NCT03755518: 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

Terminated Phase 3 Results posted Last updated 12 December 2024

What this trial tests

Phase 3 trial testing FEDRATINIB in Primary Myelofibrosis in 38 participants. Terminated before completion.

Timeline

27 March 2019

Primary endpoint
26 November 2021

8 November 2023

Quick facts

Lead sponsor	Celgene
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	38
Start date	27 March 2019
Primary completion	26 November 2021
Estimated completion	8 November 2023
Sites	35 locations across Canada, United States

Drugs / interventions tested

• FEDRATINIB (FEDRATINIB) — full drug profile →

Conditions studied

• Primary Myelofibrosis — all drugs for Primary Myelofibrosis →
• Post-Polycythemia Vera Myelofibrosis — all drugs for Post-Polycythemia Vera Myelofibrosis →
• Myelofibrosis — all drugs for Myelofibrosis →
• Post-essential Thrombocythemia Myelofibrosis — all drugs for Post-essential Thrombocythemia Myelofibrosis →

Sponsor

Celgene — full company profile →

Who can join

18 and older, any sex, with Primary Myelofibrosis or Post-Polycythemia Vera Myelofibrosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6 Primary · 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

Group	Value	95% CI
Fedratimib	25.7	12.5 – 43.3

Number of Participants of All Grade Adverse Events (AEs) and Grade 3/4 AEs Secondary · 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.

All grade

Group	Value	95% CI
Fedratimib	38

Grade 3/4

Group	Value	95% CI
Fedratimib	30

Number of Participants and Severity of Treatment Related All Grade Adverse Events (AEs) and Grade 3/4 AEs Secondary · 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.

All grade

Group	Value	95% CI
Fedratimib	34

Grade 3/4

Group	Value	95% CI
Fedratimib	13

Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin Secondary · at Cycle 4 Day 1 and Cycle 7 Day 1

Mean change from baseline in hematology laboratory analysis - hemoglobin

cycle 4 day 1

Group	Value	95% CI
Fedratimib	-1.16	± 1.431

cycle 7 day 1

Group	Value	95% CI
Fedratimib	-1.13	± 1.127

Mean Change From Baseline in Hematology Laboratory Analysis - Erythrocytes Secondary · 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

cycle 4 day 1

Group	Value	95% CI
Fedratimib	-0.60	± 0.567

cycle 7 day 1

Group	Value	95% CI
Fedratimib	-0.67	± 0.609

Mean Change From Baseline in Hematology Laboratory Analysis - Platelets, Leukocytes and Neutrophils Secondary · 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

Baseline Platelets

Group	Value	95% CI
Fedratimib	0	± 0

cycle 4 day 1 - platelets

Group	Value	95% CI
Fedratimib	13.8	± 135.86

cycle 7 day 1 - platelets

Group	Value	95% CI
Fedratimib	11.7	± 131.25

cycle 4 day 1 - leukocytes

Group	Value	95% CI
Fedratimib	-15.481	± 21.6350

cycle 7 day 1 - leukocytes

Group	Value	95% CI
Fedratimib	-15.127	± 18.5744

cycle 4 day 1 - neutrophils

Group	Value	95% CI
Fedratimib	-10.064	± 14.2661

cycle 7 day 1 - neutrophils

Group	Value	95% CI
Fedratimib	-10.495	± 13.5489

Mean Change From Baseline in the Percentage of Blasts/Leukocytes in Hematology Laboratory Analysis Secondary · 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

cycle 4 day 1

Group	Value	95% CI
Fedratimib	0.0	± 1.50

cycle 7 day 1

Group	Value	95% CI
Fedratimib	-0.2	± 1.82

Mean Change From Baseline in Chemistry Parameters Analysis - ALT, AST, Amylase, Lipase Secondary · 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

cycle 4 day 1 - ALT

Group	Value	95% CI
Fedratimib	0.7	± 18.49

cycle 7 day 1 - ALT

Group	Value	95% CI
Fedratimib	7.3	± 29.53

cycle 4 day 1 - AST

Group	Value	95% CI
Fedratimib	-0.9	± 8.71

cycle 7 day 1 - AST

Group	Value	95% CI
Fedratimib	2.3	± 11.83

cycle 4 day 1 - Amylase

Group	Value	95% CI
Fedratimib	15.1	± 17.17

cycle 7 day 1 - Amylase

Group	Value	95% CI
Fedratimib	10.5	± 15.19

cycle 4 day 1 - Lipase

Group	Value	95% CI
Fedratimib	11.6	± 19.22

cycle 7 day 1 - Lipase

Group	Value	95% CI
Fedratimib	6.4	± 13.60

Mean Change From Baseline in Chemistry Parameters Analysis - Creatinine Secondary · 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

cycle 4 day 1 - Creatinine

Group	Value	95% CI
Fedratimib	23.9	± 18.82

cycle 7 day 1 - Creatinine

Group	Value	95% CI
Fedratimib	28.5	± 23.03

Spleen Response Rate by Palpation Secondary · 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.

Group	Value	95% CI
Fedratimib	16.2	6.2 – 32.0

Symptom Response Rate Secondary · 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.

Group	Value	95% CI
Fedratimib	44.4	27.9 – 61.9

Durability of Spleen Volume Response by MRI/CT (DR) Secondary · 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.

