The study will be conducted in compliance with the International Council for Harmonisation
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good
Clinical Practice (GCP) and applicable regulatory requirements.
This is a Phase 1/2 multicenter, single arm, open-label study in Japanese subjects with DIPSS
intermediate or high-risk PMF, post-PV or post-ET MF. The study consists of 2 parts: Phase 1
part to determine safety and tolerability and a RP2D. The Phase 1 portion of the study will
explore one or more drug doses for fedratinib (300 mg and 400 mg) using a mTPI-2 design.
Following completion of dose escalation and determination of MTD and/or a RP2D, the study
will progress into the Phase 2 part to further evaluate the efficacy and safety.
The study will consist of 3 periods: a Screening Period, a Treatment Period including a
30-day follow-up after last dose visit and a survival follow-up period.
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 20 years of age at the time of signing the informed consent form (ICF)
2. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0,
1 or 2
3. Subject has diagnosis of Primary myelofibrosis (PMF) according to the 2016 World
Health Organization (WHO) criteria, or diagnosis of post-ET or post- Polycythemia vera
(PV) Myelofibrosis (MF) according to the IWG-MRT 2007 criteria, confirmed by the most
recent local pathology report
4. Subject has a Dynamic International Prognostic Scoring System (DIPSS) Risk score of
Intermediate-1 with symptom(s), Intermediate-2 or High
5. Subject has a measurable splenomegaly during the screening period as demonstrated by
spleen volume of ≥ 450 cm3 by magnetic resonance imaging (MRI) or computed tomography
(CT) scan or by palpable spleen measuring ≥ 5 cm below the left costal margin.
6. Subject must meet at least one of the following criteria of (a or b).
Note: reason to discontinue ruxolitinib treatment (lack of efficacy and/or
intolerability, etc) and physician decision as to the study participation as being
appropriate should be recorded in the case report form:
1. Previously received ruxolitinib treatment for PMF or post-PV MF or post-ET MF for
at least 14 days (exposure of < 14 days is allowed for subjects who discontinued
ruxolitinib due to intolerability or allergy).
2. Never received ruxolitinib treatment and is expected to derive clinical benefit
from this study participation based on the clinical judgement of the Investigator
Only those subjects who previously received ruxolitinib treatment are eligible
for the Phase 1 part of the study to avoid overestimating tolerability of
7. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1
or pretreatment baseline before start of last therapy prior to starting the fedratinib
8. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted.
9. Subject is willing and able to adhere to the study visit schedule and other protocol
10. A female of childbearing potential (FCBP) must:
1. Have 2 negative pregnancy tests as verified by the Investigator during screening
prior to starting fedratinib treatment. She must agree to ongoing pregnancy
testing during the course of the study, and after end of fedratinib treatment.
This applies even if the subject practices true abstinence* from heterosexual
2. Either commit to true abstinence* from heterosexual contact (which must be
reviewed on a monthly basis and source documented) or agree to use and be able to
comply with highly effective contraception** without interruption, -14 days prior
to starting investigational product, during the fedratinib treatment (including
dose interruptions), and for 30 days after discontinuation of fedratinib
3. If breastfeeding, agree to stop breastfeeding prior to the participation in the
study and not to resume breastfeeding for at least 30 days after treatment
discontinuation of the fedratinib treatment.
Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved
menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy,
or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or
amenorrhea due to other medical reasons does not rule out childbearing potential) for
at least 24 consecutive months (ie, has had menses at any time in the preceding 24
11. A male subject must:
Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a
condom during sexual contact with a pregnant female or a female of childbearing potential
while participating in the study, during dose interruptions and for at least 30 days
following fedratinib discontinuation, or longer if required by local regulations, even if
he has undergone a successful vasectomy.
True abstinence is acceptable when this is in line with the preferred and usual lifestyle
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation
methods] and withdrawal are not acceptable methods of contraception).
Agreement to use highly effective methods of contraception that alone or in combination
resulting in a failure rate of a Pearl index of less than 1% per year when used
consistently and correctly throughout the course of the study. Such methods include
combined (estrogen and progestogen containing) hormonal contraception (oral),
progestogen-only hormonal contraception associated with inhibition of ovulation (oral),
placement of an intrauterine device, placement of an intrauterine hormone-releasing system,
bilateral tubal occlusion, and vasectomized partner.
