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A Safety 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 With Concomitant Luspatercept for Subjects With Anemia (FREEDOM)

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ClinicalTrials.gov Identifier: NCT03755518
Recruitment Status : Recruiting
First Posted : November 28, 2018
Last Update Posted : August 11, 2020
Sponsor:
Collaborator:
Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE November 8, 2018
First Posted Date  ICMJE November 28, 2018
Last Update Posted Date August 11, 2020
Actual Study Start Date  ICMJE March 27, 2019
Estimated Primary Completion Date June 19, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
  • Main study - Proportion of subjects who have a ≥ 35% SVR at end of Cycle 6 [ Time Frame: At the end of Cycle 6 (each cycle is 28 days) ]
    Spleen volume response rate (RR)
  • Sub study - Adverse Events (AEs) [ Time Frame: From enrollment up until 42 days post last dose of luspatercept or 30 days post last dose of fedratinib ]
    To evaluate the safety and tolerability of luspatercept when administered concomitantly with fedratinib for the treatment of anemia in subjects with MPN-associated MF who are RBC transfusion dependent (Group A) or non-transfusion dependent (Group B).
Original Primary Outcome Measures  ICMJE
 (submitted: November 26, 2018)
Proportion of subjects who have a ≥ 35% SVR at end of Cycle 6 [ Time Frame: At the end of Cycle 6 (each cycle is 28 days) ]
Spleen volume response rate (RR)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2020)
  • Main study - Adverse Event(s) [ Time Frame: Up to 12 months post last dose ]
    Number of participants with adverse event
  • Main study - Proportion of subjects who have ≥ 50% reduction in spleen size by palpation [ Time Frame: At the end of Cycle 6 (each cycle is 28 days) ]
    Spleen response rate by palpation (RRP)
  • Main study - Symptom response rate (SRR) [ Time Frame: At the end of Cycle 6 (each cycle is 28 days) ]
    Is defined as the proportion of subjects with ≥ 50% reduction from baseline to the end of Cycle 6 in total symptom score (TSS) measured by MFSAF version 4.0.
  • Main study - To evaluate durability of spleen volume response (DR) [ Time Frame: From enrollment until treatment discontinuation (estimation of 12 months) ]
    Is defined as time from the first documented spleen response (ie, ≥ 35% reduction in spleen volume) to the first documented spleen volume reduction < 35%.
  • Main study - To evaluate the durability of spleen response by palpation (DRP) [ Time Frame: From enrollment until treatment discontinuation (estimation of 12 months) ]
    Is defined as time from the first documented palpable spleen response, according to the IWG-MRT 2013 to the time of the first documented loss of response according to the IWG-MRT 2013.
  • Main study - Durability of symptoms response (DSR) [ Time Frame: Up to 30 days post last dose ]
    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%.
  • Main study - Gastrointestinal Adverse Events [ Time Frame: Up to 30 days post last dose ]
    Incidence of subjects with Grade 3 or higher Gastrointestinal events (nausea, diarrhea, or vomiting) according to CTCAE v5.0
  • Main study - Wernicke encephalopathy (WE) [ Time Frame: Up to 30 days post last dose ]
    Occurrence of confirmed Wernicke encephalopathy events
  • Main study - Wernicke encephalopathy (WE) thiamine monitoring [ Time Frame: Up to 30 days post last dose ]
    Monitoring and correction of thiamine levels as appropriate
  • Sub study - Anemia response related to modified Hematological Improvement - Erythroid Response (HI-E) [ Time Frame: From SC1D1 through and including Sub-study Week 24 (Day 169) Also from SC1D1 through EOT ]
    it is defined as the proportion of subjects with hemoglobin increase by ≥ 1.5 g/dL OR reduction of units of RBC transfusion by an absolute number of at least 4 RBC transfusions over any consecutive 56-day (8 weeks) period compared with sub-study baseline.
  • Sub study - Anemia Response related to Reduction in Transfusion Burden [ Time Frame: From SC1D1 through and including Sub-study Week 24 (Day 169) Also from SC1D1 through EOT ]
    it is defined as the proportion of RBC transfusion dependent subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks over any consecutive 12-week period compared with sub-study baseline.
  • Sub study - Anemia Response related to Mean Hemoglobin Increase [ Time Frame: From SC1D1 through and including Sub-study Week 24 (Day 169) Also from SC1D1 through EOT ]
    it is defined as the proportion of subjects achieving a mean ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion.
  • Sub study - Anemia response related to RBC-transfusion independence [ Time Frame: From SC1D1 through and including Sub-study Week 24 (Day 169) Also from SC1D1 through EOT ]
    it is defined as the proportion of subjects who become RBC-transfusion free over any consecutive 84- day period. The response rate will be calculated using the number of responders divided by number of subjects in the sub-study Safety population.
  • Sub study - Duration of anemia response [ Time Frame: Up to 12 months post last dose ]
    Maximum duration of anemia response in each of the endpoints and groups
Original Secondary Outcome Measures  ICMJE
 (submitted: November 26, 2018)
  • Adverse Event(s) [ Time Frame: Up to 12 months post last dose ]
    Number of participants with adverse event
  • Proportion of subjects who have ≥ 50% reduction in spleen size by [ Time Frame: At the end of Cycle 6 (each cycle is 28 days) ]
    Spleen response rate by palpation (RRP)
  • Symptom response rate (SRR) [ Time Frame: At the end of Cycle 6 (each cycle is 28 days) ]
    Is defined as the proportion of subjects with ≥ 50% reduction from baseline to the end of Cycle 6 in total symptom score (TSS) measured by MFSAF version 4.0.
  • To evaluate durability of spleen volume response (DR) [ Time Frame: From enrollment until treatment discontinuation (estimation of 12 months) ]
    Is defined as time from the first documented spleen response (ie, ≥ 35% reduction in spleen volume) to the first documented spleen volume reduction < 35%.
  • To evaluate the durability of spleen response by palpation (DRP) [ Time Frame: From enrollment until treatment discontinuation (estimation of 12 months) ]
    Is defined as time from the first documented palpable spleen response, according to the IWG-MRT 2013 to the time of the first documented loss of response according to the IWG-MRT 2013.
  • Durability of symptoms response (DSR) [ Time Frame: Up to 30 days post last dose ]
    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%.
  • Gastrointestinal Adverse Events [ Time Frame: Up to 30 days post last dose ]
    Incidence of subjects with Grade 3 or higher Gastrointestinal events (nausea, diarrhea, or vomiting) according to CTCAE v5.0
  • Wernicke encephalopathy (WE) events [ Time Frame: Up to 30 days post last dose ]
    Occurrence of confirmed Wernicke encephalopathy events
  • Wernicke encephalopathy (WE) thiamine monitoring [ Time Frame: Up to 30 days post last dose ]
    Monitoring and correction of thiamine levels as appropriate
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Safety 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 With Concomitant Luspatercept for Subjects With Anemia
Official Title  ICMJE 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 Including a Sub-study With Concomitant Luspatercept for Subjects With Anemia
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 including a Sub-study with concomitant Luspatercept for subjects with anemia.

