A Trial of Fedratinib 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
=================
Brief Summary
-----------------
This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib 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 a 35% reduction in spleen size and one of the secondary objectives is to evaluate the safety of fedratinib.

Detailed Description
-----------------
This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib 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 spleen volume reduction at the end of Cycle 6 as the primary objective. The secondary objectives of the study are to further evaluate the safety and to assess and implement mitigation strategies for WE and for gastrointestinal (GI) adverse events. The study will be at multiple centers to provide access to a broad population and have assurance the results are likely to have general applicability. This is also conducted as an open-label study to collect efficacy and safety data with fedratinib use, no randomization or stratification will occur.

Official Title
-----------------
A Phase 3b, Multicenter, Single-Arm, Open-Label Efficacy and Safety Study of Fedratinib 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
-----------------
Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis

Intervention / Treatment
-----------------
* Drug: FEDRATINIB


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Main Study 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 or High Subject has a measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥ 450 cm3 by MRI or CT-scan assessment or by palpable spleen measuring ≥ 5 cm below the left costal margin. Subject has been previously exposed to ruxolitinib, while diagnosed with MF (PMF, post-ET MF or post-PV MF), and must meet at least one of the following criteria (a or b) Treatment with ruxolitinib for ≥ 3 months Treatment with ruxolitinib for ≥ 28 days complicated by any of the following: 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 fedratinib treatment. 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 Participants must agree to use effective contraception Exclusion Criteria: Main Study Exclusion Criteria Any of the following laboratory abnormalities: Platelets < 50,000/μL Absolute neutrophil count (ANC) < 1.0 x 109/L White blood count (WBC) > 100 x 10^9/L Myeloblasts > 5 % in peripheral blood Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 (as per the Modification of Diet in Renal Disease [MDRD] formula) Serum amylase or lipase > 1.5 x ULN (upper limit of normal) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x 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 Subject with signs or symptoms of encephalopathy including Wernicke's (eg, severe ataxia, ocular paralysis or cerebellar signs) Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not corrected prior to enrollment on the study 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 the start of fedratinib treatment Subject has received ruxolitinib within 14 days prior to the start of fedratinib Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating factor [G-CSF]) within 14 days prior to the start of fedratinib treatment Subject with previous exposure to Janus kinase (JAK) inhibitor(s) for more than 1 cycle other than ruxolitinib treatment Subject on treatment with aspirin with doses > 150 mg daily Subject with major surgery within 28 days before starting fedratinib treatment 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 enrollment. 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 has 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 start of fedratinib treatment Subject with life expectancy of less than 6 months.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of Fedratinib 400mg/day<br>Self-administered Investigational Product (IP) (400 mg/day) on an outpatient basis, once daily preferably 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>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6 | Percentage of participants who have a ≥ 35% SVR at end of Cycle 6 as compared to baseline. Participants with a missing MRI/CT spleen volume at the end of Cycle 6 including those who meet the criteria for progression of splenomegaly before the end of Cycle 6 will be considered non-responders. Baseline value is defined as the last value or measurement taken prior to the first dose in the study | From First Dose to end of Cycle 6 (approximately 168 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants of All Grade Adverse Events (AEs) and Grade 3/4 AEs | Number of participants and severity of all grade adverse events (AEs) and grade 3/4 AEs as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5. | From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 128 weeks) | 
| Number of Participants and Severity of Treatment Related All Grade Adverse Events (AEs) and Grade 3/4 AEs | Number of participants and severity of treatment related all grade adverse events (AEs) and grade 3/4 AEs as per NCI CTCAE. | From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks) | 
| Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin | Mean change from baseline in hematology laboratory analysis - hemoglobin | at Cycle 4 Day 1 and Cycle 7 Day 1 | 
| Mean Change From Baseline in Hematology Laboratory Analysis - Erythrocytes | Mean change from baseline in hematology laboratory analysis - erythrocytes. Baseline value is defined as the last value or measurement taken prior to the first dose in the study | at Cycle 4 Day 1 and Cycle 7 Day 1 | 
