PHASE I STUDY OF OMBRABULIN, A VASCULAR DISRUPTING AGENT (VDA), ADMINISTERED EVERY 3 WEEKS TO JAPANESE PATIENTS WITH ADVANCED SOLID TUMORS

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Abstract

Background

Ombrabulin, an analog of Combretastatin A4, is a vascular disrupting agent that destroys established tumor vasculature, causing blood perfusion shutdown and tumor necrosis. In non-Japanese patients, the recommended dose (RD) for ombrabulin single agent was established at 50 mg/m2 given every 3 weeks. A phase I study of ombrabulin as a single agent administered to Japanese patients with advanced solid tumors was carried out.

Objectives

The primary objective of the study was to determine the maximum tolerated dose (MTD) and the RD of ombrabulin in Japanese patients. Secondary objectives were the assessment of the overall safety profile, the pharmacokinetic (PK) profile and the anti-tumor activity.

Methods

This was an open-label, sequential cohort, dose escalation study of ombrabulin administered every 3 weeks. Cohorts of three or six patients were to be treated at 15.5, 25, 35 and 50 mg/m2 of ombrabulin given intravenous infusion. DLTs were to be evaluated during the first treatment cycle. RD was defined as the highest ombrabulin dose at which <33% of all evaluable patients experienced DLTs. PK of ombrabulin and its active metabolite RPR258063 were evaluated at cycle 1.

Results

A total of 15 patients (M/F, 6/9; median age, 62.0 [29–71]), including three lung cancer and two breast cancer patients, were treated with ombrabulin. The median number of cycles was 2.0 (range 1–7). No DLTs were observed up to 35 mg/m2; one out of six patients treated at 50 mg/m2 experienced DLTs: grade 2 hypertension and grade 3 diarrhea. RD/MTD was then determined at 50 mg/m2. The most frequent related adverse events at RD were diarrhea (83.3%), nausea (83.3%) and hypertension (66.7%). Neither severe myelotoxicity nor abnormal elevation in cardiac markers was observed. Of 15 patients, 5 (33.3%) had stable disease (SD) as per RECIST. Preliminary PK parameters were in the range of those observed in non-Japanese patients.

Conclusions

Treatment with ombrabulin given every 3 weeks in patients with advanced solid tumors was well tolerated with limited cardiovascular toxicity events; 33.3% of patients had SD. Results from this study in Japanese patients indicate that the ombrabulin RD is 50 mg/m2, the same as in non-Japanese patients.

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