A Study of Apatinib in Non-triple-negative Metastatic Breast Cancer

Inclusion Criteria:

●≥ 18 and ≤ 70 years of age.

• ECOG performance status of 0-1.
• Metastatic breast cancer, confirmed by histological analysis.
• Have experienced at least 1 and at most 4 regimens, and failed from the last chemotherapy regimen. Pretreated anthracycline, taxanes and capecitabine (any rational reason for no use of capecitabine is acceptable) are mandatory.
• Women diagnosed with human epidermal growth factor receptor positive (HER2+) should have failed for at least 1 anti-HER2 therapy (any rational reason for no use of anti-HER2 therapy is acceptable). HER2+ is defined as +++ staining on immunohistochemistry or FISH/CISH positive for gene amplification.
• Women diagnosed with HR+ should have failed for at least 1 hormonal therapy.
• Have failed for at least one chemotherapy regimen, but at most three regimens(including adjuvant and neo-adjuvant setting).
• Duration from the last therapy (chemotherapy, radiotherapy, target therapy and operation) is more than 4 weeks (Duration for nitroso or mitomycin is 6 weeks).
• Have at least one extracranial measurable site of disease according to RECIST 1.0 criteria that has not been previously irradiated.
• Life expectancy of more than 3 months.
• Negative serum or urine pregnancy test taken in all women within 7 days before inclusion. Sexually active women of childbearing potential must use a medically acceptable form of contraception from the beginning of the study to 8 weeks after the last dose of the investigated drug.
• Written informed consent prior to study specific screening procedures.

Exclusion Criteria:

• Triple-negative breast cancer (ER-, PR- and HER2-. HER2- is defined as 0 or 1+ staining on immunohistochemistry or FISH/CISH negative for gene amplification. )
• Pregnant or lactating women.
• Less than 4 weeks from the last clinical trial.
• Uncontrolled hypertension with mono-drug therapy (>140/90 mm Hg)；ischemia of the myocardium （≥ grade 2） or myocardial infarction；arrhythmia（≥ grade 2, QTcF > 470ms for female patients） or New York Heart Association Class III/IV
• Any factors that influence the usage of oral administration.
• The cumulative doses of doxorubicin and epirubicin before inclusion have surpassed 300 mg/m2 and 600 mg/m2, respectively.
• Duration from the last therapy (chemotherapy, radiotherapy, target therapy and operation) is less than 4 weeks (Duration for nitroso or mitomycin is less than 6 weeks).
• Confirmed brain metastasis.
• Inadequate hepatic, renal, heart, and hematologic functions (hemoglobin <90g/L, neutrophils < 1.5×10^9/L, platelets < 80×10^9/L , ALT > 2.5 x upper limit of normal (ULN)(5x for liver metastasis), AST > 2.5 x ULN (5x for liver metastasis), serum bilirubin > 1.5 x ULN, serum creatine > 1.0 x ULN, creatinine clearance rate ≤ 50ml/min, LVEF < lower limit of normal (LLN).
• Abnormal coagulative function, inclined to bleeding or is receiving thrombolytictherapy or anticoagulation.
• History of arterial/venous embolic events (such as cerebrovascular accident, TIA, deep vein thrombus,and pulmonary embolism)
• Unhealed wound (> 30 days) or bone fracture.
• Urine protein ≥++ and confirmed >1.0 g by the 24h quantity.
• Previous or present history of pulmonary fibrosis,interstitial pneumonia,pneumoconiosis,radiation pneumonitis,drug-related pneumonitis or greatly-impaired pulmonary function.
• Disability of serious uncontrolled intercurrence infection.
• Abuse of alcohol or drugs.
• Have received prior treatment with a VEGFR, PDGFR or s-SRC TKI (Bevacizumab is permitted).
• Acquired or inherent immunodeficiency； HIV infection； organ transplantation history.
• The active HBV or HCV infection or HBV DNA ≥10^4/ml.
• History of other malignancies except cured basal cell carcinoma of skin and carcinoma in-situ of uterine cervix.
• Presence of serious harm to subjects or complication to hinder the completion of the study judged by investigators