PHASE I STUDY OF OMBRABULIN IN COMBINATION WITH CISPLATIN (CDDP) 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. Ombrabulin in combination with platinum derivatives has shown synergistic antitumor activity in animal models. In non-Japanese patients, the recommended dose (RD) of this combination was established at 25 mg/m2 for ombrabulin and 75 mg/m2 for CDDP, given every 3 weeks. A phase III study using this combined therapy in advanced soft tissue sarcoma is ongoing.

Objectives

The primary objective of the study was to determine the RD of ombrabulin in combination with CDDP in Japanese patients with advanced solid tumors. Secondary objectives were the assessment of the overall safety profile, the pharmacokinetic (PK) profile and preliminary anti-tumor activity.

Methods

This was an open-label, sequential cohort, dose escalation study of ombrabulin (15.5 and 25 mg/m2) administered immediately followed by a CDDP (75 mg/m2: fixed dose) every 3 weeks. DLTs were to be evaluated during the first treatment cycle only. RD was defined as the highest ombrabulin dose at which <33% of all evaluable patients experienced DLTs. PK of ombrabulin, its active metabolite RPR258063 and total/free CDDP were evaluated at cycle 1.

Results

A total of 10 patients (M/F, 5/5; median age, 49.5 [31–67]), including three breast cancer and two esophagus cancer patients, were treated. The median number of cycles was 4.0 (range 1–6). The RD for the combination was 25 mg/m2 ombrabulin and 75 mg/m2 CDDP. No DLT or serious cardiovascular adverse events (AE) were observed. No grade 3/4 AE were observed at RD other than neutropenia, which occurred in three of the six patients. The most frequent related AEs at RD in five of the six were neutropenia, decreased appetite, nausea, hiccups, constipation and fatigue. One patient (unknown primary origin) at RD had a partial response (PR) and 5 of the 10 patients had a stable disease (SD) as per RECIST. Preliminary PK parameters were in the range of those observed in non-Japanese patients.

Conclusions

Ombrabulin in combination with CDDP in Japanese patients was well tolerated. The RD for Japanese patients was defined as 25 mg/m2 of ombrabulin and 75 mg/m2 of CDDP, identical to the one in non-Japanese patients. Tumor responses (PR and SD) were observed in different tumor types and at different ombrabulin doses.

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