Safety and Effectiveness of PRI-724 for Hepatitis C or B Virus Derived Liver Cirrhosis

Study Overview
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Brief Summary
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To investigate the safety and efficacy of PRI-724 against HCV or HBV liver cirrhosis.

Detailed Description
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【Phase I Phase】 To evaluate safety and pharmacokinetics when PRI-724 is administered to patients with HCV or HBV liver cirrhosis , and determine the recommended dose of PRI-724. 【Phase IIa phase】 To evaluate the efficacy and safety of the recommended dose of PRI-724 administered to patients with HCV or HBV liver cirrhosis.

Official Title
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Phase I / IIa Clinical Trial for Patients With Hepatitis C or B Virus Derived Liver Cirrhosis by CBP / β Catenin Inhibitor PRI-724

Conditions
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Hepatitis C, Hepatitis B, Liver Cirrhoses

Intervention / Treatment
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* Drug: PRI-724


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with liver cirrhosis caused by HCV or HBV that satisfies the following (1) or (2) and satisfies (3) Patients with serum HCV-RNA positive or HCV antibody positive Patients with serum HBV-DNA positive or HBs antigen positive confirmed liver cirrhosis by liver biopsy performed in the screening period patients who received diagnosis Patients with Child-Pugh classification in A or B status Patients who satisfy HCV cirrhosis from (1) to (3), HBV cirrhosis (4) In the case of HCV cirrhosis; Patients who have not reached SVR * with DAA therapy Patients who are difficult to implement DAA therapy Patients who have been over 24 weeks after achieving SVR * with DAA therapy In case of HBV cirrhosis; Patients who have been at least 24 weeks since the start of administration of Nucleotide analogue * SVR is SVR 12 (sustained virological response at 12 weeks after the end of administration). Patients with Performance Status 0 to 2 Patients aged 20 years or over and under 75 when acquiring informed consent Regarding participation in this trial (including liver biopsy), patients who obtained informed consent by their own voluntary intention Exclusion Criteria: Patients with HCV and HBV co-infection, patients who came to cirrhosis due to causes other than HCV or HBV, or patients whose cause of cirrhosis is unknown Patients with esophageal gastric varices determined to be treated by endoscopic examination at screening Patients with complication or previous history of primary liver cancer (excluding those who have had more than one year of hepatocarcinoma resection / radiofrequency ablation) Merger of malignant tumor or past patients (within 3 years before screening). However, the following diseases are excluded: treated basal cell carcinoma, treated lung intraepithelial carcinoma, treated cervical carcinoma, or control superficial (not invasive) bladder carcinoma Patients who can not be denied HIV, HTLV-1 or syphilis Serum creatinine value: Patients with more than 1.5 times the upper limit of the facility reference value Patients with poor control of diabetes, hypertension or heart failure Patients with psychiatric diseases judged to have the potential to influence the implementation of clinical trials Patients who have severe allergy to or contrast media Patients with HCV who have not passed the following period after treatment for HCV cirrhosis at registration. 12 weeks after the final administration of interferon 16 weeks after final administration of Ribavirin 16 weeks after final administration of DAA Patients whose dosage regimen was changed within 12 weeks prior to enrollment Patients who have history of drug or alcohol intoxication within 5 years before acquiring informed consent or who have history of drug or alcohol abuse within the past year Patients who participated in other clinical trials and clinical trials within 30 days prior to acquisition of consent, patients who used investigational drugs or investigational equipment Patients who received liver transplantation or other organ transplantation (including bone marrow transplantation) and patients who are difficult to intravenously administer Patients whose liver biopsy is expected to be difficult to perform Patients who are pregnant or nursing, or who are likely to become pregnant Male patients who do not obtain consent to contraception from the time of acquiring informed consent until the end of 12 weeks after the administration of investigational drug In addition, patients investigated by investigators or clinical trial doctors as judged unsuitable for this trial

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRI-724<br>Dose: 140, 280, 380 mg / m 2/4 hr Administration method: 【Phase I Phase】 (Level 1) 140 mg / m 2/4 hr (Level 2) 280 mg / m 2/4 hr (Level 3) 380 mg / m 2/4 hr Twice weekly, continuous 4-hour intravenous administration (tolerance of administration time: ± 15 minutes). This is one cycle and 12 cycles (12 weeks in total) are carried out. However, in Phase I phase, single dose is administered on Day - 7 (tolerance: - 7 days). 【Phase IIa phase】 Continuous intravenous administration for 4 hours twice a week at the recommended dose determined in Phase I. This is one cycle and 12 cycles (12 weeks in total) are carried out. | Drug: PRI-724<br>* twice a week for 4 hours continuous intravenous administration of PRI-724<br>* Other names: CBP-b-catenin inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious side effect expression rate | (Phase I)Serious side effect expression rate | 12 weeks after administration | 
| liver tissue fibrosis area ratio by liver biopsy | (Phase II) Amount of change from the baseline in liver tissue fibrosis area ratio by liver biopsy at 12 weeks after administration | 12 weeks after administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event Expression Ratio | Adverse Event Expression Ratio after PRI-724 treatment | 12 weeks after administration | 
| Percentage of occurrence of side effects | Percentage of occurrence of side effects after PRI-724 treatment | 12 weeks after administration | 
| Pharmacokinetic parameter | Maximum Plasma Concentration (Cmax) | 12 weeks after administration | 
| liver stiffness from Fibro Scan | Amount of change from measurement of liver stiffness by baseline from Fibro Scan at 12 weeks after administration | 12 weeks after administration | 
| Child Pugh score | Amount of change from baseline of Child-Pugh Score at 12 weeks after administration Child Pugh score (scale range 5-15) is obtained by adding the score for each parameter (encephalopathy, ascites, bilirubin, albumin, PT or INR). | 12 weeks after administration | 
| MELD score | Amount of change from baseline for MELD score at 12 weeks after administration The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing the severity of chronic liver disease and uses the subject's values for total bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin time to predict survival. MELD is calculated according to the following formula: MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43 | 12 weeks after administration | 
| modified Histological Activity Index (HAI) by liver biopsy | Change amount from baseline of modified Histological Activity Index (HAI) by liver biopsy at 12 weeks after administration | 12 weeks after administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C virus, Hepatitis B virus, liver Cirrhosis