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

Myelofibrosis Clinical Trial

— FREEDOM  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03755518
• Other study ID #: FEDR-MF-001
• Secondary ID: U1111-1223-28622
• Status: Completed
• Phase: Phase 3
• Start date: March 27, 2019
• Est. completion date: November 8, 2023

Study information

• Verified date: November 2023
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: November 8, 2023
• Est. primary completion date: November 26, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Main Study 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 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 assessment or by palpable spleen measuring = 5 cm below the left costal margin.

6. 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)

1. Treatment with ruxolitinib for = 3 months

2. 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

7. 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.

8. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted

9. Subject is willing and able to adhere to the study visit schedule and other protocol requirements

10. Participants must agree to use effective contraception

Exclusion Criteria:

Main Study Exclusion Criteria

1. Any of the following laboratory abnormalities:

1. Platelets < 50,000/µL

2. Absolute neutrophil count (ANC) < 1.0 x 109/L

3. White blood count (WBC) > 100 x 10^9/L

4. Myeloblasts > 5 % in peripheral blood

5. Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 (as per the Modification of Diet in Renal Disease [MDRD] formula)

6. Serum amylase or lipase > 1.5 x ULN (upper limit of normal)

7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x 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

6. Subject with signs or symptoms of encephalopathy including Wernicke's (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 institutional standard and not corrected prior to enrollment on the study

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 the start of fedratinib treatment

10. Subject has received ruxolitinib within 14 days prior to the start of fedratinib

11. Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating factor [G-CSF]) within 14 days prior to the start of fedratinib treatment

12. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) for more than 1 cycle other than ruxolitinib treatment

13. Subject on treatment with aspirin with doses > 150 mg daily

14. Subject with major surgery within 28 days before starting fedratinib treatment

15. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)

16. 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

17. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)

18. Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)

19. Subject with serious active infection

20. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication

21. Subject is unable to swallow capsule

22. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study

23. 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

24. Subject has any condition that confounds the ability to interpret data from the study

25. Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to start of fedratinib treatment

26. Subject with life expectancy of less than 6 months.

Related Conditions & MeSH terms

• Myelofibrosis
• Polycythemia
• Polycythemia Vera
• Post-essential Thrombocythemia Myelofibrosis
• Post-Polycythemia Vera Myelofibrosis
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• FEDRATINIB
A potent and selective inhibitor of JAK2 kinase activity

Locations

Country	Name	City	State
Canada	Local Institution - 207	London	Ontario
Canada	Local Institution - 201	Montreal	Quebec
Canada	Local Institution - 202	Montreal	Quebec
Canada	Local Institution - 205	Ottawa	Ontario
Canada	Local Institution - 204	Sherbrooke	Quebec
Canada	Local Institution - 200	Toronto	Ontario
Canada	Local Institution - 203	Vancouver	British Columbia
United States	Local Institution - 103	Ann Arbor	Michigan
United States	Local Institution - 113	Augusta	Georgia
United States	Local Institution - 117	Aurora	Colorado
United States	Local Institution - 123	Baltimore	Maryland
United States	Local Institution - 118	Bethesda	Maryland
United States	Local Institution - 130	Brooklyn	New York
United States	Local Institution - 105	Chapel Hill	North Carolina
United States	Local Institution - 109	Chicago	Illinois
United States	Local Institution - 112	Chicago	Illinois
United States	Local Institution - 111	Cincinnati	Ohio
United States	Local Institution - 127	Columbia	Maryland
United States	Local Institution - 119	Dallas	Texas
United States	Local Institution - 114	Durham	North Carolina
United States	Local Institution - 132	Fort Worth	Texas
United States	Local Institution - 110	Houston	Texas
United States	Local Institution - 100	Kansas City	Kansas
United States	Local Institution - 129	Madison	Wisconsin
United States	Local Institution - 126	Miami	Florida
United States	Local Institution - 115	New York	New York
United States	Local Institution - 124	New York	New York
United States	Local Institution - 128	Newark	New Jersey
United States	Local Institution - 121	Park Ridge	Illinois
United States	Local Institution - 106	Pittsburgh	Pennsylvania
United States	Local Institution - 101	Saint Louis	Missouri
United States	Local Institution - 120	San Antonio	Texas
United States	Local Institution - 116	Seattle	Washington
United States	Local Institution - 108	Sioux Falls	South Dakota
United States	SUNY Upstate Medical University	Syracuse	New York

Sponsors (2)