Group	Value	95% CI
Fedratimib	115.1	38.1 – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events: From first dose up to 30 days post last dose. (An average of 50.3 weeks up to a maximum of 124 weeks) All-Cause Mortality: From first dose up to LPLV PE final Database lock: approximately 56 Months.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Fedratinib

Serious: 22/38 (58%)

Deaths: 16/38

Serious adverse events (36 terms)

Reaction	System	Fedratinib
Pneumonia	Infections and infestations	—
Cardiac failure congestive	Cardiac disorders	—
Gastric haemorrhage	Gastrointestinal disorders	—
Hyperkalaemia	Metabolism and nutrition disorders	—
Acute kidney injury	Renal and urinary disorders	—
Anaemia	Blood and lymphatic system disorders	—
Neutropenia	Blood and lymphatic system disorders	—
Splenomegaly	Blood and lymphatic system disorders	—
Atrial fibrillation	Cardiac disorders	—
Atrioventricular block complete	Cardiac disorders	—
Cardiac tamponade	Cardiac disorders	—
Myocardial ischaemia	Cardiac disorders	—
Pericardial effusion	Cardiac disorders	—
Abdominal pain	Gastrointestinal disorders	—
Abdominal pain upper	Gastrointestinal disorders	—
Anal haemorrhage	Gastrointestinal disorders	—
Ascites	Gastrointestinal disorders	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	—
Hepatic failure	Hepatobiliary disorders	—
Humerus fracture	Injury, poisoning and procedural complications	—
Blood creatinine increased	Investigations	—
Hyponatraemia	Metabolism and nutrition disorders	—
Back pain	Musculoskeletal and connective tissue disorders	—
Muscular weakness	Musculoskeletal and connective tissue disorders	—

Other adverse events (105 terms — click to expand)

Reaction	System	Fedratinib
Anaemia	Blood and lymphatic system disorders	—
Constipation	Gastrointestinal disorders	—
Diarrhoea	Gastrointestinal disorders	—
Nausea	Gastrointestinal disorders	—
Thrombocytopenia	Blood and lymphatic system disorders	—
Blood creatinine increased	Investigations	—
Fatigue	General disorders	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—
Oedema peripheral	General disorders	—
Dizziness	Nervous system disorders	—
Cough	Respiratory, thoracic and mediastinal disorders	—
Pruritus	Skin and subcutaneous tissue disorders	—
Vomiting	Gastrointestinal disorders	—
Decreased appetite	Metabolism and nutrition disorders	—
Insomnia	Psychiatric disorders	—
Contusion	Injury, poisoning and procedural complications	—
Vitamin B1 decreased	Investigations	—
Hyperuricaemia	Metabolism and nutrition disorders	—
Arthralgia	Musculoskeletal and connective tissue disorders	—
Hyperkalaemia	Metabolism and nutrition disorders	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—
Peripheral sensory neuropathy	Nervous system disorders	—
Upper respiratory tract infection	Infections and infestations	—
Fall	Injury, poisoning and procedural complications	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—
Leukocytosis	Blood and lymphatic system disorders	—
Neutropenia	Blood and lymphatic system disorders	—
Abdominal pain	Gastrointestinal disorders	—
Chills	General disorders	—
Peripheral swelling	General disorders	—
Pyrexia	General disorders	—
Skin laceration	Injury, poisoning and procedural complications	—
Glomerular filtration rate decreased	Investigations	—
Hyponatraemia	Metabolism and nutrition disorders	—
Back pain	Musculoskeletal and connective tissue disorders	—
Bone pain	Musculoskeletal and connective tissue disorders	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—
Muscular weakness	Musculoskeletal and connective tissue disorders	—
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	—
Headache	Nervous system disorders	—

Most-reported serious reactions: Pneumonia, Cardiac failure congestive, Gastric haemorrhage, Hyperkalaemia, Acute kidney injury, Anaemia, Neutropenia, Splenomegaly.

Data from ClinicalTrials.gov NCT03755518 adverse events section.

Sponsor's own 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 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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting TGF-β signal transduction for fibrosis and cancer therapy.
   Peng D, Fu M, Wang M, Wei Y, et al · · 2022 · cited 752× · PMID 35461253 · DOI 10.1186/s12943-022-01569-x
2. Targeting fibrosis, mechanisms and cilinical trials.
   Zhao M, Wang L, Wang M, Zhou S, et al · · 2022 · cited 352× · PMID 35773269 · DOI 10.1038/s41392-022-01070-3
3. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis.
   Talpaz M, Kiladjian JJ. · · 2021 · cited 140× · PMID 32647323 · DOI 10.1038/s41375-020-0954-2
4. Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure.
   Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, et al · · 2020 · cited 106× · PMID 32129512 · DOI 10.1002/ajh.25777
5. STAT proteins: a kaleidoscope of canonical and non-canonical functions in immunity and cancer.
   Awasthi N, Liongue C, Ward AC. · · 2021 · cited 97× · PMID 34809691 · DOI 10.1186/s13045-021-01214-y
6. JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition.
   Luo Y, Alexander M, Gadina M, O'Shea JJ, et al · · 2021 · cited 92× · PMID 34625141 · DOI 10.1016/j.jaci.2021.08.004
7. Myelofibrosis.
   Passamonti F, Mora B. · · 2023 · cited 82× · PMID 36416738 · DOI 10.1182/blood.2022017423
8. Management of myelofibrosis after ruxolitinib failure.
   Harrison CN, Schaap N, Mesa RA. · · 2020 · cited 70× · PMID 32198525 · DOI 10.1007/s00277-020-04002-9