Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 1, pp 107–116 | Cite as

Phase I clinical and pharmacokinetic study of S-1 plus oral leucovorin in patients with metastatic colorectal cancer

  • Takayuki Yoshino
  • Ichinosuke Hyodo
  • Tomohiro Nishina
  • Hiroyuki Narahara
  • Naotoshi Sugimoto
  • Kunihiro Yoshisue
  • Narikazu Boku
Original Article
First Online:
Received:
Accepted:

Abstract

Purpose

S-1 has shown a response rate of 35% in chemonaïve patients with metastatic colorectal cancer (mCRC). Leucovorin enhances the antitumor activity of 5-fluorouracil, and concurrent oral administration of S-1 and leucovorin may represent a more active treatment option for mCRC.

Methods

S-1 (35 mg/m2) and leucovorin (25 mg/body) were orally administered twice daily to chemonaïve patients with mCRC. Predefined dose (schedule)-limiting toxicities (DLTs) during the first course and treatment continuity during the first two courses were evaluated during three periods of treatment with S-1 plus leucovorin (level 0, 2 weeks; level 1, 3 weeks; and level 2, 4 weeks), each followed by a 2-week rest. The pharmacokinetics (PK) of S-1 and leucovorin were studied on days 1 and 14 of the first course.

Results

Fifteen patients were enrolled. All three patients had DLTs at level 2, and this level was considered the maximum tolerated schedule. Level 0 was designated as the recommended schedule based on the incidences of DLTs and treatment continuity. The main toxic effects were gastrointestinal, such as diarrhea and stomatitis. There was no grade 4 adverse event or treatment-related death. The overall response rate was 67% (95% confidence interval, 38–88%). The PK profiles of S-1 plus leucovorin were similar to those in previous studies.

Conclusions

The recommended schedule was 2 weeks of S-1 plus leucovorin followed by a 2-week rest. The increased response and gastrointestinal toxicities of S-1 plus leucovorin as compared with S-1 monotherapy suggest that co-administration of leucovorin enhanced the activity of S-1.

Keywords

Colorectal cancer S-1 Leucovorin Phase I study Pharmacokinetics Recommended schedule 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

This work was sponsored by Taiho Pharmaceutical Co., Ltd., Tokyo. We thank the patients and their families for their contributions. We also thank Drs. Keisuke Aiba, Atsushi Ohtsu, and Hideo Baba for serving on the data and safety monitoring committee. We are also indebted to Drs. Yuh Sakata, Wasaburo Koizumi, Junji Tanaka, and Atsushi Sato for their extramural review of clinical data in this study. The authors thank Tetsuo Taguchi, serving as an external medical director, and Masaru Yanagawa (Taiho Pharmaceutical Co., Ltd, Tokyo, Japan) for their contributions to the study design and data analysis. We thank Peter Star of Medical Network K.K. (Tokyo, Japan) for his review of this report, funded by Taiho Pharmaceutical Co., Ltd. We would also like to thank Kouichiro Hoashi, Tomohiro Kanno, and Kazuhiro Urata, Taiho Pharmaceuticals, for overall management of the trial and drafting the manuscript.

Compliance with ethical standards

Conflict of interest

Takayuki Yoshino has received research funding for clinical trials from Glaxo Smith Kline K.K. and Boehringer Ingelheim GmbH. Ichinosuke Hyodo has received remuneration from Taiho, Chugai, Yakult, and Daiichi-Sankyo. Tomohiro Nishina, Hiroyuki Narahara, and Naotoshi Sugimoto indicated no potential conflicts of interest. Kunihiro Yoshisue is employed by Taiho. Narikazu Boku has received remuneration from Taiho.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee, national research committee, or both, as well as with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

