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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04223635
Recruitment Status : Completed
First Posted : January 10, 2020
Last Update Posted : October 9, 2020
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Tracking Information
First Submitted Date  ICMJE January 6, 2020
First Posted Date  ICMJE January 10, 2020
Last Update Posted Date October 9, 2020
Actual Study Start Date  ICMJE December 20, 2019
Actual Primary Completion Date October 2, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 7, 2020)
  • Pharmacokinetic parameter analysis: Maximum plasma concentration (Cmax) of plasma pexidartinib [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Time to reach maximum plasma concentration (Tmax) of plasma pexidartinib [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Area under the curve from time 0 to last measurable time point (AUClast) of plasma pexidartinib [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Area under the curve from time 0 to infinity (AUCinf) of plasma pexidartinib [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Elimination rate constant (kel) of plasma pexidartinib [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Terminal elimination half-life (t1/2) of plasma pexidartinib [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Total clearance (CL/F) of plasma pexidartinib [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Volume of distribution (Vz/F) of plasma pexidartinib [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 7, 2020)
  • Pharmacokinetic parameter analysis: Maximum plasma concentration (Cmax) of plasma ZAAD-1006a metabolite [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Time to reach maximum plasma concentration (Tmax) of plasma ZAAD-1006a metabolite [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Area under the curve from time 0 to last measurable time point (AUClast) of plasma ZAAD-1006a metabolite [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Area under the curve from time 0 to infinity (AUCinf) of plasma ZAAD-1006a metabolite [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Terminal elimination half-life (t1/2) of plasma ZAAD-1006a metabolite [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
  • Pharmacokinetic parameter analysis: Metabolite to parent ratio after adjusting for molecular weight (MPR) of plasma ZAAD-1006a metabolite [ Time Frame: Predose (within 60 minutes prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose ]
    MPR will be based on AUClast and AUCinf.
  • Pharmacokinetic parameter analysis: Protein binding of plasma pexidartinib and ZAAD-1006a metabolite [ Time Frame: 2.5 and 24 hours post dose ]
  • Incidence of adverse events in participants with moderate hepatic impairment [ Time Frame: Post dose through end of study, approximately 5 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Pexidartinib in Participants With Moderate Hepatic Impairment Compared With Healthy Participants
Official Title  ICMJE An Open-label, Single-dose Study to Assess the Pharmacokinetics of Pexidartinib in Subjects With Moderate Hepatic Impairment Compared to Healthy Subjects
Brief Summary The pharmacokinetics of a single dose of pexidartinib will be 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Moderate Hepatic Impairment
Intervention  ICMJE Drug: 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.
Study Arms  ICMJE
  • Experimental: Hepatic impaired
    Participants with moderate hepatic impairment who will receive a single oral dose of pexidartinib.
    Intervention: Drug: Pexidartinib
  • Experimental: Healthy controls
    Sex-, age-, and weight-matched healthy participants who will receive a single oral dose of pexidartinib.
    Intervention: Drug: Pexidartinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 7, 2020)
16
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 2, 2020
Actual Primary Completion Date October 2, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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-HCV (healthy participants), 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04223635
Other Study ID Numbers  ICMJE PL3397-A-U129
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/
Responsible Party Daiichi Sankyo, Inc.
Study Sponsor  ICMJE Daiichi Sankyo, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Study Leader Daiichi Sankyo, Inc.
PRS Account Daiichi Sankyo, Inc.
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP