Background: Gastric cancer (GC) is the second leading cause of cancer death in Japan as well as globally. Effective treatment of GC remains a therapeutic challenge. Although in the AVAGAST trial, bevacizumab was found to offer no survival benefit. Angiogenesis continues to be the standard treatment for GC, and thus, clinical trials on many anti-angiogenic drugs have been conducted. TSU-68 (orantinib) is an oral, angiokinase inhibitor targeting the vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factor receptor 1. The present study evaluated the progression-free survival (PFS) and pharmacokinetics (PK) of TSU-68 in combination with Japanese standard S-1 and cisplatin (S-1/CDDP) in patients with advanced GC. Methods: In this open-label, multicenter, randomized, controlled, parallel-group, phase II trial, patients were randomized to Arm A (S-1/CDDP) or Arm B (TSU-68 plus S-1/CDDP). All patients received oral S-1 (40-60 mg/m²) twice daily for 21 days followed by a 14 day rest plus intravenous CDDP (60 mg/m²) on Day 8, repeated every 35 days. In Arm B pts received oral TSU-68 (400 mg/dose) alone, twice daily by addition 35 days. The primary endpoint was PFS. Results: In total, 93 patients were enrolled. For Arm A [male:female ratio], n=47 [35:11]; Arm B, n=45 [30:15]; the respective median age was 63.5 and 62.0 years. The median PFS was 7.0 and 6.8 months in Arms A and B, respectively (HR, 1.23; 95%CI, 0.74 to 2.05; P=0.425); the respective response rates were 56.5% and 62.2%. The most common grade 3/4 toxicities were neutropenia (Arms A and B, 34.8% and 31.1%) and hemoglobin (Arms A and B, 26.1% and 48.9%). There were no differences in other toxicities between the 2 arms, both treatments were tolerated, and no treatment-related deaths were observed. In the PK study, although Arm B had a significantly lower plasma exposure to FT, CDHP, and Oxo compared to Arm A, the exposure to 5-FU was not different between the 2 arms. The exposure to CDDP in Arm B was significantly but slightly lower than that in arm A. Conclusions: Thus,TSU-68 plus S-1/CDDP therapy did not prolong PFS of patients with advanced GC as compared with S-1/CDDP. Clinical trial information: JapicCTI-101327.