| Eligibility |
Inclusion Criteria:
Inclusion Criteria for all subjects (Groups 1 through 4)
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.
Inclusion Criteria for Subjects with Moderate or Severe Hepatic Impairment (Groups 1
and 3)
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.
Inclusion Criteria for a Matched Healthy Subjects (Groups 2 and 4) Each matched
healthy subject must meet all the criteria listed below for entry:
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.
Exclusion Criteria:
The presence of any of the following will exclude a subject from enrollment:
1. Subject has prior history of Wernicke's encephalopathy (WE).
2. Subject has signs or symptoms of WE (eg, severe ataxia, ocular paralysis or cerebellar
signs) without documented exclusion of WE by thiamine level and brain MRI.
3. Subject has thiamine deficiency, defined as thiamine levels in whole blood below
normal range according to institutional standard and not demonstrated to be corrected
prior to enrollment into the study.
4. Subject has any significant and relevant medical condition, laboratory abnormality, or
psychiatric illness that would prevent the subject from participating in the study at
the Investigator's discretion.
5. Subject has any condition that places the subject at an unacceptable risk if he or she
were to participate in the study.
6. Subject has any condition that confounds the ability to interpret data from the study.
7. Subject is pregnant or breastfeeding.
8. Subject was exposed to an investigational drug (new chemical entity) within 30 days
preceding the first dose administration, or 5 half-lives of that investigational drug,
if known (whichever was longer).
9. Subject has used moderate or strong CYP3A4 and/or CYP2C19 inducers and/or inhibitors
(including St. John's wort) within 14 days or 5 half-lives, whichever is longer, prior
to the first dose administration. The Indiana University "Cytochrome P450 Drug
Interaction Table" should be utilized to determine inhibitors and/or inducers of
CYP3A4 (http://medicine.iupui.edu/clinpharm/ddis/table.aspx).
10. Subject has any surgical or medical condition(s) possibly affecting drug absorption,
distribution, metabolism, and excretion, eg, bariatric procedure. Subjects with
appendectomy and cholecystectomy may be included.
11. Subject donated blood or plasma within 2 weeks before dose administration to a blood
bank or blood donation center.
12. Subject has a history of drug abuse (as defined by the current version of the
Diagnostic and Statistical Manual) within 2 years before dose administration, or
positive drug screening test reflecting consumption of illicit drugs.
a. If positive drug screen in a subject with hepatic impairment is due to prescription
drug use, the specific drug and dosing regimen of the prescription drug must be
reviewed with the Sponsor's Medical Monitor to ensure lack of interference with the PK
assessments of this study, according to the protocol. The decision and its rationale
will be documented in the Trial Master File.
13. Subject has a history of alcohol abuse (as defined by the current version of the
Diagnostic and Statistical Manual) within 1 year before dose administration, or a
positive alcohol screen.
14. Subject has had a positive result to the test for human immunodeficiency virus (HIV)
antibodies at Screening.
15. Subject smokes more than 10 cigarettes per day, or the equivalent in other tobacco
products (self-reported).
16. Subject has received live vaccination (excluding seasonal flu vaccination) within 90
days of dosing.
17. Subject is part of the clinical staff personnel or a family member of the study site
staff.
18. Subject is, for any reason, deemed by the investigator to be inappropriate for this
study, including a subject who is unable to communicate or to cooperate with the
Investigator or the clinical staff.
19. Subject has a hypersensitivity to ondansetron. 4.3.1. Exclusion Criteria for Subjects
with Moderate or Severe Hepatic Impairment (Groups 1 and 3) The presence of any of the
following will exclude a hepatically-impaired subject from enrollment:
20. Subject has any serious medical condition (excluding hepatic impairment and related
complications), clinically significant laboratory abnormality not related to hepatic
impairment and related complications, or psychiatric illness that would prevent the
subject from signing the ICF and participating in the study per Investigator
discretion.
21. Subject has current hepatic encephalopathy with time- or place- disorientation,
somnolence, stupor, coma, no personality/behavior, rigidity, or hyperactive reflexes -
or has had such within 1 month of Screening. Hepatic subjects with history of grade 3
or 4 encephalopathy who are treated with concomitant medications to control
encephalopathy will receive pre-treatment score for the Child-Pugh classification.
22. Subject has a history of incipient/planned liver transplantation within 6 months of
Screening or has received a liver transplant.
Exclusion Criteria for a Matched Healthy Subject (Groups 2 and 4) Each matched healthy
subject will be excluded from entry if any of the criteria listed below are met:
23. Subject has any clinically significant laboratory abnormality that, in the opinion of
the Investigator, is considered to prevent the subject from safely completing the
study.
24. Subject has any unstable clinically significant illness within 3 months prior to the
study.
25. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study.
26. Subject has used any prescribed systemic or topical medication (including but not
limited to analgesics, anesthetics, etc) within 30 days or 5 drug half-lives
(whichever is longer) prior to the first dose administration of fedratinib.
a. A subject who has used (or will have used) a prescribed medication less than 30
days prior to (but at least 5 half-lives prior to) fedratinib dosing may be admitted
into the study if such usage is not expected by the Investigator to have persistent PK
effects at the time of fedratinib dosing. Such effects may include, but are not
limited to, cytochrome induction or covalent cytochrome inhibition. These cases must
be approved by Sponsor's Medical Monitor. The decision and its rationale will be
documented in the Trial Master File.
27. Subject has used any nonprescribed systemic or topical medication (including
vitamin/mineral supplements, and herbal medicines) within 14 days or 5 drug half-lives
(whichever is longer) prior to the first dose administration of fedratinib.
a. A subject who has used (or will have used) a nonprescribed medication less than 14
days prior to (but at least 5 half-lives prior to) fedratinib dosing may be admitted
into the study if such usage is not expected by the Investigator to have persistent PK
effects at the time of fedratinib dosing. Such effects may include, but are not
limited to, cytochrome induction or covalent cytochrome inhibition. These cases must
be approved by Sponsor's Medical Monitor. The decision and its rationale will be
documented in the Trial Master File.
28. Subject is known to have a history of hepatitis B and/or hepatitis C, or have a
positive result to the test for HIV antibodies at screening Note: Subjects who
received hepatitis B vaccination and who test positive for hepatitis B surface
antibody and negative for both hepatitis B surface antigen and hepatitis B core
antibody remain eligible for study participation.
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