Abstract B54: Phase I study of ombrabulin in combination with cisplatin (CDDP) administered every 3 weeks to Japanese patients with advanced solid tumors.
Authors: Ura Takashi , Takahashi Shunji , Yokota Tomoya , Shitara Kohei , Muro Kei , Nakano Kenji , Chin Keisho , Yokoyama Masahiro , Hatake Kiyohiko , 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. However, a narrow rim of tumor cells remains at the tumor periphery after single agent ombrabulin therapy that necessitates its combination with other anticancer therapy (ies). Ombrabulin in combination with platinum derivatives has shown synergistic activity in animal models. Dramatic decrease of tumor blood perfusion was shown by DCE-US in a clinical study when ombrabulin was given in combination with CDDP to patients (pts) with solid tumors. In Caucasian pts, the recommended dose (RD) was established at 25 mg/m2 for ombrabulin and 75 mg/m2 for CDDP, given every 3 weeks. Phase II studies in combination with taxanes and platinum salts in lung and ovarian cancers, and a Phase III study with cisplatin in advanced soft tissue sarcoma are ongoing.
Objectives: The primary objective of the study was to determine the recommended dose (RD) and the dose-limiting toxicities (DLTs) of ombrabulin in combination with cisplatin in Japanese pts with advanced solid tumors. Secondary objectives were the assessment of the overall safety profile, the pharmacokinetic (PK) profile and preliminary anti-tumor activity (RECIST).
Methods: This was an open-label, sequential-cohort, dose-escalation study of intravenous ombrabulin administered immediately followed by a CDDP infusion every 3 weeks (ClinicalTrials.gov: NCT01021150). Cohorts of 3 or 6 pts were treated at 15.5 and 25 mg/m2 of ombrabulin in combination with 75 mg/m2 of CDDP (fixed dose). 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 of ombrabulin, its metabolite RPR258063 and total/ultrafilterable CDDP were measured at Cycle 1 on Day 1, 2, 3.
Results: Ten pts (4 at 15.5 mg/m2 and 6 at 25 mg/m2) were treated (M/F, 5/5; median age, 49.5 [31–67]; and ECOG PS 0/1, 8/2). The most frequent tumor types were breast (3 pts) and esophagus (2 pts). The median number of cycles was 4.0 (range 1–6). Neither DLT nor serious cardiovascular adverse events (AE) were observed. The RD was defined at ombrabulin 25 mg/m2 and CDDP at 75 mg/m2. No grade 3/4 AE were observed at RD other than neutropenia, which occurred in 3/6 pts. The most frequent treatment-related AEs observed at RD were neutropenia (83.3%), decreased appetite (83.3%), hiccups (83.3%), constipation (83.3%), nausea (83.3%) and fatigue (83.3%). One patient (carcinoma of unknown primary) had a partial response and 5 pts had a stable disease as per RECIST. Preliminary PK parameters of ombrabulin, RPR258063 and total/ultrafilterable CDDP were in the range of those observed in non-Japanese pts.
Conclusions: In this study, ombrabulin in combination with CDDP was well tolerated in line with results of prior studies. Based on the results from this study, the RD for Japanese pts was defined as 25 mg/m2 of ombrabulin and 75 mg/m2 of CDDP, identical to the one in Caucasian pts. Antitumor activity was observed in different tumor types and at different ombrabulin doses.
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 B54.