The primary objective of the main 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.

The primary objective of the sub-study is to evaluate the safety and tolerability of Luspatercept when administered concomitantly with 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 including a Sub-study with concomitant Luspatercept for subjects with anemia.

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.

The primary objective of the sub-study is to evaluate the safety and tolerability of Luspatercept when administered concomitantly with Fedratinib for the treatment of anemia in subjects with MF who are red blood cell (RBC) transfusion dependent (Group A) or non-transfusion dependent (Group B).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Primary Myelofibrosis
  • Post-Polycythemia Vera
  • Myelofibrosis
Intervention  ICMJE
  • Drug: FEDRATINIB
    A potent and selective inhibitor of JAK2 kinase activity
  • Drug: Luspatercept
    Luspatercept will be 1.33 mg/kg administered as a subcutaneous injection concomitantly with Fedratinib.
Study Arms  ICMJE
  • Experimental: Administration of Fedratinib 400mg/day
    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.
    Interventions:
    • Drug: FEDRATINIB
    • Drug: Luspatercept
  • Experimental: Administration of Luspatercept 1.33 mg/kg
    Administered as a subcutaneous injection concomitantly with Fedratinib at 3-week (21 day) cycles
    Intervention: Drug: Luspatercept
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 26, 2018)
110
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 19, 2023
Estimated Primary Completion Date June 19, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sub-Study Inclusion Criteria