| Mean Change From Baseline in Hematology Laboratory Analysis - Platelets, Leukocytes and Neutrophils | Mean change from baseline in hematology laboratory analysis - platelets, leukocytes and neutrophils. Baseline value is defined as the last value or measurement taken prior to the first dose in the study | at Cycle 4 Day 1 and Cycle 7 Day 1 | 
| Mean Change From Baseline in the Percentage of Blasts/Leukocytes in Hematology Laboratory Analysis | Mean change from baseline in hematology laboratory analysis - blasts/leukocytes Baseline value is defined as the last value or measurement taken prior to the first dose in the study | at Cycle 4 Day 1 and Cycle 7 Day 1 | 
| Mean Change From Baseline in Chemistry Parameters Analysis - ALT, AST, Amylase, Lipase | Mean change from baseline in chemistry parameters analysis - ALT, AST, Amylase, Lipase Baseline value is defined as the last value or measurement taken prior to the first dose in the study | at Cycle 4 Day 1 and Cycle 7 Day 1 | 
| Mean Change From Baseline in Chemistry Parameters Analysis - Creatinine | Mean change from baseline in chemistry parameters analysis - Creatinine. Baseline value is defined as the last value or measurement taken prior to the first dose in the study | at Cycle 4 Day 1 and Cycle 7 Day 1 | 
| Spleen Response Rate by Palpation | Spleen response rate by palpation is the percentage of participants with a spleen response according to the IWG-MRT 2013 at the end of Cycle 6 as compared to baseline. This will be calculated for participants that have an enlarged spleen (≥ 5 cm below LCM) at baseline. Participants with a missing spleen size assessment at the end of Cycle 6 including those who meet the criteria for progression of splenomegaly before the end of Cycle 6 will be considered not to be responders. | From First Dose to end of Cycle 6 (approximately 168 days) | 
| Symptom Response Rate | Symptom response rate (SRR) is defined as the percentage of participants with ≥ 50% reduction from baseline to the end of Cycle 6 in total symptom score (TSS) measured by MFSAF version 4.0. The TSS will be defined as the sum of each of the 7 symptom scores. Participants without a baseline TSS > 0 will be considered non-evaluable (due to no place for symptom reduction) for the SRR analysis. Participants with a missing TSS at the end of Cycle 6 or who had disease progression before the end of the Cycle 6 will be considered non-responders. | From First Dose to end of Cycle 6 (approximately 168 days) | 
| Durability of Spleen Volume Response by MRI/CT (DR) | Durability of spleen volume response (DR) by MRI/CT is defined as time from the first documented spleen response (ie, ≥ 35% reduction in spleen volume) to the date of subsequent progressive disease (PD) (ie, ≥ 25% increase in spleen volume from baseline) or death, whichever is earlier. In the absence an event (ie, subsequent spleen volume reduction < 35% before the analysis is performed), the DR will be censored at the date of the last valid assessment performed before the analysis performed date. Durability of spleen volume response by MRI/CT scan will be analyzed using Kaplan-Meier method. | From First Dose to end of Cycle 6 (approximately 168 days) | 
| Durability of Spleen Response by Palpation (DRP) | Durability of spleen response by palpation (DRP) is defined as time from the date of first documented palpable spleen response, according to the IWG-MRT 2013 to the date of subsequent PD according to the IWG-MRT 2013 or death, whichever is earlier. Durability of spleen response by palpation according to the IWG-MRT 2013 criteria will be calculated for subjects that have an enlarged spleen at baseline (≥ 5 cm below LCM), and that have a spleen response by palpation. In the absence of an event (ie, no loss of spleen response by palpation) before the analysis is performed, the DRP will be censored at the date of the last valid assessment performed before the analysis performed date. Durability of spleen response by palpation will be analyzed using Kaplan-Meier (K-M) method. | From First Dose to end of Cycle 6 (approximately 168 days) | 
| Durability of Symptom Response (DSR) | Durability of symptoms response is defined as time from the first documented response in TSS (ie, reduction in TSS ≥ 50%) measured by MFSAF version 4.0 to the first documented TSS reduction < 50%. In the absence of TSS reduction < 50% before the analysis performed, the DSR will be censored at the date of the last valid assessment performed before the analysis performed date. | From First Dose to end of Cycle 6 (approximately 168 days) | 
| Number of Participants With Grade 3 or Higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy Including Wernicke's. | Number of participants with grade 3 or higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy including Wernicke's. | From first dose to end of treatment (an average of 50.3 weeks up to a maximum of 124 weeks) | 
| Number of Participants With Thiamine Levels < Lower Limit of Normal (LLN). | Number of participants with thiamine levels < LLN. LLN of thiamine is 70 nmol/L. | At Screening, Cycle 1, 2, 3, 6, 9, 15, 18, 21, 24, 27, 30 and End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks) | 
| Number of Participants With Thiamine Levels > Upper Limit of Normal (ULN). | Number of participants with thiamine levels > ULN. ULN of thiamine is 180 nmol/L. | At Screening, Cycle 1, 2, 3, 6, 9, 15, 18, 21, 24, 27, 30 and End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Myelofibrosis (MF), Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV), Post-essential thrombocythemia Myelofibrosis (Post-ET), Myeloproliferative neoplasms (MPN)