FREEDOM: 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

Sponsor

Celgene (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03755518

Collaborator

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

Enrollment

Locations

Arm

57.2

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

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	Intervention/Treatment	Phase
Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Myelofibrosis Post-essential Thrombocythemia Myelofibrosis	Drug: FEDRATINIB	Phase 3

Detailed Description

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

Actual Enrollment :

38 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 3b, Multicenter, Single-Arm, Open-Label Efficacy and Safety Study 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

Actual Study Start Date :

Mar 27, 2019

Actual Primary Completion Date :

Nov 26, 2021

Anticipated Study Completion Date :

Dec 31, 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

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

Main study - Proportion of subjects who have a ≥ 35% SVR at end of Cycle 6 [At the end of Cycle 6 (each cycle is 28 days)]
Spleen volume response rate (RR)

Secondary Outcome Measures

Main study - Adverse Event(s) [Up to 12 months post last dose]
Number of participants with adverse event
Main study - Proportion of subjects who have ≥ 50% reduction in spleen size by palpation [At the end of Cycle 6 (each cycle is 28 days)]
Spleen response rate by palpation (RRP)
Main study - Symptom response rate (SRR) [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.
Main study - Durability of spleen volume response (DR) [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
Durability of spleen response by palpation (DRP) [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
Main study - Durability of symptoms response (DSR) [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%.
Main study - Gastrointestinal Adverse Events [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
Main study - Wernicke encephalopathy (WE) [Up to 30 days post last dose]
Occurrence of confirmed Wernicke encephalopathy events
Main study - Wernicke encephalopathy (WE) thiamine monitoring [Up to 30 days post last dose]
Monitoring and correction of thiamine levels as appropriate

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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) < 1.0 x 109/L
White blood count (WBC) > 100 x 10^9/L
Myeloblasts > 5 % in peripheral blood
Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 (as per the Modification of Diet in Renal Disease [MDRD] formula)
Serum amylase or lipase > 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 < 25% of the total bilirubin
Subject is pregnant or lactating female
Subject with previous splenectomy
Subject with previous or planned hematopoietic cell transplant
Subject with prior history of encephalopathy, including Wernicke's
Subject with signs or symptoms of encephalopathy including Wernicke's (eg, severe ataxia, ocular paralysis or cerebellar signs)
Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not corrected prior to enrollment on the study
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
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 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

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
2	Baptist Health - Miami Cardiac & Vascular Institute	Miami	Florida	United States	33176
3	Augusta University - Georgia Cancer Center	Augusta	Georgia	United States	30912
4	Rush University Medical Center - University Cardiovascular Surgeons	Chicago	Illinois	United States	60612
5	The University of Chicago Medical Center - Duchossois Center for Advanced Medicine	Chicago	Illinois	United States	60637
6	Advocate Medical Group	Park Ridge	Illinois	United States	60068
7	University of Kansas Medical Center	Kansas City	Kansas	United States	66160-7314
8	St. Agnes - Medical Center	Baltimore	Maryland	United States	21229-5299
9	Center for Cancer and Blood Disorders, P.C.	Bethesda	Maryland	United States	20817
10	Local Institution - 118	Bethesda	Maryland	United States	20817
11	Maryland Oncology Hematology PA	Columbia	Maryland	United States	21044
12	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
13	Washington Univ School of Medicine	Saint Louis	Missouri	United States	63110
14	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112-2027
15	Brookdale University Hospital and Medical Center	Brooklyn	New York	United States	11212
16	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
17	Columbia University Medical Center	New York	New York	United States	10032
18	SUNY Upstate Medical University	Syracuse	New York	United States	13210
19	North Carolina Women's Hospital	Chapel Hill	North Carolina	United States	27514
20	Duke University Medical Center	Durham	North Carolina	United States	27705
21	UC Health Barrett Cancer Center	Cincinnati	Ohio	United States	45219
22	Local Institution - 106	Pittsburgh	Pennsylvania	United States	15224
23	Western Pennsylvania Cancer Institute	Pittsburgh	Pennsylvania	United States	15224
24	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
25	Local Institution - 119	Dallas	Texas	United States	75390-8852
26	UT Southwestern Medical Center Simmons Comprehensive Cancer Center	Dallas	Texas	United States	75390-8852
27	Texas Oncology- Fort Worth Cancer Center	Fort Worth	Texas	United States	76104
28	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77303
29	UT Health - San Antonio	San Antonio	Texas	United States	78229
30	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
31	University of Wisconsin Medical School	Madison	Wisconsin	United States	53792-2454
32	Providence Hematology	Vancouver	British Columbia	Canada	V6Z 2A5
33	London Health Sciences Centre	London	Ontario	Canada	N6C 6B5
34	Ottawa Hospital	Ottawa	Ontario	Canada	K1H 8L6
35	Princess Margaret Hospital University Health Network	Toronto	Ontario	Canada	M5G 2M9
36	Hopital Maisonneuve-Rosemont	Montreal	Quebec	Canada	H1T 2M4
37	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
38	Local Institution - 202	Montreal	Quebec	Canada	H3T 1E2
39	CIUSSS de l'Estrie - CHUS	Sherbrooke	Quebec	Canada	J1K 2R1