Clinical trial NCT03160833: A Study of HMPL-453 in Patients With Advanced Solid Malignancies
Official title: A Phase I/II, 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Solid Tumor, Adult
Keywords: HMPL453
solid tumor
dose escalation
Lead sponsor: Hutchmed
Sponsor class: INDUSTRY
First posted: 2017-05-19
Enrollment: 33
Sex: ALL
Minimum age (years): 25
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label, Multi-center, Dose Escalation Study
Primary purpose: TREATMENT

Brief summary: This is a dose escalation study consisting of two stages: Dose-escalation stage (stage 1): Patients 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 (quaque die) and start on the DLT (Dose Limited Toxicity) 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; Dose-Expansion Stage (Stage 2): This stage is to further evaluate the safety, tolerability, PD (pharmacodynamics) profile, and preliminary anti-tumor activity of HMPL-453 at the RP2D (recommended phase 2 dose) in approximately 10 patients with advanced solid tumor.

Detailed description: 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 ( maximum tolerated dose) 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 less than grade 2 toxicities of Common Terminology Criteria for Adverse Event ( CTC AE ) 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, pharmacokinetics (PK) profile, and preliminary anti-tumor activity of HMPL-453 at the RP2D in approximately 60 patients with advanced solid tumor. Patients with FGFR ( Fibroblast Growth Factor Receptor) dysregulated advanced solid tumors, including but not limited to advanced urothelial bladder cancer, advanced cholangiocarcinoma (patients with cancers of the gallbladder or ampulla of Vater are not eligible) and others solid tumors 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.

Eligibility criteria: 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 (Eastern Cooperative Oncology Group) performance status of 0 or 1.

Exclusion Criteria:

* Prior or current treatment with any selective FGFR inhibitor.

Primary outcomes:
measure: Incidence of DLTs by the NCI CTCAE v4.03
timeFrame: Cycle 1 (DLT assessment window 28 days)
Secondary outcomes:
measure: Incidence of AEs and clinically significant laboratory abnormalities
timeFrame: From first dose to 30 days after last dose of study treatment
measure: maximum plasma concentration (Cmax)
timeFrame: From first dose to day 56 of multiple dosing period
measure: time to reach maximum concentration (Tmax)
timeFrame: From first dose to day 56 of multiple dosing period
measure: terminal half-life (t1/2)
timeFrame: From first dose to day 56 of multiple dosing period
measure: area under the concentration-time curve (AUC0-t)
timeFrame: From first dose to day 56 of multiple dosing period
measure: apparent clearance (CL/F)
timeFrame: From first dose to day 56 of multiple dosing period
measure: Serum phosphate level increases
timeFrame: From first dose to Day 21 of the last treatment cycle
measure: Objective response rate (ORR)
timeFrame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks)
measure: Duration of response (DoR)
timeFrame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks)
measure: Disease Control Rate (DCR)
timeFrame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks)
measure: Change in tumor size
timeFrame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks)
measure: Progression free survival (PFS)
timeFrame: Every 8 weeks while being treated with HMPL-453 (expected average of 16 weeks)
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing 307 Hospital
state: Beijing
city: Guangzhou
country: China
facility: Cancer center of SYSU
state: Guangdong
Study officials:
affiliation: HMPL
name: Weiss Yang, Doctor
role: STUDY_DIRECTOR
References: