Japanese patients with mCRPC previously treated with docetaxel received cabazitaxel intravenously every 3 weeks plus daily prednisolone. In patients treated with the maximum tolerated dose of 25 mg/m(2) we evaluated adverse events including treatment-related neutropenia, prostate-specific antigen (PSA) response and objective response. RESULTS: In total, 44 patients were treated with the maximum tolerated dose. The most frequent adverse events (any grade) were neutropenia (100 %), febrile neutropenia (54.5 %), fatigue (54.5 %), nausea (52.3 %) and diarrhea (50.0 %). There were no deaths due to treatment-related adverse events. Neutropenia with prior docetaxel did not appear to influence the probability of febrile neutropenia with cabazitaxel. Most patients received therapeutic granulocyte colony-stimulating factor (G-CSF; cycle 1: 86.4 %; cycle 2 or later: 81.8 %). In the efficacy population, two of 12 patients with measurable disease had partial response (objective response rate: 16.7 %), while 10 had stable disease. PSA response rate was 29.3 % (12/41 patients). Median time to PSA progression was 3.68 months (95 % confidence interval 1.35-4.63). CONCLUSIONS: In this heavily pretreated Japanese population, the occurrence of neutropenia and febrile neutropenia was high, suggesting G-CSF prophylaxis may be required as part of toxicity management. However, the efficacy of cabazitaxel was consistent with global studies. ClinicalTrials.gov identifier: NCT01324583.

Dinuclear nickel(II) complexes with 2,5-diamino-1,4-benzoquinonediimine ligands as precatalysts for the polymerization of styrene: electronic and steric substituent effects.

Catalytic polymerization of styrene with a series of dinuclear nickel(II) complexes [{Ni(acac)}2{µ-C6H2-(N-Ph-R)4}] (R = 4-Et (1a), 4-OEt (1b), 2-OEt (1c), 2-Et (1d), and 2,6-Et2 (1e)) in the presence of methylaluminoxane was studied under various conditions to evaluate the substituent effect. The activity of 1a-1e, except 1c, increased with an increase in the reaction temperature, and the highest activity (7.46 × 10(5) g PS mol(-1) Ni h(-1)) was obtained using 1e at 70 °C. The electronic and steric properties of the ligand influenced the activity at room temperature, 50 °C, and 60 °C, steric factors barely, whereas electronic factors slightly dominated the activity at 70 °C. The activity with 1c remained constant at all temperatures, probably due to the masking of the active center by the formation of inactive N,N',O-chelate species. The obtained polymers were atactic polystyrenes with molecular weights and molecular weight distributions in the range of 15,000-43,400 and 1.71-2.14, respectively. While a clear dependence of the molecular weight and molecular weight distribution on the temperature was observed, no significant dependence on the substituent was noted.

Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

PURPOSE: The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. RESULTS: Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. CONCLUSIONS: The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.