A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.

492 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Oxaliplatin-based treatment (FOLFOX, CapeOX) combined with bevacizumab is one of the standard chemotherapies for metastatic CRC. However, several clinical studies performed using S-1 plus oxaliplatin (SOX) indicate that SOX is a treatment option for metastatic CRC. TSU-68 (orantinib) is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor and has promising efficacy and high safety. The recommended phase II dose of TSU-68 plus SOX has been determined in a phase I study. This trial aimed to evaluate the efficacy of TSU-68 in combination with SOX. Methods: We performed an open-label multicenter randomized phase II trial in Korea. Treatment-naive metastatic CRC patients with a performance status 0 or 1 were randomized in a ratio of 1:1 to receive either TSU-68 plus SOX (group A) or SOX (group B). The primary endpoint was progression-free survival (PFS). Results: We randomized 105 patients (52 patients, group A and 53 patients, group B). Median PFS was 7.0 months in group A (hazard ratio [HR], 1.057) and 7.2 months in group B (P = 0.8401). The most frequent grade 3/4 events were thrombocytopenia (9.6% vs 26.4%), neutropenia (13.5% vs 15.1%), and anemia (3.8% vs 13.2%). We observed a difference between the 2 groups in all grades of anemia (15.4% vs 32.1%), diarrhea (30.8% vs 47.2%), vomiting (50.0% vs 26.4%), and chromaturia (23.1% vs 0.0%). Analysis using a COX proportional hazard model showed that baseline interleukin 6 (IL-6) level was associated with survival benefit of TSU-68 (P = 0.012). Conclusions: TSU-68 plus SOX showed a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. Baseline serum IL-6 levels could be prognostic factors for TSU-68 efficacy. Further biomarker analysis is being performed to determine the efficacy of this treatment. Clinical trial information: JapicCTI-111403.