Vorinostat in combination with capecitabine plus cisplatin as a first-line chemotherapy for patients with metastatic or unresectable gastric cancer: phase II study and biomarker analysis

BACKGROUND: Vorinostat, a histone deacetylase (HDAC) inhibitor, was investigated in combination with capecitabine plus cisplatin (XP) as a first-line chemotherapy for patients with unresectable or metastatic gastric cancer (GC). METHODS: Eligible patients received 400 mg vorinostat once daily on days 1–14, 1000 mg m(−2) capecitabine twice daily on days 1–14, and 60 mg m(−2) cisplatin on day 1 every 3 weeks. Plasma levels of acetyl-H3, HDAC2, and p21 were measured for correlative analysis. The primary end point was the 6-month progression-free survival (PFS) rate. Secondary end points included the response rate, PFS, overall survival (OS), and safety profile. RESULTS: A total of 45 patients with HER2-negative GC were included in this study. The objective response rate was 42%. The median PFS was 5.9 months, and the 6-month PFS rate was 44.4%. The median OS was 12.7 months. Most common grade 3–4 toxicities were neutropenia (41%), fatigue (34%), anorexia (32%), thromboembolism (27%), stomatitis (14%), and thrombocytopenia (11%). High plasma acetyl-H3 and p21 levels were significantly associated with a poor OS (P=0.02 and P=0.03, respectively). CONCLUSIONS: Vorinostat-XP is a feasible first-line chemotherapy for patients with advanced GC. However, this trial did not meet its primary end point, and more adverse events were observed in comparison with the historical data of flouropyrimidine–platinium doublet regimens.