Phase 2 Study of HMPL-453 Tartrate in Advanced Intrahepatic Cholangiocarcinoma

The goal of this clinical trial is to evaluate in patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusion/rearrangement. The main questions it aims to answer are:

• To evaluate the objective response rate (ORR) of HMPL-453 tartrate in the treatment of patients with advanced intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor (FGFR) 2 fusions/rearrangements after at least one line of systemic treatment failure or intolerance Participants will receive HMPL-453 tartrate 300 mg QD orally (for 14 consecutive days \[Days 1 to 14\] followed by 7 days off \[Day 15 to 21\], 21 days as a treatment cycle.\]

This is an open-label, single-arm, multicenter phase 2 clinical study to evaluate the efficacy and safety of HMPL-453 tartrate in the treatment of patients with advanced ICC harboring FGFR2 fusions/rearrangements after at least one line of systemic treatment failure or intolerance. The study consists of cohort 1 and cohort 2.

Cohort 1: Approximately 12 patients with locally advanced unresectable or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusions/rearrangements after at least one line of systemic treatment failure or intolerance are planned to be enrolled in this cohort to receive HMPL-453 tartrate 150 mg administered orally once daily (QD) continuously in 21-day cycles.

Cohort 2: A total of approximately 113-116 patients are planned to be enrolled in this cohort, divided into safety run-in and extension phases. Approximately 6 to 9 patients with solid tumors who failed standard treatment or had intolerable toxicity will be enrolled into the first phase (safety run-in phase), to receive HMPL-453 tartrate 300 mg QD orally (for 14 consecutive days \[Day 1 to 14\], followed by 7 days off \[Day 15 to 21\], 21 days as a treatment cycle). Dose limiting toxicities (DLT) observation period consists of 28 days, in which a cycle of treatment will be received. Patients will enter second stage of cohort 2 (extension phase) after completion of safety run-in assessments. Approximately 20 patients with locally advanced unresectable or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusions/rearrangements after at least one line of systemic treatment failure or intolerance will receive HMPL-453 tartrate 300 mg QD orally administered (for 14 consecutive days \[Day 1 to 14\], followed by 7 days off \[Day 15 to 21\], 21 days as a treatment cycle). Based on the efficacy and safety data of the already enrolled patients, and after reaching an agreement with China Center for Drug Evaluation, approximately 90 additional patients with locally advanced unresectable or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusions/rearrangements after at least one line of systemic treatment failure or intolerance are being enrolled to support registration submission as the registration study stage of this study, receiving HMPL-453 tartrate 300 mg QD orally (for 14 consecutive days \[Days 1 to 14\] followed by 7 days off \[Day 15 to 21\], 21 days as a treatment cycle.

Eligibility Criteria:
Inclusion Criteria:

1. Signed the informed consent form;
2. Age ≥ 18 years;
3. Patients with histologically or cytologically confirmed locally advanced unresectable or metastatic intrahepatic cholangiocarcinoma with FGFR2 fusions/rearrangements;
4. Patients have received at least one prior systemic treatment regimen for advanced intrahepatic cholangiocarcinoma and have intolerable PD or toxicity ;
5. Measurable lesion according to RECIST v1.1, refer to the protocol
6. ECOG performance status of 0 or 1;
7. Female patients or male patients with partners of childbearing potential must take effective contraceptive measures per the protocol.

Exclusion Criteria:

1. Patients who previously received selective FGFR targeting therapy;
2. Received approved or researched systemic anti-tumor treatment within 3 weeks;
3. Radical radiotherapy within 4 weeks;
4. Have received local anti-tumor treatment within 4 weeks;
5. Major surgery requiring hospitalization or incomplete healing of the surgery incision within 4 weeks;
6. Current or prior history of retinal detachment;
7. Clinically significant cardiovascular disease such as congestive heart failure or arrhythmia;
8. Patients with acute or chronic active hepatitis B or C infection;
9. The patients with human immunodeficiency virus (HIV) infection;
10. Active infection requiring systemic treatment within 1 week;
11. History of significant abnormal calcium phosphorus metabolism;
12. Currently keratopathy confirmed by ophthalmological examination;
13. Toxicities caused by prior anti-tumor treatment have not recovered to grade 0 or 1;
14. Patients who in the opinion of the investigator may be unsuitable for participating in the study;
15. Combined with other malignant tumor or a history of other malignant tumor;
16. Patients currently has central nervous system metastases, meningeal metastases or spinal cord compression.