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 Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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

Conditions
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Primary Myelofibrosis, Post-Polycythemia Vera, Myelofibrosis

Intervention / Treatment
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* Drug: FEDRATINIB
* Drug: Best Available Therapy (BAT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is at least 18 years of age at the time of signing the informed consent form (ICF) Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2 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 Subject has a DIPSS Risk score of Intermediate-2 or High 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 Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) Subject has been previously exposed to ruxolitinib, and must meet at least one of the following criteria (a and/or b) 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 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 Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to randomization Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted Subject is willing and able to adhere to the study visit schedule and other protocol requirements A female of childbearing potential (FCBP) must: 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. 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). 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: Any of the following laboratory abnormalities: Platelets < 50 x 109/L Absolute neutrophil count (ANC) < 1.0 x 109/L White blood count (WBC) > 100 x 109/L Myeloblasts ≥ 5 % in peripheral blood Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification of Diet in Renal Disease [MDRD] formula) Serum amylase or lipase > 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) 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 Subject is pregnant or lactating female Subject with previous splenectomy Subject with previous or planned hematopoietic cell transplant Subject with prior history of encephalopathy, including Wernicke's (WE) Subject with signs or symptoms of encephalopathy, including WE (eg, severe ataxia, ocular paralysis or cerebellar signs) 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 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 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 Subject has received ruxolitinib within 14 days prior to randomization Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment Subject on treatment with aspirin with doses > 150 mg daily Subject with major surgery within 28 days prior to randomization Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis) 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 Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4) Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC) Subject with serious active infection Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication Subject is unable to swallow capsule Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study 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 Subject has any condition that confounds the ability to interpret data from the study Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization Subject with a life expectancy of less than 6 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fedratinib 400mg/day<br>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. | Drug: FEDRATINIB<br>* A potent and selective inhibitor of JAK2 kinase activity<br>|
| Active Comparator: Best Available Therapy (BAT)<br>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. | Drug: Best Available Therapy (BAT)<br>* Best available therapy (BAT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects who have ≥ 35% SVR at end of cycle 6 | Spleen volume response rate (RR) | At the end of Cycle 1 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with ≥ 50% reduction in total symptom scores measured by MFSAF at end of cycle 6 | Symptom response rate (SRR) | Up to end of Cycle 6 (each cycle is 28 days) | 
| Proportion of subjects who have ≥ 25% reduction in spleen volume at the end of cycle 6 | Spleen volume response rate (RR25) | At the end of Cycle 1 (each cycle is 28 days) | 
| Adverse Events (AEs) | Number of participants with adverse event | Up to 30 days post last dose | 
| Proportion of subjects who have ≥ 50% reduction in spleen size by palpation at end of cycle 6 | Spleen response rate by palpation (RRP) | Up to end of Cycle 6 (each cycle is 28 days) | 
| Durability of Spleen Volume Response by MRI/CT (DR) | Is defined as time from the first documented spleen response (ie, ≥ 35% reduction in spleen volume) to the first documented spleen volume reduction < 35%. | Up to end of Cycle 6 (each cycle is 28 days) | 
| Duration of ≥ 50 % reduction in spleen size by palpation for subjects with a palpable spleen at least 5 cm below the left costal margin (LCM) at baseline | From C1D1 until the 30- day follow-up after last dose visit | Up to approximately 30 months | 
| Duration of ≥ 50% reduction in total symptom scores measured by MFSAF | Durability of symptoms response (DSR) | From enrollment until 30 days post last dose | 
| Time from randomization to death due to any reason or disease progression (modified IWG-MRT 2013 including ≥ 25% increase in spleen volume by MRI/CT) | Spleen and disease progression free survival (SDPFS) | Up to 24 months from enrollment to End of Survival Follow-up | 
| Gastrointestinal Adverse Events | Incidence of subjects with Grade 3 or higher Gastrointestinal events (nausea, diarrhea, or vomiting) according to CTCAE v5.0 | Up to approximately 30 months | 
| Encephalopathy Events, including Wernicke's | Occurrence of confirmed encephalopathy events, including Wernicke's | Up to 30 days post last dose | 
| Health-Related Quality of Life (HRQoL) | To evaluate Health-Related Quality of Life (HRQoL) as measured by the European Organization for Research and Treatment of Cancer Quality of Life C30 (EORTC QLQ-C30) | Up to 30-day follow-up after last dose visit | 
| EQ-5D-5L | To evaluate Patient Reported Outcomes (PRO) as measured by the EQ-5D-5L questionnaire | Up to 20-day follow-up after last dose visit | 
| Overall Survival (OS) | Time from randomization to death due to any reason | From randomization to the End of Survival Follow-up (approximately 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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post-PV, MF, myeloproliferative neoplasms, MPN, myelofibrosis, PMF, Post-Polycythemia Vera, post-ET MF, Post-Essential Thrombocythemia Myelofibrosis