1. Phase I/II study of oral fluoropyrimidine S-1 plus oral Leucovorin as first-line treatment for metastatic colorectal cancer T. Yoshino 1, W. Koizumi 2, K. Yamaguchi 3, Y. Miyata 4, T. Kato 5, Y. Toh 6, A. Sawaki 7, I. Hyodo 8, T. Nishina 9, N. Boku 1 1 Shizuoka Cancer Center, Shizuoka, JAPAN, 2 Kitasato University East Hospital, Kanagawa, JAPAN, 3 Saitama Cancer Center, Saitama, JAPAN, 4 Saku Central Hospital, Nagano, JAPAN, 5 Minoh City Hospital, Osaka, JAPAN, 6 National Kyushu Cancer Center, Fukuoka, JAPAN, 7 Aichi Cancer Center Hospital, Nagoya, JAPAN, 8 University of Tsukuba, Tsukuba, JAPAN, 9 NHO Shikoku Cancer Center, Matsuyama, JAPAN.

2. Background: The results of phase I portion of the treatment with the oral S-1 (a new oral fluoropyrimidine) plus oral leucovorin (LV) in patients (pts) with untreated metastatic colorectal cancer (mCRC) was reported at ESMO 2006. Dose limiting toxicities (DLTs) were grade 3 stomatitis/pharyngitis, nausea, diarrhea, ileus and exanthema. The recommended doses (RDs) for this phase II portion were determined to be S-1 40-60 mg/body and LV 25 mg/body orally given twice daily on days 1 to 14 of a 28-day cycle. The PK profiles of S-1 plus LV were similar to those of S-1 monotherapy and UFT plus LV, respectively. The main purpose of this phase II portion is to evaluate the efficacy and safety of S-1 plus LV at RD level in pts with untreated mCRC. Methods: Pts were eligible as follows; unresectable mCRC with no prior chemotherapy or receiving adjuvant chemotherapy completed at least 6 months before, histologically proven adenocarcinoma, PS(ECOG) 0-2, age 20 to 75, measurable lesions, adequate organ function and written informed consent. The pts received 40-60 mg/body of S-1 plus 25 mg/body of LV twice daily as RD in this phase II portion. The primary endpoint was the objective response rates (RRs), and secondary endpoints were time to progression (TTP) and toxicities. Results: Between Sep 2004 and Jun 2006, 56 pts of 65 enrolled pts received the treatment at RD level. The objective RRs were 57% (37 of 65) for all pts and 57% (32 of 56) for pts at RD, extramurally. Disease control rates (DCRs) were 86% (56 of 65) for all pts and 86% (48 of 56) for pts at RD. Median TTP was 6.8 months for pts at RD. The median survival time is under investigation. During the 6 courses from starting the treatment, the most common grade 3/4 toxicities at RD were as follows: neutropenia, 13%; diarrhea, 27%; stomatitis, 20%; and anorexia 21%. Conclusions: A combination of S-1 plus oral LV is an effective, well tolerated, and convenient regimen in pts with untreated mCRC, without the addition of either oxaliplatin or irinotecan. This trial was supported by Taiho pharmaceutical co., Ltd., Tokyo, Japan. Updated Abstract

3. A novel oral fluoropyrimidine derivative consists of 1M tegafur (FT; prodrug of 5-FU), 0.4M of gimeracil (CDHP) and 1M of potassium oxonate (Oxo) A oral leucovorin (LV) enhances anti-tumor activity of S-1 Biological action of S-1 and Leucovorin

4. Background S-1 monotherapy showed promising activity (response rate (RR) of 37% as 1 st line chemotherapy) against previously untreated metastatic colorectal cancer (mCRC) with conventional dosage (40- 60 mg/body BID) and schedule (28 days of administration periods followed by 14 days rest) Better activity against mCRC is expected when leucovorin (LV) is orally administered with S-1 The efficacy and safety of S-1 plus oral LV have not been studied yet in clinical trials Study Rationale

