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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

  • Clinicaltrials.gov identifier

    NCT03952039

  • Recruitment Status

    Recruiting

  • First Posted

    May 16, 2019

  • Last update posted

    April 8, 2021

Study Description

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.

  • Condition or Disease:Myelofibrosis
    Post-Polycythemia Vera
    Primary Myelofibrosis
  • Intervention/Treatment: Drug: FEDRATINIB
    Drug: Best Available Therapy (BAT)
  • Phase: Phase 3

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

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 192 participants
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official 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
  • Actual Study Start Date: September 2019
  • Estimated Primary Completion Date: February 2022
  • Estimated Study Completion Date: August 2024

Arms and interventions

Arm Intervention/treatment
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.
Drug: FEDRATINIB
A potent and selective inhibitor of JAK2 kinase activity
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.
Drug: Best Available Therapy (BAT)
Best available therapy (BAT)

Outcome Measures

  • Primary Outcome Measures: 1. Proportion of subjects who have ≥ 35% SVR at end of cycle 6 [ Time Frame: At the end of Cycle 1 (each cycle is 28 days) ]
    Spleen volume response rate (RR)
  • Secondary Outcome Measures: 1. Proportion of subjects who have ≥ 50% reduction in spleen size by palpation at end of cycle 6 [ Time Frame: Up to end of Cycle 6 (each cycle is 28 days) ]
    Spleen response rate by palpation (RRP)
  • 2. Proportion of subjects with ≥ 50% reduction in total symptom scores measured by MFSAF at end of cycle 6 [ Time Frame: Up to end of Cycle 6 (each cycle is 28 days) ]
    Symptom response rate (SRR)
  • 3. Proportion of subjects who have ≥ 25% reduction in spleen volume at the end of cycle 6 [ Time Frame: At the end of Cycle 1 (each cycle is 28 days) ]
    Spleen volume response rate (RR25)
  • 4. Adverse Events (AEs) [ Time Frame: Up to 30 days post last dose ]
    Number of participants with adverse event
  • 5. Durability of Spleen Volume Response by MRI/CT (DR) [ Time Frame: Up to end of Cycle 6 (each cycle is 28 days) ]
    Is defined as time from the first documented spleen response (ie, ≥ 35% reduction in spleen volume) to the first documented spleen volume reduction < 35%.
  • 6. Duration of ≥ 50 % reduction in spleen size by palpation for subjects with a palpable spleen at least 5 cm below the left costal margin (LCM) at baseline [ Time Frame: Up to approximately 30 months ]
    From C1D1 until the 30- day follow-up after last dose visit
  • 7. Duration of ≥ 50% reduction in total symptom scores measured by MFSAF [ Time Frame: From enrollment until 30 days post last dose ]
    Durability of symptoms response (DSR)
  • 8. Time from randomization to death due to any reason or disease progression (modified IWG-MRT 2013 including ≥ 25% increase in spleen volume by MRI/CT) [ Time Frame: Up to 24 months from enrollment to End of Survival Follow-up ]
    Spleen and disease progression free survival (SDPFS)
  • 9. Gastrointestinal Adverse Events [ Time Frame: Up to approximately 30 months ]
    Incidence of subjects with Grade 3 or higher Gastrointestinal events (nausea, diarrhea, or vomiting) according to CTCAE v5.0
  • 10. Encephalopathy Events, including Wernicke's [ Time Frame: Up to 30 days post last dose ]
    Occurrence of confirmed encephalopathy events, including Wernicke's
  • 11. Health-Related Quality of Life (HRQoL) [ Time Frame: Up to 30-day follow-up after last dose visit ]
    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)
  • 12. EQ-5D-5L [ Time Frame: Up to 20-day follow-up after last dose visit ]
    To evaluate Patient Reported Outcomes (PRO) as measured by the EQ-5D-5L questionnaire
  • 13. Overall Survival (OS) [ Time Frame: From randomization to the End of Survival Follow-up (approximately 12 months) ]
    Time from randomization to death due to any reason

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:

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) 100 x 109/L

4. Myeloblasts ≥ 5 % in peripheral blood

5. Estimated glomerular filtration rate 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
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

