Primary Myelofibrosis, Post-Polycythemia Vera, Myelofibrosis
Conditions
Keywords
MF, myeloproliferative neoplasms, MPN, myelofibrosis, PMF, post-PV, Post-Polycythemia Vera, post-ET MF, Post-Essential Thrombocythemia Myelofibrosis
Brief summary
A Phase 3, multicenter, open-label, randomized study to evaluate the efficacy and safety of fedratinib compared to best available therapy (BAT) 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 35% spleen volume reduction in the fedratinib and the BAT arms.
Detailed description
This Phase 3, multicenter, randomized, two-arm, open-label study will include subjects with intermediate or high-risk (as per the DIPSS score) primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF). This study will be conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCPs). Study design includes: * A 28-day Screening Period * 2:1 Randomization to fedratinib or best available therapy (BAT) * Stratification at Randomization according to: * Spleen size by palpation: \< 15 cm below left costal margin (LCM) versus ≥ 15 cm below LCM * Platelets ≥ 50 to \< 100 x 109/L versus platelets ≥ 100 x 109/L * Refractory or relapsed to ruxolitinib treatment versus intolerant to ruxolitinib treatment * Study Treatment Period (time on study drug plus 30 days after last dose) * Subjects are allowed to crossover from BAT to the fedratinib arm after the Cycle 6 response assessment or before the Cycle 6 response assessment in the event of a confirmed progression of splenomegaly by MRI/CT scan * A Survival Follow-up Period for progression and survival
Interventions
DRUGFEDRATINIB
A potent and selective inhibitor of JAK2 kinase activity
Best available therapy (BAT)
Sponsors
Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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-2 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 and by palpable spleen measuring ≥ 5 cm below the left costal margin 6. Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) 7. Subject has been previously exposed to ruxolitinib, and must meet at least one of the following criteria (a and/or b) 1. Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response (refractory) defined as \< 10% spleen volume reduction by MRI or \< 30% decrease from baseline in spleen size by palpation or regrowth (relapsed) to these parameters following an initial response 2. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following (intolerant): * 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 8. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to randomization 9. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted 10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements 11. A female of childbearing potential (FCBP) must: 1. Have 2 negative pregnancy tests as verified by the Investigator during screening prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact. 2. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use and be able to comply with highly effective contraception without interruption, -14 days prior to starting investigational product, during the study treatment (including dose interruptions), and for 30 days after discontinuation of study treatment. Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). 12. A male subject must: Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 30 days following investigational product discontinuation, or longer if required for each compound and/or by local regulations, even if he has undergone a successful vasectomy
Exclusion criteria
1. Any of the following laboratory abnormalities: 1. Platelets \< 50 x 109/L 2. Absolute neutrophil count (ANC) \< 1.0 x 109/L 3. White blood count (WBC) \> 100 x 109/L 4. Myeloblasts ≥ 5 % in peripheral blood 5. Estimated glomerular filtration rate \< 30 mL/min/1.73 m2 (as per the Modification of Diet in Renal Disease \[MDRD\] formula) 6. Serum amylase or lipase \> 1.5 x upper limit of normal (ULN) 7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 x upper limit of normal (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 (WE) 6. Subject with signs or symptoms of encephalopathy, including WE (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 the central laboratory and not demonstrated to be corrected prior to randomization 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 randomization 10. Subject has received ruxolitinib within 14 days prior to randomization 11. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment 12. Subject on treatment with aspirin with doses \> 150 mg daily 13. Subject with major surgery within 28 days prior to randomization 14. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis) 15. 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 randomization. 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 16. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4) 17. Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC) 18. Subject with serious active infection 19. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication 20. Subject is unable to swallow capsule 21. Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study 22. 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 23. Subject has any condition that confounds the ability to interpret data from the study 24. Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization 25. Subject with a life expectancy of less than 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Spleen Volume Response Rate (RR) | From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days | Percentage of participants who have ≥ 35% spleen volume reduction (SVR) at end of cycle 6 A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment). The RRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in RRs and 95% confidence interval of the difference for fedratinib to BAT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Spleen Volume Response Rate (RR25) | From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days | Percentage of participants who have ≥ 25% spleen volume reduction (SVR) at end of cycle 6 A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment). The RRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in RRs and 95% confidence interval of the difference for fedratinib to BAT. |
| Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs | From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days | Number of participants with all grade adverse events (AEs) and grade 3 to 4 AEs |
| Number of Participants With Hematology Laboratory Abnormalities | From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days | Number of participants with hematology laboratory abnormalities in the following parameters: hemoglobin (decreased), leukocytes (increase and decrease), lymphocytes (decreased), neutrophils (segmented and band form decreased), Platelets (decreased). |
| Spleen Response Rate by Palpation (RRP) | From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days | Spleen response rate by palpation is the percentage of participants at the end of cycle 6 with a spleen response according to the IWG-MRT 2013 criteria. A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable\*\* or A baseline splenomegaly that is palpable at \> 10 cm, below the LCM, decreases by ≥ 50%\*\* Participants with a missing spleen size assessment at the end of cycle 6 including those who meet the criteria for progression of splenomegaly before end of cycle 6 will be considered not to be responders. |
| Durability of Spleen Volume Response (DR) | From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks. | Durability of spleen volume response (DR) by MRI/CT is defined as the date from the first documented spleen response (ie, ≥ 35% reduction in spleen volume) to the date of subsequent progressive disease (PD) in spleen volume per the IWG-MRT 2013 criteria or death, whichever is earlier. In the absence of an event 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 Response by Palpation (DRP) | From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks. | Durability of spleen response by palpation (DRP) is defined as time from the date of the first documented palpable spleen response, according to the IWG-MRT 2013 to the date of the subsequent PD in spleen size 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 before the analysis is performed, the DRP will be censored at the date of the last valid assessment performed before the analysis performed date. |
| Symptom Response Rate (SRR) | From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days | Percentage of participants with ≥ 50% reduction in total symptom scores measured by Myelofibrosis Symptom Assessment Form (MFSAF) 4.0 at end of cycle 6. Subjects 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. MFSAF measures the sum of 7 symptoms on a scale from 0 to 10 (0 being absent and 10 being the worst imagineable). The lower the score the better. A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment). The SRRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in SRRs and 95% confidence interval of the difference for fedratinib to BAT. |
| Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days | Number of participants with a CTCAE Grade ≥3 of nausea, diarrhea, or vomiting and any grade wernickes encephalopathy. |
| Number of Participants With Thiamine Levels Below the Lower Limit of Normal | From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days | Number of participants with thiamine levels below the lower limit of normal |
| Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | from the start of cycle 1 to cycle 7 day 1 approximately 170 days. | QLQ-C30 - The EORTC QLQ-C30 was developed to assess the quality of life of cancer patients. It consists of 30 items classified into 15 domains including 5 functional subscales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning); 3 multi-item symptom subscales (fatigue, nausea/vomiting, and pain); a global QOL subscale; and 6 single items addressing various symptoms and perceived financial impact. Scores vary from 0 (worst) to 100 (best) for the functional dimensions and GHS, and from 0 (best) to 100 (worst) for the symptom dimensions. |
| Mean Change From Baseline in EQ-5D-5L Utility Index Score | from the start of cycle 1 to cycle 7 day 1 approximately 170 days. | EQ-5D-5L - The EQ-5D-5L is a generic, self-administered preference-based measure of health. The five dimensions covered by the EQ-5D-5L include mobility, self-care, pain, usual activities, and anxiety/depression and is converted into a single summary index that can range from -0.594 to 1.0, with a score of 0 indicating death, 1.00 indicating full health, and negative scores reflecting states perceived to be worse than death. Respondent's self-rated health on a vertical, 0 to 100 scale where 100 = Best imaginable health state and 0 = Worst imaginable health state |
