503 Background: Preoperative chemoradiotherapy with 5-FU is a standard therapy for locally advanced lower rectal cancer. This therapy is useful for increasing local control rates and maintaining anal functions, but there is no evidence indicating that this therapy can extend survival. We performed a phase I study with the objective of developing a new chemoradiotherapy with irinotecan (CPT-11) and S-1, containing gimeracil, a dihydropyrimidine dehydrogenase inhibitor with radiosensitizing effect. Methods: Patients with locally advanced lower rectal cancer (T3-4, N0-2) of which the inferior border was located closer to the anal verge than to the peritoneal reflection were used for analysis. The radiation dose was 45 Gy in 25 fractions. The radiation field included the internal iliac, pararectal, and obturator lymph nodes in addition to the primary tumor and enlarged lymph nodes. S-1 was administered for five consecutive days and withdrawn for two consecutive days (administration: Days 1-5, 8-12, 22-26, and 29-33). The dose of S-1 (80, 100, 120 mg/day) was controlled in accordance with the body surface area. CPT-11 was administered on days 1, 8, 22, and 29. The initial dose of CPT-11 was 60 mg/m2 (Level 1), and the dose was increased gradually. Total mesorectal excision was performed 6-10 weeks after completion of the chemoradiotherapy. Results: 20 patients were enrolled. Excluding 2 patients who discontinued the study, 18 patients were subject to analysis. Dose-limiting toxicity (DLT) was not seen in 3 patients treated with CPT-11 at 80 mg/m2 (Level 2), but was seen in 3 of the 6 patients treated with CPT-11 at 90 mg/m2 (Level 3). DLT was seen in 3 other patients administered a Level 2 dose. At Level 2 or Level 3, DLTs, namely neutropenia, thrombocytopenia and diarrhea were seen. Level 2 was regarded as a maximum tolerated dose, and Level 1 as a recommended dose (RD). The pathological complete response rate was 28%, and the downstaging rate 56%. Conclusions: The results of the study suggest that the RD of CPT-11 is 60 mg/m2. We plan to perform a phase II study to evaluate the efficacy and safety of chemoradiotherapy with S-1 and CPT-11. Clinical trial information: UMIN000001639.