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Background <p>We developed and refined an S-1 dosage formula based on renal function, sex, and body surface area (BSA) to achieve the target area under the concentration–time curve of 5-fluorouracil in two prospective pharmacokinetic studies. The clinical validity of the refined formula (BBT formula) was evaluated using data from the two phase III trials of fist-line chemotherapy including S-1 for advanced gastric cancer, which demonstrated that overall survival and progression-free survival tended to be shorter in patients whose S-1 standard dose, based on BSA alone, was lower than that determined using the BBT formula.</p> Methods <p>Chemo-naïve patients with HER2-negative advanced gastric or gastroesophageal junction cancer, whose standard S-1 dose is lower than that determined using the BBT formula, receive S-1 at an increased dose based on the BBT formula plus oxaliplatin (130 mg/m<sup>2</sup>) and nivolumab (360 mg/body). The primary endpoint is the incidence of dose-limiting toxicity in six patients in the phase I part and the proportion of patients requiring S-1 dose reduction in a total of 20 patients, expecting 30% and rejecting 50% with an alpha error of 0.1 and beta error of 0.2. The secondary endpoints are adverse events, relative dose intensity, response rate, disease control rate, progression-free survival, and overall survival. A correlation study is conducted to investigate the immune profiles associated with efficacy.</p> Discussion <p>This phase I/II trial evaluates the safety and efficacy of S-1 at increased doses, determined by the BBT formula, in combination with oxaliplatin and nivolumab in patients with HER2-negative advanced gastric cancer, whose standard dose of S- 1 is lower than the dose recommended dose by the BBT formula.</p> Trial registration <p>This study was approved by the University of Tokyo Clinical Research Review Board (URL: <a href="https://www.ut-crescent.jp/patients/chiken_jisshi/">https://www.ut-crescent.jp/patients/chiken_jisshi/</a>, review number: 2022529SP) and was initiated at 19 institutions in June 2023 (registered as jRCTs031230127).</p>

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A phase I/II trial evaluating the safety of increased-dose S- 1 with oxaliplatin and nivolumab in HER2-negative advanced gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月12日

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  • Keisuke Baba,
  • Nobumi Suzuki,
  • Chiyo K. Imamura,
  • Eisuke Booka,
  • Masashi Takeuchi,
  • Daisuke Takahari,
  • Takeshi Kawakami,
  • Hirofumi Kawakubo,
  • Chiyoe Kitagawa,
  • Yoshiyasu Kono,
  • Keiji Ogura,
  • Yosuke Kito,
  • Kei Saito,
  • Shinzo Yamamoto,
  • Hiroya Takeuchi,
  • Toshihiro Kudo,
  • Takuya Tsunoda,
  • Takuro Mizukami,
  • Toshifumi Yamaguchi,
  • Hirokazu Shoji,
  • Kanako Saito,
  • Kenro Tanoue,
  • Eishi Baba,
  • Kengo Nagashima,
  • Narikazu Boku

摘要

Background

We developed and refined an S-1 dosage formula based on renal function, sex, and body surface area (BSA) to achieve the target area under the concentration–time curve of 5-fluorouracil in two prospective pharmacokinetic studies. The clinical validity of the refined formula (BBT formula) was evaluated using data from the two phase III trials of fist-line chemotherapy including S-1 for advanced gastric cancer, which demonstrated that overall survival and progression-free survival tended to be shorter in patients whose S-1 standard dose, based on BSA alone, was lower than that determined using the BBT formula.

Methods

Chemo-naïve patients with HER2-negative advanced gastric or gastroesophageal junction cancer, whose standard S-1 dose is lower than that determined using the BBT formula, receive S-1 at an increased dose based on the BBT formula plus oxaliplatin (130 mg/m2) and nivolumab (360 mg/body). The primary endpoint is the incidence of dose-limiting toxicity in six patients in the phase I part and the proportion of patients requiring S-1 dose reduction in a total of 20 patients, expecting 30% and rejecting 50% with an alpha error of 0.1 and beta error of 0.2. The secondary endpoints are adverse events, relative dose intensity, response rate, disease control rate, progression-free survival, and overall survival. A correlation study is conducted to investigate the immune profiles associated with efficacy.

Discussion

This phase I/II trial evaluates the safety and efficacy of S-1 at increased doses, determined by the BBT formula, in combination with oxaliplatin and nivolumab in patients with HER2-negative advanced gastric cancer, whose standard dose of S- 1 is lower than the dose recommended dose by the BBT formula.

Trial registration

This study was approved by the University of Tokyo Clinical Research Review Board (URL: https://www.ut-crescent.jp/patients/chiken_jisshi/, review number: 2022529SP) and was initiated at 19 institutions in June 2023 (registered as jRCTs031230127).