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

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/m. 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/m and in the first patient to receive 85 mg/m. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m. The AUC increased between 12 mg/m and 25 mg/m, although no differences were observed at 25-40 mg/m. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m and 25 mg/m dose levels. Based on these results, we recommend a phase II dose of 25 mg/m. 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.