To Evaluate the Efficacy and Safety of TQB3616 in Combination With Fulvestrant Versus Placebo in Combination With Fulvestrant in Previously Untreated Hormone-receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced Breast Cancer

A Randomized, Double-blind, Parallel-controlled Phase III Trial Evaluating the Efficacy and Safety of TQB3616 in Combination With Fulvestrant Versus Placebo in Combination With Fulvestrant in Previously Untreated HR-positive, HER2-negative Advanced Breast Cancer

A randomized, double-blind, parallel-controlled, multicenter trial design was used in this study. Subjects who meet the criteria will be randomly divided into 2:1 groups to receive TBQ3616 capsule combined with Fulvestrant injection (experimental group) or placebo capsule combined with fulvestrant (control group). A total of 428 subjects were required.

Inclusion Criteria:

• Subjects voluntarily participate in this study and sign informed consent with good compliance;

• Age: 18-75 years (when signing the informed consent); an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; Is expected to survive more than 3 months;

• Postmenopausal or premenopausal/perimenopausal women；

• Patients with HR-positive or HER2-negative breast cancer confirmed by pathological examination with evidence of local lesion recurrence or distant metastasis, not suitable for the surgery or radiotherapy for the purpose of cure, and there are no clinical indications of chemotherapy；

• Have a measurable lesion (RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria), or have only bone metastases；

• The main organs function well and meet the following standards：

  1. Routine blood examination should meet the following criteria: (No blood transfusion and no hematopoietic stimulation drugs within 7 days before screening)

     1. Hemoglobin (HB) ≥100 g/L;
     2. Absolute value of neutrophils (NEUT) ≥ 1.5×109/L;
     3. Platelet count (PLT) ≥ 90 ×109/L.

  2. Biochemical blood tests shall meet the following criteria：

     1. Total bilirubin (TBIL) ≤ 1.5 times normal upper limit (ULN);
     2. Alanine transferase (ALT) and aspartate transferase (AST) ≤ 2.5×ULN; ALT and AST≤ 3×ULN for patients with liver metastasis;
     3. Serum creatinine (Cr) ≤ 1.5×ULN, or creatinine clearance (Ccr) ≥ 60 mL /min；

  3. Coagulation function tests shall meet the following criteria：

     (a) Prothrombin time (PT), activated partial thrombin time (APTT), international standardized

  4. Color doppler echocardiography: Left ventricular ejection fraction (LVEF) ≥50%；

• Female subjects within reproductive age should agree to use contraceptive methods (such as intrauterine devices, birth control pills or condoms) from participating the study to 6 months after the end of the study; Serum pregnancy test result should be negative within 7 days prior to study enrollment and must be non-lactating subjects.

Exclusion Criteria:

• Associated diseases and history：

  1. The presence or current co-occurrence of other malignant tumors within 5 years, except ured cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor infiltrating basal membrane)];

  2. Multiple factors affecting oral and drug absorption (such as inability to swallow, post-gastrointestinal resection, ulcerative colitis, symptomatic/inflammatory bowel disease, chronic diarrhea and intestinal obstruction);

  3. Patients with a history of severe pneumonia such as interstitial lung disease;

  4. Unrelieved toxicity higher than GRADE 1 Common Terminology Criteria for Adverse Events (CTCAE) due to any previous anti-tumor treatment, hair loss is not included;

  5. Major surgery or significant traumatic injury within 28 days prior to randomization;

  6. Long-term unhealed wounds, ulcers or fractures;

  7. Occurrence of arteriovenous/venous thrombosis events within 6 months, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism, etc.;

  8. History of psychotropic drug abuse and can't get rid of it or with mental disorders;

  9. Subject with any severe and/or uncontrolled disease, including：

     1. Arrhythmias requiring treatment with grade≥2 myocardial ischemia, myocardial infarction, and congestive heart failure (NYHA(New York Heart Association) classification) within 6 months prior to study enrollment (including qtc≥480ms during screening period); And uncontrolled high blood pressure;
     2. Active or uncontrolled severe infection (≥CTCAE grade 2 infection) or unexplained fever > 38.5℃ within 28 days prior to randomization;
     3. Decompensated cirrhosis (Child-Pugh liver function score B or C), active hepatitis ;
     4. Patients with renal failure requiring hemodialysis or peritoneal dialysis;
     5. A history of immunodeficiency, including HIV ( Human Immunodeficiency Virus) positive or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation or hematopoietic stem cell transplantation;

• Tumor-related symptoms and treatment；

  1. Visceral crisis exists;
  2. Severe bone injury due to bone metastasis of tumor;
  3. Received radiotherapy (except palliative radiotherapy for non-target lesions) and other anti-tumor therapies (the washout period was calculated from the end of the last treatment) within 2 weeks prior to randomization;
  4. Prior medical treatment with fulvestrant, everolimus or CDK4/6 inhibitor;
  5. The presence of clinically uncontrolled pleural, ascites and pericardial effusion requiring repeated drainage or medical intervention (14 days prior to randomization);

• Known allergy to fulvestrant, Luteal Hormone Releasing Hormone (LHRH) agonists (e.g. Goserelin), TQB3616/ placebo or any supplement;

• History of live attenuated vaccine vaccination within 28 days prior to randomization or planned live attenuated vaccine vaccination during the study period;

• Participated in clinical trials of other antitumor drugs within 4 weeks pior to randomization;

• With other serious physical or mental diseases or abnormal laboratory tests that may increase the risk of study participation or interfere with the study results, or unsuitable for the study for other reasons considered by investigators.