SMP-656 for HER2-Positive Advanced Breast Cancer

NCT07726342 | Not Yet Recruiting Phase 2

• 1 other identifier: SMP-656-201
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 15

Brief Summary

The goal of this clinical trial is to learn if single-agent SMP-656 works to treat patients with HER2-positive locally advanced or metastatic breast cancer who have progressed after prior HER2-targeted topoisomerase inhibitor antibody-drug conjugate (ADC) treatment. It will also evaluate the safety of SMP-656 and identify the optimal dose for future trials. The main questions it aims to answer are: What is the objective tumor response rate (DOR, PFS, DCR, OS) of two different dose regimens of intravenous SMP-656? What are the side effects and safety risks of these two SMP-656 dose regimens? Which dose level achieves the best balance of anti-cancer activity and tolerability? This is a randomized, open-label, dose-optimization Phase II clinical trial. Participants will be randomly assigned 1:1 to receive one of two fixed doses of SMP-656 given intravenously once every 3 weeks. Participants will: Complete screening tests within 28 days before the first SMP-656 infusion to confirm eligibility Receive study treatment every 3 weeks until cancer progression, intolerable side effects, withdrawal, or other stopping criteria Have regular tumor imaging scans, physical exams, vital sign checks, and blood tests to monitor tumor response and safety Attend a safety follow-up visit 30 days after the last dose of SMP-656 Complete longer-term survival follow-up after the 30-day safety check Provide optional blood and tumor tissue samples for additional research studies

Conditions

HER2-positive Breast Cancer; Metastatic Breast Cancer; Locally Advanced Breast Cancer (LABC)

Keywords

SMP-656; Randomized Open-Label Trial; HER2; Antibody-Drug Conjugate; Trastuzumab Deruxtecan resistant; Phase II Trial; Dose Optimization; Topoisomerase Inhibitor; Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate (ORR) assessed by Independent Review Committee (IRC)

  ORR is the percentage of evaluable patients with an IRC-assessed response of complete response (CR) or partial response (PR) per RECIST v1.1.

  From the date of first dose to the date of first radiological documentation of disease progression or death, whichever occurs first (up to 24 months)

• Recommended Dose in Pivotal Clinical Trials

  Determination of pivotal trial recommended dose based on drug exposure, efficacy, and safety profiles across different dose levels.

  Through study completion, up to 24 months from first dose

Secondary Outcomes (15)

• ORR assessed by Investigators

  From the date of first dose to the date of first radiological documentation of disease progression or death, whichever occurs first (up to 24 months)

• Duration of Response (DOR)

  From first confirmed objective response (CR/PR) up to 24 months from first dose

• Progression-Free Survival (PFS)

  From the date of first dose to the date of first radiological documentation of disease progression or death, whichever occurs first (up to 24 months)

• Disease Control Rate (DCR)

  Up to 24 months from first dose

• Overall Survival (OS)

  From treatment initiation until death from any cause, assessed up to 60 months.

Other Outcomes (2)

• Genomic and Microenvironment Molecular Alterations Associated With SMP-656 Resistance

  Baseline and end-of-treatment (EOT) visit. EOT sampling is performed within 7 days after treatment discontinuation and prior to any new antitumor therapy, up to 24 months from first dose.

• Multi-Omics Biomarker Profiles Correlated With Clinical Efficacy and Prognosis

  Baseline and EOT visit. EOT sampling is performed within 7 days after treatment discontinuation and prior to any new antitumor therapy, up to 24 months from first dose.

Study Arms (2)

SMP-656 2.0 mg/kg

EXPERIMENTAL

SMP-656 2.0 mg/kg Q3W

Drug: SMP-656 Injection

SMP-656 2.2 mg/kg

EXPERIMENTAL

SMP-656 2.2 mg/kg Q3W

Drug: SMP-656 Injection

Interventions

SMP-656 Injection DRUG

SMP-656 injection administered via intravenous infusion at a dose of 2.0 mg/kg once every 3 weeks (Q3W). Treatment continues until disease progression, intolerable toxicity, voluntary withdrawal, death, or trial termination.

