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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 (FREEDOM)

Primary Purpose

Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Myelofibrosis

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
FEDRATINIB
Sponsored by
Celgene
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis focused on measuring Myelofibrosis (MF), Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV), Post-essential thrombocythemia Myelofibrosis (Post-ET), Myeloproliferative neoplasms (MPN)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Main Study 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 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 assessment or by palpable spleen measuring ≥ 5 cm below the left costal margin.
  6. 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)

    1. Treatment with ruxolitinib for ≥ 3 months
    2. 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
  7. 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.
  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 requirements
  10. Participants must agree to use effective contraception

Exclusion Criteria:

Main Study Exclusion Criteria

  1. Any of the following laboratory abnormalities:

    1. Platelets < 50,000/μL
    2. Absolute neutrophil count (ANC) < 1.0 x 109/L
    3. White blood count (WBC) > 100 x 10^9/L
    4. Myeloblasts > 5 % in peripheral blood
    5. Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 (as per the Modification of Diet in Renal Disease [MDRD] formula)
    6. Serum amylase or lipase > 1.5 x ULN (upper limit of normal)
    7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x 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
  6. Subject with signs or symptoms of encephalopathy including Wernicke's (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 institutional standard and not corrected prior to enrollment on the study
  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 the start of fedratinib treatment
  10. Subject has received ruxolitinib within 14 days prior to the start of fedratinib
  11. Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating factor [G-CSF]) within 14 days prior to the start of fedratinib treatment
  12. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) for more than 1 cycle other than ruxolitinib treatment
  13. Subject on treatment with aspirin with doses > 150 mg daily
  14. Subject with major surgery within 28 days before starting 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 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

  17. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)
  18. Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
  19. Subject with serious active infection
  20. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication
  21. Subject is unable to swallow capsule
  22. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
  23. 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
  24. Subject has any condition that confounds the ability to interpret data from the study
  25. Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to start of fedratinib treatment
  26. Subject with life expectancy of less than 6 months.

Sites / Locations

  • Local Institution - 117
  • Local Institution - 126
  • Local Institution - 113
  • Local Institution - 112
  • Local Institution - 109
  • Local Institution - 121
  • Local Institution - 100
  • Local Institution - 123
  • Local Institution - 118
  • Local Institution - 127
  • Local Institution - 103
  • Local Institution - 101
  • Local Institution - 128
  • Local Institution - 130
  • Local Institution - 115
  • Local Institution - 124
  • SUNY Upstate Medical University
  • Local Institution - 105
  • Local Institution - 114
  • Local Institution - 111
  • Local Institution - 106
  • Local Institution - 108
  • Local Institution - 119
  • Local Institution - 132
  • Local Institution - 110
  • Local Institution - 120
  • Local Institution - 116
  • Local Institution - 129
  • Local Institution - 203
  • Local Institution - 207
  • Local Institution - 205
  • Local Institution - 200
  • Local Institution - 201
  • Local Institution - 202
  • Local Institution - 204

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Administration of Fedratinib 400mg/day

