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
Clinicaltrials.gov identifier recruitment status First Posted Last update posted
NCT03755518 Active, not recruiting November 28, 2018 August 9, 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: Primary Myelofibrosis
Post-Polycythemia Vera Myelofibrosis
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 : 38 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) 100 x 10^9/L Myeloblasts > 5 % in peripheral blood Estimated glomerular filtration rate 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 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 Local Institution - 118 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 Local Institution - 202 Montreal
Canada, Quebec CIUSSS de l'Estrie - CHUS Sherbrooke
Sponsors and Collaborators
Celgene
Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
Investigator
Study Director : Bristol-Myers Squibb Bristol-Myers Squibb
More Information
Responsible Party : Celgene
ClinicalTrials.gov Identifier : NCT03755518     
Other Study ID Numbers : FEDR-MF-001, U1111-1223-2862, 2018-002237-38
First Posted : November 28, 2018
Last Update Posted : August 9, 2022
Last Verified : August 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
Primary Myelofibrosis
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders