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Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer

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Abstract

Purpose

S-1 is a novel oral fluoropyrimidine that combines tegafur with CDHP and oxonic acid. To decrease the incidence of late onset, severe diarrhea observed in a previous study, a phase I study was conducted to determine the maximum tolerated dose (MTD) of S-1 utilizing a 14-day schedule, repeated every 21 days, in patients with chemotherapy–refractory upper gastrointestinal malignancies.

Methods

S-1 was administered orally, twice-daily, at an initial dose level of 30 mg/m2/dose; doses were escalated by 5 mg/m2 at each level. A minimum of three patients were enrolled at each dose level. S-1 toxicity, antitumor activity, and pharmacokinetics were assessed. The MTD was based on the dose limiting toxicity (DLT) during the first treatment cycle.

Results

At 30 mg/m2 no DLT was observed in the first three evaluable patients. Two of the first three patients at the 35 mg/m2 dose level developed DLTs (grade 3 rash and dehydration). An additional nine patients were subsequently treated at 30 mg/m2 without DLT and this dose was established as the MTD. Common toxicities at 30 mg/m2 included diarrhea, nausea, skin rash, anorexia, and fatigue. No grade 4 toxicities were observed. One partial response was seen in a patient with gemcitabine-refractory pancreatic adenocarcinoma and ten patients with pancreatic, gastric, or gallbladder carcinomas achieved stable disease as their best response to therapy. The AUC(0–8) of 5-FU at the 30 and 35 mg/m2 dose levels were 875 ± 212 and 894 ± 151 h ng/ml, respectively.

Conclusions

In a 14-day dosing schedule, the MTD of S-1 was 30 mg/m2 and preliminary evidence of antitumor activity was seen in a North American population with refractory upper gastrointestinal malignancies.

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Acknowledgments

We thank Lukas Makris, John Ilgenfritz, Susan Cousounis, Peter Nicola, and Kathrin Krakauer for data analysis and manuscript review at BioCor, Yardley, PA. We thank Taylor S. Spear for assistance in the preparation and editing of this manuscript. M.H. Kulke is supported in part by NIH grants K23 CA 093401 and K30 HL04095.

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Authors and Affiliations

  1. Massachusetts General Hospital, 100 Blossom Street, Cox 640, Boston, MA, 02114, USA

    Andrew X. Zhu, Jeffrey W. Clark, David P. Ryan & Eileen Regan

  2. Dana-Farber Cancer Institute, 44 Binney St, Boston, MA, 02481, USA

    Jeffrey A. Meyerhardt, Peter C. Enzinger, Craig C. Earle, Charles S. Fuchs & Matthew H. Kulke

  3. Harvard Medical School, Boston, MA, USA

    Andrew X. Zhu, Jeffrey W. Clark, David P. Ryan, Jeffrey A. Meyerhardt, Peter C. Enzinger, Craig C. Earle, Charles S. Fuchs & Matthew H. Kulke

  4. Channing Laboratory, Brigham and Women’s Hospital, Boston, MA, USA

    Charles S. Fuchs

  5. Taiho Pharma, Princeton, NJ, USA

    Hiroshi Anbe, Michele Houghton, Joshua Zhang & Peter Urrea

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  1. Andrew X. Zhu
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Correspondence to Andrew X. Zhu or Matthew H. Kulke.

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Supported in part by a grant from Taiho Pharma USA Inc., Princeton, NJ, USA.

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Zhu, A.X., Clark, J.W., Ryan, D.P. et al. Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer. Cancer Chemother Pharmacol 59, 285–293 (2007). https://doi.org/10.1007/s00280-006-0265-y

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  • DOI: https://doi.org/10.1007/s00280-006-0265-y

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