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.
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.
Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin
Mean change from baseline in hematology laboratory analysis - hemoglobin
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
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
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
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
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
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
November 8, 2018
Last Updated
June 21, 2023
Sponsor
Celgene
Collaborators
Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT03755518
Brief Title
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
Acronym
FREEDOM
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 27, 2019 (Actual)
Primary Completion Date
November 26, 2021 (Actual)
Study Completion Date
September 29, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Celgene
Collaborators
Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis
Keywords
Myelofibrosis (MF), Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV), Post-essential thrombocythemia Myelofibrosis (Post-ET), Myeloproliferative neoplasms (MPN)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
38 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Administration of Fedratinib 400mg/day
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
FEDRATINIB
Intervention Description
A potent and selective inhibitor of JAK2 kinase activity
Primary Outcome Measure Information:
Title
Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6
Description
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
Time Frame
From First Dose to end of Cycle 6 (approximately 168 days)
Secondary Outcome Measure Information:
Title
Number of Participants of All Grade Adverse Events (AEs) and Grade 3/4 AEs
Description
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.
Time Frame
From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 128 weeks)
Title
Number of Participants and Severity of Treatment Related All Grade Adverse Events (AEs) and Grade 3/4 AEs
Description
Number of participants and severity of treatment related all grade adverse events (AEs) and grade 3/4 AEs as per NCI CTCAE.
Time Frame
From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks)
Title
Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin
Description
Mean change from baseline in hematology laboratory analysis - hemoglobin
Time Frame
at Cycle 4 Day 1 and Cycle 7 Day 1
Title
Mean Change From Baseline in Hematology Laboratory Analysis - Erythrocytes
Description
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
Time Frame
at Cycle 4 Day 1 and Cycle 7 Day 1
Title
Mean Change From Baseline in Hematology Laboratory Analysis - Platelets, Leukocytes and Neutrophils
Description
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
Time Frame
at Cycle 4 Day 1 and Cycle 7 Day 1
Title
Mean Change From Baseline in the Percentage of Blasts/Leukocytes in Hematology Laboratory Analysis
Description
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
Time Frame
at Cycle 4 Day 1 and Cycle 7 Day 1
Title
Mean Change From Baseline in Chemistry Parameters Analysis - ALT, AST, Amylase, Lipase
Description
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
Time Frame
at Cycle 4 Day 1 and Cycle 7 Day 1
Title
Mean Change From Baseline in Chemistry Parameters Analysis - Creatinine
Description
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
Time Frame
at Cycle 4 Day 1 and Cycle 7 Day 1
Title
Spleen Response Rate by Palpation
Description
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.
Time Frame
From First Dose to end of Cycle 6 (approximately 168 days)
Title
Symptom Response Rate
Description
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.
Time Frame
From First Dose to end of Cycle 6 (approximately 168 days)
Title
Durability of Spleen Volume Response by MRI/CT (DR)
Description
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.
Time Frame
From First Dose to end of Cycle 6 (approximately 168 days)
Title
Durability of Spleen Response by Palpation (DRP)
Description
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.
Time Frame
From First Dose to end of Cycle 6 (approximately 168 days)
Title
Durability of Symptom Response (DSR)
Description
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.
Time Frame
From First Dose to end of Cycle 6 (approximately 168 days)
Title
Number of Participants With Grade 3 or Higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy Including Wernicke's.
Description
Number of participants with grade 3 or higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy including Wernicke's.
Time Frame
From first dose to end of treatment (an average of 50.3 weeks up to a maximum of 124 weeks)
Title
Number of Participants With Thiamine Levels < Lower Limit of Normal (LLN).
Description
Number of participants with thiamine levels < LLN. LLN of thiamine is 70 nmol/L.
Time Frame
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)
Title
Number of Participants With Thiamine Levels > Upper Limit of Normal (ULN).
Description
Number of participants with thiamine levels > ULN. ULN of thiamine is 180 nmol/L.
Time Frame
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
Local Institution - 117
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Local Institution - 126
City
Miami
State/Province
Florida
ZIP/Postal Code
33176
Country
United States
Facility Name
Local Institution - 113
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
Local Institution - 112
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Local Institution - 109
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Local Institution - 121
City
Park Ridge
State/Province
Illinois
ZIP/Postal Code
60068
Country
United States
Facility Name
Local Institution - 100
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160-7314
Country
United States
Facility Name
Local Institution - 123
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21229-5299
Country
United States
Facility Name
Local Institution - 118
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20817
Country
United States
Facility Name
Local Institution - 127
City
Columbia
State/Province
Maryland
ZIP/Postal Code
21044
Country
United States
Facility Name
Local Institution - 103
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Local Institution - 101
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Local Institution - 128
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07112-2027
Country
United States
Facility Name
Local Institution - 130
City
Brooklyn
State/Province
New York
ZIP/Postal Code
11212
Country
United States
Facility Name
Local Institution - 115
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Local Institution - 124
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
SUNY Upstate Medical University
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Local Institution - 105
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27514
Country
United States
Facility Name
Local Institution - 114
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Local Institution - 111
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
Local Institution - 106
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Local Institution - 108
City
Sioux Falls
State/Province
South Dakota
ZIP/Postal Code
57105
Country
United States
Facility Name
Local Institution - 119
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390-8852
Country
United States
Facility Name
Local Institution - 132
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Local Institution - 110
City
Houston
State/Province
Texas
ZIP/Postal Code
77303
Country
United States
Facility Name
Local Institution - 120
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
Local Institution - 116
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Local Institution - 129
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792-2454
Country
United States
Facility Name
Local Institution - 203
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6Z 2A5
Country
Canada
Facility Name
Local Institution - 207
City
London
State/Province
Ontario
ZIP/Postal Code
N6C 6B5
Country
Canada
Facility Name
Local Institution - 205
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H 8L6
Country
Canada
Facility Name
Local Institution - 200
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Local Institution - 201
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H1T 2M4
Country
Canada
Facility Name
Local Institution - 202
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1E2
Country
Canada
Facility Name
Local Institution - 204
City
Sherbrooke
State/Province
Quebec
ZIP/Postal Code
J1K 2R1
Country
Canada

12. IPD Sharing Statement

Links:
URL
https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html
Description
BMS Clinical Trial Information
URL
https://www.bmsstudyconnect.com/s/US/English/USenHome
Description
BMS Clinical Trial Patient Recruiting
URL
https://www.fda.gov/Safety/MedWatch/SafetyInformation/default.htm
Description
FDA Safety Alerts and Recalls

Learn more about this trial

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

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