Inclusion Criteria:
1. Subject is at least 18 years of age at the time of signing the informed consent form
(ICF)
2. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (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-PV myelofibrosis
according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology
report
4. Subject has a DIPSS Risk score of Intermediate-2 or High
5. Subject has a measurable splenomegaly during the screening period as demonstrated by
spleen volume of ≥ 450 cm3 by MRI or CT-scan and by palpable spleen measuring ≥ 5 cm
below the left costal margin
6. Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis
Symptom Assessment Form (MFSAF)
7. Subject has been previously exposed to ruxolitinib, and must meet at least one of the
following criteria (a and/or b)
1. Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response
(refractory) defined as < 10% spleen volume reduction by MRI or < 30% decrease
from baseline in spleen size by palpation or regrowth (relapsed) to these
parameters following an initial response
2. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following
(intolerant):
- Development of a red blood cell transfusion requirement (at least 2
units/month for 2 months) or
- Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while
on treatment with ruxolitinib
8. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1
or pretreatment baseline before start of last therapy prior to randomization
9. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted
10. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements
11. A female of childbearing potential (FCBP) must:
1. Have 2 negative pregnancy tests as verified by the Investigator during screening
prior to starting study treatment. She must agree to ongoing pregnancy testing
during the course of the study, and after 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 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 study treatment (including dose
interruptions), and for 30 days after discontinuation of study 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 does
not rule out childbearing potential) for at least 24 consecutive months (ie, has had
menses at any time in the preceding 24 consecutive months).
12. 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 investigational product discontinuation, or longer if required for each compound
and/or by local regulations, even if he has undergone a successful vasectomy
Exclusion Criteria:
1. Any of the following laboratory abnormalities:
1. Platelets < 50 x 109/L
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 glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification
of Diet in Renal Disease [MDRD] formula)
6. Serum amylase or lipase > 1.5 x upper limit of normal (ULN)
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 lactating female
3. Subject with previous splenectomy
4. Subject with previous or planned hematopoietic cell transplant
5. Subject with prior history of encephalopathy, including Wernicke's (WE)
6. Subject with signs or symptoms of encephalopathy, including WE (eg, severe ataxia,
ocular paralysis or cerebellar signs)
7. Subject with thiamine deficiency, defined as thiamine levels in whole blood below
normal range according to the central laboratory and not demonstrated to be corrected
prior to randomization
8. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or
food known to be strong or moderate inducers of Cytochrome P450 3A4 (CYP3A4), or 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 randomization
10. Subject has received ruxolitinib within 14 days prior to randomization
11. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than
ruxolitinib treatment
12. Subject on treatment with aspirin with doses > 150 mg daily
13. Subject with major surgery within 28 days prior to randomization
14. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease,
autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis,
hemochromatosis, non-alcoholic steatohepatitis)
15. 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
randomization. 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
16. Subject with uncontrolled congestive heart failure (New York Heart Association
Classification 3 or 4)
17. Subject with known human immunodeficiency virus (HIV), known active infectious
Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
18. Subject with serious active infection
19. Subject with presence of any significant gastric or other disorder that would inhibit
absorption of oral medication
20. Subject is unable to swallow capsule
21. Subject with any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study
22. Subject has any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the study
23. Subject has any condition that confounds the ability to interpret data from the study
24. Subject with participation in any study of an investigational agent (drug, biologic,
device) within 30 days prior to randomization
25. Subject with a life expectancy of less than 6 months
Active, Not Recruiting
