First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tu
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PHASE I STUDIES
First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors Naohiro Okano 1 & Daisuke Naruge 1 & Kirio Kawai 1 & Takaaki Kobayashi 1 & Fumio Nagashima 1 & Hitoshi Endou 2 & Junji Furuse 1 Received: 6 February 2020 / Accepted: 11 March 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords L-type amino acid transporter 1 . JPH203 . Amino acids . Biliary tract cancer . N-acetyltransferase 2 . Phase I
Introduction Cancer cells require more glucose and amino acids than normal cells because of their rapid proliferation rate. Therefore, cancer cells tend to have higher expression of transmembrane nutrient transporters, such as those for glucose and amino acids [1]. Hosios et al. recently reported that, in cancerrelated cellular proliferation, the majority of the cell mass (blocks) is derived from non-glutamine amino acids, while the consumption of glucose and glutamine is mainly involved in metabolism (i.e., as energy sources) rather than for the cell block increase during the proliferation of normal tissues and
* Naohiro Okano [email protected] 1
Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
2
J-Pharma Co., Ltd., Yokohama, Kanagawa, Japan
cancer growth [2]. Thus, non-glutamine amino acids seem to be more important in both normal and cancer cell growth, relative to glucose for normal tissue regeneration, wh
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