Abstract C20: Phase I study of ombrabulin, a vascular disrupting agent (VDA), administered every 3 weeks to Japanese patients with advanced solid tumors.
Authors: Kurata Takayasu , Murakami Haruyasu , Fujisaka Yasuhito , Kiyota Hidemi , Nakagawa Kazuhiko , Onozawa Yusuke , Watanabe Junichiro , Yamamoto Nobuyuki , Aoyama Takekazu 
Published: June 2012

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 Caucasian patients (pts), the recommended dose (RD) for ombrabulin single agent was established at 50 mg/m2 given every 3weeks. Recently, the existence of ethnic differences was pointed out in the effects and toxicities of some molecular targeted agents among Asians and Caucasians. Therefore, a phase I study of ombrabulin as a single agent administered every 3 weeks to Japanese pts with advanced solid tumors was performed.
Objectives: The primary objective of this study was to determine the maximum tolerated dose (MTD) and the RD for Japanese pts. Secondary objectives were the assessment of the overall safety profile, the pharmacokinetic (PK) profile and the anti-tumor activity (RECIST).
Methods: This was an open-label, sequential-cohort, dose-escalation study of ombrabulin administered every three weeks (ClinicalTrials.gov: NCT00968916). Cohorts of 3 or 6 pts were treated at 15.5, 25, 35 and 50 mg/m2 of ombrabulin given over a 30 min intravenous infusion. DLTs were to be evaluated during the first treatment cycle. RD was defined as the highest ombrabulin dose at which less than 33% of all evaluable pts experienced DLTs. PK parameters of ombrabulin and its major metabolite RPR258063 were measured at Cycle 1 on Day 1 and 2.
Results: Fifteen Japanese pts were treated with ombrabulin (M/F, 6/9; median age, 62.0 [29–71]; and ECOG PS 0/1, 7/8). The most frequent tumor types were lung (6 pts), breast (2 pts) and muscle/soft tissue (2 pts). The median number of cycles was 2.0 (range 1-7). No DLTs were observed up to 35 mg/m2 and RD/MTD for Japanese pts was determined at 50 mg/m2 (maximum administered dose). One out of 6 pts treated at the RD experienced DLTs at Cycle 1: grade 2 hypertension and grade 3 diarrhea. Neither severe myelotoxicity nor abnormal elevation in cardiac markers was observed. The most frequent related AEs at RD were diarrhea (83.3%), nausea (83.3%) and hypertension (66.7%). No objective tumor response was observed; 33.3% (5/15 pts) of all pts had stable disease. Preliminary PK parameters were in the range of those observed in non-Japanese pts.
Conclusions: In this study, treatment with ombrabulin given on Day 1 every 3 weeks was well tolerated with limited cardiovascular toxicity events; 33.3% of pts had stable disease. Results from this study in Japanese pts indicate that the ombrabulin RD is 50 mg/m2, the same as in Caucasians.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C20.