SMP-656 2.0 mg/kg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Voluntarily participate in this clinical trial, understand and comply with study procedures, and provide written informed consent voluntarily;
• Female patients aged ≥ 18 years at the time of signing the informed consent form;
• Patients with histologically or cytologically confirmed unresectable HER2-positive locally advanced or metastatic breast cancer, regardless of hormone receptor (HR) status;
• HER2-positive status confirmed by testing at the study center or an accredited laboratory, where HER2 positivity is defined as IHC 3+, or IHC 2+ with positive fluorescence in situ hybridization (FISH+) results;
• Patients with HER2-positive locally advanced or metastatic breast cancer who have received prior treatment with one TOP inhibitor ADC targeting HER2 (e.g., DS-8201 and other ADCs with topoisomerase inhibitor payloads), and have experienced disease progression after no more than three lines of standard therapy for recurrent or metastatic disease; 1) Endocrine monotherapy is excluded from the abovementioned standard therapy lines; 2) Disease recurrence occurring within 12 months following neoadjuvant or adjuvant chemotherapy will be regarded as progression after first-line standard therapy;
• Have at least one measurable target lesion per the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) ;
• ECOG performance status 0-1;
• Expected survival ≥ 3 months;
• Bone marrow, hepatic, renal and coagulation function shall be deemed adequate based on laboratory tests performed within 7 days prior to the first dose of the investigational product. Blood transfusion or growth factor supportive therapy is prohibited within 14 days before the first administration of the investigational product：
• Bone marrow function: absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; platelet count (PLT) ≥ 80 × 10⁹/L; hemoglobin (Hb) ≥ 90 g/L;
• Hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN); total serum bilirubin (TBIL) ≤ 1.5 × ULN, with the following exceptions;
• For participants with confirmed liver metastases: AST and/or ALT ≤ 5 × ULN;
• For participants diagnosed with Gilbert's syndrome: TBIL ≤ 3 × ULN;
• Serum albumin ≥ 30 g/L;
• Renal function: Creatinine clearance (CrCL) ≥ 50 mL/min (calculated via the Cockcroft-Gault formula), OR serum creatinine ≤ 1.5 × ULN;

You may not qualify if:

• Patients with inflammatory breast cancer;
• Have received eribulin in prior lines of therapy;
• Have received prior treatment with ADCs carrying tubulin inhibitor payloads for recurrent or metastatic disease;
• Prior anti-tumor therapy consisting of utidelone or vinca alkaloids as the last regimen;
• Patients with a known history of severe hypersensitivity to inetetamab, SMP-656, or any of their excipients;
• Patients with meningeal metastases;
• Patients with active central nervous system (CNS) metastases are excluded, with the following exception: symptomatic CNS metastases limited to supratentorial region and/or cerebellum (i.e., no midbrain, pons, medulla oblongata or spinal cord metastases) that have received local therapy, with neurological symptoms stabilized for at least 2 weeks prior to the first dose of investigational product, and no requirement for steroid therapy or receiving prednisone ≤10 mg/day (or equivalent corticosteroids) ;
• Patients diagnosed with any other malignancy (other than the study tumor type) within 5 years prior to the first dose of the investigational product, except curatively treated localized malignancies such as basal cell carcinoma of the skin;
• Previous, current or suspected interstitial lung disease (ILD), drug-induced interstitial lung disease; or clinically significant active pneumonia identified at screening; or radiation pneumonitis, or other severe pulmonary disorders impairing respiratory function, which in the Investigator's judgment may interfere with the detection or management of investigational product-related pulmonary toxicity;
• Patients with a clinically significant history of cardiovascular disease, including but not limited to： (1) Left ventricular ejection fraction (LVEF) \< 50%; congestive heart failure with New York Heart Association (NYHA) functional class \> 2; (2) Have experienced myocardial infarction, unstable angina, severe pericardial disease or severe myocardial disease within the previous 6 months; (3) Presence of cardiac valve regurgitation or stenosis requiring therapeutic intervention; (4) Any supraventricular or ventricular arrhythmia requiring treatment or intervention; poorly controlled malignant arrhythmias despite medication; complete left bundle branch block, second-degree or third-degree atrioventricular block; (5) QTc interval \> 470 ms at screening (for female participants), or known family history of long QT syndrome; (6) Uncontrolled hypertension (defined as systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg despite antihypertensive medication, or prior history of hypertensive crisis or hypertensive encephalopathy) ;
• History of arterial or venous thromboembolic events within 6 months prior to the first dose of the investigational product, such as cerebrovascular accident, deep vein thrombosis and pulmonary embolism;
• Participants with uncontrollable pleural effusion, pericardial effusion or ascites as judged by the Investigator, which requires repeated drainage once every two weeks or more frequently. Participants with indwelling pleural catheters are permitted to enroll;
• Have received live attenuated vaccines within 4 weeks prior to the first dose of the investigational produc, or plan to receive live attenuated vaccines during the study;
• Patients with severe infection within 4 weeks prior to the first dose of the investigational product, including but not limited to bacteremia or severe pneumonia requiring hospitalization; or active infection with CTCAE Grade ≥2 requiring systemic antibiotic therapy within 2 weeks before the first dose (prophylactic antibiotics excluded) ;
• Patients meeting any of the following criteria will be excluded: patients with active hepatitis B or hepatitis C；For patients positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb), enrollment is permitted only if quantitative hepatitis B virus DNA (HBV-DNA) is below the upper limit of normal (ULN) of the study site laboratory；For patients positive for hepatitis C antibody (HCV-Ab), enrollment is permitted only if HCV RNA is below the ULN of the study site laboratory；Positive human immunodeficiency virus (HIV) antibody test; active syphilis infection; active tuberculosis infection;