The presence of any of the following will exclude a subject from enrollment:
1. Any of the following laboratory abnormalities:
1. Platelets < 50 x 109/L (without platelet transfusion)
2. Absolute neutrophil count (ANC) < 1.0 x 109/L
3. White blood count (WBC) > 100 x 109/L
4. Myeloblasts ≥ 5 % in peripheral blood
5. Estimated creatinine clearance < 30 mL/min (as estimated by Cockcroft-Gault
6. Serum amylase or lipase > 1.5 x upper limit of normal
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper
limit of normal (ULN)
8. Total bilirubin > 1.5 x ULN, subject's total bilirubin between 1.5 - 3.0 x ULN
are eligible if the direct bilirubin fraction is < 25% of the total bilirubin.
2. Subject is pregnant or breastfeeding female.
3. Subject with previous splenectomy
4. Subject with previous or planned hematopoietic Stem-cell transplantation (SCT)
5. Subject with prior history of Encephalopathy, including Wernicke encephalopathy (WE)
6. Subject with signs or symptoms of encephalopathy, including WE (eg, severe ataxia,
ocular paralysis or cerebellar signs) without documented exclusion of WE by thiamine
level and brain MRI
7. Subject with thiamine deficiency, defined as thiamine levels in whole blood below
normal range according to institutional standard and not demonstrated to be corrected
prior to starting the fedratinib treatment
8. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or
food known to be strong or moderate inducers of Cytochrome P450 (CYP) 3A4, and dual
CYP2C19 and CYP3A4 inhibitors
9. Subject on any chemotherapy, immunomodulatory drug therapy (eg, thalidomide,
interferon-alpha), anagrelide, immunosuppressive therapy, systemic corticosteroids >
10 mg/day prednisone or equivalent. Subjects who have had prior exposure to
hydroxyurea (eg, Hydrea) in the past may be enrolled into the study as long as it has
not been administered within 14 days prior to starting the fedratinib treatment.
10. Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating
factor [G-CSF]) within 14 days prior to starting the fedratinib treatment
11. Subject with previous exposure to JAK inhibitor(s) other than ruxolitinib treatment
12. Subject has received ruxolitinib within 14 days prior to starting the fedratinib
13. Subject on treatment with aspirin with doses > 150 mg daily
14. Subject with major surgery within 28 days prior to starting the fedratinib treatment
15. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease,
autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis,
hemochromatosis, non-alcoholic steatohepatitis)
16. Subject with prior malignancy other than the disease under study unless the subject
has not required treatment for the malignancy for at least 3 years prior to the start
of fedratinib treatment. However, subject with the following history/concurrent
conditions provided successfully treated may enroll: non-invasive skin cancer, in situ
cervical cancer, carcinoma in situ of the breast, incidental histologic finding of
prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging
system), or is free of disease and on hormonal treatment only
17. Subject with uncontrolled congestive heart failure (New York Heart Association
Classification 3 or 4)
18. Seropositive for and with evidence of active viral infection with hepatitis B virus
1. Subject who are hepatitis B surface antigen (HBsAg) negative but HB core
anti-body (HBcAb) positive or HBsAb positive are eligible in case HBV viral
deoxyribonucleoside (DNA) negative
2. Subject who had HBsAg positive but show non-detectable viral DNA for at least 6
months prior to starting the fedratinib treatment where appropriate anti-viral
treatment should have been given/considered to prevent HBV reactivation based on
the standard practice are eligible
3. Subject who are seropositive because of hepatitis B virus vaccine are eligible
19. Seropositive for and with active viral infection with hepatitis C virus (HCV)
• Subject who had hepatitis C but show no detectable HCV viral ribonucleotide (RNA)
for at least 6 months prior to starting the fedratinib treatment are eligible.
20. Evidence of human immunodeficiency virus (HIV) infection.
21. Subject with serious active infection
22. Subject with presence of any significant gastric or other disorder that would inhibit
absorption of oral medication
23. Subject is unable to swallow capsule
24. Subject with any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study
25. Subject has any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if the subject were to participate in the
26. Subject has any condition that confounds the ability to interpret data from the study
27. Subject with participation in any study of an investigational agent (drug, biologic,
device) within 30 days prior to starting the fedratinib treatment
28. Subject with a life expectancy of less than 6 months from the planned first dose of