Contacts and Locations

Contacts

Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

Locations

Australia, New South Wales
Saint Vincent's Hospital
Darlinghurst

Australia, South Australia
Royal Adelaide Hospital
Adelaide

Australia, Victoria
Peninsula Private Hospital
Frankston

Australia
Eastern Health Clinical School
Box Hill

Australia
Alfred Hospital
Melbourne

Austria
Medical University of Graz
Graz

Austria
Medical University Innsbruck
Innsbruck

Austria
Elisabethinen Hospital Linz
Linz

Austria
Salzburger Landkliniken St. Johanns-Spital
Salzburg

Austria
Medical University of Vienna
Vienna

Austria
Klinikum Wels-Grieskirchen GmbH
Wels

Austria
Hanusch Krankenhaus
Wien

Belgium
AZ Sint-Jan AV Brugge
Brugge

Belgium
Cliniques Universitaires Saint-Luc
Bruxelles

Belgium
Centre Hospitalier de Jolimont-Lobbes
La Louvière-(Haine St-Paul)

Belgium
UZ Leuven
Leuven

Belgium
Centre Hospitalier Universitaire de Liege - Sart Tilman
Liege

Belgium
Cliniques Universitaires UCL de Mont-Godine
Yvoir

China
Peking University People's Hospital
Beijing

China
Peking Union Medical College Hospital
Beijing

China
Fujian Medical University Union Hospital
Fuzhou

China
Guangdong General Hospital
Guangzhou, Guangdong

China
Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University
Nanjing

China
Chinese Academy of Medical Sciences & Peking Union Medical College
Tianjin

China
Henan Cancer Hospital
Zhengzhou

Czechia
Fakultni Nemocnice Brno
Brno

Czechia
Fakultni Nemocnice Ostrava
Ostrava-Poruba

Czechia
Vseobecna Fakultni Nemocnice v Praze
Prague 2

France
CHU d'Angers
Angers

France
CHRU de Brest - Hopital Morvan
Brest

France
Centre Hospitalier de Lens
Lens Cedex

France
CHRU Claude Huriez
Lille

France
CHU Nice Hopital de L'Archet 2
Nice Cedex 3

France
Centre Hospitalier Universitaire de Nimes - Hopital Universitaire Caremeau
Nimes Cedex 9

France
Hopital Saint Louis
Paris

France
CHRU - Hopital du Haut Leveque
Pessac

France
Centre Hospitalier Lyon Sud - Hospices Civils de Lyon Groupement Hospitalier Sud
Pierre-Benite

France
CHU La Miletrie
Poitiers Cedex

France
CHU Strasbourg - Hopital Civil
Strasbourg

France
Institut Universitaire du Cancer de Toulouse - Oncopole
Toulouse Cedex 9

Germany
Unviversitatsklinikum Aachen
Aachen

Germany
Klinikum der Johann Wolfgang Goethe Universitat
Frankfurt am Main

Germany
Universitaetsklinikum Halle Saale
Halle

Germany
Universitaetsklinikum Jena
Jena

Germany
Universitaetsklinikum Magdeburg A oeR
Magdeburg

Germany
University of Heidelberg - Universitatsklinikum Mannheim
Mannheim

Germany
Johannes Wiesling Klinikum Minden
Minden

Germany
TU München - Klinikum rechts der Isar
München

Germany
Universitaetsklinikum Ulm
Ulm

Hungary
Semmelweis Egyetem
Budapest

Hungary
Petz Aladar Megyei Oktato Korhaz
Gyor

Hungary
Somogy Megyei Kaposi Mor Oktato Korhaz
Kaposvar

Hungary
SzSzB Megyei Korhazak es Egyetemi Oktatokorhaz
Nyiregyhaza

Hungary
Szegedi Tudomanyegyetem - Szent-Gyorgyi Albert Klinikai Kozpont
Szeged

Ireland
Cork University Hospital
Cork

Ireland
Mater Misericordiae University Hospital
Dublin

Ireland
St. James' Hospital
Dublin

Italy
A.O.U. di Bologna Policlinico S.Orsola-Malpighi
Bologna

Italy
ASST Spedali Civili P.O. di Brescia
Brescia

Italy
Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele - Ospedale Gaspare Rodolico
Catania

Italy
Azienda Ospedaliero-Universitaria Careggi
Firenze

Italy
IRCSS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena
Milano

Italy
Ospedale Cardarelli
Naples

Italy
Fondazione IRCCS Policlinico San Matteo
Pavia

Italy
Policlinico Umberto I - Universita La Sapienza
Roma

Italy
Universita Cattololica del Sacro Cuore
Roma

Italy
Azienda Ospedaliera S. Andrea - Università La Sapienza
Roma

Italy
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
Torino

Italy
Azienda Ospedaliero-Universitaria Santa Maria della Misericordia die Udine
Udine

Italy
Universita degli Studi dell'Insubria - Ospedale di Circolo e Fondazione Macchi - Varese
Varese