Sponsors & Collaborators

• Chengdu SciMount Pharmatech Co., Ltd.: lead

Study Sites (15)

The Second Affiliated Hospital of Anhui Medical University

Hefei, Anhui, China

Location

Beijing Cancer Hospital

Beijing, Beijing Municipality, China

Location

Cancer Hospital, Chinese Academy of Medical Sciences

Beijing, Beijing Municipality, China

Location

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, China

Location

The Fourth Hospital of Hebei Medical University

Shijiazhuang, Hebei, China

Location

Henan Provincial People's Hospital

Zhengzhou, Henan, China

Location

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, China

Location

Zhongnan Hospital of Wuhan University

Wuhan, Hubei, China

Location

The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University

Changsha, Hunan, China

Location

Zhongda Hospital, Southeast University

Nanjing, Jiangsu, China

Location

Liaoning Cancer Hospital & Institute

Shenyang, Liaoning, China

Location

Shandong Cancer Hospital and Institute

Jinan, Shandong, China

Location

The First Affiliated Hospital of Xi'an Jiaotong University

Xi’an, Shanxi, China

Location

Sichuan Cancer Hospital & Institute

Chengdu, Sichuan, China

Location

Sir Run Run Shaw Hospital, Zhejiang University School of Medicine

Hangzhou, Zhejiang, China

Location

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Central Study Contacts

Binghe Xu

CONTACT

86-18519281183; xubinghe@medmail.com.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Eligible female patients with HER2-positive locally advanced or metastatic breast cancer who progressed after prior HER2-targeted topoisomerase inhibitor ADC therapy will be randomized 1:1 to receive intravenous SMP-656 at either 2.0 mg/kg or 2.2 mg/kg once every 3 weeks. Stage 1 will enroll 15 subjects per dose arm (total 30 participants). A pre-specified interim analysis will be performed upon completion of Stage 1 enrollment by the SRC: If significant differences in efficacy and safety between arms substantially alter risk-benefit balance, the inferior dose cohort will close, and an additional 15 subjects will be enrolled only to the superior cohort. If no clinically meaningful inter-arm differences are observed, 15 more participants will be randomized 1:1 to each dose group. Total planned enrollment ranges from 45 to 60 subjects. All participants will receive continuous study treatment.

Study Record Dates

• First Submitted: July 13, 2026
• First Posted: July 24, 2026
• Study Start: July 16, 2026
• Primary Completion (Estimated): July 7, 2027
• Study Completion (Estimated): October 20, 2027
• Last Updated: July 24, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

CN (15)