Anti-HER2 Therapy + Fulvestrant/Capecitabine in Women With HR+, HER2+, Non-visceral Metastases Stage IV Breast Cancer
Anti-HER2 Therapy + Fulvestrant/Capecitabine in Women With HR+, HER2+, Non-visceral Metastases Stage IV Breast Cancer
The purpose of this study is to evaluate the effectiveness of anti-HER2 therapy plus
 Fulvestrant or Capecitabine in women with hormone receptor positive (HR+), human epidermal
 growth factor receptor 2 positive (HER2+), non-visceral metastases, stage IV breast cancer.
This is a prospective, randomized, 2-arm, multicenter study to compare the safety and
 efficiency of anti-HER2 therapy (Trastuzumab ± Pertuzumab) plus fulvestrant versus anti-HER2
 therapy (Trastuzumab ± Pertuzumab) plus capecitabine in women with hormone receptor positive
 (HR+), human epidermal growth factor receptor 2 positive (HER2+), non-visceral metastases,
 stage IV breast cancer. Subjects will be randomized into one of two treatment arms. Arm A
 subjects will receive the anti-HER2 therapy plus fulvestrant. Arm B subjects will receive the
 anti-HER2 therapy plus capecitabine. The use of Pertuzumab depends on patients' choices.
Inclusion Criteria:

 1. Patients provided written informed consent

 2. Postmenopausal or premenopausal or perimenopausal women aged 18-75 years:

 1. ≥60 years, or bilateral ovariectomy was previously performed, or

 2. <60 years, natural postmenopausal status (defined as a continuous period of at
 least 12 months following spontaneous cessation without other pathological or
 physiological causes), estrogen (E2) and follicle-stimulating hormone (FSH) are
 present at postmenopausal levels

 3. Premenopausal or perimenopausal women, willing to receive luteinizing hormone
 (LHRH) stimulation during the study

 3. Histologically or cytologically confirmed HR-positive (ER/PR≥10%), HER2-positive (IHC
 3+ or ISH+) breast cancer

 4. At least one measurable non-visceral metastatic lesion (liver, lung, pleura,
 pericardium, peritoneum, kidney, adrenal, brain or leptomeningeal metastases are
 excluded), HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+), (≥10 mm on
 T1-weighted, gadolinium-enhanced MRI) (RECIST v1.1)

 5. Previous treatment with HER2 inhibitors to be discontinued prior to first study
 treatment administration (at least 14 days for trastuzumab and other antibodies, at
 least 7 days for lapatinib)

 6. Previous chemotherapy, biological or target therapy to recurrent or metastatic disease
 are not allowed; Previous radiotherapy allowed, but radiotherapy must have been
 discontinued at least 14 days prior to first study treatment administration.

 7. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2

 8. Life expectancy > 24 weeks

 9. left ventricular ejection fraction (LVEF) of 50% or higher at baseline (within 42 days
 before randomization)

 10. Previous adjuvant chemotherapy treatment is allowed

 11. Previous adjuvant trastuzumab treatment is allowed

 12. Hormone therapy must have been discontinued at least 1 month prior to recruitment

 13. Patients with good compliance

 14. Patients must have recovered to baseline condition or to Common Terminology Criteria
 for Adverse Events (CTCAE) version 5.0 grade = 1 from any acute CTCAE v. 5.0 grade =2
 side effects of previous treatments

 15. Without infection of human immunodeficiency virus (HIV) on central laboratory assay
 results prior to randomization

 16. Alanine aminotransferase (ALT) </= 2.5 × the upper limit of normal (ULN), Aspartate
 aminotransferase (AST) </= 2.5 × ULN prior to randomization

 17. Total bilirubin (TBIL) </= 1.25 × ULN

 18. Alkaline phosphatase (ALK) </= 2.5 × ULN

 19. Gamma glutamyl transpeptidase (GGT) </= 2.5 × ULN

 20. Serum total bilirubin (TBil) </= 1.5 × ULN

 21. Serum creatinine (Scr) </= 1.5 × ULN

 22. WBC >/= 3×109/L, Blood neutrophil count >/= 1×109/L, Platelet count >/= 100×109/L, HB
 >/= 9 g/dL

 23. Albumin >/= 30g/L

 24. Women of child-bearing age who had a negative serum pregnancy test (within 14 days
 before randomization) should take effective contraceptive measures

 Exclusion Criteria:

 1. Primary and metastatic lesion lack of histological or cytological confirmation of
 HR-positive (ER/PR≥10%), HER2-positive (IHC 3+ or ISH+)

 2. Breast cancer with visceral metastases (liver, lung, pleura, pericardium, peritoneum,
 kidney, adrenal, brain or leptomeningeal metastases)

 3. Inflammatory breast cancer

 4. Having a life-threatening metastatic visceral disease, defined as extensive liver
 damage or brain or leptomeninges damage (past or present) or symptomatic pulmonary
 lymphatic diffusion. Patients with discrete pulmonary parenchyma metastasis were
 eligible if the investigators determined that their respiratory function was not
 significantly impaired by the disease.

 5. Disease progression or recurrence within 12 months after neo/adjuvant endocrine
 therapy

 6. Unable to tolerate endocrine therapy, including those who with symptoms, who have
 spread to the viscera, and who are at risk for short-term life-threatening
 complications (including uncontrolled thorax, pericardium, or abdominal cavity
 exudation, pulmonary lymphangitis, and more than 50% liver damage).

 7. CT or MRI confirmed the presence of brain or leptomeningeal metastases.

 8. Any other current malignancy or malignancy diagnosed within the past five years (other
 than breast cancer, carcinoma in situ of the cervix, skin basal cell carcinoma or
 squamous cell carcinoma), unless radical treatment is performed and there is no
 evidence of recurrence or metastasis within the last 5 years.

 9. Non- visceral metastatic lesions cannot be evaluated by RECIST v1.1

 10. Active infection with human immunodeficiency virus (HIV) prior to first study
 treatment administration.

 11. History of participating any other clinical trials within 30 days prior to
 randomization

 12. Known hypersensitivity (Grade 3 or 4) to Pertuzumab, Trastuzumab, Fulvestrant or
 Capecitabine or the excipients of any of the trial drugs

 13. Pregnancy or lactation

 14. Uncontrolled illnesses including symptomatic congestive heart failure, unstable angina
 pectoris, cardiac arrhythmia requiring therapy, myocardial infarction within the past
 6 months, or active infection

 15. severe pulmonary and renal disease

 16. Patients with GI tract disease resulting in an inability to take oral medication,
 malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
 affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative
 colitis)

 17. Legal incompetence or limitation.

 18. Considered unable to complete the study or sign the informed consent due to a medical
 or mental disorder by the investigator.