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

NCT ID: NCT03952039

Last Updated: 2025-08-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 202 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-09
• Study Completion Date: 2025-07-28

Brief Summary

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. The primary objective of the study is to evaluate the percentage of subjects with at least 35% spleen volume reduction in the fedratinib and the BAT arms.

Detailed Description

This Phase 3, multicenter, randomized, two-arm, open-label study will include subjects with intermediate or high-risk (as per the DIPSS score) primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF). This study will be conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCPs).

Study design includes:

• A 28-day Screening Period
• 2:1 Randomization to fedratinib or best available therapy (BAT)
• Stratification at Randomization according to:

• Spleen size by palpation: < 15 cm below left costal margin (LCM) versus ≥ 15 cm below LCM
• Platelets ≥ 50 to < 100 x 109/L versus platelets ≥ 100 x 109/L
• Refractory or relapsed to ruxolitinib treatment versus intolerant to ruxolitinib treatment
• Study Treatment Period (time on study drug plus 30 days after last dose)
• Subjects are allowed to crossover from BAT to the fedratinib arm after the Cycle 6 response assessment or before the Cycle 6 response assessment in the event of a confirmed progression of splenomegaly by MRI/CT scan
• A Survival Follow-up Period for progression and survival

Conditions

Primary Myelofibrosis; Post-Polycythemia Vera; Myelofibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

FEDRATINIB

Intervention Type: DRUG

A potent and selective inhibitor of JAK2 kinase activity

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.

Group Type: ACTIVE_COMPARATOR

Best Available Therapy (BAT)

Intervention Type: DRUG

Best available therapy (BAT)

Interventions

FEDRATINIB

A potent and selective inhibitor of JAK2 kinase activity

Intervention Type: DRUG

Best Available Therapy (BAT)

Best available therapy (BAT)

