An Efficacy and Safety Study of Fedratinib Compared to Best Available Therapy in Subjects With DIPSS-intermediate or High-risk Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib

Phase 3

Active, not recruiting

Conditions: Primary Myelofibrosis
Myelofibrosis
Post-Polycythemia Vera

Interventions: Drug: Best Available Therapy (BAT)
Drug: FEDRATINIB

Registration Number: NCT03952039

Lead Sponsor: Celgene

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

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 202

Inclusion Criteria

Subject is at least 18 years of age at the time of signing the informed consent form (ICF)
Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2
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
Subject has a DIPSS Risk score of Intermediate-2 or High
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
Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF)
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
Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to randomization
Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
Subject is willing and able to adhere to the study visit schedule and other protocol requirements
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).
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

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
Subject is pregnant or lactating female
Subject with previous splenectomy
Subject with previous or planned hematopoietic cell transplant
Subject with prior history of encephalopathy, including Wernicke's (WE)
Subject with signs or symptoms of encephalopathy, including WE (eg, severe ataxia, ocular paralysis or cerebellar signs)
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
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
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
Subject has received ruxolitinib within 14 days prior to randomization
Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment
Subject on treatment with aspirin with doses > 150 mg daily
Subject with major surgery within 28 days prior to randomization
Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)
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
Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)
Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
Subject with serious active infection
Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication
Subject is unable to swallow capsule
Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
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
Subject has any condition that confounds the ability to interpret data from the study
Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization
Subject with a life expectancy of less than 6 months

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Best Available Therapy (BAT)	Best Available Therapy (BAT)	Best-available Investigator-selected therapy included a number of available compounds to treat MF and/or its symptoms and was chosen by the investigator for each subject. Therapy changed at different times during the treatment period. No investigational agents (e.g. not approved for the treatment of any indication) were allowed. BAT also included the choice of no treatment.
Fedratinib 400mg/day	FEDRATINIB	Will include up to 128 subjects receiving fedratinib 400 mg self-administered Investigational Product (IP) on an outpatient basis, once daily preferably together with food during an evening meal at the same time each day in consecutive 4-week (28-day) cycles.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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).
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.
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.
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.
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).

