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    Summary
    EudraCT Number:2018-003411-21
    Sponsor's Protocol Code Number:FEDR-MF-002
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-07-31
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2018-003411-21
    A.3Full title of the trial
    A Phase 3, multicenter, open-label, randomized study to evaluate the efficacy and safety of fedratinib compared to best available therapy in subjects with DIPSS - intermediate or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis and previously treated with ruxolitinib (The “FREEDOM-2” trial)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing current standard therapies with fedratinib for the treatment of myelofibrosis (either diagnosed alone or after polycythemia vera or essential thrombocytopenia) in subjects who have previously received ruxolitinib
    A.3.2Name or abbreviated title of the trial where available
    The Freedom 2 trial
    A.4.1Sponsor's protocol code numberFEDR-MF-002
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorImpact Biomedicines, Inc., a Wholly Owned Subsidiary of Celgene Corporation
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBristol-Meyers Squibb International Corporation
    B.5.2Functional name of contact pointGSM-CT
    B.5.3 Address:
    B.5.3.1Street AddressParc de l'Alliance-Avenue de Finlande, 4
    B.5.3.2Town/ cityBraine-l'Alleud
    B.5.3.3Post code1420
    B.5.3.4CountryBelgium
    B.5.6E-mailclinical.trials@bms.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Inrebic
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/10/794, EU/3/10/810, EU/3/10/811
    D.3 Description of the IMP
    D.3.1Product nameFedratinib
    D.3.2Product code SAR302503
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNfedratinib
    D.3.9.1CAS number 1374744-69-0
    D.3.9.2Current sponsor codefedratinib
    D.3.9.3Other descriptive nameFEDRATINIB
    D.3.9.4EV Substance CodeSUB126288
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary myelofibrosis, post-polycythemia vera myelofibrosis , or post-essential thrombocythemia myelofibrosis
    E.1.1.1Medical condition in easily understood language
    Cancer of the bone marrow where normal blood cell growth is affected and collagen fibers begin to develop in the marrow
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10028537
    E.1.2Term Myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the percentage of subjects with at least 35% spleen volume reduction in the fedratinib and the BAT arms.
    E.2.2Secondary objectives of the trial
    - To evaluate myelofibrosis (MF)-associated symptoms as measured by the Myelofibrosis Symptom Assessment Form (MFSAF)
    - To evaluate the percentage of subjects with at least 25% spleen volume reduction (SVR)
    - To evaluate the safety of fedratinib
    - To evaluate the reduction of spleen size by palpation
    - To evaluate durability of spleen response by MRI/CT and by palpation
    - To evaluate the durability of symptoms response
    - To evaluate spleen and disease progression free survival
    - To assess the effectiveness of the risk mitigation strategy for gastrointestinal events and Encephalopathy including Wernicke's
    - To evaluate Health-Related Quality of Life (HRQoL) as measured by the European Organization for Research and Treatment of Cancer Quality of Life C30 (EORTC QLQ-C30)
    - To evaluate Patient Reported Outcomes (PRO) as measured by the EQ-5D-5L questionnaire
    - To evaluate Overall Survival (OS)
    E.2.3Trial contains a sub-study No
    E.3Principal 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,
    onfirmed by the most recent local pathology report
    4. Subject has a DIPSS Risk score of Intermediate-2 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 and by palpable spleen measuring ≥ 5 cm below the left costal margin
    6. Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF)
    7. Subject has been previously exposed to ruxolitinib, and must meet at least one of the following criteria (a and/or b)
    a. Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response (refractory) defined as < 10% spleen volume reduction by MRI or < 30% decrease from baseline in spleen size by palpation or regrowth (relapse) to these parameters following an initial response
    b. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following (intolerant):
     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
    8. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to randomization
    9. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
    10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
    11. A female of childbearing potential (FCBP) must:
    a. Have 2 negative pregnancy tests as verified by the Investigator during screening prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
    b. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use and be able to comply with highly effective contraception without interruption, –14 days prior to starting investigational product, during the study treatment (including dose
    interruptions), and for 30 days after discontinuation of study treatment.
    12. A male subject must:
    Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 30 days following investigational product discontinuation, or longer if required for each compound and/or by local regulations, even if he has undergone a successful vasectomy.
    E.4Principal exclusion criteria
    1. Any of the following laboratory abnormalities:
    a. Platelets < 50 x 10^9/L
    b. Absolute neutrophil count (ANC) < 1.0 x 10^9/L
    c. White blood count (WBC) > 100 x 10^9/L
    d. Myeloblasts ≥ 5 % in peripheral blood
    e. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification of Diet in Renal Disease [MDRD] formula)
    f. Serum amylase or lipase > 1.5 x upper limit of normal (ULN)
    g. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN)
    h. 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 (WE)
    6. Subject with signs or symptoms of encephalopathy, including WE (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 the central laboratory and not demonstrated to be corrected prior to randomization
    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 randomization
    10. Subject has received ruxolitinib within 14 days prior to randomization
    11. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment
    12. Subject on treatment with aspirin with doses > 150 mg daily
    13. Subject with major surgery within 28 days prior to randomization
    14. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)
    15. 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 randomization. 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
    16. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)
    17. Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
    18. Subject with serious active infection
    19. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication
    20. Subject is unable to swallow capsule
    21. Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
    22. 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
    23. Subject has any condition that confounds the ability to interpret data from the study
    24. Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization
    25. Subject with a life expectancy of less than 6 months
    E.5 End points
    E.5.1Primary end point(s)
    Spleen volume response rate (RR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    From Screening to the end of Cycle 6
    E.5.2Secondary end point(s)
    1. Symptom response rate (SRR)
    2. Spleen volume response rate (RR25)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. From C1D1 to the end of Cycle 6
    2. From Screening to the end of Cycle 6
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Best available therapy (BAT)
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    China
    Korea, Republic of
    Russian Federation
    United Kingdom
    Austria
    Belgium
    Czechia
    France
    Germany
    Hungary
    Ireland
    Italy
    Netherlands
    Poland
    Portugal
    Spain
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days2
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 96
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 105
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 163
    F.4.2.2In the whole clinical trial 201
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-10-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-04
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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