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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)

  • Clinicaltrials.gov identifier

    NCT03755518

  • Recruitment Status

    Active, not recruiting

  • First Posted

    November 28, 2018

  • Last update posted

    June 23, 2022

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.

  • Condition or Disease:Myelofibrosis
    Primary Myelofibrosis
    Post-Polycythemia Vera Myelofibrosis
    Post-essential Thrombocythemia Myelofibrosis
  • Intervention/Treatment: Drug: FEDRATINIB
  • Phase: Phase 3

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.

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 110 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official 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
  • Actual Study Start Date: March 2019
  • Estimated Primary Completion Date: November 2021
  • Actual Study Completion Date: December 2023

Arms and interventions

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

Outcome Measures

  • 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

Eligibility Criteria

  • 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 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.

Contacts and Locations

Contacts

Locations

United States, Colorado
University of Colorado Cancer Center
Aurora

United States, Florida
Baptist Health - Miami Cardiac & Vascular Institute
Miami

United States, Georgia
Augusta University - Georgia Cancer Center
Augusta

United States, Illinois
Rush University Medical Center - University Cardiovascular Surgeons
Chicago

United States, Illinois
The University of Chicago Medical Center - Duchossois Center for Advanced Medicine
Chicago

United States, Illinois
Advocate Medical Group
Park Ridge

United States, Kansas
University of Kansas Medical Center
Kansas City

United States, Maryland
St. Agnes - Medical Center
Baltimore

United States, Maryland
Center for Cancer and Blood Disorders, P.C.
Bethesda

United States, Maryland
Maryland Oncology Hematology PA
Columbia

United States, Michigan
University of Michigan Comprehensive Cancer Center
Ann Arbor

United States, Missouri
Washington Univ School of Medicine
Saint Louis

United States, New Jersey
Newark Beth Israel Medical Center
Newark

United States, New York
Brookdale University Hospital and Medical Center
Brooklyn

United States, New York
Icahn School of Medicine at Mount Sinai
New York

United States, New York
Columbia University Medical Center
New York

United States, New York
SUNY Upstate Medical University
Syracuse

United States, North Carolina
North Carolina Women's Hospital
Chapel Hill

United States, North Carolina
Duke University Medical Center
Durham

United States, Ohio
UC Health Barrett Cancer Center
Cincinnati

United States, Pennsylvania
Local Institution - 106
Pittsburgh

United States, Pennsylvania
Western Pennsylvania Cancer Institute
Pittsburgh

United States, South Dakota
Avera Cancer Institute
Sioux Falls

United States, Texas
Local Institution - 119
Dallas

United States, Texas
UT Southwestern Medical Center Simmons Comprehensive Cancer Center
Dallas

United States, Texas
Texas Oncology- Fort Worth Cancer Center
Fort Worth

United States, Texas
The University of Texas MD Anderson Cancer Center
Houston

United States, Texas
UT Health - San Antonio
San Antonio

United States, Washington
Fred Hutchinson Cancer Research Center
Seattle

United States, Wisconsin
University of Wisconsin Medical School
Madison

Canada, British Columbia
Providence Hematology
Vancouver

Canada, Ontario
London Health Sciences Centre
London

Canada, Ontario
Ottawa Hospital
Ottawa

Canada, Ontario
Princess Margaret Hospital University Health Network
Toronto

Canada, Quebec
Hopital Maisonneuve-Rosemont
Montreal

Canada, Quebec
Jewish General Hospital
Montreal

Canada, Quebec
CIUSSS de l'Estrie - CHUS
Sherbrooke

Sponsors and Collaborators

Celgene

Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation

Investigators

Study Director: Bristol-Myers Squibb Bristol-Myers Squibb

More Information

  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT03755518 History of Changes
  • Other Study ID Numbers: FEDR-MF-001, U1111-1223-2862, 2018-002237-38
  • First Posted: November 28, 2018 Key Record Dates
  • Last Update Posted: June 23, 2022
  • Last Verified: June 2022
  • 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: Polycythemia Vera
    Neoplasms by Site
    Primary Myelofibrosis
    Polycythemia
    Thrombocytosis
    Thrombocythemia, Essential
    Myeloproliferative Disorders
    Bone Marrow Diseases
    Hematologic Diseases
    Bone Marrow Neoplasms
    Hematologic Neoplasms
    Neoplasms
    Blood Platelet Disorders
    Blood Coagulation Disorders
    Hemorrhagic Disorders