A Phase 3 interventional study of FEDRATINIB in Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis and Myelofibrosis, sponsored by Celgene. Terminated at 35 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-12-12.
Sponsored by Celgene · Phase 3, Interventional, and Treatment
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.
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.
Main Study Inclusion Criteria
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)
Treatment with ruxolitinib for ≥ 28 days complicated by any of the following:
Exclusion Criteria:
Main Study Exclusion Criteria
Any of the following laboratory abnormalities:
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
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
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)
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.
Time frame: 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 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.
Time frame: From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks)
Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin
Mean change from baseline in hematology laboratory analysis - hemoglobin
Time frame: at Cycle 4 Day 1 and Cycle 7 Day 1
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
Time frame: at Cycle 4 Day 1 and Cycle 7 Day 1
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
Time frame: at Cycle 4 Day 1 and Cycle 7 Day 1
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
Time frame: at Cycle 4 Day 1 and Cycle 7 Day 1
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
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
Time frame: at Cycle 4 Day 1 and Cycle 7 Day 1
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.
Time frame: From First Dose to end of Cycle 6 (approximately 168 days)
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.
Time frame: From First Dose to end of Cycle 6 (approximately 168 days)
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)
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)
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)
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.
Time frame: From first dose to end of treatment (an average of 50.3 weeks up to a maximum of 124 weeks)
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.
Time frame: 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 > Upper Limit of Normal (ULN).
Number of participants with thiamine levels \> ULN. ULN of thiamine is 180 nmol/L.
Time frame: 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 Clinically Notable Laboratory Results, Grade 3 or 4
Number of participants with clinically notable laboratory results, Grade 3 or 4
Time frame: From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks)
| Milestone | Fedratimib |
|---|---|
| Started | 38 |
| Completed | 0 |
| Not completed | 38 |
| Withdrew: Lack of efficacy | 10 |
| Withdrew: Adverse event | 7 |
| Withdrew: Study terminated by sponsor | 5 |
| Withdrew: Death | 1 |
| Withdrew: Withdrawal by subject | 3 |
| Withdrew: Progressive disease | 4 |
| Withdrew: Bone marrow transplant | 4 |
| Withdrew: Physicians decision | 1 |
| Withdrew: Relapse | 1 |
| Withdrew: Withdrawal by investigator for non compliance | 1 |
| Withdrew: Withdrawal by pi | 1 |
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
| Percentage of participants | Fedratimib |
|---|---|
| Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6 | 25.7 (12.5 to 43.3) |
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.
| Participants | Fedratimib |
|---|---|
| All grade | 38 |
| Grade 3/4 | 30 |
Number of participants and severity of treatment related all grade adverse events (AEs) and grade 3/4 AEs as per NCI CTCAE.
| Participants | Fedratimib |
|---|---|
| All grade | 34 |
| Grade 3/4 | 13 |
Mean change from baseline in hematology laboratory analysis - hemoglobin
| g/dL | Fedratimib |
|---|---|
| cycle 4 day 1 | -1.16 ± 1.431 |
| cycle 7 day 1 | -1.13 ± 1.127 |
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
| 10¹²Cells/L | Fedratimib |
|---|---|
| cycle 4 day 1 | -0.60 ± 0.567 |
| cycle 7 day 1 | -0.67 ± 0.609 |
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
| 10⁹Cells/L | Fedratimib |
|---|---|
| Baseline Platelets | 0 ± 0 |
| cycle 4 day 1 - platelets | 13.8 ± 135.86 |
| cycle 7 day 1 - platelets | 11.7 ± 131.25 |
| cycle 4 day 1 - leukocytes | -15.481 ± 21.6350 |
| cycle 7 day 1 - leukocytes | -15.127 ± 18.5744 |
| cycle 4 day 1 - neutrophils | -10.064 ± 14.2661 |
| cycle 7 day 1 - neutrophils | -10.495 ± 13.5489 |
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
| Percentage of blasts/leukocytes | Fedratimib |
|---|---|
| cycle 4 day 1 | 0.0 ± 1.50 |
| cycle 7 day 1 | -0.2 ± 1.82 |
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
| U/L | Fedratimib |
|---|---|
| cycle 4 day 1 - ALT | 0.7 ± 18.49 |
| cycle 7 day 1 - ALT | 7.3 ± 29.53 |
| cycle 4 day 1 - AST | -0.9 ± 8.71 |
| cycle 7 day 1 - AST | 2.3 ± 11.83 |
| cycle 4 day 1 - Amylase | 15.1 ± 17.17 |
| cycle 7 day 1 - Amylase | 10.5 ± 15.19 |
| cycle 4 day 1 - Lipase | 11.6 ± 19.22 |
| cycle 7 day 1 - Lipase | 6.4 ± 13.60 |
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
| umol/L | Fedratimib |
|---|---|
| cycle 4 day 1 - Creatinine | 23.9 ± 18.82 |
| cycle 7 day 1 - Creatinine | 28.5 ± 23.03 |
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.
| Percentage of Participants | Fedratimib |
|---|---|
| Spleen Response Rate by Palpation | 16.2 (6.2 to 32.0) |
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.
| Percentage of participants | Fedratimib |
|---|---|
| Symptom Response Rate | 44.4 (27.9 to 61.9) |
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.
| Weeks | Fedratimib |
|---|---|
| Durability of Spleen Volume Response by MRI/CT (DR) | 115.1 (38.1 to NA) |
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.
| Weeks | Fedratimib |
|---|---|
| Durability of Spleen Response by Palpation (DRP) | 134.9 (33.3 to NA) |
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.
