This is a multicenter, open-label, dose escalation, and expansion human clinical study to observe the safety, tolerability, pharmacokinetics, and pharmacodynamics of XZP-3621 in single and multiple oral administrations in advanced NSCLC subjects with ALK rearrangement or ROS1 rearrangement, and to initially explore the efficacy of XZP-3621.The study was divided into two parts: dose escalation and dose expansion.~Dose escalation part:~The purpose of this section was to determine MTD and RP2D doses in advanced NSCLC subjects with ALK rearrangement or ROS1 rearrangement detected in tumor tissue samples or blood samples (test method is not limited).The safety and PK of single dose in human subjects in each group were first studied. After PK blood sample was collected 72 hours after single dose on day 1, continuous dose was administered once a day for 4 weeks to confirm the safety and pharmacokinetic characteristics of single dose and continuous dose.~In this study, Modified Fibonacci method was used for dose escalation. One subject was enrolled at the initial dose of 50mg. After that, according to the 3+3 dose escalation principle, the dose of 100mg (100%), 200mg (100%), 300mg (50%), 400mg (33%), 500mg (25%), 600mg (20%)and so on was incremented successively. Starting from the 100mg Qd dose group, 3 NSCLC subjects with ALK rearrangement or ROS1 rearrangement should be included per dose.If less than 3 NSCLC subjects were ALK rearrangement in any dose group due to inclusion of ROS1, and no ≥1 PR was observed in this group, additional ALK rearrangement NSCLC subjects should be added until the requirements are met. However, as long as the number of subjects in the corresponding dose group who have completed DLT observations meets the 3+3 principle of escalation, the addition of subjects to the ALK rearrangement should not affect the normal escalation of the next dose group.~Dose expansion part:~In the dose escalation study, if 2 out of 3 ALK rearrangement NSCLC subjects have a partial response (PR) or complete response (CR) after all subjects in the dose escalation study have completed DLT evaluation and confirmed that the dose is safe, that is, a dose extension study is performed from this dose to the MTD dose group. Each dose was reenrolled in about 15 NSCLC subjects with ALK rearrangement or ROS1 rearrangement demonstrated by Ventana immunohistochemistry or FISH or RT-PCR.~Subjects were treated with XZP-3621 for a 28-day treatment cycle, with continuous administration of or XZP-3621 until disease progression occurs, or an intolerable toxic reaction impeding further treatment occurs, or the investigator determines that the subject's current condition is unsuitable for further treatment, the informed consent is withdrawn, or the subject dies. RECIST efficacy was evaluated once every two treatment cycles.~During treatment, dose adjustments (both up and down) can be made according to protocol based on subjects' tolerance and the occurrence of adverse events related to the study drug. Only one dose reduction of the study drug is permitted.
This is a multicenter, open-label, dose escalation, and expansion human clinical study to observe the safety, tolerability, pharmacokinetics, and pharmacodynamics of XZP-3621 in single and multiple oral administrations in advanced NSCLC subjects with ALK rearrangement or ROS1 rearrangement, and to initially explore the efficacy of XZP-3621.The study was divided into two parts: dose escalation and dose expansion.