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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

NCT03952039

Description:

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.

Related Conditions:
  • Primary Myelofibrosis
  • Secondary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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 MULTICENTER, OPEN-LABEL, RANDOMIZED STUDY TO EVALUATE THE EFFICACY AND SAFETY 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

Clinical Trial IDs

  • ORG STUDY ID: FEDR-MF-002
  • SECONDARY ID: U1111-1223-2962
  • SECONDARY ID: 2018-003411-21
  • NCT ID: NCT03952039

Conditions

  • Primary Myelofibrosis
  • Polycythemia Vera
  • Thrombocytosis

Interventions

DrugSynonymsArms
FEDRATINIBFedratinib 400mg/day
Best Available Therapy (BAT)Best Available Therapy (BAT)

Purpose

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
    

Trial Arms

NameTypeDescriptionInterventions
Fedratinib 400mg/dayExperimentalWill include up to 128 subjects receiving fedratinib 400 mg self-administered 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.
  • FEDRATINIB
Best Available Therapy (BAT)Active ComparatorBest-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.
  • Best Available Therapy (BAT)

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 Wernicke encephalopathy (WE)

          6. Subject with signs or symptoms of WE (eg, severe ataxia, ocular paralysis or
             cerebellar signs) without documented exclusion of WE by thiamine level and brain MRI

          7. Subject with thiamine deficiency, defined as thiamine levels in whole blood below
             normal range according to institutional standard 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 inducers of Cytochrome P450 3A4 (CYP3A4), sensitive CYP3A4
             substrates with narrow therapeutic range, sensitive Cytochrome P450 2C19 (CYP2C19)
             substrates with narrow therapeutic range, or sensitive Cytochrome P450 2D6 (CYP2D6)
             substrates with narrow therapeutic range

          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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of subjects who have ≥ 35% SVR at end of cycle 6
Time Frame:At the end of Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Spleen volume response rate (RR)

Secondary Outcome Measures

Measure:Proportion of subjects with ≥ 50% reduction in total symptom scores measured by MFSAF at end of cycle 6
Time Frame:Up to end of Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Symptom response rate (SRR)
Measure:Proportion of subjects who have ≥ 25% reduction in spleen volume at the end of cycle 6
Time Frame:At the end of Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Spleen volume response rate (RR25)
Measure:Adverse Events (AEs)
Time Frame:Up to 30 days post last dose
Safety Issue:
Description:Number of participants with adverse event
Measure:Proportion of subjects who have ≥ 50% reduction in spleen size by palpation at end of cycle 6
Time Frame:Up to end of Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Spleen response rate by palpation (RRP)
Measure:Durability of Spleen Volume Response by MRI/CT (DR)
Time Frame:Up to end of Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Is defined as time from the first documented spleen response (ie, ≥ 35% reduction in spleen volume) to the first documented spleen volume reduction < 35%.
Measure:Duration of ≥ 50 % reduction in spleen size by palpation for subjects with a palpable spleen at least 5 cm below the left costal margin (LCM) at baseline
Time Frame:Up to approximately 30 months
Safety Issue:
Description:From C1D1 until the 30- day follow-up after last dose visit
Measure:Duration of ≥ 50% reduction in total symptom scores measured by MFSAF
Time Frame:From enrollment until 30 days post last dose
Safety Issue:
Description:Durability of symptoms response (DSR)
Measure: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:Up to 24 months from enrollment to End of Survival Follow-up
Safety Issue:
Description:Spleen and disease progression free survival (SDPFS)
Measure:Gastrointestinal Adverse Events
Time Frame:Up to approximately 30 months
Safety Issue:
Description:Incidence of subjects with Grade 3 or higher Gastrointestinal events (nausea, diarrhea, or vomiting) according to CTCAE v5.0
Measure:Wernicke encephalopathy (WE) events
Time Frame:Up to 30 days post last dose
Safety Issue:
Description:Occurrence of confirmed Wernicke encephalopathy events
Measure:Health-Related Quality of Life (HRQoL)
Time Frame:Up to 30-day follow-up after last dose visit
Safety Issue:
Description:To evaluate Health-Related Quality of Life (HRQoL) as measured by the European Organization for Research and Treatment of Cancer Quality of Life C30 (EORTC QLQ-C30)
Measure:EQ-5D-5L
Time Frame:Up to 20-day follow-up after last dose visit
Safety Issue:
Description:To evaluate Patient Reported Outcomes (PRO) as measured by the EQ-5D-5L questionnaire
Measure:Overall Survival (OS)
Time Frame:From randomization to the End of Survival Follow-up (approximately 12 months)
Safety Issue:
Description:Time from randomization to death due to any reason

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Celgene

Trial Keywords

  • MF
  • myeloproliferative neoplasms
  • MPN
  • myelofibrosis
  • PMF
  • post-PV
  • Post-Polycythemia Vera
  • post-ET MF
  • Post-Essential Thrombocythemia Myelofibrosis

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