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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03755518
Recruitment Status : Active, not recruiting
First Posted : November 28, 2018
Last Update Posted : August 9, 2022
Sponsor:
Collaborator:
Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
Information provided by (Responsible Party):
Celgene

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.


Condition or disease Intervention/treatment Phase
Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Myelofibrosis Post-essential Thrombocythemia Myelofibrosis Drug: FEDRATINIB Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 27, 2019
Actual Primary Completion Date : November 26, 2021
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
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.
Drug: FEDRATINIB
A potent and selective inhibitor of JAK2 kinase activity




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. Main study - Adverse Event(s) [ Time Frame: Up to 12 months post last dose ]
    Number of participants with adverse event

  2. 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)

  3. 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.

  4. Main study - Durability of spleen volume response (DR) [ Time Frame: From screening to the end of treatment visit (estimation of 12 months) ]
    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

  5. Durability of spleen response by palpation (DRP) [ Time Frame: Up to 30 days post last dose ]
    Is defined as time from the date of first documented palpable spleen response, according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 to the date of subsequent PD according to the IWG-MRT 2013 or death, whichever is earlier

  6. 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%.

  7. 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

  8. Main study - Wernicke encephalopathy (WE) [ Time Frame: Up to 30 days post last dose ]
    Occurrence of confirmed Wernicke encephalopathy events

  9. Main study - Wernicke encephalopathy (WE) thiamine monitoring [ Time Frame: Up to 30 days post last dose ]
    Monitoring and correction of thiamine levels as appropriate



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03755518


Locations
Show Show 39 study locations
Sponsors and Collaborators
Celgene
Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
Investigators
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Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
Additional Information:
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Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT03755518    
Other Study ID Numbers: FEDR-MF-001
U1111-1223-2862 ( Other Identifier: WHO )
2018-002237-38 ( EudraCT Number )
First Posted: November 28, 2018    Key Record Dates
Last Update Posted: August 9, 2022
Last Verified: August 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Celgene:
Myelofibrosis (MF)
Primary Myelofibrosis (PMF)
Post-Polycythemia Vera Myelofibrosis (Post-PV)
Post-essential thrombocythemia Myelofibrosis (Post-ET)
Myeloproliferative neoplasms (MPN)
Additional relevant MeSH terms:
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Polycythemia Vera
Primary Myelofibrosis
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders