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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03952039




Registration number
NCT03952039
Ethics application status
Date submitted
6/05/2019
Date registered
16/05/2019

Titles & IDs
Public title
An Efficacy and Safety Study 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
Scientific title
A Phase 3, Multicenter, Open-label, Randomized Study to Evaluate the Efficacy and Safety of Fedratinib Compared to Best Available Therapy (BAT) 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
Secondary ID [1] 0 0
U1111-1223-2962
Secondary ID [2] 0 0
FEDR-MF-002
Universal Trial Number (UTN)
Trial acronym
FREEDOM2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Primary Myelofibrosis 0 0
Post-Polycythemia Vera 0 0
Myelofibrosis 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - FEDRATINIB
Treatment: Drugs - Best Available Therapy (BAT)

Experimental: Fedratinib 400mg/day - Will include up to 128 subjects receiving fedratinib 400 mg self-administered Investigational Product (IP) on an outpatient basis, once daily preferably together with food during an evening meal at the same time each day in consecutive 4-week (28-day) cycles.

Active comparator: Best Available Therapy (BAT) - Best-available Investigator-selected therapy included a number of available compounds to treat MF and/or its symptoms and was chosen by the investigator for each subject. Therapy changed at different times during the treatment period. No investigational agents (e.g. not approved for the treatment of any indication) were allowed. BAT also included the choice of no treatment.


Treatment: Drugs: FEDRATINIB
A potent and selective inhibitor of JAK2 kinase activity

Treatment: Drugs: Best Available Therapy (BAT)
Best available therapy (BAT)
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Spleen Volume Response Rate (RR)
Timepoint [1] 0 0
From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Secondary outcome [1] 0 0
Symptom Response Rate (SRR)
Timepoint [1] 0 0
From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary outcome [2] 0 0
Spleen Volume Response Rate (RR25)
Timepoint [2] 0 0
From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Secondary outcome [3] 0 0
Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs
Timepoint [3] 0 0
From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary outcome [4] 0 0
Number of Participants With Hematology Laboratory Abnormalities
Timepoint [4] 0 0
From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary outcome [5] 0 0
Spleen Response Rate by Palpation (RRP)
Timepoint [5] 0 0
From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary outcome [6] 0 0
Durability of Spleen Volume Response (DR)
Timepoint [6] 0 0
From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Secondary outcome [7] 0 0
Durability of Spleen Response by Palpation (DRP)
Timepoint [7] 0 0
From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Secondary outcome [8] 0 0
Durability of Symptoms Response (DSR)
Timepoint [8] 0 0
From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Secondary outcome [9] 0 0
Assessment of the Effectiveness of Risk Mitigation Strategy for =3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy
Timepoint [9] 0 0
From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Secondary outcome [10] 0 0
Number of Participants With Thiamine Levels Below the Lower Limit of Normal
Timepoint [10] 0 0
From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary outcome [11] 0 0
Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline
Timepoint [11] 0 0
from the start of cycle 1 to cycle 7 day 1 approximately 170 days.
Secondary outcome [12] 0 0
Mean Change From Baseline in EQ-5D-5L Utility Index Score
Timepoint [12] 0 0
from the start of cycle 1 to cycle 7 day 1 approximately 170 days.
Secondary outcome [13] 0 0
Time to Spleen and Disease Progression Free Survival (SDPFS)
Timepoint [13] 0 0
From randomization to the End of Survival Follow-up
Secondary outcome [14] 0 0
Overall Survival
Timepoint [14] 0 0
From Randomization to the end of Survival Follow Up

Eligibility
Key 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-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)

1. 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 (relapsed) to these parameters following an initial response
2. 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:

1. 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.
2. 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.

Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any of the following laboratory abnormalities:

1. Platelets < 50 x 109/L
2. Absolute neutrophil count (ANC) < 1.0 x 109/L
3. White blood count (WBC) > 100 x 109/L
4. Myeloblasts = 5 % in peripheral blood
5. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification of Diet in Renal Disease [MDRD] formula)
6. Serum amylase or lipase > 1.5 x upper limit of normal (ULN)
7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (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 (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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
9/09/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
23/06/2025
Actual
Sample size
Target
Accrual to date
Final
202
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 0 0
Local Institution - 103 - Darlinghurst
Recruitment hospital [2] 0 0
Local Institution - 101 - Adelaide
Recruitment hospital [3] 0 0
Local Institution - 105 - Box Hill
Recruitment hospital [4] 0 0
Local Institution - 102 - Frankston
Recruitment hospital [5] 0 0
Local Institution - 100 - Melbourne
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
5000 - Adelaide
Recruitment postcode(s) [3] 0 0
3128 - Box Hill
Recruitment postcode(s) [4] 0 0
3199 - Frankston
Recruitment postcode(s) [5] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Graz
Country [2] 0 0
Austria
State/province [2] 0 0
Innsbruck
Country [3] 0 0
Austria
State/province [3] 0 0
Linz
Country [4] 0 0
Austria
State/province [4] 0 0
Salzburg
Country [5] 0 0
Austria
State/province [5] 0 0
Vienna
Country [6] 0 0
Austria
State/province [6] 0 0
Wels
Country [7] 0 0
Austria
State/province [7] 0 0
Wien
Country [8] 0 0
Belgium
State/province [8] 0 0
Brugge
Country [9] 0 0
Belgium
State/province [9] 0 0
Bruxelles
Country [10] 0 0
Belgium
State/province [10] 0 0
La Louvière-(Haine St-Paul)
Country [11] 0 0
Belgium
State/province [11] 0 0
Leuven
Country [12] 0 0
Belgium
State/province [12] 0 0
Liege
Country [13] 0 0
Belgium
State/province [13] 0 0
Yvoir
Country [14] 0 0
China
State/province [14] 0 0
Beijing
Country [15] 0 0
China
State/province [15] 0 0
Guangzhou, Guangdong
Country [16] 0 0
China
State/province [16] 0 0
Tianjin
Country [17] 0 0
China
State/province [17] 0 0
Zhengzhou
Country [18] 0 0
Czechia
State/province [18] 0 0
Brno
Country [19] 0 0
Czechia
State/province [19] 0 0
Ostrava-Poruba
Country [20] 0 0
Czechia
State/province [20] 0 0
Prague 2
Country [21] 0 0
France
State/province [21] 0 0
Angers
Country [22] 0 0
France
State/province [22] 0 0
Brest
Country [23] 0 0
France
State/province [23] 0 0
Lens Cedex
Country [24] 0 0
France
State/province [24] 0 0
Lille
Country [25] 0 0
France
State/province [25] 0 0
Nice Cedex 3
Country [26] 0 0
France
State/province [26] 0 0
Nimes Cedex 9
Country [27] 0 0
France
State/province [27] 0 0
Paris
Country [28] 0 0
France
State/province [28] 0 0
Pessac
Country [29] 0 0
France
State/province [29] 0 0
Pierre-Benite
Country [30] 0 0
France
State/province [30] 0 0
Poitiers Cedex
Country [31] 0 0
France
State/province [31] 0 0
Strasbourg
Country [32] 0 0
France
State/province [32] 0 0
Toulouse Cedex 9
Country [33] 0 0
Germany
State/province [33] 0 0
Aachen
Country [34] 0 0
Germany
State/province [34] 0 0
Frankfurt am Main
Country [35] 0 0
Germany
State/province [35] 0 0
Halle
Country [36] 0 0
Germany
State/province [36] 0 0
Jena
Country [37] 0 0
Germany
State/province [37] 0 0
Magdeburg
Country [38] 0 0
Germany
State/province [38] 0 0
Mannheim
Country [39] 0 0
Germany
State/province [39] 0 0
Minden
