A phase I/II study of cetuximab (cet) in combination with S-1 and oxaliplatin (SOX) in first-line treatment for metastatic colorectal cancer (mCRC) (JACCRO CC-06).

Abstract

571 Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC. COIN trial indicated that the use of cet in combination with capacitabine and oxaliplatin should not be recommended. However, the safety and efficacy of cet plus SOX are not clear. To evaluate the safety and clinical efficacy of the combination, we conducted a multi-center phase I/II study. Methods: In this trial, we assigned pts with KRAS wild type (wt), EGFR-expressing tumor and no prior chemotherapy to receive cet (initial dose 400, and 250 mg/m2 weekly) followed by SOX (oxaliplatin on day 1 and S-1 40 mg/m2 twice daily on days 1-14). The treatment was repeated every 3 weeks. The phase I part was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) according to the dose adaptation schedule of oxaliplatin (100 mg/m2 for level 1 and 130 mg/m2 for level 2). In the following phase II part, the enrolled pts were treated with the RD. The primary endpoint was response rate (RR) evaluated by the external review board according to RECIST criteria v1.1. Secondary endpoints included PFS, OS, and safety. In addition, we prospectively evaluated early tumor shrinkage (ETS). Results: A total of 67 pts were enrolled from January 2012 to February 2013. In the phase I part, level 2 was determined to be the RD. The MTD was not determined because dose limiting toxicity was not confirmed in level 2. In the phase II part, 59 pts including 6 pts of phase I cohort were assessable for the efficacy. The median age was 64 years, 51% of pts were male, and ECOG PS 0 was observed in 85% of pts. The median course of treatment was 5 (range 1-14). The RR was 62.7% (95%CI, 50.4 to 75.1) and ETS was observed in 72% of pts. In safety analysis, grade 3 or worse adverse events were platelet count decreased (13.1%), neutropenia (8.2%), anorexia (11.7%), rash acneform (6.7%) and peripheral neuropathy (3.3%). Conclusions: We determined the RD of cet plus SOX treatment in pts with mCRC. This combination is tolerable at full doses of cet and SOX, with manageable toxicities, and demonstrates advantages in RR for pts with KRAS wt tumor. Updated safety and efficacy data will be presented. Clinical trial information: UMIN000007022.