References

  1. 1.
    Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905–914CrossRefPubMedGoogle Scholar
  2. 2.
    de Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947PubMedGoogle Scholar
  3. 3.
    Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30CrossRefPubMedGoogle Scholar
  4. 4.
    Falcone A, Ricci S, Brunetti I et al (2007) Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 25:1670–1676CrossRefPubMedGoogle Scholar
  5. 5.
    Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019CrossRefPubMedGoogle Scholar
  6. 6.
    Loupakis F, Cremolini C, Masi G et al (2014) Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371:1609–1618CrossRefPubMedGoogle Scholar
  7. 7.
    Van Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30:3499–3506CrossRefPubMedGoogle Scholar
  8. 8.
    Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499–508CrossRefPubMedGoogle Scholar
  9. 9.
    Van Cutsem E, Kohne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417CrossRefPubMedGoogle Scholar
  10. 10.
    Douillard JY, Siena S, Cassidy J et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705CrossRefPubMedGoogle Scholar
  11. 11.
    Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303–312CrossRefPubMedGoogle Scholar
  12. 12.
    Mayer RJ, Van Cutsem E, Falcone A et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372:1909–1919CrossRefPubMedGoogle Scholar
  13. 13.
    Van Cutsem E, Twelves C, Cassidy J et al (2001) Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 19:4097–4106PubMedGoogle Scholar
  14. 14.
    Hoff PM, Ansari R, Batist G et al (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 19:2282–2292PubMedGoogle Scholar
  15. 15.
    Cassidy J, Clarke S, Diaz-Rubio E et al (2008) Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006–2012CrossRefPubMedGoogle Scholar
  16. 16.
    Shirasaka T, Shimamato Y, Ohshimo H et al (1996) Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 7:548–557CrossRefPubMedGoogle Scholar
  17. 17.
    Shirasaka T, Shimamoto Y, Fukushima M (1993) Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 53:4004–4009PubMedGoogle Scholar
  18. 18.
    Takechi T, Nakano K, Uchida J et al (1997) Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 39:205–211CrossRefPubMedGoogle Scholar
  19. 19.
    Sakuramoto S, Sasako M, Yamaguchi T et al (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 357:1810–1820CrossRefPubMedGoogle Scholar
  20. 20.
    Koizumi W, Narahara H, Hara T et al (2008) S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9:215–221CrossRefPubMedGoogle Scholar
  21. 21.
    Ueno H, Ioka T, Ikeda M et al (2013) Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 31:1640–1648CrossRefPubMedGoogle Scholar
  22. 22.
    Yamada Y, Takahari D, Matsumoto H et al (2013) Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol 14:1278–1286CrossRefPubMedGoogle Scholar
  23. 23.
    Taguchi T, Inuyama Y, Kanamaru R et al (1997) Phase I study of S-1. S-1 Study Group. Gan To Kagaku Ryoho 24:2253–2264PubMedGoogle Scholar
  24. 24.
    van Groeningen CJ, Peters GJ, Schornagel JH et al (2000) Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. J Clin Oncol 18:2772–2779PubMedGoogle Scholar
  25. 25.
    Hoff PM, Saad ED, Ajani JA et al (2003) Phase I study with pharmacokinetics of S-1 on an oral daily schedule for 28 days in patients with solid tumors. Clin Cancer Res 9:134–142PubMedGoogle Scholar
  26. 26.
    Ohtsu A, Baba H, Sakata Y et al (2000) Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. Br J Cancer 83:141–145CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Shirao K, Ohtsu A, Takada H et al (2004) Phase II study of oral S-1 for treatment of metastatic colorectal carcinoma. Cancer 100:2355–2361CrossRefPubMedGoogle Scholar
  28. 28.
    Thirion P, Michiels S, Pignon JP et al (2004) Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol 22:3766–3775CrossRefPubMedGoogle Scholar
