A Study of Vorasidenib in Participants With Moderate or Mild Hepatic Impairment and Matched Participants With Normal Hepatic Function

Servier

Status and phase: Completed; Phase 1

Conditions: Hepatic Impairment

Treatments: Drug: Vorasidenib

Study type: Interventional

Funder types: Other

Identifiers

NCT05674474

PKH-95032-008

Details and patient eligibility

About

The primary purpose of this study is to estimate the effect of moderate or mild hepatic impairment on the pharmacokinetic (PK) profile of a single oral dose of 20 mg vorasidenib in participants with hepatic impairment relative to healthy matched control participants with normal hepatic function.

Enrollment: 16 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria for All Participants:

• Have a body mass index of 18 to 40 kilograms per square meter (kg/m^2).
• Female participants of childbearing potential must use 2 effective methods of birth control during the study and for 90 days after the last dose of vorasidenib or be surgically sterile, or postmenopausal.
• Male participants with female partners of childbearing potential must be sterile, or willing to use 2 effective methods of birth control from Screening until at least 90 days after the last dose of the study drug, or practice abstinence during the study.
• Non-smoker or uses ≤10 cigarettes per day as judged by the investigator.
• Agree to comply with all protocol requirements for the duration of the study.
• Able to provide written informed consent prior to any procedure required by the study.

Inclusion Criteria for Healthy Participants Only:

• Have normal hepatic function.

Inclusion Criteria for Participants with Hepatic Impairment Only:

• Have chronic (more than 6 months) and stable hepatic impairment (i.e., no acute episodes of illness within 30 days before Screening due to deterioration of hepatic function) as assessed by a Child-Pugh classification score of moderate (7 to 9 points) and, if Stage 2 enrolls, mild (5 to 6 points).
• The subject has grade 0 or grade 1 hepatic encephalopathy, considered stable per investigator assessment, without exacerbation within the 6 months prior to Screening.
• The subject has a QTcF of ≤480 msec.

Exclusion Criteria for All Participants:

• Have a history or clinical manifestations of a significant neurological, renal, cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic, or psychiatric disease that would preclude study participation, as judged by the investigator.
• Have a history (within 5 years) or presence of malignancy, except for adequately treated basal cell and squamous cell carcinoma of the skin.
• The subject is a woman of childbearing potential who is pregnant, lactating, or planning to become pregnant within 90 days after the last dose of study drug or the subject is on oral contraceptive pills within 14 days or 5 half-lives (whichever is longer) prior to the first dose administration and during the study.
• Have received any vaccine or used any prescription (excluding hormone replacement therapy) or over-the-counter medications, including herbal or nutritional supplements, within 30 days before the first dose of the study drug.
• Have a positive test result for hepatitis B surface antigen or antibodies to hepatitis C virus.
• Have a positive test result for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• Have a positive test result for human immunodeficiency virus (HIV) types 1 or 2 antibodies.
• Have used strong or moderate CYP1A2 inhibitors and/or inducers within 14 days or 5 half-lives, whichever is longer, prior to the first dose administration. .
• Have used any gastric acid reducing agents (eg, proton-pump inhibitors, H2-receptor antagonists, antacids) or drugs that can prolong the QT interval for 28 days or 5 drug half-lives (whichever is longer) prior to the first dosing and throughout the study
• Have a history of severe and/or uncontrolled ventricular arrhythmias or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome).
• Have a history of alcoholism or drug abuse within 3 months before Screening or excessive alcohol consumption.
• Unable or unwilling to abstain from recreational drugs, alcohol, caffeine, xanthine-containing beverages or food (e.g., coffee, tea, chocolate, and caffeinated sodas, colas), grapefruit, grapefruit juice, Seville oranges, or products containing any of these, from 48 hours prior to study drug dosing until discharge.
• Involved in strenuous activity (i.e., >30 minutes [min] per day) or contact sports within 48 hours of the first dose of the study drug or during the study.
• Have a history of relevant drug and/or food allergies (i.e., allergy to drugs with the same class effect as vorasidenib or any excipients, or any significant food allergy).
• Have received study drug in another investigational study within 30 days of dosing.

Exclusion Criteria for Participants with Hepatic Impairment Only:

• Have ascites that requires paracentesis every 4 weeks or less frequently.
• Have evidence of hepatorenal syndrome or hepatic encephalopathy.
• Have a history of incipient/planned liver transplantation within 6 months of Screening or have received a liver transplant.
• Have amylase and/or lipase levels ≥3 x upper limit of normal (ULN). Presence of 8 x ULN elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin and international normalized ratio (INR) of 3.5 for the hepatic impaired group.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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16 participants in 2 patient groups

Group A: Normal Hepatic Function

Experimental group

Description:

Participants with normal hepatic function will receive a single oral dose of 20 mg (2 × 10 mg) vorasidenib tablets on Day 1.

Treatment:

Drug: Vorasidenib

Group B: Moderate or Mild Hepatic Impairment

Experimental group

Description:

Stage 1: Participants with moderate hepatic impairment (Child-Pugh \[C-P\] Class B, score of 7 to 9) will receive a single oral dose of 20 mg (2 × 10 mg) vorasidenib tablets on Day 1. Stage 2: Participants with mild hepatic impairment (C-P Class A, score of 5 to 6) will receive a single oral dose of 20 mg (2 × 10 mg) vorasidenib tablets on Day 1. Stage 2 will be conducted if a clinically meaningful increase in exposure of vorasidenib is observed in participants with moderate hepatic impairment in Stage 1.

Treatment:

Drug: Vorasidenib