Study of Pexidartinib in Participants With Moderate Hepatic Impairment Compared With Healthy Participants

NCT ID: NCT04223635

Last Updated: 2021-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-07
• Study Completion Date: 2020-10-02

Brief Summary

The pharmacokinetics of a single dose of pexidartinib was investigated in participants with impaired hepatic function and compared with healthy control participants with normal hepatic function.

Detailed Description

Pexidartinib is an orally administered tyrosine kinase inhibitor, currently approved in the US for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery.

The primary objective of this study is to determine the plasma pharmacokinetics (PK) of pexidartinib after a single oral dose of 200 mg in participants with moderate hepatic impairment (HI) as defined by National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria compared to the healthy controls participants with normal hepatic function.

Conditions

Moderate Hepatic Impairment

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Hepatic impaired

Participants with moderate hepatic impairment who will receive a single oral dose of pexidartinib.

Group Type: EXPERIMENTAL

Pexidartinib

Intervention Type: DRUG

Single, 200-mg capsule will be administered orally on Day 1 with 240 mL of water, following an overnight fast of at least 10 hours.

Healthy controls

Sex-, age-, and weight-matched healthy participants who will receive a single oral dose of pexidartinib.

Group Type: EXPERIMENTAL

Pexidartinib

Intervention Type: DRUG

Single, 200-mg capsule will be administered orally on Day 1 with 240 mL of water, following an overnight fast of at least 10 hours.

Interventions

Pexidartinib

Single, 200-mg capsule will be administered orally on Day 1 with 240 mL of water, following an overnight fast of at least 10 hours.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Screening: Male and female participants, 18 y to 75 years of age, inclusive, with body mass index (BMI) 18 kg/m^2 to 40 kg/m^2, inclusive at Screening.

Participants with hepatic impairment (HI) are required to have:

• Documented history of chronic liver disease diagnosed by ultrasonography, computed tomography scan, liver biopsy, or magnetic resonance imaging or history of chronic (>6 months) hepatitis B virus or hepatitis C virus infection.
• Moderate HI as assessed by the National Cancer Institute-Organ Dysfunction Working Group (NCI-ODWG) criteria (total bilirubin [TBIL] >1.5 to 3x upper limit of normal [ULN]) not due to Gilbert's syndrome.
• Normal or nonclinically relevant findings at physical examination and normal limits or nonclinically relevant deviations in clinical laboratory evaluations, with exception of findings that in the opinion of investigator are consistent with participant's HI.
• Clinical stability in the opinion of the investigator.
• Female participants (both, healthy and HI participants) who are of non-childbearing potential must be:

• Surgically sterile (ie, bilateral tubal ligation or removal of both ovaries and/or uterus at least 6 months prior to dosing, or Essure® with hysterosalpingogram [documentation to confirm tubal occlusion 12 weeks after procedure]).
• Naturally postmenopausal (spontaneous cessation of menses) for at least 12 consecutive months prior to dosing, confirmed by follicle stimulating hormone (FSH) or estradiol testing.
• Female participants (both, healthy and HI subjects) who are of childbearing potential must agree to barrier method of contraceptive therapy or refrain from sexual intercourse to prevent pregnancy until 1 month post dose. If the participant is on oral contraceptive, the participant needs to use the barrier method in addition to oral contraceptive. Female participants must refrain from breastfeeding for at least 2 weeks post dose.
• Male participants (both, healthy and HI subjects) must surgically sterile or agree to use double barrier methods of contraception from Check-in until 1 month after the dose of pexidartinib. Also, male participants must not donate sperm from Check-in until 1 month after pexidartinib administration.

Exclusion Criteria

• Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the Screening assessment that could interfere with the objectives of the study or the safety of the participant
• Participants with primary biliary cirrhosis or primary sclerosing cholangitis
• Concomitant medication (moderate or strong inhibitor or inducer of CYP3A4 [eg, itraconazole, rifampin], CYP2C9 [eg, fluconazole, carbamazepine] and uridine 5'-diphospho-glucuronosyltransferase (UGT) [eg, probenecid, rifampin]) within 2 weeks before dosing and throughout study
• History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (with the exception of appendectomy, hernia repair, and/or cholecystectomy)
• Presence or history of severe adverse reaction to any drug (except penicillin)
• A positive drugs of abuse screen (unless the drug is medically prescribed by a licensed health care provider) or alcohol breath test at Screening or at Check-in on Day -2 or a participant who will not agree to smoke ≤10 cigarettes or equivalent per day from Screening up to Enrollment, and is unable to be restricted to ≤5 cigarettes per day and for 6 hours post dose during their period of residence in the clinical unit
• Concomitant use of medications known to affect the elimination of serum creatinine (eg, trimethoprim or cimetidine) and inhibitors of renal tubular secretion (eg, probenecid) within 60 days of Day -2
• History or presence of an abnormal ECG, which, in the investigator's opinion, is clinically significant and/or a QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥450 milliseconds (ms) and ≥470 ms for healthy male and female participants, respectively, and >500 ms for participants with HI at Screening
• Consumption of alcohol-within 72 hours prior to Check-in and caffeine-containing beverages within 48 hours prior to Check-in and during confinement
• Consumption of more than 28 units of alcohol per week for males or 14 units of alcohol per week for females, where 1 unit of alcohol equals one-half pint of beer, 4 ounces (oz) of wine, or 1 oz of spirits, or significant history of alcoholism or drug/chemical abuse within the last 2 years
• Positive serology for HBsAg and anti-hepatitis C virus (HCV) (healthy participants), hepatitis A virus (HAV) immunoglobulin M, or anti-HIV Type 1 and Type 2 (all participants)
• Loss of more than 450 mL blood during the 3 months before the trial (eg, as a blood donor)
• Current enrollment in or have not yet completed at least 30 days or 5 elimination half-lives, whichever is longer, since receiving an investigational device or product, or receipt of other investigational agents within 30 days of pexidartinib

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Daiichi Sankyo

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Study Leader

Role: STUDY_DIRECTOR

Daiichi Sankyo

Locations

Clinical Pharmacology of Miami, LLC.

Miami, Florida, United States

Orlando Clinical Research Center

Orlando, Florida, United States

Countries

United States

References

Zahir H, Greenberg J, Hsu C, Marbury TC, Lasseter KC, Xu LA, Tap WD, Healey JH, Stacchiotti S, LaCreta F. Effect of Mild and Moderate Hepatic Impairment (Defined by Child-Pugh Classification and National Cancer Institute Organ Dysfunction Working Group Criteria) on Pexidartinib Pharmacokinetics. J Clin Pharmacol. 2022 Aug;62(8):992-1005. doi: 10.1002/jcph.2042. Epub 2022 Mar 31.

Reference Type: DERIVED

PMID: 35247274 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

PL3397-A-U129

Identifier Type: -

Identifier Source: org_study_id