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An exploration of trifluridine/tipiracil in combination with irinotecan in patients with pretreated advanced gastric cancer

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Summary

Background. Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer, but their efficacies are limited. We investigated the combination of FTD/TPI and irinotecan for such patients. Methods. Patients who were refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) and treated with irinotecan (100 [Level 1] or 125 [Level 2] mg/m2 on days 1 and 15) and FTD/TPI (35 mg/m2/dose, twice daily, on days 1–5 and 8–12 [Level A] or on days 1–5 and days 15–19 [Level B]) of a 28-day cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D); the secondary endpoint was the disease control rate (DCR). Results. Eleven patients were enrolled: 2 at Level 1A, 3 at Level 1B, and 6 at Level 2B. DLTs occurred in 2/2 patients at Level 1A and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved a partial response, and the DCR was 72.7% (95% CI, 39.0%-94.0%). The median progression-free survival and overall survival periods were 3.0 months (95% CI, 0.92-not reached) and 10.2 months (95% CI, 2.2-not reached), respectively. Conclusion. The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B; this level was associated with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation of the efficacy of RP2D treatment is necessary.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was sponsored by Taiho Pharmaceutical.

Funding

This investigation was funded by TAIHO PHARMACEUTICAL CO., LTD.

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Authors and Affiliations

  1. Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan

    Takuro Mizukami & Takako Eguchi Nakajima

  2. Department of Gastroenterology, Chiba Cancer Center, Chiba, Japan

    Keiko Minashi & Yusuke Amanuma

  3. Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan

    Hiroki Hara & Naoki Takahashi

  4. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan

    Tomohiro Nishina & Akio Nakasya

  5. Medical Informatics, St. Marianna University School of Medicine, Kawasaki, Japan

    Masaki Takahashi

  6. Department of Early Clinical Development, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Takako Eguchi Nakajima

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  1. Takuro Mizukami
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Contributions

All authors contributed to the study conception and design. Patient recruitment was performed by Takuro Mizukami, Keiko Minashi, Hiroki Hara, Tomohiro Nishina, Yusuke Amanuma, Naoki Takahashi, Akio Nakasha, Masaki Takahashi, and Takako Eguchi Nakajima. Data collection and analysis were performed by Masaki Takahashi. The first draft of the manuscript was written by Takuro Mizukami and Takako Eguchi Nakajima. All authors revised and approved the final manuscript.

Corresponding author

Correspondence to Takako Eguchi Nakajima.

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Ethics approval

All considerations regarding the protection of human subjects were performed in accordance with the ICH Harmonized Guidelines for Good Clinical Practice, the ethical principles of which originate from the Declaration of Helsinki, and all applicable regulatory requirements.

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Informed consent was obtained from all individual participants included in the study.

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Not applicable.

Conflict of interest

Dr. Mizukami reports grants and personal fees from Taiho Pharmaceutical, Eli Lilly Japan, and Ono pharmaceutical as well as personal fees from Otsuka Pharmaceutical Factory, Asahi Kasei Pharmaceutical, Merck Biopharma, Sanofi, and Takeda Pharmaceutical. Dr. Hara grants, and personal fees from Bayer, Chugai, Daiichi Sankyo, Merck Biopharma, MSD, Ono, and Taiho, as well as grants from Astellas, AstraZeneca, BeiGene, Boehringer Ingelheim, Dainippon Sumitomo, Eisai, Elevar Therapeutics, GSK, Incyte, Pfizer, personal fees from Bristol-Myers Squibb, Lilly, Sanofi, and Yakult. Dr. Nakajima reports grants and personal fees from Taiho Pharmaceutical Co., Sumitomo Dainippon Pharma Co., Ono Pharmaceutical Co., Amgen, Takeda Pharmaceutical Co., Chugai Pharmaceutical Co., Sanofi K.K., Nippon Kayaku Co., MSD K.K., Eli Lilly Japan K.K., Daiichi Sankyo Co., Merck Serono Co. as well as a grant from Eisai Co., and personal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Novartis Japan, Bayer Yakuhin, Pfizer Japan Inc., Yakult Honsha Co., Nipro Co, Celltrion Healthcare Japan, Teijin Pharma, Sawai Pharmaceutical Co.. Drs. Minashi, Nishina, Amanuma, Naoki Takahashi, Nakasya, Masaki Takahashi have nothing to disclose.

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Mizukami, T., Minashi, K., Hara, H. et al. An exploration of trifluridine/tipiracil in combination with irinotecan in patients with pretreated advanced gastric cancer. Invest New Drugs 40, 614–621 (2022). https://doi.org/10.1007/s10637-022-01223-9

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