A Clinical Study of SYS6023 Combination Therapy for Advanced Breast Cancer

This is an open-label, multicenter Phase II clinical study conducted in subjects with advanced breast cancer.

The study aims to evaluate the safety/tolerability, pharmacokinetics, and preliminary efficacy of SYS6023 in combination with other agents in subjects with advanced breast cancer.

Eligible subjects will receive SYS6023 in combination with HB1901 or KN026, with each treatment cycle lasting 3 weeks, until disease progression, intolerable toxicity, initiation of new anti-tumor therapy, withdrawal of informed consent, loss to follow-up, or death, whichever occurs first.

Inclusion criteria

• 1. Age ≥ 18 years old;
• 2. Histologically or cytologically confirmed unresectable locally advanced or metastatic breast cancer:
• 3. Sufficient tumor specimens must be provided for biomarker testing (human epidermal growth factor receptor 3-HER3), preferably obtained during or after the most recent treatment period; During safety run-in period, subjects who cannot provide sufficient tissue samples may be screened after sponsor's evaluation and approval;
• 4. Documented disease progression or intolerability with the most recent systemic anti-tumor treatment;
• 5. According to RECIST 1.1, at least one evaluable lesion (safety run-in period) or measurable lesion (cohort expansion phase);
• 6. ECOG PS score 0-1;
• 7. Expected survival ≥ 3 months;
• 8. Adequate organ function with laboratory tests meeting criteria (no blood transfusion or hematopoietic growth factor therapy within 14 days before testing): ANC ≥ 1.5 × 10^9/L PLT ≥ 100 × 10^9/L Hb ≥ 90 g/L TBIL ≤ 1.5 × ULN ALT, AST ≤ 2.5 × ULN; for participants with liver metastasis, ALT and AST ≤ 5 × ULN Creatinine clearance rate (Ccr) > 35 mL/min (calculated according to Cockcroft-Gault formula) Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; International normalized ratio (INR) ≤ 1.5 × ULN Left ventricular ejection fraction (LVEF) ≥ 55% (only applicable to Cohort 2)
• 9. Eligible individuals with reproductive potential must agree to use reliable contraceptive methods (hormonal contraceptives, barrier methods, or abstinence) with their partners during the trial and for at least 7 months after the last dose; Women of childbearing potential must have a negative blood pregnancy test within 7 days before enrollment;
• 10. Fully understand this clinical trial and voluntarily sign the written informed consent form.

Exclusion criteria

• 1. Prior treatment with HER3-targeted ADC therapy;
• 2. Applicable to Cohort 1: a. Prior treatment with any topoisomerase I inhibitor-loaded ADC therapy; b. Current presence or impending visceral crisis that has caused or may cause impending organ damage and/or other life-threatening complications;
• 3. Applicable to Cohort 2: a. Prior exposure to anthracyclines with cumulative dose exceeding 360 mg/m^2doxorubicin equivalent; b. LVEF once dropped to < 40% during prior anti-HER2 drug therapy, or symptomatic CHF occurred;
• 4. History of other malignancies within 3 years before randomization/first dose or concurrent active malignancies (except cured localized tumors such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, carcinoma in situ of the cervix, carcinoma in situ of the breast, etc., which are allowed to enroll);
• 5. Untreated (including those detected during screening period) or unstable brain parenchymal metastasis, spinal cord metastasis or compression, carcinomatous meningitis. Subjects with treated stable brain metastases may be considered for enrollment (Note: refers to participants who have received local brain treatment, whose symptoms are stable, imaging tests show stability for at least 28 days before randomization/first dose, no evidence of progressive brain edema, and no need for glucocorticoids or other symptom control measures);
• 6. Adverse reactions from prior anti-tumor therapy have not recovered to CTCAE 6.0 grade ≤ 1 (except for toxicities such as alopecia that researchers judge to have no safety risk);
• 7. Major surgery within 28 days before randomization/first dose, or planned to undergo systemic or local tumor resection during the study period;
• 8. History of severe bleeding risk (e.g., gastrointestinal varices) or bleeding diathesis, any gastrointestinal bleeding or other bleeding of ≥ CTCAE grade 2 within 28 days before randomization/first dose; Abdominal fistula, gastrointestinal perforation or abdominal abscess within 6 months before randomization/first dose;
• 9. History of severe cardiovascular disease, including but not limited to:

• Acute coronary syndrome within 6 months before randomization/first dose;
• Stroke or transient ischemic attack within 6 months before randomization/first dose;
• Pulmonary embolism or deep vein thrombosis within 3 months before randomization/first dose (intermuscular vein thrombosis may be enrolled if assessed as low risk by researchers);
• CHF with NYHA functional classification ≥ II;
• Documented history of cardiomyopathy that has not currently recovered;
• Pericarditis;
• Severe arrhythmia, such as ventricular arrhythmia requiring clinical intervention, II-III degree atrioventricular block, etc.;
• Baseline average QTcF > 450 ms (calculated using Fridericia formula), or history or family history of long QT syndrome;
• Uncontrolled hypertension (defined as persistent systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 100 mmHg despite antihypertensive medication);
• 10. Presence of non-infectious lung disease/pneumonia requiring treatment at randomization/first dose, or history of interstitial lung disease/pneumonia requiring glucocorticoid treatment during prior anti-tumor therapy;
• 11. Active bacterial, fungal or viral infection within 14 days before randomization/first dose (defined as requiring intravenous anti-bacterial, anti-fungal or anti-viral drug therapy). Individuals receiving prophylactic anti-infective therapy without clinical manifestations of active infection may be considered for enrollment;
• 12. Active hepatitis B or hepatitis C, defined as HBsAg positive and HBV DNA > 2000 IU/mL for active hepatitis B; defined as HCV-Ab positive and HCV RNA > ULN for active hepatitis C;
• 13. History of immunodeficiency or positive HIV antibody test during screening;
• 14. Use of strong CYP3A4 inducers or inhibitors, OATP1B1 or OATP1B3 inhibitors before randomization/first dose (within 5 half-lives of inducer or inhibitor) or need to use such drugs during study treatment;
• 15. Known or suspected hypersensitivity to the study drug or its components;
• 16. Lactating women;
• 17. Presence of other conditions that may interfere with participants' participation in study procedures, not in line with participants' maximum benefit from participating in the study, or affect study results: such as history of mental illness, drug abuse or substance abuse, any other clinically significant disease or condition, etc.