Overview

The study includes Phase I dose escalation and expansion and Phase II combination therapy. It uses a multicenter, open-label, non-randomized design to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of TQB3126 in breast cancer. Phase I dose escalation uses a Rolling 6 design after accelerated titration at the first dose, with dose decisions reviewed by the Safety Review Committee. Dose expansion includes two cohorts of approximately 20-60 participants each. The study also explores relationships between drug exposure and efficacy/safety, including concentration-QTc assessment using Holter electrocardiograms.

Eligibility

Inclusion Criteria:

1. Subjects voluntarily participate in this study, sign the informed consent form, and demonstrate good treatment compliance.
2. Aged 18 to 75 years at the time of informed consent signature; Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; estimated survival expectancy of more than 3 months.
3. Histopathologically confirmed breast cancer.
4. Documented disease progression confirmed by clinical or imaging evidence during or after the most recent prior systemic therapy prior to the first study drug administration.
5. Have evaluable lesions per RECIST v1.1 criteria (measurable lesions; or bone-only metastases with at least one osteolytic or mixed lesion).
6. Adequate tissue samples shall be provided at screening for gene mutation testing to clarify genetic status.
7. Laboratory test results meet the criteria specified in the protocol (blood routine, liver and renal function, coagulation function, cardiac ultrasound Left Ventricular Ejection Fraction(LVEF) and other indicators are all within the protocol-specified ranges).
8. Subjects of childbearing potential must agree to use effective contraceptive measures throughout the study and for 6 months after study completion (the same requirement applies to male subjects); serum or urine pregnancy test result is negative within 7 days prior to enrollment.

Exclusion Criteria:

1. Other malignant tumors within 5 years prior to first dose, except those cured by single surgical treatment with at least 5 years of disease-free survival, or cured differentiated thyroid cancer, cervical carcinoma in situ, non-melanoma skin cancer, or superficial bladder tumors.
2. Conditions affecting intravenous access or blood sampling, or multiple factors affecting oral drug administration/absorption (e.g., inability to swallow, chronic diarrhea, intestinal obstruction).
3. Unresolved toxicity from prior therapy of Grade \>1 (CTCAE v6.0), except Grade 2 alopecia, Grade 2 anemia, clinically insignificant laboratory abnormalities, or hypothyroidism stable on hormone replacement therapy.
4. Major surgery, significant traumatic injury within 4 weeks before first dose, anticipated need for major surgery during the study, or long-standing unhealed fracture.
5. Any bleeding event of Grade \>=3 within 4 weeks before first dose.
6. Arterial/venous thrombotic events within 6 months before first dose (e.g., cerebrovascular accident, deep vein thrombosis, pulmonary embolism), excluding catheter-related or superficial venous thrombosis.
7. Active viral hepatitis that is poorly controlled (Hepatitis B Virus (HBV)/Hepatitis C Virus (HCV)-infected subjects meeting protocol-specified criteria may be enrolled).
8. Active syphilis infection requiring treatment.
9. Active tuberculosis, idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced or radiation pneumonitis requiring treatment, or history of/current interstitial lung disease (ILD).
10. History of psychotropic substance abuse unable to be discontinued, mental disorders, epilepsy requiring treatment, or severe psychiatric/neurological disease.
11. Planned or prior allogeneic bone marrow or solid organ transplantation.
12. Decompensated cirrhosis (Child-Pugh Class B or C) or history of hepatic encephalopathy.
13. Significant cardiovascular disease, including New York Heart Association(NYHA) Class \>II heart failure, clinically significant ventricular arrhythmia, unstable angina, myocardial infarction within 12 months, markedly prolonged QT interval corrected by Fridericia's formula (QTcF), or personal/family history of congenital long QT syndrome.
14. Poorly controlled hypertension (resting systolic BP \>=160 mmHg or diastolic BP \>=100 mmHg on at least 2 measurements \>=24 hours apart).
15. Active or uncontrolled serious infection (Grade \>=2).
16. Renal failure requiring hemodialysis or peritoneal dialysis; or history of/current nephrotic syndrome (except cured) or chronic nephritis.
17. History of immunodeficiency, including HIV infection or other acquired/congenital immunodeficiency diseases.
18. Poorly controlled autoimmune disease requiring immunosuppressants or systemic corticosteroids for immunosuppression, continued within 7 days before first dose (except low-dose corticosteroids).
19. Clinically significant endometrial abnormalities (including hyperplasia, dysfunctional uterine bleeding, etc.).
20. Tumor-related conditions/treatments: anti-cancer therapy within 3 weeks before first dose or still within the drug's washout period; prior local radiotherapy not meeting protocol-specified interval or target lesion requirements; use of National Medical Products Administration (NMPA)-approved proprietary Chinese medicine with anti-tumor indications within 1 week before first dose; imaging showing tumor invasion of major vessels with risk of fatal hemorrhage; uncontrolled pleural effusion/ascites/moderate-or-greater pericardial effusion requiring repeated drainage; known leptomeningeal metastasis or uncontrolled brain metastasis symptoms; severe skeletal-related events due to bone metastases.
21. Known hypersensitivity to the study drug or its excipients.
22. Participation in and use of another investigational anti-tumor drug within 4 weeks before first dose.
23. Any concomitant disease or condition that, in the investigator's judgment, seriously endangers subject safety or study compliance, or any other reason making the subject unsuitable for enrollment.