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

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

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03755518

Acronym

FREEDOM

Enrollment

Registered

2018-11-28

Start date

2019-03-27

Completion date

2023-11-08

Last updated

2024-12-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis

Keywords

Myelofibrosis (MF), Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV), Post-essential thrombocythemia Myelofibrosis (Post-ET), Myeloproliferative neoplasms (MPN)

Brief summary

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.

Interventions

DRUGFEDRATINIB

A potent and selective inhibitor of JAK2 kinase activity

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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 < 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 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 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
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.

Countries

Canada, United States

Participant flow

Participants by arm

Arm	Count
Fedratimib 400 mg/day PO (4 x 100 mg capsules)	38
Total	38

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	7
Overall Study	Bone Marrow Transplant	4
Overall Study	Death	1
Overall Study	Lack of Efficacy	10
Overall Study	Physicians Decision	1
Overall Study	Progressive Disease	4
Overall Study	Relapse	1
Overall Study	Study Terminated by Sponsor	5
Overall Study	Withdrawal by Investigator for Non Compliance	1
Overall Study	Withdrawal by PI	1
Overall Study	Withdrawal by Subject	3

Baseline characteristics

Characteristic	Fedratimib
Age, Continuous	68.4 Years STANDARD_DEVIATION 7.69
EE Population	35 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	37 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants
MFSAF Population	36 Participants
Palpation evaluable population	37 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	5 Participants
Race (NIH/OMB) Black or African American	1 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants
Race (NIH/OMB) White	30 Participants
Sex: Female, Male Female	16 Participants
Sex: Female, Male Male	22 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	16 / 38
other Total, other adverse events	38 / 38
serious Total, serious adverse events	22 / 38

Outcome results

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

Time frame: From First Dose to end of Cycle 6 (approximately 168 days)

Population: Efficacy evaluable population

Arm	Measure	Value (NUMBER)
Fedratimib	Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6	25.7 Percentage of participants

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.

Time frame: From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 59.32 Weeks)

Population: Palpation Evaluable Population, responders only

Arm	Measure	Value (MEDIAN)
Fedratimib	Durability of Spleen Response by Palpation (DRP)	134.9 Weeks

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.

Time frame: From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 59.40 Weeks)

Population: EE population, Responders only

Arm	Measure	Value (MEDIAN)
Fedratimib	Durability of Spleen Volume Response by MRI/CT (DR)	115.1 Weeks

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.

Time frame: From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 31.33 Weeks)

Population: MFSAF population, Responders only

Arm	Measure	Value (MEDIAN)
Fedratimib	Durability of Symptom Response (DSR)	20.1 Weeks

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

Time frame: at Cycle 4 Day 1 and Cycle 7 Day 1