A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

Background To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer. Patients and methods S-1 and CPT-11 doses were escalated using a standard 3 + 3 design. S-1 was administered orally at 70 mg/m(2) (levels 1-3) or 80 mg/m(2) (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175 mg/m(2) (level 1), 200 mg/m(2) (level 2), 225 mg/m(2) (levels 3 and 4), or 250 mg/m(2) (level 5). Treatment was repeated every 3 weeks, unless disease progression or severe toxicities were observed. Results Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5 days. The RD was determined at level 4 (80 mg/m(2) S-1 and 225 mg/m(2) CPT11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5. Conclusions The RDs of CPT-11 and S-1 were determined as 225 and 80 mg/m(2), respectively, and further phase II trials are warranted.