A Pharmacokinetics and Tolerability Study of Fedratinib in Subjects With Moderate and Severe Hepatic Impairment

Inclusion Criteria

• •Subjects must satisfy the following criteria to be enrolled in the study:
• •1. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• •2. Subject is willing and able to adhere to the study visit schedule and other protocol requirements, including the restrictions
• •3. Subject is male, or non-pregnant and non-nursing female ≥ 18 and ≤ 75 years of age at the time of signing the Informed Consent Form (ICF).
• •4. Subject has body mass index (BMI) ≥ 18 and ≤ 40 kg/m2 at screening.
• •5. Female subjects NOT of childbearing potential must:
• •a. Have been surgically sterilized (hysterectomy or bilateral oophorectomy; proper documentation required) at least 6 months before Screening, or postmenopausal (defined as 24 consecutive months without menses before Screening, with a follicle-stimulating hormone \[FSH\] level in the post-menopausal range according to the laboratory used at Screening); FSH to be performed at the discretion of the Investigator in consultation with the Sponsor's Medical Monitor.
• •6. A female of childbearing potential (FCBP) must:
• •1. Have a negative pregnancy test as verified by the Investigator at Screening and Baseline (prior to starting study treatment). She must agree to ongoing pregnancy testing during the course of the study, as applicable, and after the end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
• •2. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis, as applicable, and source documented) or agree to use, and be able to comply with, any one of the following highly effective contraception methods without interruption, beginning at least 14 days prior to dosing, during the study treatment, and for at least 30 days after the last dose of IP.
• •* Hormonal contraception (eg, birth control pills, intravaginal ring, transdermal patch, injection, implant); intrauterine device (IUD); tubal ligation; or a partner with a vasectomy. The chosen form of birth control must be effective by the time the subject receives the first dose of IP.
• •7. Male subjects must:
• •a. Practice true abstinence (which must be reviewed monthly, as applicable, and source documented) or agree to use a barrier method of birth control (condoms not made from natural \[animal\] membrane \[latex condoms are recommended\]) during sexual contact with a pregnant female or FCBP while receiving study treatment, and for at least 30 days after the last dose of IP, even if he has undergone a successful vasectomy.
• •8. Subject has clinical laboratory safety test results that are within normal limits or acceptable to the Investigator.
• •9. Subject is afebrile (febrile is defined as ≥ 38°C or 100.3°F), with supine systolic blood pressure (BP) ≥ 90 and ≤ 160 mm Hg, supine diastolic BP ≥ 50 and ≤ 100 mm Hg, and pulse rate ≥ 40 and ≤ 100 beats per minute at Screening.
• •Each subject with moderate or severe hepatic impairment must also meet all the criteria listed below for entry:
• •10. Subject has moderate or severe hepatic impairment or cirrhosis due to chronic hepatic disease and/or prior alcohol use.
• •11. Subject has moderate (Group 1) or severe (Group 3) hepatic impairment as defined by Child-Pugh Score.
• •* Group 1 subjects (moderate hepatic impairment) are required to have documented confirmation of the diagnosis of cirrhosis made by biopsy, laparoscopy, or imaging study with a Child-Pugh score of ≥ 7 to ≤ 9 at Screening.
• •* Group 3 subjects (severe hepatic impairment) are required to have documented confirmation of the diagnosis of cirrhosis made by biopsy, laparoscopy, or imaging study with a Child-Pugh score of ≥ 10 to ≤ 13 at Screening.
• •If biopsy or laparoscopy is not performed prior to Screening, subjects can be included only if they have chronic liver disease and objective evidence of portal hypertension (ascites diagnosis by imaging or varices), or current medication for consequences of portal hypertension.
• •Subjects should be enrolled into the group corresponding to the Child-Pugh classification score that most accurately reflects the most severe hepatic disease classification within the past 6 months (based on past medical history or physical examination observation).
• •\*Note: If a Child-Pugh score was previously calculated and documented in the last 6 months, and it is more severe than the one calculated at Screening, then that previous value will be used for study entry purposes. If the Screening Child-Pugh score is more severe, then it will be used. If no score was calculated in the 6 months prior to Screening, then the score obtained at Screening will be used. Adequate documentation should be provided to substantiate the Child-Pugh score assigned to each subject.
• •12. Subject must be medically stable for at least 1 month before Screening with clinically acceptable medical history, PE, clinical laboratory tests, vital signs, and 12-lead ECGs consistent with the underlying stable hepatic impairment condition, as judged by the Investigator.
• •13. Subject must be stable on a concomitant medication regimen (defined as not starting a new medication\[s\] or a change in the dosage or frequency of the concomitant medication\[s\] within 7 days or 5 half-lives \[whichever is longer\] before dosing with fedratinib).
• •14. Subject may be treated with diuretics for ascites. Subjects with severe ascites at time of enrollment may be included at the discretion of the Investigator.
• •15. Subject may have a history of encephalopathy; however, they must be on stable treatment for at least 1 month prior to Screening, and must not have had an acute encephalopathic episode in the 1 month prior to Screening.
• •16. Subjects must not have history of hepatorenal syndrome or hemolysis.
• •17. Subject has a normal or clinically acceptable 12-lead ECG at Screening (QTcF ≤ 480 msec).
• •18. Subject must have estimated creatinine clearance ≥ 60 mL/min at Screening as calculated by the Cockcroft-Gault formula.
• •19. Subject is free of any clinically significant disease that would interfere with the study evaluations.
• •20. Subject has liver-related laboratory test results within the respective reference ranges or judged as clinically acceptable by the Investigator.
• •21. Subject must match a subject in Groups 1 or 3, as needed, with respect to sex, age (± 10 years), and weight (± 13.6 kg \[30 pounds\]).
• •22. Subject is in good health as determined by past medical history, PE, vital signs, ECG, and clinical laboratory safety tests. Clinical laboratory safety tests (ie, hematology, chemistry, and urinalysis) and 12-lead ECGs must be within normal limits or clinically acceptable as judged by the Investigator.
• •23. Subject has a normal or clinically acceptable 12-lead ECG at Screening. In addition:
• •1. If male, subject has a QTcF value ≤ 450 msec at Screening.
• •2. If female, subject has a QTcF value ≤ 470 msec at Screening.