Country [40] 0 0
Germany
State/province [40] 0 0
Ulm
Country [41] 0 0
Hungary
State/province [41] 0 0
Budapest
Country [42] 0 0
Hungary
State/province [42] 0 0
Györ
Country [43] 0 0
Hungary
State/province [43] 0 0
Kaposvar
Country [44] 0 0
Hungary
State/province [44] 0 0
Nyiregyhaza
Country [45] 0 0
Hungary
State/province [45] 0 0
Szeged
Country [46] 0 0
Ireland
State/province [46] 0 0
Cork
Country [47] 0 0
Ireland
State/province [47] 0 0
Dublin
Country [48] 0 0
Italy
State/province [48] 0 0
Bologna
Country [49] 0 0
Italy
State/province [49] 0 0
Brescia
Country [50] 0 0
Italy
State/province [50] 0 0
Catania
Country [51] 0 0
Italy
State/province [51] 0 0
Firenze
Country [52] 0 0
Italy
State/province [52] 0 0
Milano
Country [53] 0 0
Italy
State/province [53] 0 0
Naples
Country [54] 0 0
Italy
State/province [54] 0 0
Pavia
Country [55] 0 0
Italy
State/province [55] 0 0
Roma
Country [56] 0 0
Italy
State/province [56] 0 0
Torino
Country [57] 0 0
Italy
State/province [57] 0 0
Udine
Country [58] 0 0
Italy
State/province [58] 0 0
Varese
Country [59] 0 0
Italy
State/province [59] 0 0
Verona
Country [60] 0 0
Korea, Republic of
State/province [60] 0 0
Seongnam-si
Country [61] 0 0
Korea, Republic of
State/province [61] 0 0
Seoul
Country [62] 0 0
Netherlands
State/province [62] 0 0
Maastricht
Country [63] 0 0
Netherlands
State/province [63] 0 0
Nijmegen
Country [64] 0 0
Poland
State/province [64] 0 0
Poznan
Country [65] 0 0
Poland
State/province [65] 0 0
Warszawa
Country [66] 0 0
Poland
State/province [66] 0 0
Wroclaw
Country [67] 0 0
Russian Federation
State/province [67] 0 0
Moscow
Country [68] 0 0
Russian Federation
State/province [68] 0 0
Novosibirsk
Country [69] 0 0
Russian Federation
State/province [69] 0 0
Saint Petersburg
Country [70] 0 0
Russian Federation
State/province [70] 0 0
Saint-Petersburg
Country [71] 0 0
Russian Federation
State/province [71] 0 0
St Petersburg
Country [72] 0 0
Russian Federation
State/province [72] 0 0
Vladikavkaz
Country [73] 0 0
Spain
State/province [73] 0 0
Alicante
Country [74] 0 0
Spain
State/province [74] 0 0
Badalona (Barcelona)
Country [75] 0 0
Spain
State/province [75] 0 0
Barakaldo
Country [76] 0 0
Spain
State/province [76] 0 0
Barcelona
Country [77] 0 0
Spain
State/province [77] 0 0
Gerona
Country [78] 0 0
Spain
State/province [78] 0 0
Las Palmas de Gran Canaria
Country [79] 0 0
Spain
State/province [79] 0 0
Madrid
Country [80] 0 0
Spain
State/province [80] 0 0
Malaga
Country [81] 0 0
Spain
State/province [81] 0 0
Murcia
Country [82] 0 0
Spain
State/province [82] 0 0
Salamanca
Country [83] 0 0
Spain
State/province [83] 0 0
Santa Cruz de Tenerife
Country [84] 0 0
Spain
State/province [84] 0 0
Santiago de Compostela
Country [85] 0 0
Spain
State/province [85] 0 0
Valencia
Country [86] 0 0
United Kingdom
State/province [86] 0 0
Lancashire
Country [87] 0 0
United Kingdom
State/province [87] 0 0
Nottinghamshire
Country [88] 0 0
United Kingdom
State/province [88] 0 0
Birmingham
Country [89] 0 0
United Kingdom
State/province [89] 0 0
Boston
Country [90] 0 0
United Kingdom
State/province [90] 0 0
London
Country [91] 0 0
United Kingdom
State/province [91] 0 0
Oxford

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Celgene
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bristol-Myers Squibb
Address 0 0
Bristol-Myers Squibb
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Clinical study report (CSR), Analytic code
When will data be available (start and end dates)?
See Plan Description
Available to whom?
See Plan Description
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT03952039