| Time to Spleen and Disease Progression Free Survival (SDPFS) | From randomization to the End of Survival Follow-up | Time from randomization to death due to any reason or disease progression (modified IWG-MRT 2013 including ≥ 25% increase in spleen volume by MRI/CT). |
| Overall Survival | From Randomization to the end of Survival Follow Up | Time from randomization to death due to any reason |
| Durability of Symptoms Response (DSR) | From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks. | The DSR 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. |
Countries
Australia, Austria, Belgium, China, Czechia, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Russia, South Korea, Spain, United Kingdom
Participant flow
Pre-assignment details
201 participants randomized and treated
Participants by arm
| Arm | Count |
|---|---|
| Fedratinib Fedratinib 400mg/Day PO(4x100mg capsules) | 134 |
| Best Available Therapy (BAT) Best available therapy regimen (BAT) may include any Investigator-selected treatment and is not limited to approved JAK inhibitors (used according to the prescribing information), chemotherapy (eg, hydroxyurea), anagrelide, corticosteroid, hematopoietic growth factor, immunomodulating agent, androgens, interferon, and may also include no treatment and symptom directed treatment. BAT may not include investigational agents, fedratinib (if approved during the course of the study) and hematopoietic stem cell transplantation. | 67 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 22 | 8 |
| Overall Study | Death | 13 | 6 |
| Overall Study | Lack of Efficacy | 12 | 2 |
| Overall Study | Other Reasons | 12 | 4 |
| Overall Study | Physician Decision | 9 | 3 |
| Overall Study | Progressive Disease | 6 | 4 |
| Overall Study | Withdrawal by Participant | 17 | 12 |
Baseline characteristics
| Characteristic | Best Available Therapy (BAT) | Total | Fedratinib |
|---|---|---|---|
| Age, Continuous | 67.6 Years STANDARD_DEVIATION 8.16 | 68.4 Years STANDARD_DEVIATION 8.58 | 68.7 Years STANDARD_DEVIATION 8.79 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 11 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 163 Participants | 106 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 27 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 14 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 22 Participants | 19 Participants |
| Race (NIH/OMB) White | 58 Participants | 164 Participants | 106 Participants |
| Sex: Female, Male Female | 37 Participants | 96 Participants | 59 Participants |
| Sex: Female, Male Male | 30 Participants | 105 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 43 / 134 | 7 / 67 | 11 / 46 |
| other Total, other adverse events | 128 / 134 | 57 / 67 | 45 / 46 |
| serious Total, serious adverse events | 72 / 134 | 21 / 67 | 16 / 46 |
Outcome results
Primary
Spleen Volume Response Rate (RR)
Percentage of participants who have ≥ 35% spleen volume reduction (SVR) at end of cycle 6 A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment). The RRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in RRs and 95% confidence interval of the difference for fedratinib to BAT.
Time frame: From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Population: Intent to Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fedratinib | Spleen Volume Response Rate (RR) | 35.8 Percentage of Participants |
| Best Available Therapy (BAT) | Spleen Volume Response Rate (RR) | 6.0 Percentage of Participants |
Comparison: Stratified analysis (based on CRF)p-value: <0.000195% CI: [19.9, 39.4]Cochran-Mantel-Haenszel
Secondary
Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy
Number of participants with a CTCAE Grade ≥3 of nausea, diarrhea, or vomiting and any grade wernickes encephalopathy.
Time frame: From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fedratinib | Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | ≥3 grade Diarrhea | 2 Participants |
| Fedratinib | Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | ≥3 grade Nausea | 1 Participants |
| Fedratinib | Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | ≥3 grade Vomitting | 0 Participants |
| Fedratinib | Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | Any Grade Wernickes Encephalopathy | 1 Participants |
| Best Available Therapy (BAT) | Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | Any Grade Wernickes Encephalopathy | 0 Participants |
| Best Available Therapy (BAT) | Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | ≥3 grade Diarrhea | 0 Participants |
| Best Available Therapy (BAT) | Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | ≥3 grade Vomitting | 0 Participants |
| Best Available Therapy (BAT) | Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy | ≥3 grade Nausea | 0 Participants |
Secondary
Durability of Spleen Response by Palpation (DRP)
Durability of spleen response by palpation (DRP) is defined as time from the date of the first documented palpable spleen response, according to the IWG-MRT 2013 to the date of the subsequent PD in spleen size 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 before the analysis is performed, the DRP will be censored at the date of the last valid assessment performed before the analysis performed date.