Trial Locations

Locations (107): Local Institution - 153
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Wels, Austria
Local Institution - 155
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Linz, Austria
Local Institution - 151
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Salzburg, Austria
Local Institution - 200
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Brugge, Belgium
Local Institution - 150
🇦🇹
Vienna, Austria
Local Institution - 152
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Vienna, Austria
Local Institution - 202
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Bruxelles, Belgium
Local Institution - 205
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La Louvière-(Haine St-Paul), Belgium
Local Institution - 201
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Leuven, Belgium
Local Institution - 204
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Liege, Belgium
Local Institution - 203
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Yvoir, Belgium
Local Institution - 555
🇨🇳
Beijing, China
Local Institution - 550
🇨🇳
Guangzhou, Guangdong, China
Local Institution - 553
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Tianjin, China
Local Institution - 700
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Brno, Czechia
Local Institution - 702
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Ostrava-Poruba, Czechia
Local Institution - 557
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Zhengzhou, China
Local Institution - 701
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Prague 2, Czechia
Local Institution - 255
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Angers, France
Local Institution - 260
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Nice Cedex 3, France
Local Institution - 250
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Nimes Cedex 9, France
Local Institution - 252
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Paris, France
Local Institution - 256
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La Louvière-(Haine St-Paul), France
Local Institution - 254
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Lens Cedex, France
Local Institution - 259
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Lille, France
Local Institution - 258
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Pessac, France
Local Institution - 257
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Pierre-Benite, France
Local Institution - 261
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Poitiers Cedex, France
Local Institution - 251
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Strasbourg, France
Local Institution - 253
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Toulouse Cedex 9, France
Local Institution - 302
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Aachen, Germany
Local Institution - 304
🇩🇪
Minden, Germany
Local Institution - 305
🇩🇪
Ulm, Germany
Local Institution - 308
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Frankfurt am Main, Germany
Local Institution - 306
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Halle, Germany
Local Institution - 303
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Jena, Germany
Local Institution - 307
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Magdeburg, Germany
Local Institution - 600
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Budapest, Hungary
Local Institution - 301
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Mannheim, Germany
Local Institution - 601
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Györ, Hungary
Local Institution - 602
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Kaposvar, Hungary
Local Institution - 604
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Nyiregyhaza, Hungary
Local Institution - 603
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Szeged, Hungary
Local Institution - 751
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Cork, Ireland
Local Institution - 350
🇮🇹
Firenze, Italy
Local Institution - 358
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Milano, Italy
Local Institution - 752
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Dublin, Ireland
Local Institution - 750
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Dublin, Ireland
Local Institution - 353
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Bologna, Italy
Local Institution - 363
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Brescia, Italy
Local Institution - 362
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Naples, Italy
Local Institution - 354
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Catania, Italy
Local Institution - 357
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Pavia, Italy
Local Institution - 356
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Roma, Italy
Local Institution - 361
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Roma, Italy
Local Institution - 359
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Roma, Italy
Local Institution - 355
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Torino, Italy
Local Institution - 360
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Udine, Italy
Local Institution - 352
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Varese, Italy
Local Institution - 364
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Verona, Italy
Local Institution - 900
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Seongnamsi, Korea, Republic of
Local Institution - 905
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Seoul, Korea, Republic of
Local Institution - 901
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Seoul, Korea, Republic of
Local Institution - 903
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Seoul, Korea, Republic of
Local Institution - 904
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Seoul, Korea, Republic of
Local Institution - 851
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Moscow, Russian Federation
Local Institution - 902
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Seoul, Korea, Republic of
Local Institution - 402
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Maastricht, Netherlands
Local Institution - 400
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Nijmegen, Netherlands
Local Institution - 803
🇵🇱
Poznan, Poland
Local Institution - 801
🇵🇱
Warszawa, Poland
Local Institution - 802
🇵🇱
Wroclaw, Poland
Local Institution - 855
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Moscow, Russian Federation
Local Institution - 853
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Moscow, Russian Federation
Local Institution - 857
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Novosibirsk, Russian Federation
Local Institution - 451
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Alicante, Spain
Local Institution - 452
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Badalona (Barcelona), Spain
Local Institution - 852
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Saint Petersburg, Russian Federation
Local Institution - 854
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Saint-Petersburg, Russian Federation
Local Institution - 850
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St Petersburg, Russian Federation
Local Institution - 458
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Barakaldo, Spain
Local Institution - 859
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Vladikavkaz, Russian Federation
Local Institution - 450
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Barcelona, Spain
Local Institution - 462
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Gerona, Spain
Local Institution - 461
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Las Palmas de Gran Canaria, Spain
Local Institution - 453
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Madrid, Spain
Local Institution - 459
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Madrid, Spain
Local Institution - 454
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Murcia, Spain
Local Institution - 455
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Salamanca, Spain
Local Institution - 457
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Malaga, Spain
Local Institution - 463
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Santa Cruz de Tenerife, Spain
Local Institution - 460
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Santiago de Compostela, Spain
Local Institution - 456
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Valencia, Spain
Local Institution - 504
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Manchester, Lancashire, United Kingdom
Local Institution - 503
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Boston, United Kingdom
Local Institution - 501
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London, United Kingdom
Local Institution - 506
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Nottingham, Nottinghamshire, United Kingdom
Local Institution - 505
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London, United Kingdom
Local Institution - 502
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Birmingham, United Kingdom
Local Institution - 500
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Oxford, United Kingdom
Local Institution - 101
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Adelaide, South Australia, Australia
Local Institution - 105
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Box Hill, Victoria, Australia
Local Institution - 103
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Darlinghurst, New South Wales, Australia
Local Institution - 102
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Frankston, Victoria, Australia
Local Institution - 100
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Melbourne, Australia
Local Institution - 156
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Graz, Austria
Local Institution - 154
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Innsbruck, Austria

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3 months ago

FREEDOM2 Trial Shows Fedratinib's Efficacy and Safety in Myelofibrosis

Fedratinib (Inrebic) showed significant spleen volume reduction (SVR35) in myelofibrosis patients post-ruxolitinib, with 36% achieving SVR35 vs 6% in best available therapy (BAT) group. Gastrointestinal adverse effects were more common but manageable, and proactive thiamine supplementation reduced deficiency risk.