Study design and drug administration
toxicities, DLTs
DISEASE
This was a phase Ia, multicenter, open-label, dose-escalation study of SYHA1813. The overall study design is presented in Supplementary Fig. S1. The primary endpoints were the safety and tolerability of SYHA1813, including the occurrence of dose-limiting toxicities (DLTs) and the establishment of the maximum tolerated dose (MTD). Secondary endpoints included determination of the PK profile and preliminary antitumor activity based on the objective response rate (ORR), and disease control rate (DCR), as well as exploration of potential biomarkers related to SYHA1813 therapy. The study was approved by the National Medical Products Administration (NMPA) for clinical trials. We conducted the study according to the ethical principles of the Declaration of Helsinki and Good Clinical Practices guidelines. The study was approved by an institutional review board at each participating site. All patients provided written informed consent. The study was registered at chictr.org.cn (trial registration ID: ChiCTR2100045380).The maximum recommended starting dose (based body weight 60 kg) of 11 mg was estimated based on 1/6 of the highest non-severely toxic dose in the beagle dog study. Based on further safety considerations, 5 mg was selected as the starting dose in human subjects. In the dose-escalation study, patients were enrolled sequentially to receive a single oral dose of SYHA1813 (5, 15, 30, 60, 100, 150, and 200 mg) followed by a 3-day observation period with safety and PK assessments, subsequent once-daily treatment at the same dose level during 21-day multiple-dose period followed by a 4-day observation period with safety, PK and efficacy assessments. From the second cycle onwards, the study drug was given every day (3 weeks/cycle) if the treatment was well tolerated and beneficial.