This was a multicenter, randomized, double-blind, phase III trial. This clinical study evaluates the efficacy and safety of Apatinib in patients with advanced liver cancer who have progressed on Systemic Therapy (Chemotherapy and/or Targeted Therapy).

Approximately 400 patients who meet the entry criteria will be randomly assigned in a 2:1 ratio to Apatinib or placebo (1/3 chance to receive placebo).

Primary endpoint of the study is overall survival.

Inclusion Criteria:

1. ≥ 18 years old.

2. Conform to the clinical diagnosis standard strictly or histological or cytological confirmation of HCC (hepatocellular carcinoma) who cannot benefit from treatments of established efficacy with higher priority such as resection, local ablation,and with at least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST 1.1.

3. Failure or intolerance to prior treatment with chemotherapy and/or targeted therapy (Failure is defined as documented radiological progression according to the radiology charter. Intolerance is defined as ≥ grade 4 hematologic toxicities, ≥ grade 3 non-hematologic toxicities ≥ grade 2 heart, liver or kidney damage).

4. Systemic therapy must have been completed ≥2 weeks before randomization (AEs due to prior treatment ≤ grade 1).

5. Liver function status Child-Pugh Class A or B (score≤7).

6. Barcelona Clinic Liver Cancer stage Category B or C.

7. Eastern Cooperative Oncology Group Performance Status of 0 or 1 within 1 week before randomization.

8. Life expectancy of at least 12 weeks.

9. HBV DNA ≤ 2000IU/ml or 1×10E+4 copy/ml.

10. Adequate bone marrow, liver and renal function as assessed by the following laboratory tests conducted within 1 week before randomization.

    HB ≥ 90g/L; ANC≥1.5×10E+9/L; PLT≥80×10E+9/L; ALB ≥ 29g/L; ALT and AST < 5×ULN; TBIL ≤1.5×ULN; Cr ≤1.5×ULN

11. Women of childbearing potential and men must agree to use adequate contraception .

Exclusion Criteria:

1. Any local treatment (included but not limited: resection, radiotherapy, TAE, TACE, TAI, RFA or PEI) within 4 weeks of randomization.
2. Known hepatic duct carcinoma, mixed cell carcinoma or fibrolamellar hepatocellular carcinoma, known history or suffering from other cancer(except of cured skin basal cell carcinoma or carcinoma in situ of cervix).
3. Patients who will receive liver transplantation.
4. Ascites with clinical symptoms, i.e. require Abdominal paracentesis or drainage treatment such as or Child-Pugh Score>2.
5. Hypertension and unable to be controlled within normal level following treatment of anti-hypertension agents (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg).
6. Suffered from grade II or above myocardial ischemia or myocardial infarction, uncontrolled arrhythmias (including QT interval male ≥ 450 ms, female≥ 470 ms).
7. Grade III-IV cardiac insufficiency, according to NYHA criteria or echocardiography check: LVEF<50%.
8. Factors to affect oral administration（such as Patients unable to swallow oral medications, chronic diarrhea and ileus etc. situations evidently affect drug oral medication and absorption）.
9. Previous digestive tract bleeding history within 6 months or evident gastrointestinal bleeding tendency, such as,：Esophageal varices with bleeding risk, local active ulcerative lesions, fecal occult blood≥（++）；if fecal occult blood（+），gastroscope check is required.
10. The Within 28 days ahead of randomization, experience abdomen fistula, gastrointestinal perforation, or abdominal abscess
11. Coagulation abnormalities (INR > 1.5 x ULN, or PT > ULN +4 seconds), with bleeding tendency or are receiving thrombolytic or anticoagulant therapy;
12. Occurrence of central nervous system metastatic or known brain metastatic;
13. Objective evidence of previous or current pulmonary fibrosis history, interstitial pneumonia, Pneumoconiosis, radiation pneumonitis, drug-related pneumonia, Pulmonary function damaged seriously etc.
14. Proteinuria ≥ (++) or 24 hours total urine protein > 1.0 g.
15. Received powerful inhibitor of CYP3A4 within 7 days or powerful inducer of CYP3A4 within 12 days before randomization.
16. Pregnant or breast-feeding women; patients with fertility will not or there is no way to adopt effective contraceptive measures.
17. Mental disorders history, or Psychotropic drug abuse history.
18. Patients who has bone metastasis, has received Palliative radiotherapy (radiotherapy area > 5% marrow area).

approximately 5 years

Same event may appear as both an adverse event (AE) and serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event.