Princeton, NJ, United States
Princeton, NJ, United States

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Chuah B.,National University of Singapore | Goh B.-C.,National University of Singapore | Lee S.-C.,National University of Singapore | Soong R.,National University of Singapore | And 9 more authors.
Cancer Science | Year: 2011

S-1 is an oral fluoropyrimidine anti-neoplastic agent that is converted by CYP2A6 to 5-fluorouracil (5FU). We prospectively studied the pharmacokinetics and pharmacodynamics of S-1 in two groups of East Asian and Caucasian patients with solid malignancy refractory to standard chemotherapy, or for which 5FU was indicated, to elucidate differences in relation to CYP2A6 genotype and phenotype. S-1 was given orally at 30mg/m2 b.i.d. for 14days every 21days. Dose normalized AUC0-48h for tegafur (P=0.05) and gimeracil (P=0.036) were higher in East Asians; conversely, AUC0-48h of fluoro-β-alanine was higher in Caucasians (P=0.044). Exposure to 5FU was similar in both groups (P=0.967). Mean cotinine:nicotine ratio was 54% higher in the Caucasian group (P=0.03), and correlated with oral clearance of tegafur (r=0.59; P=0.002). Grade 3/4 gastrointestinal toxicities were more common in Caucasians than Asians (21%vs 0%). Treatment with S-1 yields no significant difference in 5FU exposure between Caucasians and East Asians. © 2010 Japanese Cancer Association.

Sandler A.,Oregon Health And Science University | Graham C.,Charleston Cancer Center | Baggstrom M.,University of Washington | Herbst R.,University of Texas M. D. Anderson Cancer Center | And 3 more authors.
Journal of Thoracic Oncology | Year: 2011

S-1 is a rationally designed oral agent that combines the 5-fluorouracil prodrug tegafur with gimeracil and oteracil, which inhibit 5-fluorouracil degradation by dihydropyrimidine dehydronase and phosphorylation within the gastrointestinal tract, respectively, to increase antineoplastic activity while reducing gastrointestinal toxicity. We investigated the activity and toxicity of S-1 in combination with cisplatin in patients with unresectable non-small cell lung cancer (NSCLC). Methods: Cisplatin, 75 mg/m 2, was administered intravenously on day 1, with S-1, 25 mg/m 2 PO two times a day, days 1 to 14, every 21 days for a maximum of six cycles. Primary end point was overall response. Results: A total of 58 patients received at least one cycle of protocol-specified therapy. The best overall response rate was 23.2% (95% confidence interval: 13.0-36.4), and the disease control rate was 67.9%. The median progression-free survival was 4.0 months (95% confidence interval: 3.3-5.5). There did not appear to be any relationship between response to therapy and tumor histology. The most frequently reported adverse events of G3 or more (≥10%) were neutropenia (28%), hyponatremia (19%), diarrhea (17%), hypokalemia (12%), fatigue (10%), dehydration (10%), and deep vein thrombosis (10%). Conclusions: Although the S-1 + cisplatin regimen used in this study appeared to have a similar level of antitumor activity and toxicity to that of established cisplatin-based doublets in NSCLC, the protocol-specified criteria of sufficient efficacy to warrant further study with an objective response rate ≥30% was not achieved. Therefore, while S-1 appears to be a promising agent in NSCLC, further evaluation should be conducted to determine the optimal S-1-based regimen to take forward for additional study. Copyright © 2011 by the International Association for the Study of Lung Cancer.

Chung K.Y.,Cancer Centers of the Carolinas | Saito K.,Taiho Pharma United States | Zergebel C.,Taiho Pharma United States | Hollywood E.,Sloan Kettering Cancer Center | And 2 more authors.
Oncology | Year: 2011

Background: S-1 is a novel oral agent combining the 5-fluorouracil (FU) prodrug tegafur with gimeracil and oteracil, which inhibit 5-FU degradation by dihydropyrimidine dehydrogenase and phosphorylation within the gastrointestinal tract, respectively. The study was designed to identify the maximum tolerable dose and the dose-limiting toxicities of two schedules of S-1 combined with oxaliplatin and bevacizumab, in advanced solid tumor patients. Methods: Schedule A: S-1 was administered orally at 20 mg/m 2 twice daily for 14 consecutive days, escalated by 5 mg/m 2, with fixed-dose intravenous bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m 2 on day 1 of each 3-week cycle. Schedule B: S-1 was administered at 25 mg/m 2 twice daily for 7 consecutive days, escalated by 5 mg/m 2, with fixed-dose intravenous bevacizumab 5 mg/kg and oxaliplatin 85 mg/m 2 on day 1 of each 2-week cycle. Results: The maximum tolerated dose and recommended phase II dose of S-1 was 25 mg/m 2 twice daily for 14 days for schedule A and 35 mg/m 2 twice daily for 7 days for schedule B. The most common dose-limiting toxicities were grade 3 diarrhea. Both regimens were well tolerated. No pharmacokinetic interactions between oxaliplatin and S-1 components were observed. Conclusions: S-1, oxaliplatin and bevacizumab can be administered with acceptable safety and tolerability and without evidence of pharmacokinetic interactions. Copyright © 2011 S. Karger AG.

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