Time frame: From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Population: Participants with spleen response by palpation at any time
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fedratinib | Durability of Spleen Response by Palpation (DRP) | 118.3 Weeks |
| Best Available Therapy (BAT) | Durability of Spleen Response by Palpation (DRP) | 47.1 Weeks |
Secondary
Durability of Spleen Volume Response (DR)
Durability of spleen volume response (DR) by MRI/CT is defined as the date from the first documented spleen response (ie, ≥ 35% reduction in spleen volume) to the date of subsequent progressive disease (PD) in spleen volume per the IWG-MRT 2013 criteria or death, whichever is earlier. In the absence of an event before the analysis is performed, the DR will be censored at the date of the last valid assessment performed before the analysis performed date.
Time frame: From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Population: Participants with spleen volume response at any time
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fedratinib | Durability of Spleen Volume Response (DR) | 86.3 Weeks |
| Best Available Therapy (BAT) | Durability of Spleen Volume Response (DR) | NA Weeks |
Secondary
Durability of Symptoms Response (DSR)
The DSR 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 baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Population: Participants with a symptom response at any time
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fedratinib | Durability of Symptoms Response (DSR) | 12.1 Weeks |
| Best Available Therapy (BAT) | Durability of Symptoms Response (DSR) | 10.1 Weeks |
Secondary
Mean Change From Baseline in EQ-5D-5L Utility Index Score
EQ-5D-5L - The EQ-5D-5L is a generic, self-administered preference-based measure of health. The five dimensions covered by the EQ-5D-5L include mobility, self-care, pain, usual activities, and anxiety/depression and is converted into a single summary index that can range from -0.594 to 1.0, with a score of 0 indicating death, 1.00 indicating full health, and negative scores reflecting states perceived to be worse than death. Respondent's self-rated health on a vertical, 0 to 100 scale where 100 = Best imaginable health state and 0 = Worst imaginable health state
Time frame: from the start of cycle 1 to cycle 7 day 1 approximately 170 days.
Population: EQ-5D-5L evaluable population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fedratinib | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C2D1 | 0.1086 Scores on a Scale | Standard Deviation 0.20188 |
| Fedratinib | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C3D1 | 0.1093 Scores on a Scale | Standard Deviation 0.2395 |
| Fedratinib | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C4D1 | 0.1214 Scores on a Scale | Standard Deviation 0.20634 |
| Fedratinib | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C5D1 | 0.1068 Scores on a Scale | Standard Deviation 0.21395 |
| Fedratinib | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C6D1 | 0.0594 Scores on a Scale | Standard Deviation 0.26864 |
| Fedratinib | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C7D1 | 0.0853 Scores on a Scale | Standard Deviation 0.24019 |
| Best Available Therapy (BAT) | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C6D1 | 0.0658 Scores on a Scale | Standard Deviation 0.24229 |
| Best Available Therapy (BAT) | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C2D1 | 0.0705 Scores on a Scale | Standard Deviation 0.22881 |
| Best Available Therapy (BAT) | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C5D1 | 0.0321 Scores on a Scale | Standard Deviation 0.23607 |
| Best Available Therapy (BAT) | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C3D1 | 0.1142 Scores on a Scale | Standard Deviation 0.26247 |
| Best Available Therapy (BAT) | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C7D1 | 0.1066 Scores on a Scale | Standard Deviation 0.25848 |
| Best Available Therapy (BAT) | Mean Change From Baseline in EQ-5D-5L Utility Index Score | C4D1 | 0.0366 Scores on a Scale | Standard Deviation 0.2647 |
Secondary
Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline
QLQ-C30 - The EORTC QLQ-C30 was developed to assess the quality of life of cancer patients. It consists of 30 items classified into 15 domains including 5 functional subscales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning); 3 multi-item symptom subscales (fatigue, nausea/vomiting, and pain); a global QOL subscale; and 6 single items addressing various symptoms and perceived financial impact. Scores vary from 0 (worst) to 100 (best) for the functional dimensions and GHS, and from 0 (best) to 100 (worst) for the symptom dimensions.
Time frame: from the start of cycle 1 to cycle 7 day 1 approximately 170 days.
