Safety, Tolerability of OP-724 in Patients With Primary Biliary Cholangitis (Phase I)

Study Overview
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Brief Summary
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To evaluate the safety and pharmacokinetics of OP-724 and to determine the recommended dose of OP-724 against Primary Biliary Cholangitis patients.

Detailed Description
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This trial is a phase I trial aimed at examining the safety and tolerability of OP-724 in patients with primary biliary cholangitis and determining the recommended dose. The subjects are patients diagnosed with primary biliary cholangitis and diagnosed as progress of fibrosis (Scheuer stage III or higher) as a result of liver tissue examination. As a dosing schedule, OP-724 is intravenously administered twice a week (4 hours) for 12 weeks. However, once 7 days prior to the first cycle of administration, a dose scheduled for the first cycle will be administered once by continuous intravenous administration for 4 hours, and safety and pharmacokinetics will be evaluated on the day of administration to the next day after administration. The dose level shall be 3 doses (140 mg/m2/4hrs, 280 mg/m2/4hrs [starting dose], 380 mg/m2/4hrs), of which 2 doses shall be registered for up to 6 patients each. The safety and pharmacokinetic data after OP-724 administration will be decided comprehensively to determine the recommended dose in the next phase.

Official Title
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An Open-Label, Dose-Finding Study for the CBP / β-catenin Inhibitor OP-724 in Patients With Primary Biliary Cholangitis (Phase I)

Conditions
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Primary Biliary Cholangitis (PBC), Liver Cirrhosis, Biliary

Intervention / Treatment
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* Drug: OP-724


