SMP-656 for HER2-Positive Advanced Breast Cancer

This is a randomized, open-label, dose-optimization Phase II clinical trial to assess the efficacy and safety of single-agent SMP-656 in patients with HER2-positive unresectable locally advanced or metastatic breast cancer who progressed after prior HER2-targeted topoisomerase inhibitor ADC therapy.

The trial plans to enroll approximately 45-60 participants. Eligible participants must have received one prior HER2-targeted topoisomerase inhibitor ADC (e.g., DS-8201 or other ADCs with topoisomerase inhibitor payloads) and experienced disease progression after a maximum of three lines of standard systemic therapy for recurrent/metastatic disease (single-agent endocrine therapy excluded).

Two dose cohorts selected based on Phase I data: 2.0 mg/kg and 2.2 mg/kg. Participants will be randomized 1:1 to each dose cohort, with 15 subjects enrolled per cohort in Stage 1. An interim analysis will be conducted after Stage 1 enrollment completion:

• If statistically significant differences in safety/efficacy between cohorts are identified that materially impact risk-benefit assessment, the inferior cohort will be closed, and the superior cohort will accrue an additional 15 subjects to complete the trial.
• If no meaningful inter-cohort differences are observed, randomization will continue 1:1 with an additional 15 subjects per cohort.

The investigational product will be administered intravenously once every 3 weeks (Q3W). All participants will receive long-term treatment until the first occurrence of any of the following events: intolerable toxicity, disease progression (judged by the investigator that further treatment cannot provide clinical benefit), loss to follow-up, death, voluntary withdrawal, or study completion/early termination of the trial, whichever comes first.

A Safety Review Committee (SRC) will be established for this trial. Based on the results of interim analysis assessments, the SRC shall judge and determine the further research of each dose group, and make decisions on the key clinical trial doses.

The study consists of a screening period (from the time participants sign the informed consent form up to prior to the first study drug administration, with a maximum duration of 28 days), a treatment period (from the first study drug administration to permanent discontinuation of study drug), and a follow-up period (post-discontinuation safety follow-up and survival follow-up).

During the treatment period, all participants shall undergo tumor imaging assessments every 6 weeks (±7 days) starting from the first dose administration. Imaging assessments will not be affected by interrupted or delayed study drug administration. Investigators will assess antitumor efficacy in accordance with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Assessments will continue until the earliest occurrence of any of the following events: disease progression, withdrawal of informed consent, loss to follow-up, death, initiation of new antitumor therapy, or trial conclusion (including trial completion and early trial termination), whichever comes first.

Safety Follow-up All participants shall complete a safety follow-up visit at 30 days ± 7 days after the last dose of the investigational product.

If the End of Treatment (EOT) visit for early discontinuation or treatment completion coincides with the scheduled safety follow-up timepoint, duplicate assessments are not required.

If the actual completion date of the early discontinuation/treatment completion (EOT) visit falls beyond the scheduled safety follow-up window due to objective reasons (e.g., delayed dosing), duplicate assessments are also not required. Failure to complete the dedicated safety follow-up in such circumstances shall not be deemed a protocol deviation (PD).

Survival Follow-up After completion of the safety follow-up, investigators will collect survival information for all participants every 3 months (±14 days) via telephone interviews, review of participants' medical records or outpatient medical files. Survival follow-up will continue until any of the following occurs: withdrawal of informed consent by the participant, loss to follow-up, death, or trial termination.

Inclusion criteria

• 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;
• Coagulation function: International Normalized Ratio (INR) ≤ 1.5 × ULN, and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;
• 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

• 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;
• 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;
• 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;
• 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;
• 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;
• 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;
• 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;
• 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;
• 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;
• Prior documented history of neurological or psychiatric disorders, including epilepsy or dementia;
• Female Patients who are pregnant, breastfeeding, or planning to become pregnant during the study;
• 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 .