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

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

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

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.

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.

  1. Histologically, chronic non-suppurative destructive cholangitis (CNSDC) is found and the laboratory findings are consistent as PBC.
  2. A positive antimitochondrial antibody (AMA) with no histologic findings of CNSDC but showing a histology consistent with PBC.
  3. 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.