Treatment of Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of arginine hydrochloride combined with trimetazidine hydrochloride tablets in the treatment of patients with hepatocellular carcinoma.

Detailed Description
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Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths in the world. Because HCC is insidious and early diagnosis is difficult, most patients have locally advanced or distant metastasis at the time of diagnosis. So they are not suitable candidates for curative treatments by resection or transplantation. Currently, Sorafenib is the only choice approved by FDA for advanced HCC, although it prolongs the survival for less than 3 months. Recently, metabolomics studies of HCC have shown that typical Warburg effect was observed in hepatoma carcinoma cells. Arginine hydrochloride is a new anticancer drug in the treatment of liver cancer, which is mainly aimed at the pathway of energy metabolism. Trimetazidine hydrochloride may play an anti-tumor role by inhibiting fatty acid oxidation. The investigators have been proceeding this trial to evaluate the efficacy and safety of arginine hydrochloride combined with trimetazidine hydrochloride tablets in the treatment of patients with hepatocellular carcinoma.

Official Title
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The Efficacy and Safety of Arginine Hydrochloride Combined With Trimetazidine Hydrochloride Tablets in the Treatment of Patients With Hepatocellular Carcinoma. A Multicenter, Open, Randomized, Prospective Study

Conditions
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HCC

Intervention / Treatment
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* Other: Basic drugs therapy of HCC
* Drug: Arginine hydrochloride
* Drug: Trimetazidine hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Ages 18-65 years 2. The diagnosis of HCC: in accordance with diagnostic and treating standards on primary liver cancer (2011 Edition) or histological/cytological diagnosis of recurrent / metastatic primary liver cancer 3. Un-resectable HCC (single or multiple metastasis of HCC after surgery, TACE, or radio frequency ablation; surgery cannot be tolerated because of some basic diseases); Patients with treatment failure or non tolerance to sorafenib. ｛note: Definition of treatment failure: progression of disease during treatment or recurrence of disease after the end of treatment(accepting sorafenib and other molecular targeted therapies must be at least 14 days); Definition of intolerance: ≥ grade Ⅳ hematological toxicity or ≥ grade III non hematologic toxicity or ≥ grade Ⅱ heart, liver, kidney and other organ damage｝;Refusing surgical treatment and volunteering join the group 4. first-line systematic treatment failure (or residual lesion) was over 2 weeks from the study enrolled (time for signature of informed consent) and the adverse events were almost normal (NCI-CTCAE≤ grade Ⅰ） 5. Child-Pugh liver function class A/B (score: ≤ 9) 6. Barcelona stage (BCLC) B-C 7. Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale in one week before admission 8. Estimated survival time > 3 months 9. HBV DNA<2000 IU/ml（10^4 copies/ml); or HBV DNA≥2000 IU/ml and are accepting effective antiviral therapy 10. The major organ function is normal. that is meeting the following standards: Blood routine examination: (No blood transfusion, no G-CSF and no medication were corrected within 14 days before screening) a.HB≥80g/L； b.ANC≥1.5×109/L；c.PLT≥50×109/L； Biochemical examination: (ALB was not transfused within 14 days before screening) a.ALB ≥29 g/L； b.ALT和AST<5ULN；c.TBIL ≤3ULN；d.creatinine ≤1.5ULN( albumin and bilirubin, two indicators of Child-Pugh liver function class, can only have one for 2 points) 11. For women of childbearing age, the results of serum/urine pregnancy tests must be negative within 7 days before initiation of treatment. All men and women who participate in the study have to take reliable contraceptive measures within the trial and eight weeks after the trial is completed 12. volunteers must signed informed consent Exclusion Criteria: 1. Patients with hepatobiliary cell carcinoma, mixed cell carcinoma or lamellar cell carcinoma; in the past (within 5 years) or at the same time suffering from other untreated malignant tumors; excluding cured basal cell carcinoma and carcinoma in situs of cervix 2. Patients who are undergoing liver transplantation or have a history of organ transplantation(excluding the patient who has undergone liver transplantation before) 3. Patients with an allergic history of arginine hydrochloride and trimetazidine hydrochloride 4. Patients with renal insufficiency 5. The blood pressure can not be reduced to the normal range by the antihypertensive drug treatment in patients with hypertension(systolic pressure>140 mmHg, diastolic pressure>90 mmHg) 6. Patients with myocardial ischemia or myocardial infarction over grade II or a poorly controlled arrhythmia (including QTc interval: men ≥ 450 ms; women ≥ 470 ms) 7. Cardiac functional insufficiency of grade III to IV according to NYHA standard; echocardiography: LVEF<50% 8. Many factors that influence oral medication, such as unable to swallow; chronic diarrhea; intestinal obstruction; the situations which significantly affect the use and absorption of drugs 9. With a history of alimentary tract hemorrhage or a definite tendency of gastrointestinal bleeding, such as