5. Level 2 (S-1 28 days administration) is the maximum tolerated dose (MTD) of this combination therapy Level 0 (S-1 14 days administration) is the recommended dose (RD), in terms of the continuity of planned 2 courses without any cessation or dose reduction DLTs were diarrhea, stomatitis/pharyngitis, nausea, ileus, and exanthema S-1 plus oral LV may be promising treatment against untreated mCRC, achieving a high response rate of 66.7 % (95% confidence interval; 38.4~88.2 %) The PK parameters of S-1/LV, especially 5-FU and 5-MeTHF, were similar to those of S-1 alone and UFT/LV, respectively Summary of Phase I portion Administration periods of S-1/LV Dosage of S-1: 40-60 mg/body BID Dosage of LV: 25 mg/body BID administered orally together with S-1

6. Summary of Phase I portion (continue) ** The PK parameters were recalculated using those from two previous studies 1,2). The values of concentrations at the same sampling time with the present S-1/LV study were used in calculation, and the data from patients with gastrectomy were excluded from this analysis. 1) Hirata K. et al., Clin Cancer Res 5 2000-2005 (1999) 2) Shirao K. et al., J Clin Oncol 22 (17) 3466-3474 (2004) PK parameter

7. Objectives To assess the response rate of S-1/LV at the RD To evaluate the following at the RD Primary endpoint Secondary endpoints Time to progression (TTP) Time to treatment failure (TTF) Overall survival (OS) the safety profile the efficacy about

8. Key Eligibility Criteria Histologically or pathologically confirmed colorectal adenocarcinoma Advanced, metastatic and unresectable cancer with measurable disease Age 20 – 75 years No prior chemotherapy for the metastatic disease. The adjuvant chemotherapy was allowed if chemotherapy had finished more than 180 days before the entry. Performance Status (ECOG scale) : 0-2 Adequate hematological, renal and liver function Written informed consent Life expectancy ＞ 90 days

9. Treatment S-1+LV p.o. BID 2 wks-on 2wks-off S-1: 40-60 mg/body BID Initial dosage (tegafur equivalent) < 1.25 1.25 - < 1.5 <1.5 40 mg BID 50 mg BID 60 mg BID Body surface area (m 2 ) LV: 25 mg/body BID administered orally together with S-1 -

10. Statistical Analysis RR of S-1 monotherapy was 16.7% - 39.5% Defined as minimum activity was 30% and target activity was 50%  error was 0.05 and  error was 0.2 We estimated 54 patients (pts) of full analysis set were required

11. Results of phase I/II portion at the recommended dose Period From October 2005 to June 2006 Center 12 centers Patient 56 pts (6 pts – phase I portion) Response RECIST (extramurally) Safety NCI CTCAE v3.0 Patients and Assessments

12. Patients Characteristics n=56 (RD)

13. Treatment Courses Total courses during the 6 courses from starting the treatment

14. Efficacy Response Rate CI: Confidence Interval *: reviewed extramurally

15. Relative Dose Intensity (RDI) of S-1 During the 6 courses from starting the treatment RDI(%) is calculated by actual DI based on planed DI

16. Time to Progression (TTP) TTP; 203 days (6.8 Months) [ 95 ％ CI; 164.0 ～ 241.0]

17. Time to Treatment Failure (TTF) TTF; 182 days (6.0 Months) [ 95 ％ CI; 164.0 ～ 237.0]

18. Overall Survival (OS) MST: not reached Median follow-up time : 447 days

19. Common Toxicities During the 6 courses from starting the treatment CTCAE v3.0

20. Reason for treatment Discontinuation Progressive disease48 pts Rescue surgery due to tumor shrinkage 1 pts Toxicity 2 pts Pt’s refusal 1 pts Total52 pts level 0 (RD): Four pts are ongoing

21. Summary Major adverse reactions are gastrointestinal toxicities, without Gr4 severe toxicities There are no treatment-related death and the incidence of treatment discontinuation due to toxicity is only 3.8% Promising anti-cancer effect of S-1 with oral LV is shown in this study

22. A combination of S-1 plus oral LV is an effective, well tolerated, and convenient regimen in pts with untreated mCRC Further investigations of this combination chemotherapy with adding other active agents, such as oxaliplatin and bevacizumab, are warranted Conclusions

23. References Ohtsu A, et al. Br J Cancer. 2000;83:141-145 Hyodo I, et al. ESMO 2006. Abstract #349P Shirao K, et al. Cancer 2004; 100: 2355-2361 Sugimachi K, et al. Oncology. 1999;57:202-210