Phase I/II Clinical Study Evaluating the Safety, Tolerability, Pharmacokinetics/Pharmacodynamics, and Antitumor Activity of JSKN003 in Chinese Subjects With Advanced Solid Tumors

A total of eight dose groups (Q3W, intravenous administration on the first day of each cycle) were designed in the dose escalation period. The dose groups were 1.0, 2.1, 4.2, 5.2, 6.3, 7.3, 8.4 and 10.5 mg/kg. The BOIN design, incorporating accelerated titration, was used, and the DLT observation period was set at 21 days.

The specific steps for implementing the BOIN design in the clinical trial are as follows:

1. Perform the accelerated titration as follows: Assign the first patient to dose level 1. If this patient does not develop dose-limiting toxicity (DLT), the second patient will be treated at the next higher dose level. Treat one patient at a time and continue the dose-escalation process until the first DLT is observed, or a second grade 2 toxicity occurs, or the highest dose is reached. Two more patients were then treated on the current dose. After that, follow steps 2 and 3 and take the number of cases in each group as 3 to treat the follow-up patients.
2. Assign the dose to the next group of subjects according to the dose rise and fall rule shown in the Bayesian Optimal interval (BOIN) decision table.
3. Repeat Step 2 until the set maximum sample size of 45 or the number of evaluable subjects treated at the current dose reaches 12 and the current decision is to maintain the current dose according to the rise and fall rule of the dose rise and fall decision table.

After the dose escalation period was completed, order preserving regression was used to determine MTD. This calculation can be achieved by "Select MTD" in BOIN online software (Zhou et al., 2020). Specifically, the dose whose toxicity rate is closest to the target toxicity rate estimated by isotropic regression is identified as the MTD. During the dose escalation period, the sponsor may, with the approval of the SMC, expand in the appropriate dose group based on the safety, efficacy and external data obtained during the dose escalation period, as long as the number of patients in the extended dose group is consistent with the total sample size during the dose expansion period. Safety monitoring can still be conducted based on the exclusion boundary in the decision table during dose expansion. The patient data of the extended dose group were not involved in the up-down dose decision and the isotonic regression calculation during the dose escalation period.

The Safety Monitoring Committee (SMC) will perform ongoing safety assessment during the dose escalation period. The safety data of each dose group should be reviewed and approved by the SMC before initiating the administration of the next dose group. If additional safety, efficacy, and PK data are required for a dose group by SMC resolution, subjects may continue enrollment in this dose group after completing the BOIN dose eescalation; If the SMC has decided that a dose group can proceed to the cohort extension phase, it is permitted to proceed directly to the cohort extension phase in that dose group. The composition and responsibilities of the SMC will be further detailed in the SMC Constitution.