Skip to main content
SpringerLink
Log in

Phase I trial of Uracil-Tegafur (UFT) plus oral leucovorin: 14-day schedule

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

We previously reported results of a Phase II trial of UFT [Taiho Pharmaceutical Ltd., Tokyo, Japan; (BMS-200604) Bristol-Myers Squibb, Princeton, NJ], an oral 4:1 molar concentration of uracil and tegafur, plus oral leucovorin for metastatic colorectal carcinoma (Pazdur et al, J. Clin. Oncol. 12:2296-2300, 1994]. Our results demonstrated that a 28-day schedule of this combination produced a response rate similar to that obtained with conventional intravenous fluorouracil (5-FU)-plus-leucovorin regimens but without the severe or life-threatening neutropenia or oral mucositis that complicates intravenous 5-FU regimens. The current Phase I trial examines the dose-limiting toxic effects and maximum tolerated dose of a 14-consecutive-day schedule of UFT plus oral leucovorin in 14 patients who had histologically proven cancer and had received prior chemotherapy. The daily UFT plus leucovorin dose was divided into three doses administered orally every 8 hours. In this study, the UFT dose was escalated while the leucovorin dose remained at 150 mg/day. Of the 14 patients, 4 were initially treated at the 350-mg/m2/day UFT level for 14 days without any dose-limiting toxic reactions. Subsequently, another 7 patients were treated at the 400-mg/m2/day level; grade 3 diarrhea developed in 3 of these 7 (with severe abdominal cramping in 2 cases and severe nausea and vomiting unresponsive to antiemetics in the third). To better define the starting dose for phase II studies, an additional 3 patients were treated at the 350-mg/m2/day dose level. Of the total 7 patients treated at 350 mg/m2/day, grade 3 toxic events (diarrhea) developed in 2 patients. Grade 1-2 toxic effects noted at this level included fatigue, stomatitis, skin rash, abdominal pain, nausea, and vomiting. Neither partial nor complete responses were observed in this trial. The maximum tolerated dose of this schedule is 350 mg/m2/day UFT plus 150 mg/day oral leucovorin. However, because of this schedule's inferior dose intensity compared with that of the 28-day schedule of UFT plus leucovorin, subsequent development of UFT in the United States has focused on the 28-day regimen.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fujii S, Ikenaka K, Fukushima M and Shirasaka T: Effect of uracil and its derivatives on antitumor activity of 5-fluorouracil 1-(2-tetrahydrofuryl)-5-fluorouracil. Kagaku Ryoho 69:763–772, 1978

    Google Scholar 

  2. Fujii S, Okuda H, Toide H, Watanabe N, Taira K, Hashimoto S: Studies on the fate of FT-207, an antitumor agent. Absorption, tissue distribution, and excretion. Pharmacokinet 8:589–595, 1974

    Google Scholar 

  3. Taguchi T, Nakano Y, Fujita M, Tominaga T, Takami M, Usukane M, Takahasi A, Kato T, Tei N, Kitamura M, Maeda T, Ishida T, Shiba S: Clinical studies of the anticancer activity of FT-207. Jpn J Cancer Clinics 18:550–553, 1972

    Google Scholar 

  4. Taguchi T, Nakano Y, Jikuya K and Fujii S: Effect of uracil on the antitumor activity of ftorafur. Jpn J Cancer Chemother 5:1161–1165, 1978

    Google Scholar 

  5. Fujii S, Kitano S, Ikenaka K, Shirasaka T: Studies on coadministration of uracil or cytosine on antitumor activity of FT-207 or 5-FU derivatives. Jpn J Cancer Chemother 6:377–384, 1979

    Google Scholar 

  6. Ikenaka K, Shirasaka T, Kitano S and Fujii S: Effect of uracil on metabolism of 5-fluorouracil in vitro. Gann 70:353–359, 1979

    Google Scholar 

  7. Saitoh T, Kagaya T, Takebe T, Ishii K: The enhancement of the antitumor effect of FT-207 coadministered with uracil on the transplanted ductal adenocarcinoma of the Syrian golden hamster pancreas. Jpn J Cancer Chemother 9:2168–2174, 1982

    Google Scholar 

  8. Suemasu K, Nomoto C, Higashi Y: Concentration of 5-FU level in the tissue and blood of the patients with breast cancer by prcoperative administration of UFT. Jpn J Cancer Chemother 9:667–671, 1982

    Google Scholar 

  9. Tsujimoto T, Sakai S, Murata M, Sasaki R: Concentrations of 5-FU in the tissue and serum of the patients with head and neck malignant tumors by preoperative administration of UFT. Jpn J Cancer Chemother 10:78–83, 1983

