Phase I clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors.

PURPOSE: Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses. METHODS: Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m(2) with two chemotherapy doublets; OCD, 75 mg/m(2) cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m(2) docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m(2) (cohort 3) or 200 mg/m(2) (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. RESULTS: Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m(2)). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3-4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported. CONCLUSIONS: The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m(2) ombrabulin with 75 mg/m(2) cisplatin/75 mg/m(2) docetaxel or 200 mg/m(2) paclitaxel/AUC6 carboplatin, every 3 weeks.

Docetaxel 75 mg/m(2) is active and well tolerated in patients with metastatic or recurrent gastric cancer: a phase II trial.

OBJECTIVE: The aim of the present study was to confirm the efficacy and tolerability of docetaxel 75 mg/m(2) in a population of Korean patients with advanced gastric cancer. METHODS: Patients with metastatic or locally recurrent gastric cancer received docetaxel 75 mg/m(2) by intravenous infusion every 3 weeks. Objective response rate was the primary endpoint. RESULTS: Forty-five patients were enrolled. Most showed adenocarcinomas of the gastric antrum and/or body of the stomach. All showed metastases and two-thirds retained the primary tumour. Forty-four patients received at least one docetaxel infusion ('treated' population), with 40 patients evaluable for response. A total of 159 cycles (median three cycles) were administered, with mean duration of treatment 10.9 weeks. The objective response rate in the treated population was 15.9% (17.5% in the per protocol population), with stable disease in 25.0% of patients and progressive disease in 50.0%. Grade 3-4 neutropenia occurred in 36 (81.8%) patients and 36.1% of cycles. However, febrile neutropenia occurred in only two (4.5%) patients and 1.3% of cycles. Grade 3 anorexia, experienced by two patients (4.5%) and during 1.9% of cycles, was the most frequent non-haematological adverse event possibly or probably related to docetaxel. No grade 4 non-haematological events occurred. CONCLUSION: This study suggests that docetaxel 75 mg/m(2) is active in metastatic or locally recurrent adenocarcinoma with a low incidence of grade 3-4 adverse events. Docetaxel warrants further study in combination regimens for advanced gastric cancer.