An Efficacy and Safety Study of Fedratinib Compared to Best Available Therapy in Subjects With DIPSS-intermediate or High-risk Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib

Study Purpose

A Phase 3, multicenter, open-label, randomized study to evaluate the efficacy and safety of fedratinib compared to best available therapy (BAT) in subjects with DIPSS (Dynamic International Prognostic Scoring System)-intermediate or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF) and previously treated with ruxolitinib. The primary objective of the study is to evaluate the percentage of subjects with at least 35% spleen volume reduction in the fedratinib and the BAT arms.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT03952039
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Celgene
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Vishwanath Gharpure, MD
Principal Investigator Affiliation	Celgene Corporation
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	IndustryIndustry
Overall Status	Recruiting
Countries	Australia, Austria, Belgium, China, Czechia, France, Germany, Hungary, Ireland, Italy, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, United Kingdom
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Primary Myelofibrosis, Post-Polycythemia Vera, Myelofibrosis

Additional Details

This Phase 3, multicenter, randomized, two-arm, open-label study will include subjects with intermediate or high-risk (as per the DIPSS score) primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF). This study will be conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCPs). Study design includes:

- A 28-day Screening Period.

- 2:1 Randomization to fedratinib or best available therapy (BAT) - Stratification at Randomization according to: - Spleen size by palpation: < 15 cm below left costal margin (LCM) versus ≥ 15 cm below LCM.

- Platelets ≥ 50 to < 100 x 109/L versus platelets ≥ 100 x 109/L.

- Refractory or relapsed to ruxolitinib treatment versus intolerant to ruxolitinib treatment.

- Study Treatment Period (time on study drug plus 30 days after last dose) - Subjects are allowed to crossover from BAT to the fedratinib arm after the Cycle 6 response assessment or before the Cycle 6 response assessment in the event of a confirmed progression of splenomegaly by MRI/CT scan.

- A Survival Follow-up Period for progression and survival

Arms & Interventions

Arms

Experimental: Fedratinib 400mg/day

Will include up to 128 subjects receiving fedratinib 400 mg self-administered Investigational Product (IP) on an outpatient basis, once daily preferably together with food during an evening meal at the same time each day in consecutive 4-week (28-day) cycles.

Active Comparator: Best Available Therapy (BAT)

Best-available Investigator-selected therapy included a number of available compounds to treat MF and/or its symptoms and was chosen by the investigator for each subject. Therapy changed at different times during the treatment period. No investigational agents (e.g. not approved for the treatment of any indication) were allowed. BAT also included the choice of no treatment.

Interventions

Drug: - FEDRATINIB

A potent and selective inhibitor of JAK2 kinase activity

Drug: - Best Available Therapy (BAT)

Best available therapy (BAT)

Contact a Trial Team

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International Sites

Saint Vincent's Hospital, Darlinghurst, New South Wales, Australia

Status

Recruiting

Address

Saint Vincent's Hospital

Darlinghurst, New South Wales, 2010

Site Contact

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