A Phase Ⅰ/Ⅱa Study of HMPL-A251 in Participants With Advanced or Metastatic HER2-expressing Solid Tumors

A Phase Ⅰ/Ⅱa Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity and Preliminary Efficacy of HMPL-A251 in Participants With Advanced or Metastatic HER2-Expressing Solid Tumors

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.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumors, Adult
• Intervention / Treatment: Drug: HMPL-A251; Drug: HMPL-A251

Detailed Description

• To evaluate the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE) of HMPL-A251 in participants with previously treated HER2+ solid tumors
• To characterize the safety and preliminary efficacy of HMPL-A251 at RDEs to determine recommended dose(s) for phase 2 (RP2D) or phase 3 (RP3D) in participants with selected HER2-expressing solid tumors

• Study Type: Interventional
• Enrollment (Estimated): 147
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Peking University First Hospital
    • Contact: Shikai Wu; Phone Number: +86 18910715326; Email: skywu4329@sina.com
  • Changsha, China
    • Recruiting
    • Hunan Cancer Hospital
    • Contact: Quchang Oyang; Phone Number: 0731-89762161; Email: Oyqc1969@126.com
  • Guangzhou, China
    • Recruiting
    • Sun Yat-sen University Cancer Center
    • Contact: Shusen Wang; Phone Number: 020-87342693; Email: Wangshus@susucc.org.cn
  • Hefei, China
    • Recruiting
    • The First Affiliated Hospital of Anhui Medical University
    • Contact: Yingying Du; Phone Number: 0551-65908511; Email: duyy1980@126.com
  • Shanghai, China
    • Not yet recruiting
    • Fudan University Shanghai Cancer Center
    • Contact: Xiaohua Wu
  • Shenyang, China
    • Not yet recruiting
    • The First Hospital of China Medical University
    • Contact: Funan Liu
  • Zhengzhou, China
    • Recruiting
    • Henan Cancer Hospital
    • Contact: Min Yan; Phone Number: +86 157 1385 7388; Email: ym200678@163.com
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Recruiting
      • SCRI HealthONE
      • Contact: Gerald Falchook; Phone Number: 940-365-6217; Email: bianca.reyes@scri.com
  • Florida
    • Plantation, Florida, United States, 33322
      • Recruiting
      • BRCR Global
      • Contact: Harshad Amin; Phone Number: 561-447-0614; Email: alejandrop@brcrglobal.com
    • Plantation, Florida, United States, 33322
      • Not yet recruiting
      • Florida Clinical Trials Group LLC (Plantation)
      • Contact: Harshad Amin
    • Tamarac, Florida, United States, 33321
      • Not yet recruiting
      • Florida Clinical Trials Group LLC (Tamarac)
      • Contact: Chintan Ghandi
  • New Jersey
    • East Brunswick, New Jersey, United States, 08816
      • Not yet recruiting
      • START New Jersey
      • Contact: Bruno Fang
  • New York
    • New York, New York, United States, 10065
      • Not yet recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Vicky Makker
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic Taussig Cancer Center
      • Contact: WenWee Ma; Phone Number: 216-559-9815; Email: keaneyh@ccf.org
  • Texas
    • San Antonio, Texas, United States, 78229
      • Not yet recruiting
      • Mays Cancer Center
      • Contact: Daruka Mahadevan
  • Washington
    • Tacoma, Washington, United States, 98405
      • Not yet recruiting
      • Northwest Medical Specialties, PLLC
      • Contact: Jorge Chaves

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically confirmed unresectable advanced or metastatic disease.
2. Have at least one measurable lesion per RECIST v1.1;
3. Life expectancy ≥ 12 weeks;
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1;
5. Weight ≥ 35 kg;

Exclusion Criteria:

1. An established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus.
2. Use of strong inhibitors 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;
3. 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);
4. Baseline blood amylase or lipase exceeds the normal range and are judged by the investigators to be clinically significant;
5. Spinal cord compression, leptomeningeal disease, or clinically active central nervous system (CNS) metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms;
6. Major surgery within 28 days prior to the first dose of study drug. Participants must have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of study drug(s);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A(Phase I); Dose Escalation	Drug: HMPL-A251; Six 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.; Drug: HMPL-A251; Participants 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.
Experimental: Part B(Phase IIa); Dose Expansion/Dose Optimization	Drug: HMPL-A251; Six 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.; Drug: HMPL-A251; Participants 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Approximately 12 months
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.	Approximately 12 months
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).	Approximately 24 months
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.	At least 6 weeks post dose of first participant up to approximately 24 months
Recommended doses for phase II or III studies (RP2D or RP3D) of HMPL-A251	The RP2D or RP3D 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; PK data; efficacy data.	Approximately 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease control rate (DCR)	The proportion of participants with BOR of confirmed CR, confirmed PR, or stable disease (SD) lasting at least 5 weeks.	Approximately 2 years
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.	Approximately 2 years
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)	Approximately 2 years
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.	Approximately 2 years
Overall survival (OS)	Every 12 weeks (± 7 days) until death, withdrawal of consent for follow-up, lost to follow-up or end of study, whichever occurs first.	Approximately 2 years
Pharmacokinetic Analysis(Cmax)	Maximum Observed Serum Concentration	Each cycle(21-day cycle), From C9, every 4 cycles, Approximately 12 months
Pharmacokinetic Analysis(Tmax)	Time to Peak Plasma Concentration	Each cycle(21-day cycle), From C9, every 4 cycles, Approximately 12 months
Pharmacokinetic Analysis((AUC)	Area Under the Concentration Versus Time Curve	Each cycle(21-day cycle), From C9, every 4 cycles, Approximately 12 months
To evaluate the immunogenicity of HMPL-A251	Incidence of anti-drug antibody and neutralizing antibody against HMPL-A251	Each cycle(21-day cycle), From C9, every 4 cycles, Approximately 12 months

Collaborators and Investigators

• Sponsor: Hutchmed

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2025
• Primary Completion (Estimated): November 30, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: November 11, 2025
• First Submitted That Met QC Criteria: November 13, 2025
• First Posted (Actual): November 14, 2025

Study Record Updates

• Last Update Posted (Actual): May 27, 2026
• Last Update Submitted That Met QC Criteria: May 25, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: 2025-251-GLOB1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No