Neoadjuvant Study of DV in Combination Toripalimab or Sequence Chemotherapy in HR-negative, HER2 Low-expressing Breast Cancer

A Randomized, Multicenter, Open-Label Phase II Neoadjuvant Study to Evaluate the Safety and Efficacy of Disitamab Vedotin in Combination Toripalimab or Sequence Chemotherapy in Participants With HR-negative, HER2 Low-expressing Breast Cancer

The purpose of this study is to evaluate the Safety and Efficacy of Neoadjuvant study of DV in combination Toripalimab i or sequence chemotherapy in HR-negative, HER2 low-expressing Breast Cancer

This is an open-label, randomized, multicenter, Phase II Neoadjuvant Therapy Study designed to evaluate the Safety and Efficacy of Neoadjuvant study of DV in combination Toripalimab or sequence chemotherapy in HR-negative, HER2 low-expressing Breast Cancer The primary objectives of the study are to explore combination neoadjuvant therapy in participants with previously untreated HR-negative, HER2 low-expressing breast cancer, by assessment of tpCR and EFS.

Inclusion Criteria:

1. Voluntarily participate and sign the informed consent form;

2. Ages≥18 years;

3. Invasive breast tumour tissue with low HER2 expression confirmed by the central laboratory, defined as HER2 protein expression of IHC 1+ or IHC 2+ with no amplification by in situ hybridisation (ISH) (according to the Breast Cancer HER2 Detection Guidelines, 2019 edition) by immunohistochemistry; and specimens from the primary site of the tumour for HER2 detection (wax blocks, biopsies, or fresh tissues are acceptable) are available for HER2 detection

4. Tumour hormone receptor (HR)-negative, defined as IHC-stained invasive carcinoma with a proportion of cells positive for both ER and PgR nuclear staining of <1% according to ASCO/CAP guideline 2020;

5. Histologically confirmed invasive carcinoma of the breast according to AJCC 8th edition investigator-assessed clinical staging T1cN1-2M0, or T2-3N0-2M0

6. 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 the research centre;

7. ECOG PS 0 or 1 point

8. At least one measurable lesion according to RECIST v1.1 criteria;

9. Cardiac function: New York Heart Association (NYHA) class <3; left ventricular ejection fraction ≥55%;

10. 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):

    1. haemoglobin ≥ 90 g/L;
    2. absolute neutrophil count (ANC) ≥ 1.5 × 109 /L;
    3. platelets ≥ 100 × 109 /L;
    4. serum total bilirubin ≤ 1.5 times the Upper Limit of Normal (ULN);
    5. Albuminous Transaminase (AST) and Albuminous Transaminase (ALT) ≤ 2.5 × ULN;
    6. International Normalised Ratio (INR) and Activated Fractional Thromboplastin Time ≤ 1.5 × ULN;
    7. Creatinine Clearance (CrCl) ≥ 60 mL/min according to the Cockcroft-Gault formula method;

11. Female 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 .
    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 .
    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

12. Male subjects of fertile potential who meet the following criteria:

    1. It is necessary to agree not to donate sperm from the time of signing the informed consent form until at least 4 months after the last dose of study drug.
    2. If sexual intercourse with a person of childbearing potential is likely to result in pregnancy, continuous use of at least 2 acceptable contraceptives, at least 1 of which must be highly effective, beginning at the time of informed consent and continuing until at least 4 months after the last dose of study drug. Beginning at the time of informed consent and continuing for at least 4 months after the last dose of study drug.
    3. If sex with a pregnant or breastfeeding patient, condom use must be continuous from the time of informed consent and continue until at least 4 months after the last dose of study drug.

13. 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. Use of investigational drugs or major surgery within 4 weeks prior to start of study drug administration
5. Live or live attenuated vaccine administered within 4 weeks prior to the start of study drug administration or planned to be administered during the study period
6. History of previous allogeneic haematopoietic stem cell transplantation or organ transplantation
7. Prior treatment with PD-(L)1, PD-L2, CTLA4 inhibitors and other antibody-coupled drugs;
8. 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;
9. History of interstitial lung disease requiring treatment or current severe lung disease including, but not limited to, active tuberculosis, interstitial lung disease;
10. Ongoing active infection that requires systemic treatment;
11. Have an active autoimmune disease requiring systemic treatment within the past 2 years (e.g., use of corticosteroids or immunosuppressive drugs, etc.), allowing for relevant replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency)
12. A clear past or present history of a neurological or psychiatric disorder, including epilepsy or dementia
13. Ongoing grade ≥2 sensory or motor neuropathy;
14. Concomitant disease that, in the investigator's judgement, is a serious hazard to the subject's safety or interferes with the subject's ability to complete the clinical study;
15. Positive HIV test results; patients with active hepatitis B or C (HBsAg positivity accompanied by HBV DNA titres above the upper limit of normal; HCVAb positivity accompanied by HCV RNA titres above the upper limit of normal); and persistent coronavirus (COVID-19) infection.
16. Hypersensitivity reactions or delayed hypersensitivity reactions to components of Disitamab Vedotin and Toripalimab or analogues are known;
17. Known hypersensitivity or delayed hypersensitivity to epirubicin, cyclophosphamide, carboplatin preparations or components or similar drugs;
18. Other malignancy within 5 years prior to signing the informed consent (except for non-melanoma skin cancer, cervical carcinoma in situ or other tumours that have been effectively treated and are considered cured);