Abstract
Purpose
This phase I study was conducted to evaluate the safety and pharmacokinetics of YM155, a potent, selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer (NSCLC).
Methods
The pimary objectives were to evaluate the safety and tolerability of YM155 at escalating doses (3.6, 4.8, 6.0, and 8.0 mg/m2/days) administered every 3 weeks as continuous intravenous infusion over 168 h in combination with erlotinib at a fixed dose (150 mg, once a day). Secondary objectives were to assess the pharmacokinetics of YM155, antitumor activity, and the relationship between biomarkers and efficacy. The changes in survivin expression in biopsied tumor pre- and post-YM155 administration and serum cytokine levels were also analyzed.
Results
Fifteen patients were treated. The most common YM155-related adverse event was the presence of urine microalbumin, whereas grades 3/4 toxicities were rare. One patient who received 4.8 mg/m2/days YM155 developed a dose-limiting grade 2 serum creatinine elevation. YM155 exposure in plasma showed dose proportionality across all dose ranges tested. No pharmacokinetic interaction occurred between YM155 and erlotinib. The serum cytokines IL-8, G-CSF, and MIP-1b showed decreasing trends in patients who achieved progression-free survival of ≥ 12 weeks. Durable stable disease for ≥ 24 weeks was observed in two patients.
Conclusion
Up to 8.0 mg/m2/days YM155 administered every 3 weeks in combination with erlotinib exhibited a favorable safety profile and moderate clinical efficacy. These results suggest that inhibiting survivin is a potential therapeutic strategy for select patients with EGFR TKI refractory NSCLC.
Trial registration
UMIN000031912 at UMIN Clinical Trials Registry (UMIN-CTR).
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Acknowledgements
The authors would like to thank the patients, their families, all other investigators, and all investigational site members involved in this study. The authors were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.
Funding
This investigator-initiated clinical trial was funded by grants-in-aid for scientific research from the Ministry of Health, Labor and Welfare, Japan (2012–2015). The new investigational drug (YM155) was provided by Astellas Pharma (Tokyo, Japan).
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Toshio Shimizu reports research grants from Novartis, Eli Lilly, Daiichi-Sankyo, Bristol-Myers Squibb, Eisai, AbbVie, AstraZeneca, Takeda Oncology, Incyte, Chordia Therapeutics, 3D-Medicine, Symbio Pharmaceuticals, PharmaMar, Five Prime, and Astellas Pharma outside the submitted work; and reports advisor role at Takeda Pharmaceutical Co., Ltd. Kazuhiko Nakagawa reports research grants from MSD KK, AstraZeneca, ICON Japan, Astellas, Takeda, Novartis, Eli Lilly, Quintiles Inc., Bristol Myers Squibb, CMIC Shift Zero K.K., Taiho Pharmaceutical, Eisai, Parexel International Corp., Nippon Boehringer Ingelheim, Ono Pharmaceutical, Kissei Pharmaceutical, IQVIA, Pfizer, A2 Healthcare Corp, Kyowa Hakko Kirin, EPS Corporation, Abbvie, Chugai Pharmaceutical, Daiichi-Sankyo, SymBio Pharmaceuticals, Bayer, and Merck Serono outside the submitted work; and reports consulting or advisor role at Astellas Pharma Inc. and Takeda Pharmaceutical Co., Ltd. Isamu Okamoto reports grants from Boehringer Ingelheim, during the study; grants and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Lilly, Bristol-Myers Squibb, and Chugai Pharma; grants from Astellas Pharma, Novartis, and AbbVie; personal fees from Pfizer, outside the submitted work. Masayuki Takeda received honoraria from Novartis Pharma, Chugai Pharma, ONO Pharmaceutical, and Boehringer Ingelheim. Maiko Morishita is an employee of Astellas Pharma. The remaining authors have no potential conflicts of interest to report.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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Shimizu, T., Nishio, K., Sakai, K. et al. Phase I safety and pharmacokinetic study of YM155, a potent selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer. Cancer Chemother Pharmacol 86, 211–219 (2020). https://doi.org/10.1007/s00280-020-04112-1
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DOI: https://doi.org/10.1007/s00280-020-04112-1