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (1) Of the confirmed patients * of primary biliary cholangitis, patients with progressive fibrosis (Scheuer classification stage III or higher) by liver biopsy. * The diagnosis of primary biliary cholangitis (PBC) is based on the diagnostic criteria (2015) of Study and research on refractory liver and biliary diseases. That is, one that corresponds to any one of the following is diagnosed as PBC. Histologically, chronic non-suppurative destructive cholangitis (CNSDC) is found and the laboratory findings are consistent as PBC. A positive antimitochondrial antibody (AMA) with no histologic findings of CNSDC but showing a histology consistent with PBC. There is no experience of histologic search, but AMA is positive and it is considered as PBC from clinical image and course. (2) Patients with Performance Status 0 to 2. (3) Patients aged 20 years or over and under 75 when acquiring informed consent. (4) Regarding participation in this trial (including liver biopsy), patients who obtained informed consent by their own voluntary intention. Exclusion Criteria: (1) Patients who have liver fibrosis other than primary biliary cholangitis or patients whose cause of liver fibrosis is unknown. (2) Patients with esophageal gastric varices determined to be treated by endoscopic examination at screening. (3) Patients with complication or previous history of primary liver cancer (excluding those who have had more than one year of hepatocarcinoma resection / radiofrequency ablation). (4) 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. (5) Patients who can not be denied hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-cell leukemia virus 1 (HTLV-1) or syphilis. (6) Serum creatinine value: Patients with more than 1.5 times the upper limit of the facility reference value. (7) Patients with poor control of diabetes, hypertension or heart failure. (8) Patients with psychiatric diseases judged to have the potential to influence the implementation of clinical trials. (9) Patients who have severe allergy to or contrast media. (10) Patients whose dosage regimen was changed within 12 weeks prior to enrollment. (11) 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. (12) 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. (13) Patients who received liver transplantation or other organ transplantation (including bone marrow transplantation) and patients who are difficult to intravenously administer. (14) Patients whose liver biopsy is expected to be difficult to perform. (15) Patients who are pregnant or nursing, or who are likely to become pregnant. (16) 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. (17) 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: OP-724<br>Dose: 140, 280, 380 mg/m2/4 hrs Administration method: [Level 1] 140 mg/m2/4 hours [Level 2] 280 mg/m2/4 hours (starting dose) [Level 3] 380 mg/m2/4 hours Continuous intravenous administration will be done for 4 hours twice a week. This procedure will be as one cycle and 12 cycles (12 weeks in total) will be conducted. On 7 days prior to the first cycle administration, a dose scheduled in the first cycle will be administered with continuous intravenous for 4 hours and the safety and pharmacokinetics on the day of administration to the next day after administration will be evaluated. | Drug: OP-724<br>* Twice a week for 4 hours continuous intravenous administration of OP-724<br>* Other names: PRI-724 (former name);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence Rate of Serious Adverse Events (Side Effects) | Occurrence Rate of Serious Adverse Events (Side Effects) whose causal relationship with the investigational drug can not be denied. The data will be aggregated by each adverse event and cohort. | 28 days after the last administration of OP-724 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression Ratio of Adverse Events | The data will be aggregated by each adverse event and cohort. | 28 days after the last administration of OP-724 | 
| Percentage of Occurrence of Side Effects | The data will be aggregated by each side effect and cohort. | 28 days after the last administration of OP-724 | 
| Drug Concentration (OP-724 and C-82) in Plasma | The data will be aggregated by each cohort. | A) Single administration part: pre-dose and post-dose at 0.5, 1, 2, 4, 5, 9 and 24 hours. / B) Continuous administration part: pre-dose and post-dose at 4 hours on Day 1 and 4 in Cycle 1, 5, 9 and 12 (each cycle is 7 days) | 
| Parameters on Pharmacokinetics (OP-724 and C-82) : Maximum Plasma Concentration (Cmax) | The data will be aggregated by each cohort. | A) Single administration part: pre-dose and post-dose at 0.5, 1, 2, 4, 5, 9 and 24 hours. / B) Continuous administration part: pre-dose and post-dose at 4 hours on Day 1 and 4 in Cycle 1, 5, 9 and 12 (each cycle is 7 days) | 
| Parameters on Pharmacokinetics (OP-724 and C-82) : Area Under the Curve (AUC 0-24h) | The data will be aggregated by each cohort. | A) Single administration part: pre-dose and post-dose at 0.5, 1, 2, 4, 5, 9 and 24 hours. / B) Continuous administration part: pre-dose and post-dose at 4 hours on Day 1 and 4 in Cycle 1, 5, 9 and 12 (each cycle is 7 days) | 
| Liver Tissue Fibrotic Area Ratio by Liver Biopsy | Amount of change from baseline in liver tissue fibrotic area ratio by liver biopsy at 12 weeks after administration. The data will be aggregated by each cohort. | 12 weeks after administration of OP-724 | 
| Liver Stiffness by Fibro Scan | Amount of change from baseline of liver stiffness by Fibro Scan at 12 weeks after administration. The data will be aggregated by each cohort. | 12 weeks after administration of OP-724 | 
| Child-Pugh Score | Amount of change from baseline of Child-Pugh Score at 12 weeks after administration. Child Pugh score (scale range 5-15 points, the severity increases sequentially from 5 to 15 points) is obtained by adding the score for each parameter (hepatic encephalopathy, ascites, bilirubin, albumin, PT). Based on the total points score (Child-Pugh Score) of each diagnostic parameter shown above, the severity of the disease is classified into Grades A to C shown below. The data will be aggregated by each cohort and score. Grade A: 5-6 points -> Compensated cirrhosis Grade B: 7-9 points -> Decompensated cirrhosis Grade C: 10-15 points -> Decompensated cirrhosis | 12 weeks after administration of OP-724 | 
| MELD Score | Amount of change from baseline in 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 score = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43 The data will be aggregated by each cohort and score. | 12 weeks after administration of OP-724 | 
| Modified Histological Activity Index (HAI) | Amount of change from baseline of modified Histological Activity Index (HAI) and classification of Nakanuma et al. by liver biopsy at 12 weeks after administration. The data will be aggregated by each cohort and index | 12 weeks after administration of OP-724 | 
| Serum Alkaline Phosphatase (ALP) Level | Amount of change from baseline in serum ALP level at 12 weeks after administration. The data will be aggregated by each cohort and Child-Pugh score. | 12 weeks after administration of OP-724 | 
| Serum Total Bilirubin Value | Amount of change from baseline in serum total bilirubin value at 12 weeks after administration. The data will be aggregated by each cohort and Child-Pugh score. | 12 weeks after administration of OP-724 | 
| Enhanced Liver Fibrosis Panel (ELF) Score | Amount of change from baseline of ELF score at 12 weeks after administration. Observation items: hyaluronic acid, procollagen III peptide, TIMP-1 * ELF score = 2.278 + 0.851 ln (hyaluronic acid) + 0.75 ln (P3 NP) + ln (TIMP). The data will be aggregated by each cohort and score. | 12 weeks after administration of OP-724 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Biliary Cholangitis (PBC), Liver Cirrhosis, Biliary, Cholangitis, Chronic Nonsuppurative Destructive, Liver Cirrhosis, Obstructive, Secondary Biliary Cholangitis, Primary Biliary Cirrhosis, Secondary Biliary Cirrhosis