DV in Combination With Pertuzumab With or Without Toripalimab Neoadjuvant Therapy With HER2-positive Breast Cancer

The purpose of this study is to evaluate the efficacy and safety of Disitamab Vedotin in combination with Pertuzumab with or without Toripalimab neoadjuvant therapy in patients with HER2-positive breast cancer.

This is an open-label, randomized, multicenter, Phase II Study designed to evaluate safety and efficacy of Disitamab Vedotin in combination with Pertuzumab with or without Toripalimab neoadjuvant therapy inr patients with HER2-positive breast cancer.

The primary objectives of the study are to explore combination neoadjuvant therapy in participants with previously untreated HER2-positive breast cancer, by assessment of pCR .

Eligibility Criteria:
Inclusion Criteria:

1. Voluntarily participate and sign the informed consent form;
2. Ages≥18 years;
3. Histopathologically confirmed invasive breast cancer, clinical stage T2-3 (tumor diameter \> 2 cm), cN0- 3, M0;
4. Invasive breast tumour tissue confirmed HER2-positive by the central laboratory, defined as HER2 protein expression of IHC 3+ by immunohistochemistry (IHC) or IHC 2+ with amplification by in situ hybridisation (ISH) (according to the HER2 Guidelines for Breast Cancer, 2019 edition); and specimens from the primary site of the tumour for HER2 testing (wax blocks, sections or fresh tissue are acceptable) can be provided for HER2 testing;
5. Subjects who tolerate and are scheduled to undergo radical breast cancer surgery and have not received any prior anti-tumour systemic therapy for breast cancer, as assessed by site.
6. At least one measurable lesion according to RECIST v1.1 criteria;
7. Cardiac function: New York Heart Association (NYHA) class \<3; left ventricular ejection fraction ≥55%;
8. Bone marrow or organ function, the following criteria should be met within 7 days prior to study dosing (normal values are based on the clinical trial centre, no transfusion of blood, haematopoietic stimulating factors, albumin or blood products within 14 days prior to the test): haemoglobin ≥ 90 g/L; absolute neutrophil count (ANC) ≥ 1.5 × 109 /L; platelets ≥ 100 × 109 /L; serum total bilirubin ≤ 1.5 times the Upper Limit of Normal (ULN); Albuminous Transaminase (AST) and Albuminous Transaminase (ALT) ≤ 2.5 × ULN; International Normalised Ratio (INR) and Activated Fractional Thromboplastin Time ≤ 1.5 × ULN; and Creatinine Clearance (CrCl) ≥ 50 mL/min according to the Cockcroft-Gault formula method;
9. Subjects of childbearing potential who meet the following criteria:

   1. A serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of β-human chorionic gonadotropin \[β-hCG\]) must be negative within 72 hours prior to the first dose of study intervention. Subjects with false-positive results and confirmed non-pregnancy will be eligible for participation in the study.
   2. Must agree to contraception for the duration of the study and for at least 6 months after the last dose of study drug (7 months after the last dose of patulizumab).
   3. Must agree not to breastfeed or donate eggs from the time of signing the informed consent until 6 months after the last dose of study drug (7 months after the last dose of patulizumab).
   4. If sexually active and likely to result in pregnancy, use of at least 2 acceptable contraceptive methods, at least 1 of which must be highly effective, must be continued from the time of informed consent for at least 6 months after the last dose of study drug (7 months after the last dose of patulizumab).
10. Subjects of childbearing potential who meet the following criteria:

    1. Must agree not to donate sperm from the time of signing the informed consent until at least 4 months after the last dose of study drug (7 months after the last dose of patulizumab).
    2. If sexual intercourse with a person of childbearing potential is likely to result in pregnancy, the use of at least 2 acceptable forms of contraception, at least 1 of which must be highly effective, must be continuous, beginning at the time of informed consent and continuing until at least 4 months after the last dose of study drug (7 months after the last dose of patuximab).
    3. If sex with a pregnant or breastfeeding patient, condom use must be continued from the start of informed consent and continue until at least 4 months after the last dose of study drug (7 months after the last dose of patuximab).

12. Be able to understand the requirements of the trial and be willing and able to comply with the trial and follow up procedural arrangements.

Exclusion Criteria:

1. With bilateral invasive breast cancer
2. Previous history of invasive breast cancer
3. Previous carcinoma in situ of the breast with adjuvant endocrine therapy within 5 years of surgery
4. Prior treatment with PD-(L)1, PD-L2, CTLA4 inhibitors and other antibody-coupled drugs
5. Prior anti-HER2 therapy including but not limited to ADC
6. Use of investigational drugs or major surgery within 4 weeks prior to start of study drug administration
7. Vaccination with live or live attenuated vaccine within 4 weeks prior to the start of study drug administration or planned for the duration of the study;
8. History of previous allogeneic haematopoietic stem cell transplantation or organ transplantation;
9. Uncontrolled or significant cardiovascular disease, including (but not limited to): any of the following within 6 months prior to the first dose: e.g., congestive heart failure (NYHA class III or IV), myocardial infarction or cerebral infarction (except for lacunar cerebral infarction), pulmonary embolism, unstable angina, or arrhythmia requiring treatment at screening; primary cardiomyopathy (e.g., dilated cardiomyopathy, Primary cardiomyopathies (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, indeterminate cardiomyopathy); history of clinically significant prolongation of the QTc period, grade II type II AV block or grade III AV block or QTc interval (F method) \>470 msec (women) or \>450 msec (men); atrial fibrillation (EHRA grade ≥2b); uncontrolled hypertension that is judged by the investigator to be unsuitable; and Hypertension, judged by the investigator to be unsuitable for participation in the study;
10. History of interstitial lung disease requiring treatment or current severe lung disease including, but not limited to, active tuberculosis, interstitial lung disease;
11. A clear past or present history of a neurological or psychiatric disorder, including epilepsy or dementia;
12. Persistent grade ≥2 sensory or motor neuropathy;
13. Active infection requiring systemic therapy; active infection requiring systemic therapy ≤7 days prior to study drug administration, with routine antimicrobial prophylaxis permitted; positive HIV test results; patients with active hepatitis B or C (HBsAg positivity with HBV DNA titres above the upper limit of normal; HCVAb positivity with HCV RNA titres above the upper limit of normal); and persistent coronavirus (COVID-19) infection.
14. Active autoimmune disease requiring systemic treatment within the past 2 years (e.g., use of corticosteroids or immunosuppressive drugs, etc.), allowing for related replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement for adrenal or pituitary insufficiency);
15. Other malignancy within 5 years prior to signing the Informed Consent Form (with the exception of non-melanoma skin cancer, cervical carcinoma in situ, limited prostate cancer, stage I endometrial cancer, or other tumours that have been effectively treated and are considered to have been cured);
16. Hypersensitivity reactions or delayed hypersensitivity reactions to certain components of vedicilizumab, patulizumab and treprostinil or similar drugs are known;
17. A concomitant disease that, in the judgement of the investigator, is a serious hazard to the safety of the subject or interferes with the subject's ability to complete the clinical study;