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First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors

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Summary

This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12–85 mg/m2. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m2 and in the first patient to receive 85 mg/m2. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m2. The AUC∞ increased between 12 mg/m2 and 25 mg/m2, although no differences were observed at 25–40 mg/m2. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m2 dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m2 and 25 mg/m2 dose levels. Based on these results, we recommend a phase II dose of 25 mg/m2. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203. Clinical trial registration: UMIN000016546.

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Acknowledgments

The authors thank Masuhiro Yoshitake and Yoshinori Bamba for their support in the NAT2 analysis.

Funding

This study was sponsored by J-Pharma Co., Ltd.

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Authors and Affiliations

  1. Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan

    Naohiro Okano, Daisuke Naruge, Kirio Kawai, Takaaki Kobayashi, Fumio Nagashima & Junji Furuse

  2. J-Pharma Co., Ltd., Yokohama, Kanagawa, Japan

    Hitoshi Endou

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  1. Naohiro Okano
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Contributions

Conception and design, N.O., H.E., and J.F.; Administrative support, H.E.; Provision of study materials or patients, N.O., D.N., K.K., T.K., F.N., and J.F.; Collection and assembly of data, N.O., D.N., K.K., T.K., F.N., and J.F.; Data analysis and interpretation, N.O., D.N., F.N., H.E., and J.F.; Manuscript writing, All authors.; Final approval of manuscript, All authors.

Corresponding author

Correspondence to Naohiro Okano.

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Conflict of interest

Okano N. received personal fees from Merck Serono, Taiho, Eisai and J-Pharma. Naruge D. declares that he has no conflict of interest. Kawai K. declares that he has no conflict of interest. Kobayashi T. declares that he has no conflict of interest. Nagashima F. received personal fees from Taiho, Chugai, Yakult, Sumitomo Dainippon, Merck Serono, Takeda, Kyowa Hakko Kirin, Sanofi Mochida, Janssen and Nestle. Endou H. received salary from J-Pharma, and has pending patents for LAT1, JPH203 and application of JPH203 in Phase I study of solid tumors. Furuse J. received grants from J-Pharma, Taiho, Sumitomo Dainippon, Janssen, Daiichi Sankyo, MSD, Yakult, Takeda, Chugai, Ono, Astellas, Zeria, Novartis, Nanocarrier, Shionogi, Onco Therapy Science, Eli Lilly Japan, Bayer, Bristol-Myers Squibb, Merck Serono, Kyowa Hakko Kirin, Eisai, NanoCarrier, Mochida, Baxalta and Sanofi, and received personal fees from Taiho, Chugai, Yakult, Sumitomo Dainippon, Eli Lilly Japan, Astellas, Ono, Pfizer, Bayer, Novartis, Merck Serono, Takeda, Eisai, MSD, Shionogi, J-Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Sanofi, Sandoz, Otsuka, Zeria, Fujifilm, Astra Zeneca, Asahi Kasei, Shire, Mochida, Nippon Kayaku, EA pharma, Sawai and Teijin Pharma.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board and with the 1964 Helsinki declaration and its later amendments. This article does not contain any studies with animals performed by any of the authors.

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

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Okano, N., Naruge, D., Kawai, K. et al. First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors. Invest New Drugs 38, 1495–1506 (2020). https://doi.org/10.1007/s10637-020-00924-3

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