A Dose Escalation Study to Assess the Safety and Tolerability of HMPL-453 in Patients With Advanced Solid Malignancies

A Phase I, Open-label, Multi-center, Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of HMPL-453 in Patients With Advanced Solid Malignancies

This is a first-time-in-human, phase I, open-label, dose-escalation study of HMPL-453 in patients with advanced or metastatic solid malignancies who have failed or are intolerable to standard therapies or for whom no standard therapies exist. There are preliminary two stages in this study: a dose-escalation stage (stage 1) and a dose-expansion stage (stage 2). We will decide whether to conduct stage 2 or not one month after the last patient included in stage 1.

Dose-escalation stage (stage 1): Patients participating in the dose-escalation stage will take a single dose of HMPL-453 on Day 1 and will be followed for one week for safety observations. After one week of observation, if no safety issues occur, patients can continue multiple dosing of HMPL-453 QD and start on the DLT assessment cycles. Each cycle consists of 28-days. Patients are required to draw blood samples for PK and safety analysis at specific time points during the treatment.

The 3+3 design will be employed for the dose escalation and MTD determination. To limit the number of patients being exposed to potentially ineffective doses, one patient will be enrolled and dosed in the initial dose cohort. If there are no DLT or < 2 CTCAE grade 2 toxicities occur in the first treatment cycle, then the study will be escalated to the next dose cohort. Otherwise, the trial will revert to a standard 3+3 design.

Dose-Expansion Stage (Stage 2): This stage is to further evaluate the safety, tolerability, PD profile, and preliminary anti-tumor activity of HMPL-453 at the RP2D in approximately 10 patients with advanced solid tumor. Patients with FGFR dysregulated advanced solid tumors, including but not limited to, advanced gastric cancer, advanced urothelial bladder cancer, or advanced cholangiocarcinoma (patients with cancers of the gallbladder or ampulla of Vater are not eligible) are preferred to be enrolled.

Expansion stage will begin after dose-escalation stage is completed and the MTD/RP2D has been determined. Patients will receive HMPL-453 with 28-day treatment cycles until disease progression, death, intolerable toxicity, no longer benefiting from the study treatment per investigator's discretion, or withdrawal of consent, whichever comes first.

Inclusion Criteria:

• In the dose escalation stage, patients with locally advanced, or metastatic solid tumor who have failed, or intolerable to, standard therapies or for whom no standard therapies exist will be enrolled.
• In the dose expansion stage, patients with locally advanced, or metastatic solid tumor and FGFR dysregulation who have failed or intolerable to standard therapies or no standard therapies exist are to be enrolled.
• In the dose escalation stage: evaluable or measurable disease according to RECIST Version 1.1. In the dose expansion stage: measurable disease according to RECIST Version 1.1.
• Life expectancy of at least 12 weeks.
• ECOG performance status of 0 or 1

Exclusion Criteria:

• Prior or current treatment with any selective FGFR inhibitor.