Overview

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

Eligibility

Inclusion Criteria:

1. Voluntarily participate in this clinical trial, understand and comply with study procedures, and provide written informed consent voluntarily.
2. Female patients aged ≥ 18 years at the time of signing the informed consent form.
3. Patients with histologically or cytologically confirmed unresectable HER2-positive locally advanced or metastatic breast cancer, regardless of hormone receptor (HR) status.
4. 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.
5. 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.

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; 6. Have at least one measurable target lesion per the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) .

7\. ECOG performance status 0-1. 8. Expected survival ≥ 3 months. 9. 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;
• Coagulation function: International Normalized Ratio (INR) ≤ 1.5 × ULN, and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

  10\. Women of childbearing potential (WOCBP) must agree to use highly effective contraception or maintain abstinence from the time of informed consent signature through 6 months after the last administration of the investigational product；For WOCBP, serum pregnancy testing performed within 7 days prior to the first dose of the investigational product must yield a negative result.

Exclusion Criteria:

1. Patients with inflammatory breast cancer.
2. Have received eribulin in prior lines of therapy.
3. Have received prior treatment with an ADC with a tubulin inhibitor payload for recurrent or metastatic disease following prior treatment with an ADC with a topoisomerase inhibitor payload.
4. Prior anti-tumor therapy consisting of utidelone or vinca alkaloids as the last regimen.
5. Patients with a known history of severe hypersensitivity to inetetamab, SMP-656, or any of their excipients.
6. Patients with meningeal metastases.
7. 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).
8. 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.
9. History of interstitial lung disease (ILD) requiring corticosteroid intervention; current or suspected ILD; or has evidence of clinically significant active pneumonia at screening; or has active radiation pneumonitis requiring ongoing medical therapy; or has other severe pulmonary disease impairing respiratory function.
10. 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).
11. 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.
12. 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.
13. 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.
14. 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) .
15. 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.
16. Patients with unresolved prior anti-tumor treatment-related toxicities (alopecia excluded) remaining at Grade \>1 or not recovered to baseline, except adverse events (AEs) deemed not to pose a safety risk by the Investigator.
17. Patients with Grade ≥2 peripheral neuropathy; or prior history of Grade ≥3 neurotoxicity / peripheral neuropathy; or permanent discontinuation of previous anti-tumor treatment due to neurotoxicity or peripheral neuropathy.
18. Patients with a history of allogeneic stem cell transplantation or solid organ transplantation, or those planning to receive allogeneic stem cell transplantation or solid organ transplantation during the study.
19. Patients who have participated in any other clinical trial within 4 weeks or 5 half-lives prior to the first dose of the investigational product, whichever is shorter.
20. Patients who received radiotherapy within 4 weeks prior to the first dose of the investigational product are excluded, except palliative radiotherapy administered for symptom control within 2 weeks before the first dose of investigational product.
21. Patients who received systemic anti-tumor therapy within 4 weeks prior to the first dose of the investigational product are excluded, except for the following： 1) Enrollment is permitted only if at least 6 weeks have elapsed between the completion of prior nitrosourea or mitomycin chemotherapy and the first dose of the investigational product; 2) Enrollment is allowed only if a minimum of 1 week has passed between the discontinuation of prior small-molecule targeted therapy and the first dose of the investigational product; 3) Enrollment is permitted only if a minimum of 2 weeks have elapsed between discontinuation of prior traditional Chinese medicine with anti-tumor effects and the first dose of the investigational product.
22. articipants who have undergone major surgery within 4 weeks prior to the first dose of the investigational product, or are expected to receive major surgery during the study period (diagnostic surgery excluded); those who received diagnostic or minimally invasive surgery within 1 week before the first dose are also excluded.
23. Patients requiring long-term treatment with corticosteroids or immunosuppressive agents (e.g., active autoimmune diseases requiring systemic therapy). Replacement therapies such as thyroxine, insulin, or physiological corticosteroid replacement for adrenal or pituitary insufficiency are permitted.
24. Prior documented history of neurological or psychiatric disorders, including epilepsy or dementia.
25. Female Patients who are pregnant, breastfeeding, or planning to become pregnant during the study.
26. Patients with severe concomitant diseases that may compromise patient safety or interfere with study completion as judged by the Investigator (e.g., severe hypertension, diabetes mellitus, thyroid disorders), or any other conditions deemed inappropriate for study participation by the Investigator.