Clinical trial NCT03952039: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Primary Myelofibrosis
Post-Polycythemia Vera
Myelofibrosis
Keywords: MF
myeloproliferative neoplasms
MPN
myelofibrosis
PMF
post-PV
Post-Polycythemia Vera
post-ET MF
Post-Essential Thrombocythemia Myelofibrosis
Lead sponsor: Celgene
Sponsor class: INDUSTRY
Collaborators: name: Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
First posted: 2019-05-16
Enrollment: 202
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Spleen Volume Response Rate (RR)
timeFrame: From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Secondary outcomes:
measure: Symptom Response Rate (SRR)
timeFrame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
measure: Spleen Volume Response Rate (RR25)
timeFrame: From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
measure: Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs
timeFrame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
measure: Number of Participants With Hematology Laboratory Abnormalities
timeFrame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
measure: Spleen Response Rate by Palpation (RRP)
timeFrame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
measure: Durability of Spleen Volume Response (DR)
timeFrame: From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
measure: Durability of Spleen Response by Palpation (DRP)
timeFrame: From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
measure: Durability of Symptoms Response (DSR)
timeFrame: From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
measure: Assessment of the Effectiveness of Risk Mitigation Strategy for ≥3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy
timeFrame: From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
measure: Number of Participants With Thiamine Levels Below the Lower Limit of Normal
timeFrame: From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
measure: Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline
timeFrame: from the start of cycle 1 to cycle 7 day 1 approximately 170 days.
measure: Mean Change From Baseline in EQ-5D-5L Utility Index Score
timeFrame: from the start of cycle 1 to cycle 7 day 1 approximately 170 days.
measure: Time to Spleen and Disease Progression Free Survival (SDPFS)
timeFrame: From randomization to the End of Survival Follow-up
measure: Overall Survival
timeFrame: From Randomization to the end of Survival Follow Up
Other outcomes:
Locations:
city: Darlinghurst
country: Australia
facility: Local Institution - 103
state: New South Wales
city: Adelaide
country: Australia
facility: Local Institution - 101
state: South Australia
city: Box Hill
country: Australia
facility: Local Institution - 105
state: Victoria
city: Frankston
country: Australia
facility: Local Institution - 102
state: Victoria
city: Melbourne
country: Australia
facility: Local Institution - 100
city: Graz
country: Austria
facility: Local Institution - 156
city: Innsbruck
country: Austria
facility: Local Institution - 154
city: Linz
country: Austria
facility: Local Institution - 155
city: Salzburg
country: Austria
facility: Local Institution - 151
city: Vienna
country: Austria
facility: Local Institution - 150
city: Vienna
country: Austria
facility: Local Institution - 152
city: Wels
country: Austria
facility: Local Institution - 153
city: Brugge
country: Belgium
facility: Local Institution - 200
city: Bruxelles
country: Belgium
facility: Local Institution - 202
city: La Louvière-(Haine St-Paul)
country: Belgium
facility: Local Institution - 205
city: Leuven
country: Belgium
facility: Local Institution - 201
city: Liege
country: Belgium
facility: Local Institution - 204
city: Yvoir
country: Belgium
facility: Local Institution - 203
city: Beijing
country: China
facility: Local Institution - 555
city: Guangzhou, Guangdong
country: China
facility: Local Institution - 550
city: Tianjin
country: China
facility: Local Institution - 553
city: Zhengzhou
country: China
facility: Local Institution - 557
city: Brno
country: Czechia
facility: Local Institution - 700
city: Ostrava-Poruba
country: Czechia
facility: Local Institution - 702
city: Prague 2
country: Czechia
facility: Local Institution - 701
city: Angers
country: France
facility: Local Institution - 255
city: La Louvière-(Haine St-Paul)
country: France
facility: Local Institution - 256
city: Lens Cedex
country: France
facility: Local Institution - 254
city: Lille
country: France
facility: Local Institution - 259
city: Nice Cedex 3
country: France
facility: Local Institution - 260
city: Nimes Cedex 9
country: France
facility: Local Institution - 250
city: Paris
country: France
facility: Local Institution - 252
city: Pessac
country: France
facility: Local Institution - 258
city: Pierre-Benite
country: France
facility: Local Institution - 257
city: Poitiers Cedex
country: France
facility: Local Institution - 261
city: Strasbourg
country: France
facility: Local Institution - 251
