This is a first-in-human (FIH), phase Ⅰ/Ⅱa, open-label, multicenter clinical study of HMPL-A251 monotherapy in adult participants with unresectable, advanced or metastatic HER2-expressing solid tumors.
Histologically confirmed unresectable advanced or metastatic disease.
Have at least one measurable lesion per RECIST v1.1;
Life expectancy ≥ 12 weeks;
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1;
An established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus.
Use of strong inhibitors or strong inducers of cytochrome P450 3A4 enzyme (CYP3A4), and inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) within 5 elimination half-lives or 2 weeks (whichever is longer) before the first dose of study drug;
Toxicity from prior anti-tumor therapy has not recovered to Grade 1 or baseline prior to the first dose of study drug (except alopecia). Participants with chronic Grade 2 toxicities may be eligible after discussion between the investigator and Sponsor Medical Monitor (e.g., Grade 2 chemotherapy-induced neuropathy);
Baseline blood amylase or lipase exceeds the normal range and are judged by the investigators to be clinically significant;
Sequential
HMPL-A251
DrugSix dose cohorts are planned for the Dose Escalation phase; at least three participants with solid tumors will be enrolled in each dose cohort. Bayesian optimal interval design with backfill (BF-BOIN, Zhao, 2023) will be used to guide dose escalation and determine the MTD and/or RDE of HMPL-A251. All study participants will receive HMPL-A251 as IV infusion until PD, intolerable toxicity, or other protocol-specified criteria for ending study treatment, whichever occurs first.
HMPL-A251
DrugParticipants will be randomized in a 1:1 ratio to receive treatment in two RDEs levels (approximately 15 participants per dose level) for each cohort. All study participants will receive HMPL-A251 as IV infusion until PD, intolerable toxicity, or other protocol-specified criteria for ending study treatment, whichever occurs first.
Maximum Tolerated Dose (MTD)
At least three participants will be enrolled in each dose cohort. Bayesian optimal interval design with backfill (BF-BOIN) will be used to guide dose escalation and to determine the MTD of HMPL-A251
Recommended doses for expansion (RDE)
The RDE will be selected by evaluating all available data from the following criteria under consideration: Determination of MTD achieved during the dose escalation part; Safety data obtained across all different doses tested; Tolerability data, such as chronic toxicities, discontinuations, or withdrawals for toxicity that occur beyond the DLT period; PK data collected at the time of evaluation; Preliminary efficacy data.
Overview of Treatment-emergent Adverse Events (TEAEs)
All TEAEs will be graded according to NCI CTCAE v6.0 and coded using the Medical Dictionary for Regulatory Activities (MedDRA).
Objective Response Rate (ORR)
ORR is defined as the proportion of participants with Best objective response (BOR) of confirmed complete response (CR) or partial response (PR), as per investigator's assessment according to RECIST v1.1.
Disease control rate (DCR)
The proportion of participants with BOR of confirmed CR, confirmed PR, or stable disease (SD) lasting at least 5 weeks.
Duration of response (DoR)
Only applies to participants whose BOR is confirmed CR or PR and is defined as the time from the first occurrence of objective tumor response (CR or PR) to the date of first radiographic PD or death due to any cause.
Time to response (TTR)
Only applies to participants whose BOR is confirmed CR or PR and is defined as the time from the first dose of study dose to the first occurrence of objective tumor response (CR or PR)
Progression-free survival (PFS)
The time from the first dose of study drug to the date of first radiographic PD per RECIST v1.1 or death due to any cause, whichever occurs first.