  29. 29.
    Douillard JY, Hoff PM, Skillings JR et al (2002) Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3605–3616CrossRefPubMedGoogle Scholar
  30. 30.
    Carmichael J, Popiela T, Radstone D et al (2002) Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617–3627CrossRefPubMedGoogle Scholar
  31. 31.
    Van Cutsem E, Findlay M, Osterwalder B et al (2000) Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 18:1337–1345PubMedGoogle Scholar
  32. 32.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  33. 33.
    Cancer Therapy Evaluation Program (2006) Common terminology criteria for adverse events v3.0. In. Aug 9, 2006. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed 17 Oct 2016
  34. 34.
    Matsushima E, Yoshida K, Kitamura R (1997) Determination of S-1 (combined drug of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate) and 5-fluorouracil in human plasma and urine using high-performance liquid chromatography and gas chromatography-negative ion chemical ionization mass spectrometry. J Chromatogr B Biomed Sci Appl 691:95–104CrossRefPubMedGoogle Scholar
  35. 35.
    Shirao K, Hoff PM, Ohtsu A et al (2004) Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV. J Clin Oncol 22:3466–3474CrossRefPubMedGoogle Scholar
  36. 36.
    Ueno H, Okusaka T, Ikeda M et al (2005) An early phase II study of S-1 in patients with metastatic pancreatic cancer. Oncology 68:171–178CrossRefPubMedGoogle Scholar
  37. 37.
    Ueno H, Okusaka T, Ikeda M et al (2004) Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 91:1769–1774CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Koizumi W, Boku N, Yamaguchi K et al (2010) Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer. Ann Oncol 21:766–771CrossRefPubMedGoogle Scholar
  39. 39.
    Denda T, Li J, Xu R, Xu J et al (2012) Phase II study of S-1 plus leucovorin (a new 1-week treatment regimen followed by a 1-week rest period) in patients with untreated metastatic colorectal cancer in Japan and China. J Clin Oncol 30(Suppl 4): abstr 598Google Scholar
  40. 40.
    Yamazaki K, Kuwano H, Ojima H et al (2015) A randomized phase II study of combination therapy with S-1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer. Cancer Chemother Pharmacol 75:569–577CrossRefPubMedGoogle Scholar
  41. 41.
    Nishina T, Kato T, Yamazaki K et al (2015) A phase II study of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA) in patients with unresectable metastatic colorectal cancer. Cancer Chemother Pharmacol 76:547–553CrossRefPubMedGoogle Scholar
  42. 42.
    Ueno M, Okusaka T, Omuro Y et al (2016) A randomized phase II study of S-1 plus oral leucovorin versus S-1 monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer. Ann Oncol 27:502–508CrossRefPubMedGoogle Scholar
  43. 43.
    Hironaka S, Sugimoto N, Yamaguchi K et al (2016) S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial. Lancet Oncol 17:99–108CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Takayuki Yoshino
    • 1
  • Ichinosuke Hyodo
    • 2
  • Tomohiro Nishina
    • 3
  • Hiroyuki Narahara
    • 4
  • Naotoshi Sugimoto
    • 5
  • Kunihiro Yoshisue
    • 6
  • Narikazu Boku
    • 7
  1. 1.Department of Gastroenterology and Gastrointestinal OncologyNational Cancer Center Hospital EastKashiwaJapan
  2. 2.Division of GastroenterologyUniversity of TsukubaTsukubaJapan
  3. 3.Department of Gastrointestinal Medical OncologyNational Hospital Organization Shikoku Cancer CenterMatsuyamaJapan
  4. 4.Division of Clinical Research CenterHyogo Prefectural Nishinomiya HospitalNishinomiyaJapan
  5. 5.Department of Clinical OncologyOsaka Medical Center for Cancer and Cardiovascular DiseasesOsakaJapan
  6. 6.Pharmacokinetics Research Laboratories, Tsukuba Research CenterTaiho Pharmaceutical Co., LtdTsukubaJapan
  7. 7.Department of Gastrointestinal OncologyNational Cancer Institute HospitalTokyoJapan

Personalised recommendations