    Google Scholar 

  10. Ota K, Taguchi T, Kimura K: Report on nationwide pooled data and cohort investigation in UFT Phase II studies. Cancer Chemother Pharmacol 22:333–338, 1988

    Google Scholar 

  11. Murakami M, Ota K: Clinical results of UFT therapy for malignant tumors under cooperative study. Jpn J Cancer Chemother 7:1579–1586, 1980

    Google Scholar 

  12. Watanabe H, Yamamoto S, Naito T: Clinical results of oral UFT therapy under cooperative study. Jpn J Cancer Chemother 7:1588–1596, 1980

    Google Scholar 

  13. Dorr RT, Von Hoff DD: 5-Fluorouracil. In: RT Dorr and DD Von Hoff (eds), Cancer Chemotherapy Handbook, pp. 500–515. Norwalk, Connecticut: Appleton & Lange, 1994

    Google Scholar 

  14. Poon MA, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA: Biochemical modulation of fluorouracil with leucovorin. Confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol 9:1967–1972, 1991

    Google Scholar 

  15. The Advanced Colorectal Cancer Meta-analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer. Evidence in terms of response rate. J Clin Oncol 10:896–903, 1992

    Google Scholar 

  16. Pazdur R, Lassere Y, Rhodes V, Ajani JA, Sugarman SM, Patt YZ, Jones DV, Markowitz AB, Abbruzzese JL, Bready B, Levin B: Phase II trial of uracil and tegafur plus oral leucovorin. An effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 12:2296–2300, 1994

    Google Scholar 

  17. Saltz LB, Leichman CG, Young CW, Muggia FM, Conti JA, Spieff R, Jeffers S, Leichman LP: A fixed-ratio combination of uracil and ftorafur (UFT) with low dose leucovorin. Cancer 75:782–785, 1995

    Google Scholar 

  18. Pazdur R: New agents in the treatment of colorectal carcinoma: Tomudex, UFT, and doxifluridine. Cancer Invest 13(suppl 1):28–29, 1994

    Google Scholar 

  19. Jaiyesimi I, Pazdur R, Rhodes V, Lassere Y, Soo E, Bready B: Phase I study of tegafur plus uracil co-administered with oral leucovorin. Proc Am Soc Clin Oncol 12:164, 1994

    Google Scholar 

  20. Pazdur R, Lassere Y, Bready B, Soh L, Soo E, Ajani JA, Sugarman S, Patt Y: Phase I study of UFT plus oral folinic acid: 28 day schedule. Ann Oncol 5(suppl 5):135, 1994 (abstract)

    Google Scholar 

  21. Ajani JA, Welch SR, Raber MN, Fields WS, Krakoff IH: Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest 8:147–159, 1990

    Google Scholar 

  22. Mini E, Moroson BA, Bertino JR: Cytotoxicity of floxuridine and 5-fluorouracil in human T-lymphoblast leukemia cells. Enhancement by leucovorin. Cancer Treat Rep 71:381–389, 1987

    Google Scholar 

  23. Vokes EE, Choi KE, Schilsky RL, Moran WJ, Guarnieri CM, Weichselbaum RR, Panje WR: Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer. J Clin Oncol 6:618–626, 1988

    Google Scholar 

  24. Houghton JA, Houghton PJ, Wooten RS: Mechanism of induction of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2′deoxyuridine. Cancer Res 39: 2406–24134, 1979

    Google Scholar 

  25. Shirasaka T, Shimamoto Y, Fukushima M: Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 53:4004–4009, 1993

    Google Scholar 

  26. Hill M, Norman A, Cunningham D, Findlay M, Watson M, Nicolson V, Webb A, Middleton G, Ahmed F, Hickish R, Nicolson M, O'Brien M, Iveson T, Iveson A and Evans C: Impact of protracted venous infusion fluorouracil with or without interferon alfa-2b on tumor response, survival, and quality of life in advanced colorectal cancer. J Clin Oncol 13:2317–2323, 1995

    Google Scholar 

  27. Friedman MA and Ignoffo RH: A review of the United States clinical experience of the fluoropyrmidine, ftorafur (NSC 148958]. Cancer Treat Rev 7:205–213, 1980

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Divisions of Medicine and Pharmacy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Richard Pazdur, Yvonne Lassere, Enrique Diaz-Canton, Beth Bready & Dah H. Ho

Authors
  1. Richard Pazdur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yvonne Lassere
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Enrique Diaz-Canton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beth Bready
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dah H. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pazdur, R., Lassere, Y., Diaz-Canton, E. et al. Phase I trial of Uracil-Tegafur (UFT) plus oral leucovorin: 14-day schedule. Invest New Drugs 15, 123–128 (1997). https://doi.org/10.1023/A:1005808822565

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005808822565

Search

Navigation