Study of Apatinib After Systemic Therapy in Patients With Hepatocellular Carcinoma(AHELP)
Condition: Carcinoma, Hepatocellular
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Apatinib; Placebo
Intervention MeSH terms: Apatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 400.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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).