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

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Who Have a = 35% Spleen Volume Reduction (SVR) at End of Cycle 6	Percentage of participants who have a = 35% SVR at end of Cycle 6 as compared to baseline. Participants with a missing MRI/CT spleen volume at the end of Cycle 6 including those who meet the criteria for progression of splenomegaly before the end of Cycle 6 will be considered non-responders. Baseline value is defined as the last value or measurement taken prior to the first dose in the study	From First Dose to end of Cycle 6 (approximately 168 days)
Secondary	Number of Participants of All Grade Adverse Events (AEs) and Grade 3/4 AEs	Number of participants and severity of all grade adverse events (AEs) and grade 3/4 AEs as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.	From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 128 weeks)
Secondary	Number of Participants and Severity of Treatment Related All Grade Adverse Events (AEs) and Grade 3/4 AEs	Number of participants and severity of treatment related all grade adverse events (AEs) and grade 3/4 AEs as per NCI CTCAE.	From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks)
Secondary	Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin	Mean change from baseline in hematology laboratory analysis - hemoglobin	at Cycle 4 Day 1 and Cycle 7 Day 1
Secondary	Mean Change From Baseline in Hematology Laboratory Analysis - Erythrocytes	Mean change from baseline in hematology laboratory analysis - erythrocytes.; Baseline value is defined as the last value or measurement taken prior to the first dose in the study	at Cycle 4 Day 1 and Cycle 7 Day 1
Secondary	Mean Change From Baseline in Hematology Laboratory Analysis - Platelets, Leukocytes and Neutrophils	Mean change from baseline in hematology laboratory analysis - platelets, leukocytes and neutrophils.; Baseline value is defined as the last value or measurement taken prior to the first dose in the study	at Cycle 4 Day 1 and Cycle 7 Day 1
Secondary	Mean Change From Baseline in the Percentage of Blasts/Leukocytes in Hematology Laboratory Analysis	Mean change from baseline in hematology laboratory analysis - blasts/leukocytes; Baseline value is defined as the last value or measurement taken prior to the first dose in the study	at Cycle 4 Day 1 and Cycle 7 Day 1
Secondary	Mean Change From Baseline in Chemistry Parameters Analysis - ALT, AST, Amylase, Lipase	Mean change from baseline in chemistry parameters analysis - ALT, AST, Amylase, Lipase; Baseline value is defined as the last value or measurement taken prior to the first dose in the study	at Cycle 4 Day 1 and Cycle 7 Day 1
Secondary	Mean Change From Baseline in Chemistry Parameters Analysis - Creatinine	Mean change from baseline in chemistry parameters analysis - Creatinine.; Baseline value is defined as the last value or measurement taken prior to the first dose in the study	at Cycle 4 Day 1 and Cycle 7 Day 1
Secondary	Spleen Response Rate by Palpation	Spleen response rate by palpation is the percentage of participants with a spleen response according to the IWG-MRT 2013 at the end of Cycle 6 as compared to baseline. This will be calculated for participants that have an enlarged spleen (= 5 cm below LCM) at baseline. Participants with a missing spleen size assessment at the end of Cycle 6 including those who meet the criteria for progression of splenomegaly before the end of Cycle 6 will be considered not to be responders.	From First Dose to end of Cycle 6 (approximately 168 days)
Secondary	Symptom Response Rate	Symptom response rate (SRR) is defined as the percentage of participants with = 50% reduction from baseline to the end of Cycle 6 in total symptom score (TSS) measured by MFSAF version 4.0. The TSS will be defined as the sum of each of the 7 symptom scores. Participants without a baseline TSS > 0 will be considered non-evaluable (due to no place for symptom reduction) for the SRR analysis. Participants with a missing TSS at the end of Cycle 6 or who had disease progression before the end of the Cycle 6 will be considered non-responders.	From First Dose to end of Cycle 6 (approximately 168 days)
Secondary	Durability of Spleen Volume Response by MRI/CT (DR)	Durability of spleen volume response (DR) by MRI/CT 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. In the absence an event (ie, subsequent spleen volume reduction < 35% before the analysis is performed), the DR will be censored at the date of the last valid assessment performed before the analysis performed date. Durability of spleen volume response by MRI/CT scan will be analyzed using Kaplan-Meier method.	From First Dose to end of Cycle 6 (approximately 168 days)
Secondary	Durability of Spleen Response by Palpation (DRP)	Durability of spleen response by palpation (DRP) is defined as time from the date of first documented palpable spleen response, according to the IWG-MRT 2013 to the date of subsequent PD according to the IWG-MRT 2013 or death, whichever is earlier. Durability of spleen response by palpation according to the IWG-MRT 2013 criteria will be calculated for subjects that have an enlarged spleen at baseline (= 5 cm below LCM), and that have a spleen response by palpation. In the absence of an event (ie, no loss of spleen response by palpation) before the analysis is performed, the DRP will be censored at the date of the last valid assessment performed before the analysis performed date. Durability of spleen response by palpation will be analyzed using Kaplan-Meier (K-M) method.	From First Dose to end of Cycle 6 (approximately 168 days)
Secondary	Durability of Symptom Response (DSR)	Durability of symptoms response 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%. In the absence of TSS reduction < 50% before the analysis performed, the DSR will be censored at the date of the last valid assessment performed before the analysis performed date.	From First Dose to end of Cycle 6 (approximately 168 days)
Secondary	Number of Participants With Grade 3 or Higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy Including Wernicke's.	Number of participants with grade 3 or higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy including Wernicke's.	From first dose to end of treatment (an average of 50.3 weeks up to a maximum of 124 weeks)
Secondary	Number of Participants With Thiamine Levels < Lower Limit of Normal (LLN).	Number of participants with thiamine levels < LLN.; LLN of thiamine is 70 nmol/L.	At Screening, Cycle 1, 2, 3, 6, 9, 15, 18, 21, 24, 27, 30 and End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks)
Secondary	Number of Participants With Thiamine Levels > Upper Limit of Normal (ULN).	Number of participants with thiamine levels > ULN.; ULN of thiamine is 180 nmol/L.	At Screening, Cycle 1, 2, 3, 6, 9, 15, 18, 21, 24, 27, 30 and End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks)

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