city: Toulouse Cedex 9
country: France
facility: Local Institution - 253
city: Aachen
country: Germany
facility: Local Institution - 302
city: Frankfurt am Main
country: Germany
facility: Local Institution - 308
city: Halle
country: Germany
facility: Local Institution - 306
city: Jena
country: Germany
facility: Local Institution - 303
city: Magdeburg
country: Germany
facility: Local Institution - 307
city: Mannheim
country: Germany
facility: Local Institution - 301
city: Minden
country: Germany
facility: Local Institution - 304
city: Ulm
country: Germany
facility: Local Institution - 305
city: Budapest
country: Hungary
facility: Local Institution - 600
city: Györ
country: Hungary
facility: Local Institution - 601
city: Kaposvar
country: Hungary
facility: Local Institution - 602
city: Nyiregyhaza
country: Hungary
facility: Local Institution - 604
city: Szeged
country: Hungary
facility: Local Institution - 603
city: Cork
country: Ireland
facility: Local Institution - 751
city: Dublin
country: Ireland
facility: Local Institution - 752
city: Dublin
country: Ireland
facility: Local Institution - 750
city: Bologna
country: Italy
facility: Local Institution - 353
city: Brescia
country: Italy
facility: Local Institution - 363
city: Catania
country: Italy
facility: Local Institution - 354
city: Firenze
country: Italy
facility: Local Institution - 350
city: Milano
country: Italy
facility: Local Institution - 358
city: Naples
country: Italy
facility: Local Institution - 362
city: Pavia
country: Italy
facility: Local Institution - 357
city: Roma
country: Italy
facility: Local Institution - 356
city: Roma
country: Italy
facility: Local Institution - 361
city: Roma
country: Italy
facility: Local Institution - 359
city: Torino
country: Italy
facility: Local Institution - 355
city: Udine
country: Italy
facility: Local Institution - 360
city: Varese
country: Italy
facility: Local Institution - 352
city: Verona
country: Italy
facility: Local Institution - 364
city: Seongnamsi
country: Korea, Republic of
facility: Local Institution - 900
city: Seoul
country: Korea, Republic of
facility: Local Institution - 905
city: Seoul
country: Korea, Republic of
facility: Local Institution - 901
city: Seoul
country: Korea, Republic of
facility: Local Institution - 903
city: Seoul
country: Korea, Republic of
facility: Local Institution - 904
city: Seoul
country: Korea, Republic of
facility: Local Institution - 902
city: Maastricht
country: Netherlands
facility: Local Institution - 402
city: Nijmegen
country: Netherlands
facility: Local Institution - 400
city: Poznan
country: Poland
facility: Local Institution - 803
city: Warszawa
country: Poland
facility: Local Institution - 801
city: Wroclaw
country: Poland
facility: Local Institution - 802
city: Moscow
country: Russian Federation
facility: Local Institution - 855
city: Moscow
country: Russian Federation
facility: Local Institution - 851
city: Moscow
country: Russian Federation
facility: Local Institution - 853
city: Novosibirsk
country: Russian Federation
facility: Local Institution - 857
city: Saint Petersburg
country: Russian Federation
facility: Local Institution - 852
city: Saint-Petersburg
country: Russian Federation
facility: Local Institution - 854
city: St Petersburg
country: Russian Federation
facility: Local Institution - 850
city: Vladikavkaz
country: Russian Federation
facility: Local Institution - 859
city: Alicante
country: Spain
facility: Local Institution - 451
city: Badalona (Barcelona)
country: Spain
facility: Local Institution - 452
city: Barakaldo
country: Spain
facility: Local Institution - 458
city: Barcelona
country: Spain
facility: Local Institution - 450
city: Gerona
country: Spain
facility: Local Institution - 462
city: Las Palmas de Gran Canaria
country: Spain
facility: Local Institution - 461
city: Madrid
country: Spain
facility: Local Institution - 453
city: Madrid
country: Spain
facility: Local Institution - 459
city: Malaga
country: Spain
facility: Local Institution - 457
city: Murcia
country: Spain
facility: Local Institution - 454
city: Salamanca
country: Spain
facility: Local Institution - 455
city: Santa Cruz de Tenerife
country: Spain
facility: Local Institution - 463
city: Santiago de Compostela
country: Spain
facility: Local Institution - 460
city: Valencia
country: Spain
facility: Local Institution - 456
city: Manchester
country: United Kingdom
facility: Local Institution - 504
state: Lancashire
city: Nottingham
country: United Kingdom
facility: Local Institution - 506
state: Nottinghamshire
city: Birmingham
country: United Kingdom
facility: Local Institution - 502
city: Boston
country: United Kingdom
facility: Local Institution - 503
city: London
country: United Kingdom
facility: Local Institution - 501
city: London
country: United Kingdom
facility: Local Institution - 505
city: Oxford
country: United Kingdom
facility: Local Institution - 500
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: