Accepted for/Published in: JMIR Research Protocols
Date Submitted: Nov 17, 2025
Date Accepted: Jan 20, 2026
Date Submitted to PubMed: Jan 27, 2026
Flopropione, a cysteine-conjugate-β-lyase 1 inhibitor, for prevention of cisplatin-induced nephrotoxicity: protocol for a randomized, open-label, proof-of-concept phase I/IIa trial
ABSTRACT
Background:
Cisplatin-induced nephrotoxicity (CIN) is a major dose-limiting adverse event that can lead to both acute and chronic kidney injury. The formation of thiol–cisplatin conjugates within renal tubular cells has been implicated as a key mechanism underlying CIN. Flopropione is an inhibitor of cysteine conjugate β-lyase 1, an enzyme that catalyzes the formation of the thiol-cisplatin conjugate, which may prevent CIN.
Objective:
We designed a clinical trial to evaluate the safety of flopropione in patients receiving cisplatin-based chemotherapy to explore its efficacy in preventing CIN.
Methods:
This is a phase I/IIa, single-center, randomized, open-label trial conducted in patients undergoing cisplatin therapy. Participants are randomized at a 5:2 ratio per cohort to receive either flopropione or no treatment. On the day of cisplatin administration, the flopropione group receives oral flopropione twice daily (80 mg in Cohort 1, 160 mg in Cohort 2, and 240 mg in Cohort 3). On the following day, all cohorts receive three doses of 80 mg of oral flopropione. A step-up dose escalation design is adopted, progressing from Cohort 1 to 3 after confirming safety at each level. The primary endpoint is the safety of flopropione use in combination with cisplatin, and the secondary endpoints include changes in the levels of urinary biomarkers of nephrotoxicity, such as neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and kidney injury molecule-1. Blood and urine samples are collected within 48 h before cisplatin administration and at 24 h, 48 h, and 1 week after initiation for safety and efficacy assessments.
Results:
The first participant was registered in July 2024. As of the date of manuscript submission in November 2025, participant registration is ongoing. The final participant will complete the study by December 2025. Publication of results is expected by the end of 2026.
Conclusions:
This study is expected to promote drug discovery targeting cysteine conjugate β-lyase 1, with particular focus on flopropione and related compounds. Clinical Trial: Japan Registry of Clinical Trials jRCTs041220021; https://jrct.mhlw.go.jp/en-latest-detail/jRCTs041220021
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