Intervention Type: DRUG

Eligibility Criteria

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

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

INDUSTRY

Sponsor Role: collaborator

Celgene

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bristol-Myers Squibb

Role: STUDY_DIRECTOR

Bristol-Myers Squibb

Locations

Local Institution - 103

Darlinghurst, New South Wales, Australia

Local Institution - 101

Adelaide, South Australia, Australia

Local Institution - 105

Box Hill, Victoria, Australia

Local Institution - 102

Langwarrin, Victoria, Australia

Local Institution - 100

Melbourne, , Australia

Local Institution - 156

Graz, , Austria

Local Institution - 154

Innsbruck, , Austria

Local Institution - 155

Linz, , Austria

Local Institution - 151

Salzburg, , Austria

Local Institution - 150

Vienna, , Austria

Local Institution - 152

Vienna, , Austria

Local Institution - 153

Wels, , Austria

Local Institution - 200

Bruges, , Belgium

Local Institution - 202

Brussels, , Belgium

Local Institution - 205

La Louvière-(Haine St-Paul), , Belgium

Local Institution - 201

Leuven, , Belgium

Local Institution - 204

Liège, , Belgium

Local Institution - 203

Yvoir, , Belgium

Local Institution - 555

Beijing, , China

Local Institution - 550

Guangzhou, Guangdong, , China

Local Institution - 553

Tianjin, , China

Local Institution - 557

Zhengzhou, , China

Local Institution - 700

Brno, , Czechia

Local Institution - 702

Ostrava-Poruba, , Czechia

Local Institution - 701

Prague, , Czechia

Local Institution - 255

Angers, , France

Local Institution - 256

Brest, , France

Local Institution - 254

Lens, , France

Local Institution - 259

Lille, , France

Local Institution - 260

Nice, , France

Local Institution - 250

Nîmes, , France

Local Institution - 252

Paris, , France

Local Institution - 258

Pessac, , France

Local Institution - 257

Pierre-Bénite, , France

Local Institution - 261

Poitiers, , France

Local Institution - 251

Strasbourg, , France

Local Institution - 253

Toulouse, , France

Local Institution - 302

Aachen, , Germany

Local Institution - 308

Frankfurt am Main, , Germany

Local Institution - 306

Halle, , Germany

Local Institution - 303

Jena, , Germany

Local Institution - 307

Magdeburg, , Germany

Local Institution - 301

Mannheim, , Germany

Local Institution - 304

Minden, , Germany

Local Institution - 305

Ulm, , Germany

Local Institution - 600

Budapest, , Hungary

Local Institution - 601

Győr, , Hungary

Local Institution - 602

Kaposvár, , Hungary

Local Institution - 604

Nyíregyháza, , Hungary

Local Institution - 603

Szeged, , Hungary

Local Institution - 751

Cork, , Ireland

Local Institution - 752

Dublin, , Ireland

Local Institution - 750

Dublin, , Ireland

Local Institution - 353

Bologna, , Italy

Local Institution - 363

Brescia, , Italy

Local Institution - 354

Catania, , Italy

Local Institution - 350

Florence, , Italy

Local Institution - 358

Milan, , Italy

Local Institution - 362

Naples, , Italy

Local Institution - 357

Pavia, , Italy

Local Institution - 356

Roma, , Italy

Local Institution - 361

Roma, , Italy

Local Institution - 359

Roma, , Italy

Local Institution - 355

Torino, , Italy

Local Institution - 360

Udine, , Italy

Local Institution - 352

Varese, , Italy

Local Institution - 364

Verona, , Italy

Local Institution - 402

Maastricht, , Netherlands

Local Institution - 400

Nijmegen, , Netherlands

Local Institution - 803

Poznan, , Poland

Local Institution - 801

Warsaw, , Poland

Local Institution - 802

Wroclaw, , Poland

Local Institution - 855

Moscow, , Russia

Local Institution - 851

Moscow, , Russia

Local Institution - 853

Moscow, , Russia

Local Institution - 857

Novosibirsk, , Russia

Local Institution - 852

Saint Petersburg, , Russia

Local Institution - 854

Saint Petersburg, , Russia

Local Institution - 850

Saint Petersburg, , Russia

Local Institution - 859

Vladikavkaz, , Russia

Local Institution - 900

Seongnam-si, , South Korea

Local Institution - 905

Seoul, , South Korea

Local Institution - 901

Seoul, , South Korea

Local Institution - 903

Seoul, , South Korea

Local Institution - 904

Seoul, , South Korea

Local Institution - 902

Seoul, , South Korea

Local Institution - 451

Alicante, , Spain

Local Institution - 452

Badalona (Barcelona), , Spain

Local Institution - 458

Barakaldo, , Spain

Local Institution - 450

Barcelona, , Spain

Local Institution - 462

Girona, , Spain

Local Institution - 461

Las Palmas de Gran Canaria, , Spain

Local Institution - 453

Madrid, , Spain

Local Institution - 459

Madrid, , Spain

Local Institution - 457

Málaga, , Spain

Local Institution - 454

Murcia, , Spain

Local Institution - 455

Salamanca, , Spain

Local Institution - 463

Santa Cruz de Tenerife, , Spain

Local Institution - 460

Santiago de Compostela, , Spain

Local Institution - 456

Valencia, , Spain

Local Institution - 504

Manchester, Lancashire, United Kingdom

Local Institution - 506

Nottingham, Nottinghamshire, United Kingdom

Local Institution - 502

Birmingham, , United Kingdom

Local Institution - 503

Boston, , United Kingdom

Local Institution - 501

London, , United Kingdom

Local Institution - 505

London, , United Kingdom

Local Institution - 500

Oxford, , United Kingdom

Countries

Australia; Austria; Belgium; China; Czechia; France; Germany; Hungary; Ireland; Italy; Netherlands; Poland; Russia; South Korea; Spain; United Kingdom

References

Harrison CN, Mesa R, Talpaz M, Al-Ali HK, Xicoy B, Passamonti F, Palandri F, Benevolo G, Vannucchi AM, Mediavilla C, Iurlo A, Kim I, Rose S, Brown P, Hernandez C, Wang J, Kiladjian JJ. Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Haematol. 2024 Oct;11(10):e729-e740. doi: 10.1016/S2352-3026(24)00212-6. Epub 2024 Sep 9.

Reference Type: DERIVED

PMID: 39265613 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html

BMS Clinical Trial Information

https://www.BMSClinicalTrials.com

BMS Clinical Trial Patient Recruiting

Other Identifiers

U1111-1223-2962

Identifier Type: REGISTRY

Identifier Source: secondary_id

2018-003411-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

FEDR-MF-002

Identifier Type: -

Identifier Source: org_study_id