varices of fundus of stomach and esophagus with bleeding risk; local active ulcer lesions; fecal occult blood ≥（++） 10. Abdominal fistula, gastrointestinal perforation, or abdominal abscess occurred within 28 days before participating the study 11. Dysfunction of blood coagulation(INR>2.0 or PT> 16s，APTT > 43s、TT > 21s，Fbg < 2g/L), having a tendency to bleed or undergoing thrombolysis or anticoagulant therapy; ascites with clinical symptoms, that is requiring therapeutic abdominal paracentesis or drainage or Child-Pugh score ≥2 12. Patients of central nervous system metastasis or brain metastasis 13. Objective evidence of pulmonary fibrosis history, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug associated pneumonia, and severe lung function impairment in the past and at present 14. Urine routine showed that urine protein ≥++ or the urine protein in 24 hours>1.0 g 15. Patients who have been treated with potent CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, telithromycin, troleandomycin, erythromycin, cimetidine and so on) within 28 days before participating the study, or potent CYP3A4 inducers (dexamethasone, phenytoin, rifampin, rifabutin, carbamazepine, phenobarbitone and so on) within 12 days before participating the study 16. Pregnant or lactating women; fertile patients who are unwilling or unable to adopt effective contraceptives 17. Patients with mental sickness or the history of psychotropic drug abuse 18. Patients who had bone metastases received palliative radiotherapy within 4 weeks before participating the study (radiotherapy area > 5% bone marrow region) 19. Patients with severe infection (unable to control the infection effectively) 20. The treatment history affecting this program or its efficacy, such as stem cell transplantation, immune regulation (including PD-1 and other test regimens) recently (within half a year) 21. The researchers believe that any other factors unsuitable for entering into the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: One-drug Regimes<br>Basic drugs therapy of HCC | Other: Basic drugs therapy of HCC<br>* Basic drugs include: 1. Molecular targeted drugs for HCC：apatinib; 2. Antiviral drugs (ETV or TDF) should be given to patients who were infected with HBV or HCV; 3. Patients with liver dysfunction should be treated with conventional hepatoprotective agents drugs (including glycyrrhizin, reduced glutathione, vitamin C，etc); 4. Patients with ascites symptoms should be treated with furosemide and spironolactone according to the urine volume, and they also should be treated with proton pump inhibitors in the prevention of gastrointestinal bleeding; 5. Other basic diseases were treated routinely.<br>* Other names: BDT;|
| Experimental: Two-Drug Regimens<br>Basic drugs therapy of HCC; Arginine hydrochloride | Other: Basic drugs therapy of HCC<br>* Basic drugs include: 1. Molecular targeted drugs for HCC：apatinib; 2. Antiviral drugs (ETV or TDF) should be given to patients who were infected with HBV or HCV; 3. Patients with liver dysfunction should be treated with conventional hepatoprotective agents drugs (including glycyrrhizin, reduced glutathione, vitamin C，etc); 4. Patients with ascites symptoms should be treated with furosemide and spironolactone according to the urine volume, and they also should be treated with proton pump inhibitors in the prevention of gastrointestinal bleeding; 5. Other basic diseases were treated routinely.<br>* Other names: BDT;Drug: Arginine hydrochloride<br>* Arginine hydrochloride injection 5g/dose; 40g/d; ivgtt; sustained medication for 24 days; drug withdrawal for 4 days.<br>* Other names: AH;|
| Experimental: Three-Drug Regimens<br>Basic drugs therapy of HCC; Arginine hydrochloride;Trimetazidine hydrochloride | Other: Basic drugs therapy of HCC<br>* Basic drugs include: 1. Molecular targeted drugs for HCC：apatinib; 2. Antiviral drugs (ETV or TDF) should be given to patients who were infected with HBV or HCV; 3. Patients with liver dysfunction should be treated with conventional hepatoprotective agents drugs (including glycyrrhizin, reduced glutathione, vitamin C，etc); 4. Patients with ascites symptoms should be treated with furosemide and spironolactone according to the urine volume, and they also should be treated with proton pump inhibitors in the prevention of gastrointestinal bleeding; 5. Other basic diseases were treated routinely.<br>* Other names: BDT;Drug: Arginine hydrochloride<br>* Arginine hydrochloride injection 5g/dose; 40g/d; ivgtt; sustained medication for 24 days; drug withdrawal for 4 days.<br>* Other names: AH;Drug: Trimetazidine hydrochloride<br>* Trimetazidine hydrochloride tablets 20mg/tablet, 40mg, twice a day.<br>* Other names: TH;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | from start of treatment to death from any cause, or last known date of survival | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Time from start of treatment until the first documented event of symptomatic progression or death. | 24 months | 
| Disease Control Rate (DCR) | the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease | 28 days | 
| Objective Response Rate(ORR) | Proportion of patients with reduction in tumor burden of a predefined amount | 28 days | 
| biomarker | decrease in tumor markers | approximately 24 months | 
| Chinese Quality of Life Questionnaire - EORTC QLQ-C30 score | The overall enjoyment of life. | approximately 36 months |