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

Phase 3

Terminated

• Conditions: Primary Myelofibrosis; Post-Polycythemia Vera Myelofibrosis; Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis
• Interventions: Drug: FEDRATINIB

• Registration Number: NCT03755518
• Lead Sponsor: Celgene

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.

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 Timeline

• Study First Submitted: 2018-11-08
• Study First Submitted QC: 2018-11-26
• Study First Posted: 2018-11-28
• Study Start: 2019-03-27
• Primary Completion: 2021-11-26
• Results First Submitted: 2022-11-22
• Results First Submitted QC: 2023-02-13
• Results First Posted: 2023-03-09
• Study Completion: 2023-11-08
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-11
• Last Update Posted: 2024-12-12

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 38

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Administration of Fedratinib 400mg/day	FEDRATINIB	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6	From First Dose to end of Cycle 6 (approximately 168 days)	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

Secondary Outcome Measures

Name	Time	Method
Number of Participants of All Grade Adverse Events (AEs) and Grade 3/4 AEs	From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 128 weeks)	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.
Number of Participants and Severity of Treatment Related All Grade Adverse Events (AEs) and Grade 3/4 AEs	From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks)	Number of participants and severity of treatment related all grade adverse events (AEs) and grade 3/4 AEs as per NCI CTCAE.
Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin	at Cycle 4 Day 1 and Cycle 7 Day 1	Mean change from baseline in hematology laboratory analysis - hemoglobin
Mean Change From Baseline in Hematology Laboratory Analysis - Erythrocytes	at Cycle 4 Day 1 and Cycle 7 Day 1	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
Mean Change From Baseline in Hematology Laboratory Analysis - Platelets, Leukocytes and Neutrophils	at Cycle 4 Day 1 and Cycle 7 Day 1	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
Mean Change From Baseline in the Percentage of Blasts/Leukocytes in Hematology Laboratory Analysis	at Cycle 4 Day 1 and Cycle 7 Day 1	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
Mean Change From Baseline in Chemistry Parameters Analysis - ALT, AST, Amylase, Lipase	at Cycle 4 Day 1 and Cycle 7 Day 1	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
Mean Change From Baseline in Chemistry Parameters Analysis - Creatinine	at Cycle 4 Day 1 and Cycle 7 Day 1	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
Spleen Response Rate by Palpation	From First Dose to end of Cycle 6 (approximately 168 days)	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.
Symptom Response Rate	From First Dose to end of Cycle 6 (approximately 168 days)	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.
Durability of Spleen Volume Response by MRI/CT (DR)	From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 59.40 Weeks)	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.
Durability of Spleen Response by Palpation (DRP)	From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 59.32 Weeks)	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.
Durability of Symptom Response (DSR)	From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 31.33 Weeks)	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.
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)	Number of participants with grade 3 or higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy including Wernicke's.
Number of Participants With Thiamine Levels > Upper Limit of Normal (ULN).	At Cycle 1, 2, 3, and every 3 cycles afterwards till End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks)	Number of participants with thiamine levels \> ULN.; ULN of thiamine is 180 nmol/L.
Number of Participants With Thiamine Levels < Lower Limit of Normal (LLN).	At Cycle 1, 2, 3, and every 3 cycles afterwards till End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks)	Number of participants with thiamine levels \< LLN.; LLN of thiamine is 70 nmol/L.
Number of Participants With Clinically Notable Laboratory Results, Grade 3 or 4	From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks)	Number of participants with clinically notable laboratory results, Grade 3 or 4

Trial Locations

Locations (35)

Local Institution - 117; 🇺🇸 Aurora, Colorado, United States

Local Institution - 126; 🇺🇸 Miami, Florida, United States

Local Institution - 113; 🇺🇸 Augusta, Georgia, United States

Local Institution - 112; 🇺🇸 Chicago, Illinois, United States

Local Institution - 109; 🇺🇸 Chicago, Illinois, United States

Local Institution - 121; 🇺🇸 Park Ridge, Illinois, United States

Local Institution - 100; 🇺🇸 Kansas City, Kansas, United States

Local Institution - 123; 🇺🇸 Baltimore, Maryland, United States

Local Institution - 118; 🇺🇸 Bethesda, Maryland, United States

Local Institution - 127; 🇺🇸 Columbia, Maryland, United States

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