Clinical Study to Evaluate the Efficacy and Safety of TQB2440 Injection/Perjeta® Combined With Trastuzumab and Docetaxel in the Treatment of Patients With Early or Locally Advanced Breast Cancer.

A Multicenter, Randomized, Double-blind, Parallel-controlled Clinical Study to Evaluate the Efficacy and Safety of TQB2440 Injection/Perjeta ® Combined With Trastuzumab and Docetaxel in Patients With Early or Locally Advanced ER/ PR-negative HER2-positive Breast Cancer.

This is a multicenter, randomized, double-blind, parallel-controlled Phase III study to evaluate the efficacy and safety of TQB2440 injection/Perjeta® combined with trastuzumab and docetaxel in patients with early or locally advanced ER/ PR-negative HER2-positive breast cancer. The trial is scheduled to enroll 412 participants. The sample size was estimated based on 20 treatment cycles and 6 recurrence visits.

Inclusion Criteria:

• The subjects voluntarily joined the study, signed the informed consent, and the compliance was good;

• Age: 18-75 years old (when signing the informed consent form); Eastern Cooperative Oncology Group Physical condition scoring criteria score: 0-1; Survival is expected to exceed 3 months;

• Patients with primary breast cancer confirmed by histopathology or cytology；

• Primary tumor diameter > 2 cm measured by local standard assessment method, or lymph node positive lesions confirmed by clinical or imaging examination;

• The investigators determined that this was consistent with the American Joint Committee on Cancer (AJCC) 8th Edition of breast cancer Tumor Node Metastasis stage II-III C (T2-T4 plus any N, or any T plus N1-3, M0) and histologically proven invasive breast cancer. A patient with invasive breast cancer must have a solid lesion capable of coarse needle biopsy;

• Laboratory tests confirmed HER2 positive, defined as a 3+ immunohistochemical result or a positive Fluorescence in situ hybridization double probe (2018 edition of American Society of Clinical Oncology/College of American Pathologists HER2 Testing Guidelines)

• The confirmed estrogen receptor (ER) and progesterone receptor (PgR) were negative;

• The patient agrees to undergo a mastectomy when surgical criteria are met after neoadjuvant therapy;

• Major organs function well, meeting the following criteria:

  1. Blood routine test criteria (no blood transfusion within 7 days prior to screening, no hematopoietic stimulant drug correction):

     1. Hemoglobin (HGB) ≥90g/L;
     2. Neutrophil absolute value (NEUT) ≥1.5×10^9/L;
     3. Platelet count (PLT) ≥ 100×10^9/L;
     4. Leukocyte ≥2.5×10^9/L;

  2. Biochemical tests must meet the following criteria:

     1. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);
     2. Alanine transferase (ALT) and aspartate transferase (AST) ≤ 1.5×ULN.
     3. Serum creatinine (CR) ≤1.5×ULN or creatinine clearance (CCR) ≥50 ml/min (creatinine clearance calculated according to Cockcroft-Gault formula);

  3. The coagulation function test should meet the following criteria:

     1. Prothrombin time (PT), activated partial thromboplastin time (APTT), International Normalized ratio (INR) ≤ 1.5×ULN (no anticoagulant therapy), if the patient is receiving anticoagulant therapy, as long as the PT is within the intended range of anticoagulant drug use;

• For women who are not menopausal (menopause is defined as non-treaty-induced menopause for ≥12 months) or who are not surgically sterilized (removal of ovaries and/or uterus): Consent is required to remain abstinent during treatment and for at least 7 months after the last study treatment, or to take a single or combined annual failure rate of < 1% of non-hormonal contraception;

• For women of childbearing age, premenopausal or postmenopausal abstinence of less than 12 months, and who have not been surgically sterilized, serological pregnancy tests are negative.

Exclusion Criteria:

• Patients with stage IV metastatic breast cancer or other cancers that investigators determined could not be radically removed by neoadjuvant therapy;

• Bilateral invasive breast cancer;

• Patients with breast cancer who have previously received anti-tumor therapy, such as chemotherapy, endocrine therapy or anti-HER2 biotherapy, or who have undergone breast surgery (other than diagnostic biopsies for primary breast cancer);

• Occurred or present with other malignant tumors within 3 years. Patients with the following two conditions can be enrolled: other malignancies treated with a single operation, achieving continuous 5-year disease-free survival (DFS); Cured cervical carcinoma in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (cancer in situ) and T1 (tumor infiltrating basal membrane)];

• Major surgical treatment, open biopsy, or significant traumatic injury (except for diagnostic biopsies for primary breast cancer) received within 28 days before the start of study treatment;

• A wound or fracture that has not healed for a long time.

• Arteriovenous thrombosis occurred within 6 months, such as cerebrovascular accident (including temporary ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism;

• Subject who have a history of psychotropic substance abuse and are unable to abstain or have mental disorders;

• Subjects with any severe and/or uncontrolled disease, including:

  1. Patients with a history of critical hypertension or hypertensive encephalopathy; Or uncontrolled high blood pressure (systolic blood pressure >150 mmHg after taking antihypertensive drugs, or diastolic blood pressure >100 mmHg);
  2. Heart failure or systolic dysfunction (LVEF < 55%) diagnosis history;
  3. Have grade 2 myocardial ischemia or myocardial infarction, arrhythmia (including QTc ≥450 ms in men, QTc ≥470 ms in women, and grade 2 congestive heart failure (NYHA rating);
  4. Angina pectoris requiring treatment with anti-angina medication;
  5. Valvular heart disease of clinical significance;
  6. Screening period confirmed hepatitis C virus (HCV) positive, human immunodeficiency virus (HIV) positive, syphilis treponema specific antibody positive, HBsAg positive and peripheral blood hepatitis B virus DNA (HBV DNA) titer beyond the normal range;

• Within 2 weeks before the start of the study treatment, the patients were treated with Chinese patent medicines (including compound Cantharides capsule, Kangai injection, Kanglaite capsule/injection, Aidi injection, Brucea javanica oil injection/capsule, Xiaoaiping tablet/injection, Cinobufacini capsule, etc.) which had clear anti-tumor indications in the China National Medicinal Products Administration (NMPA) approved drug label;

• Patients whose imaging (Computed Tomography or Magnetic Resonance Imaging) shows that the tumor has invaded an important blood vessel or who are judged by the investigator to be highly likely to invade an important blood vessel during subsequent studies and cause a fatal hemorrhage;

• Active autoimmune disease requiring systemic treatment (such as use of disease-modifying drugs, corticosteroids, or immunosuppressants) occurred within 2 years prior to study treatment initiation. Replacement therapies (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic;

• Subjects diagnosed with immune deficiency or is receiving systemic glucocorticoid therapy or any other form of immunosuppressive therapy. (Dose >10mg/ day of prednisone or other therapeutic hormone) and continued use within 2 weeks of initial administration;

• Other comorbidities that interfere with planned treatment include severe lung dysfunction/disease, active or uncontrolled severe infection (≥ Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 grade 2 infection)

• Allergy to any investigational drug or any ingredient or excipient in the drug;

• Subjects had participated in clinical trials of other antineoplastic drugs within 4 weeks before the group;

• Participants who, in the investigator's judgment, have a concomitant medical condition that seriously endangers the safety of the subjects or interferes with the completion of the study, or who are deemed unsuitable for enrollment for other reasons.