  1. Subject must understand and voluntarily sign an optional sub-study ICF prior to any sub study-related assessments/procedures being conducted
  2. Subject must have been taking fedratinib for at least 32 weeks (~ 8 cycles)
  3. Subject must be on a stable dose of fedratinib for at least 16 weeks (~ 4 cycles) [no dose level changes] in the time immediately up to the projected date of enrollment (SC1D1)
  4. Subject has anemia defined as either:

    1. Group A - Transfusion dependent (TD) anemia

      • RBC-transfusion frequency: 4 to 12 RBC units/84 days immediately up to the SC1D1 date (Sub-study Cycle 1 Day 1), with no interval of > 6 weeks (42 days) without an RBC transfusion.
      • Subjects must have a Hgb value of < 11.5 g/dL on SC1D1 prior to luspatercept administration.
    2. Group B - Non-transfusion dependent (NTD) anemia

      • RBC-transfusion frequency: < 4 RBC units/84 days immediately up to the SC1D1 date.

    OR

    • At least 3 Hgb levels of ≤ 9.5 g/dL recorded on ≥ 3 different days, including the day of dosing, in the 84-day period immediately up to Sub-study C1D1 date. There must be ≥ 14 days in between each Hgb measurement. No subjects with an interval ≥ 42 days between hemoglobin measurements will be enrolled.

    Baseline is defined as the 84-day rolling period (3 cycles at 28 days each) prior to Sub-study Cycle 1 Day 1. Any transfusions given either at a Hgb ≤ 7 or for a Hgb ≤ 9.5 g/dL with symptoms will be counted towards baseline transfusion needs. Transfusions given only for bleeding or infections will not be counted towards eligibility baseline transfusion requirements.

  5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

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.

Sub- Study Exclusion Criteria

  1. Subject with anemia from causes other than MPN-associated MF or JAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration).
  2. Subject with any of the following laboratory abnormalities at SC1D1:

    1. Neutrophils < 1 x 10^9/L
    2. White blood count (WBC) > 100 x 10^9/L
    3. Platelets < 50 x 10^9/L or > 1000 x 10^9/L
    4. Peripheral blood myeloblasts > 5%.
    5. Estimated glomerular filtration rate < 40 mL/min/1.73 m^2 (via the 4-variable modification of diet in renal disease [MDRD] formula)
    6. Aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3.0 x upper limit of normal (ULN)
    7. Direct bilirubin ≥ 2 x ULN (higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis))
  3. Subject with diastolic blood pressure ≥ 90 mmHg or systolic blood pressure ≥ 140 mmHg before SC1D1 despite appropriate treatment.
  4. 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 is allowed:

    1. Basal or squamous cell carcinoma of the skin
    2. Carcinoma in situ of the cervix
    3. Carcinoma in situ of the breast
    4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
  5. Subject with stroke, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to SC1D1.
  6. Subject with major surgery within 2 months up to the enrollment date. Subject must have completely recovered from any previous surgery immediately up to the enrollment date.
  7. Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction < 35%.
  8. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
  9. Subject with prior therapy of luspatercept or sotatercept.
  10. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational products (see luspatercept IB).
  11. Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of

    ≥ 2 units of packed red cells) in the last 6 months prior to enrollment.

  12. Subject use of erythropoietin-stimulating agents (ESA) ≤ 56 days prior to SC1D1.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Daniel Aversa, MS 908.499.9666 daversa@celgene.com
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03755518
Other Study ID Numbers  ICMJE FEDR-MF-001
U1111-1223-2862 ( Other Identifier: WHO )
2018-002237-38 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
Investigators  ICMJE
Study Director: Shelo Rose, MD Celgene
PRS Account Celgene
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP