754 - A Phase I Trial of Bortezomib in Combination with Epirubicin, Carboplatin and Capecitabine (ECARBOX) in advanced Gastric and Gastro-Oesophageal Junction (GOJ) Adenocarcinoma

Abstract

ABSTRACT Background Combination chemotherapy is the treatment of choice for patients with advanced oesophago-gastric cancer and efforts to incorporate novel agents into chemotherapy regimens have been problematic. Bortezomib (Velcade®) attenuates the action of the transcription factor NF-κB, and has shown preclinical activity alone and in combination with chemotherapy in oesophago-gastric cell lines. Design A Phase I dose-escalation study using a 3 + 3 design was performed with Bortezomib (Velcade®) in combination with Epirubicin 50 mg/m2 day1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg/m2 BD days 1-21 every 21 days, in advanced or metastatic gastro-oesophageal adenocarcinoma. Bortezomib was administered at four dose levels of 0.7, 1.0, 1.3 and 1.6 mg/m2 on days 1 + 8. Due to myelotoxicity the dose of capecitabine was reduced to 500 mg/m2 after the first patient cohort. The primary end point was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX with secondary end points of radiological response rate (RR) and toxicity. Results 20 patients, 18 evaluable for response, were enrolled (6 gastric, 9 GOJ and 3 oesophageal), 2 were Stage III and 16 Stage IV. The overall RR was 33.3% with 6 patients achieving a partial response. An additional 7 patients had stable disease for an overall Disease Control Rate (DCR) of 61.1%. Common grade 3/4 adverse events included nausea, fatigue, anaemia, neutropenia and thrombocytopenia. The first 3 patients developed grade 4 neutropenia and pyrexia resulting in a protocol amendment reducing the Capecitabine dose to 500 mg/m2 BD. Bortezomib-induced pulmonary infiltrates occurred in one patient treated at dose level 2, requiring discontinuation of Bortezomib and withdrawal from the study. Recruitment is ongoing at dose level 4 and the MTD is yet to be defined. Conclusions The addition of Bortezomib to amended combination chemotherapy for locally advanced or metastatic gastro-oesophageal adenocarcinoma has not been previously investigated and is well tolerated. Response rates are comparable with standard chemotherapy and updated data will be presented. Disclosure All authors have declared no conflicts of interest.