Population: EORTC QOL-C30 evaluable population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Nausea and Vomitting | -1.7 Scores on a Scale | Standard Deviation 15.32 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Global Heath Status | 10.3 Scores on a Scale | Standard Deviation 27.42 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Cognitivie Functioning | 1.7 Scores on a Scale | Standard Deviation 19.83 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Physical Functioning | 8.2 Scores on a Scale | Standard Deviation 19.57 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Pain | -12.9 Scores on a Scale | Standard Deviation 25.88 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Role Functioning | 8.1 Scores on a Scale | Standard Deviation 34.26 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Fatigue | -15.2 Scores on a Scale | Standard Deviation 29.34 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Appetite Loss | -19.5 Scores on a Scale | Standard Deviation 32.84 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Dyspnea | -9.0 Scores on a Scale | Standard Deviation 31.04 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Constipation | -0.5 Scores on a Scale | Standard Deviation 31.34 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Social Functioning | 6.5 Scores on a Scale | Standard Deviation 29.18 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Diarrhea | 5.3 Scores on a Scale | Standard Deviation 27.19 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Insomnia | -11.4 Scores on a Scale | Standard Deviation 30.5 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Financial Difficulties | 3.9 Scores on a Scale | Standard Deviation 21.03 |
| Fedratinib | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Emotional Functioning | 7.0 Scores on a Scale | Standard Deviation 19.63 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Financial Difficulties | 1.6 Scores on a Scale | Standard Deviation 12.81 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Emotional Functioning | 5.6 Scores on a Scale | Standard Deviation 25.86 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Cognitivie Functioning | 5.6 Scores on a Scale | Standard Deviation 17.74 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Social Functioning | 0.0 Scores on a Scale | Standard Deviation 27.89 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Fatigue | -16.4 Scores on a Scale | Standard Deviation 33.81 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Nausea and Vomitting | -9.5 Scores on a Scale | Standard Deviation 28.17 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Pain | -9.5 Scores on a Scale | Standard Deviation 33.57 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Dyspnea | -22.2 Scores on a Scale | Standard Deviation 35.49 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Insomnia | -7.9 Scores on a Scale | Standard Deviation 25.61 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Global Heath Status | 13.1 Scores on a Scale | Standard Deviation 26.16 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Physical Functioning | 11.1 Scores on a Scale | Standard Deviation 26.61 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Role Functioning | 12.7 Scores on a Scale | Standard Deviation 40.79 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Appetite Loss | -20.6 Scores on a Scale | Standard Deviation 35.71 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Constipation | -9.5 Scores on a Scale | Standard Deviation 35.19 |
| Best Available Therapy (BAT) | Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline | Diarrhea | 6.3 Scores on a Scale | Standard Deviation 17.06 |
Secondary
Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs
Number of participants with all grade adverse events (AEs) and grade 3 to 4 AEs
Time frame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fedratinib | Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs | All Grade AEs | 132 Participants |
| Fedratinib | Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs | Grade 3 and 4 AEs | 88 Participants |
| Best Available Therapy (BAT) | Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs | All Grade AEs | 65 Participants |
| Best Available Therapy (BAT) | Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs | Grade 3 and 4 AEs | 29 Participants |
Secondary
Number of Participants With Hematology Laboratory Abnormalities
Number of participants with hematology laboratory abnormalities in the following parameters: hemoglobin (decreased), leukocytes (increase and decrease), lymphocytes (decreased), neutrophils (segmented and band form decreased), Platelets (decreased).