Italy
Azienda Ospedaliera Universitaria Integrata di Verona
Verona

Korea, Republic of
Seoul National University Bundang Hospital
Seongnam-si

Korea, Republic of
Samsung Medical Center
Seoul

Korea, Republic of
Seoul St Marys Hospital College of Medicine The Catholic University of Korea
Seoul

Korea, Republic of
Soon Chun Hyang University Hospital Seoul
Seoul

Korea, Republic of
Seoul National University Hospital
Seoul

Korea, Republic of
Asan Medical Center
Seoul

Netherlands
UMC Maastricht
Maastricht

Netherlands
Radboud University Medical Center
Nijmegen

Poland
Szpital Kliniczny im. H.Swiecickiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
Poznan

Poland
Instytut Hematologii i Transfuzjologii w Warszawie
Warszawa

Poland
Akademicki Szpital Kliniczny im. Jana Mikulicza-Radeckiego
Wroclaw

Russian Federation
FSBI Hematology Research Center Ministry of Healthcare of the Russian Federation
Moscow

Russian Federation
Moscow State Healthcare Institution City clinical hospital n.a. S.P.Botkin
Moscow

Russian Federation
City Clinical Hospital 40
Moscow

Russian Federation
Novosibirsk State Medical University (NSMU)
Novosibirsk

Russian Federation
Russian Research Institute of Hematology and Transfusiology of the Federal Biomedical Agency
Saint Petersburg

Russian Federation
Pavlov First Saint Petersburg State Medical University
Saint-Petersburg

Russian Federation
Federal Centre of Heart, Blood and Endocrinology of Rosmed technlologies V.A. Almazov
St Petersburg

Russian Federation
State Budgetary Healthcare Organization
Vladikavkaz

Spain
Complejo Hospitalario Universitario A Coruna
A Coruna

Spain
Hospital General Universitario de Alicante
Alicante

Spain
Hospital Universitari Germans Trias i Pujol
Badalona (Barcelona)

Spain
Hospital Universitario Cruces
Barakaldo

Spain
Hospital Clinic de Barcelona
Barcelona

Spain
Instituto Catalan de Oncologia de Girona
Gerona

Spain
Hospital Universitario de Gran Canaria Dr. Negrin
Las Palmas de Gran Canaria

Spain
Hospital Ramon y Cajal
Madrid

Spain
Hospital Universitario 12 de Octubre
Madrid

Spain
Hospital Universitario Virgen de la Victoria
Malaga

Spain
Hospital General Universitario Morales Meseguer
Murcia

Spain
Universitario de Salamanca - Hospital Clinico
Salamanca

Spain
Hospital Universitario de Tenerife
Santa Cruz de Tenerife

Spain
Hospital Clinico Universitario de Santiago
Santiago de Compostela

Spain
Hospital Clinico Universitario de Valencia
Valencia

United Kingdom
University Hospitals Birmingham NHS Foundation Trust - Queen Elizabeth Hospital
Birmingham

United Kingdom
United Lincolnshire Hospitals NHS Trust
Boston

United Kingdom
Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
London

United Kingdom
Imperial College Hammersmith Hospital
London

United Kingdom
The Christie NHS Foundation Trust
Manchester

United Kingdom
Nottingham City Hospital
Nottingham

United Kingdom
The Churchill Hospital
Oxford

Sponsors and Collaborators

Celgene

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

Investigators

Study Director: Vishwanath Gharpure, MD Celgene Corporation

More Information

  • Responsible Party: Celgene
  • ClinicalTrials.gov Identifier: NCT03952039 History of Changes
  • Other Study ID Numbers: FEDR-MF-002, U1111-1223-2962, 2018-003411-21
  • First Posted: May 16, 2019 Key Record Dates
  • Last Update Posted: April 8, 2021
  • Last Verified: March 2021
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Yes
  • Plan Description: 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 Materials: Study Protocol, Statistical Analysis Plan (SAP), Informed Consent Form (ICF), Clinical Study Report (CSR), Analytic Code
  • Time Frame: See Plan Description
  • Access Criteria: See Plan Description
  • URL: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Celgene: MPN
    Post-Essential Thrombocythemia Myelofibrosis
    MF
    PMF
    myelofibrosis
    post-PV
    Post-Polycythemia Vera
    post-ET MF
    myeloproliferative neoplasms
  • Additional relevant MeSH terms: Polycythemia Vera
    Primary Myelofibrosis
    Polycythemia
    Thrombocytosis
    Thrombocythemia, Essential