P-283 Paclitaxel plus valproic acid versus paclitaxel alone as second or third line therapy for advanced gastric cancer: a randomized phase 2 trial

Abstract

Introduction: Gastric cancer is the fifth most common malignancy, and the third leading cause of cancer mortality worldwide. The combination of fluoropyrimidine and platinum is standard first‐line chemotherapy, and weekly paclitaxel (wPTX) has become the preferable second‐line chemotherapy in Japan. Although numerous clinical studies have considered the efficacy of molecular targeted agents combined with conventional chemotherapy, efficacy in gastric cancer was demonstrated only by trastuzumab as a first‐line and ramucirumab as a second‐line treatment. Other candidates for molecular targeted therapy are needed. Histone deacetylase (HDAC) inhibitors have been shown to have anti‐proliferative activity through cell cycle arrest, differentiation, and apoptosis in gastric cancer cells. One HDAC inhibitor, valproic acid (VPA), also inhibits tumor growth by inducing apoptosis and enhances the efficacy of paclitaxel in a mouse xenograft model of gastric cancer. wPTX plus VPA as a second‐line chemotherapy is expected to improve survival in gastric cancer patients. Methods: A multi‐center randomized phase II study was conducted to compare the effects of wPTX alone and wPTX plus VPA at 18 centers in the Hokuriku region of Japan. Patients aged 20 years or older with previously treated advanced gastric adenocarcinoma were randomly assigned in a 1:1 ratio to receive PTX 80 mg/m2 intravenously on day 1, 8, 15, every 4 weeks or PTX plus VPA 15 mg/kg/day divided into two daily doses. Random assignment was carried out at the data center using a minimization method with the following adjustment factors: ECOG PS (0 to 1 vs 2), prior chemotherapy (first‐line vs second‐line), and measurable lesions (presence vs absence). The primary endpoint was overall survival (OS) rate, and secondary endpoints were progression‐free survival (PFS) rate and safety analysis. Results: Between Jun 1, 2011, and Jun 30, 2014, 66 patients were enrolled and randomly assigned to receive wPTX (n = 33) or wPTX plus VPA (n = 33). Median OS was 9.8 months in wPTX group and 8.7 months in wPTX plus VPA group (HR 1.19; 95% CI 0.702‐2.026; p = 0.51). Median PFS was 4.5 months in wPTX group and 3.0 months in wPTX plus VPA group (HR 1.29; 95% CI 0.753‐2.211; p = 0.35). Grade 3 to 4 adverse events were neutropenia (3.1%), pleuritis (1.6%), liver injury (1.6%), brain infarction (1.6%), and rupture of aorta (1.6%). Conclusion: No statistically significant difference was observed between wPTX and wPTX plus VPA for OS.