| Weeks | Fedratimib |
|---|---|
| Durability of Symptom Response (DSR) | 20.1 (11.0 to 48.0) |
Number of participants with grade 3 or higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy including Wernicke's.
| Participants | Fedratimib |
|---|---|
| Nausea | 0 |
| Vomitting | 0 |
| Diarrhea | 0 |
| Encephalopathy | 0 |
| Wernickes Encephalopathy | 0 |
Number of participants with thiamine levels \< LLN. LLN of thiamine is 70 nmol/L.
| Participants | Fedratimib |
|---|---|
| Cycle 1 | 0 |
| Cycle 2 | 2 |
| Cycle 3 | 2 |
| Cycle 6 | 0 |
| Cycle 9 | 0 |
| Cycle 12 | 0 |
| Cycle 15 | 0 |
| Cycle 18 | 0 |
| Cycle 21 | 0 |
| Cycle 24 | 0 |
| Cycle 27 | 0 |
| Cycle 30 | 0 |
| Cycle 33 | 0 |
| Cycle 36 | 0 |
| Cycle 39 | 0 |
| Cycle 42 | 0 |
| Cycle 45 | 0 |
| Cycle 48 | 0 |
| Cycle 51 | 0 |
| cycle 54 | 0 |
| End of Treatment | 1 |
| Total number of participants with thiamine <LLN | 5 |
Number of participants with thiamine levels \> ULN. ULN of thiamine is 180 nmol/L.
| Participants | Fedratimib |
|---|---|
| Cycle 1 | 21 |
| Cycle 2 | 9 |
| Cycle 3 | 9 |
| Cycle 6 | 6 |
| Cycle 9 | 5 |
| Cycle 12 | 4 |
| Cycle 15 | 7 |
| Cycle 18 | 4 |
| Cycle 21 | 4 |
| Cycle 24 | 3 |
| Cycle 27 | 2 |
| Cycle 30 | 2 |
| Cycle 33 | 2 |
| Cycle 36 | 0 |
| Cycle 39 | 2 |
| Cycle 42 | 1 |
| Cycle 45 | 1 |
| Cycle 48 | 3 |
| Cycle 51 | 1 |
| Cycle 54 | 0 |
| End of Treatment | 9 |
| Total number of participants with thiamine > ULN | 28 |
Number of participants with clinically notable laboratory results, Grade 3 or 4
| Participants | Fedratimib |
|---|---|
| GFR from Creatinine adjusted for BSA (mL/min/1.73m²) | 7 |
| Gamma Glytamyl Transferase (U/L) | 2 |
| Lipase (U/L) | 2 |
| Potassium (mmol/L) | 1 |
| Sodium (mmol/L) | 4 |
| Triglycerides (mmol/L) | 1 |
| Hemoglobin (g/dL) | 20 |
| Leukocytes (10⁹/L) | 5 |
| Lymphocytes (10⁹/L) | 7 |
| Neutrophils, Segmented (10⁹/L) | 4 |
| Neutrophils, Segmented and Band Form (10⁹/L) | 2 |
| Platelets (10⁹/L) | 10 |
| Prothrombin INR (ratio) | 1 |
Collected over 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.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Fedratinib | 16/38 (42.1%) | 22/38 (57.9%) | 38/38 (100%) |
| Event | Fedratinib |
|---|---|
| PneumoniaInfections and infestations | 4/38 |
| Cardiac failure congestiveCardiac disorders | 2/38 |
| Gastric haemorrhageGastrointestinal disorders | 2/38 |
| HyperkalaemiaMetabolism and nutrition disorders | 2/38 |
| Acute kidney injuryRenal and urinary disorders | 2/38 |
| AnaemiaBlood and lymphatic system disorders | 1/38 |
| NeutropeniaBlood and lymphatic system disorders | 1/38 |
| SplenomegalyBlood and lymphatic system disorders | 1/38 |
| Atrial fibrillationCardiac disorders | 1/38 |
| Atrioventricular block completeCardiac disorders | 1/38 |
| Event | Fedratinib |
|---|---|
| AnaemiaBlood and lymphatic system disorders | 23/38 |
| ConstipationGastrointestinal disorders | 19/38 |
| DiarrhoeaGastrointestinal disorders | 17/38 |
| NauseaGastrointestinal disorders | 16/38 |
| ThrombocytopeniaBlood and lymphatic system disorders | 15/38 |
| Blood creatinine increasedInvestigations | 14/38 |
| FatigueGeneral disorders | 12/38 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 12/38 |
| Oedema peripheralGeneral disorders | 10/38 |
| DizzinessNervous system disorders | 10/38 |
| Age, Continuous(Years) | Fedratimib |
|---|---|
| Mean | 68.4 ± 7.69 |
| Sex: Female, Male(Participants) | Fedratimib |
|---|---|
| Female | 16 |
| Male | 22 |
| Ethnicity (NIH/OMB)(Participants) | Fedratimib |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 37 |
| Unknown or Not Reported | 1 |
| Race (NIH/OMB)(Participants) | Fedratimib |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 5 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 1 |
| White | 30 |
| More than one race | 0 |
| Unknown or Not Reported | 2 |
| EE Population(Participants) | Fedratimib |
|---|---|
| Number | 35 |
| MFSAF Population(Participants) | Fedratimib |
|---|---|
| Number | 36 |
| Palpation evaluable population(Participants) | Fedratimib |
|---|---|
| Number | 37 |
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