Time frame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Neutrophils, segmented and band from decreased All Grades | 34 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Platelets Decreased Grade 4 | 3 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Lymphocytes Decreased Grade 3 | 20 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Hemoglobin Decreased All Grades | 129 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Neutrophils, segmented and band from decreased Grade 3 | 11 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Hemoglobin Decreased Grade 3 | 62 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Lymphocytes Decreased All Grades | 49 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Hemoglobin Decreased Grade 4 | 0 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Neutrophils, segmented and band from decreased Grade 4 | 0 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Decreased All Grades | 41 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Lymphocytes Decreased Grade 4 | 1 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Decreased Grade 3 | 8 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Platelets Decreased All Grades | 73 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Decreased Grade 4 | 1 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Increased Grade 4 | 0 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Increased All Grades | 4 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Platelets Decreased Grade 3 | 24 Participants |
| Fedratinib | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Increased Grade 3 | 4 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Platelets Decreased Grade 3 | 10 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Increased Grade 4 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Lymphocytes Decreased All Grades | 20 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Lymphocytes Decreased Grade 3 | 7 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Lymphocytes Decreased Grade 4 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Neutrophils, segmented and band from decreased All Grades | 15 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Neutrophils, segmented and band from decreased Grade 3 | 4 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Neutrophils, segmented and band from decreased Grade 4 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Platelets Decreased All Grades | 43 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Increased Grade 3 | 4 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Platelets Decreased Grade 4 | 2 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Hemoglobin Decreased All Grades | 64 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Hemoglobin Decreased Grade 3 | 20 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Hemoglobin Decreased Grade 4 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Decreased All Grades | 19 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Decreased Grade 3 | 3 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Decreased Grade 4 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Hematology Laboratory Abnormalities | Leukocytes Increased All Grades | 4 Participants |
Secondary
Number of Participants With Thiamine Levels Below the Lower Limit of Normal
Number of participants with thiamine levels below the lower limit of normal
Time frame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fedratinib | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 1 | 3 Participants |
| Fedratinib | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 2 | 13 Participants |
| Fedratinib | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 3 | 11 Participants |
| Fedratinib | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 4 | 1 Participants |
| Fedratinib | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 5 | 1 Participants |
| Fedratinib | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 6 | 2 Participants |
| Best Available Therapy (BAT) | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 5 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 1 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 4 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 2 | 0 Participants |
| Best Available Therapy (BAT) | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 6 | 1 Participants |
| Best Available Therapy (BAT) | Number of Participants With Thiamine Levels Below the Lower Limit of Normal | Cycle 3 | 1 Participants |
Secondary
Overall Survival
Time from randomization to death due to any reason
Time frame: From Randomization to the end of Survival Follow Up
Secondary
Spleen Response Rate by Palpation (RRP)
Spleen response rate by palpation is the percentage of participants at the end of cycle 6 with a spleen response according to the IWG-MRT 2013 criteria. A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable\*\* or A baseline splenomegaly that is palpable at \> 10 cm, below the LCM, decreases by ≥ 50%\*\* Participants with a missing spleen size assessment at the end of cycle 6 including those who meet the criteria for progression of splenomegaly before end of cycle 6 will be considered not to be responders.
Time frame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Population: Intent to Treat Population with baseline spleen size ≥5 cm below the lower costal margin (LCM)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fedratinib | Spleen Response Rate by Palpation (RRP) | 28.4 Percentage of Participants |
| Best Available Therapy (BAT) | Spleen Response Rate by Palpation (RRP) | 7.7 Percentage of Participants |
95% CI: [10, 29.7]Greenland and Robins method
Secondary
Spleen Volume Response Rate (RR25)
Percentage of participants who have ≥ 25% spleen volume reduction (SVR) at end of cycle 6 A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment). The RRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in RRs and 95% confidence interval of the difference for fedratinib to BAT.
Time frame: From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Population: Intent to Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fedratinib | Spleen Volume Response Rate (RR25) | 47.0 Percentage of Participants |
| Best Available Therapy (BAT) | Spleen Volume Response Rate (RR25) | 13.4 Percentage of Participants |
Comparison: Stratified analysis (based on CRF)p-value: <0.000195% CI: [21.9, 45.1]Cochran-Mantel-Haenszel
Secondary
Symptom Response Rate (SRR)
Percentage of participants with ≥ 50% reduction in total symptom scores measured by Myelofibrosis Symptom Assessment Form (MFSAF) 4.0 at end of cycle 6. Subjects 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. MFSAF measures the sum of 7 symptoms on a scale from 0 to 10 (0 being absent and 10 being the worst imagineable). The lower the score the better. A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment). The SRRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in SRRs and 95% confidence interval of the difference for fedratinib to BAT.
Time frame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Population: ITT population with non-zero baseline TSS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fedratinib | Symptom Response Rate (SRR) | 34.1 Percentage of Participants |
| Best Available Therapy (BAT) | Symptom Response Rate (SRR) | 16.9 Percentage of Participants |
p-value: 0.003395% CI: [4.8, 29.4]Cochran-Mantel-Haenszel
Secondary
Time to Spleen and Disease Progression Free Survival (SDPFS)
Time from randomization to death due to any reason or disease progression (modified IWG-MRT 2013 including ≥ 25% increase in spleen volume by MRI/CT).
Time frame: From randomization to the End of Survival Follow-up