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A Study of Fedratinib in Japanese 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)

NCT04446650

Description:

The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. This is a Phase 1/2 multicenter, single arm, open-label study in Japanese subjects with DIPSS intermediate or high-risk PMF, post-PV or post-ET MF. The study consists of 2 parts: Phase 1 part to determine safety and tolerability and a RP2D. The Phase 1 portion of the study will explore one or more drug doses for fedratinib (300 mg and 400 mg) using a mTPI-2 design. Following completion of dose escalation and determination of MTD and/or a RP2D, the study will progress into the Phase 2 part to further evaluate the efficacy and safety. The study will consist of 3 periods: a Screening Period, a Treatment Period including a 30-day follow-up after last dose visit and a survival follow-up period.

Related Conditions:
  • Myelofibrosis Transformation in Essential Thrombocythemia
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Fedratinib in Japanese 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)
  • Official Title: A Phase 1/2, Multicenter, Single-arm, Open-label Study to Evaluate the Efficacy and Safety of Fedratinib in Japanese 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)

Clinical Trial IDs

  • ORG STUDY ID: FEDR-MF-003
  • SECONDARY ID: U1111-1252-2577
  • NCT ID: NCT04446650

Conditions

  • Primary Myelofibrosis

Interventions

DrugSynonymsArms
FedratinibFedratinib Administration

Purpose

The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. This is a Phase 1/2 multicenter, single arm, open-label study in Japanese subjects with DIPSS intermediate or high-risk PMF, post-PV or post-ET MF. The study consists of 2 parts: Phase 1 part to determine safety and tolerability and a RP2D. The Phase 1 portion of the study will explore one or more drug doses for fedratinib (300 mg and 400 mg) using a mTPI-2 design. Following completion of dose escalation and determination of MTD and/or a RP2D, the study will progress into the Phase 2 part to further evaluate the efficacy and safety. The study will consist of 3 periods: a Screening Period, a Treatment Period including a 30-day follow-up after last dose visit and a survival follow-up period.

Trial Arms

NameTypeDescriptionInterventions
Fedratinib AdministrationExperimentalThe fedratinib dose is 300 or 400 mg/day PO (3 or 4 x 100 mg capsules) to be self-administered orally once daily continuously on an outpatient basis, preferably together with food during an evening meal, the same time each day.
  • Fedratinib

Eligibility Criteria

        Inclusion Criteria:

        Subjects must satisfy the following criteria to be enrolled in the study:

          1. Subject is ≥ 20 years of age at the time of signing the informed consent form (ICF)

          2. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (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- Polycythemia vera
             (PV) Myelofibrosis (MF) according to the IWG-MRT 2007 criteria, confirmed by the most
             recent local pathology report

          4. Subject has a Dynamic International Prognostic Scoring System (DIPSS) Risk score of
             Intermediate-1 with symptom(s), Intermediate-2 or High

          5. Subject has a measurable splenomegaly during the screening period as demonstrated by
             spleen volume of ≥ 450 cm3 by magnetic resonance imaging (MRI) or computed tomography
             (CT) scan or by palpable spleen measuring ≥ 5 cm below the left costal margin.

          6. Subject must meet at least one of the following criteria of (a or b).

             Note: reason to discontinue ruxolitinib treatment (lack of efficacy and/or
             intolerability, etc) and physician decision as to the study participation as being
             appropriate should be recorded in the case report form:

               1. Previously received ruxolitinib treatment for PMF or post-PV MF or post-ET MF for
                  at least 14 days (exposure of < 14 days is allowed for subjects who discontinued
                  ruxolitinib due to intolerability or allergy).

               2. Never received ruxolitinib treatment and is expected to derive clinical benefit
                  from this study participation based on the clinical judgement of the Investigator
                  Only those subjects who previously received ruxolitinib treatment are eligible
                  for the Phase 1 part of the study to avoid overestimating tolerability of
                  fedratinib.

          7. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1
             or pretreatment baseline before start of last therapy prior to starting the fedratinib
             treatment.

          8. Subject must understand and voluntarily sign an ICF prior to any study-related
             assessments/procedures being conducted.

          9. Subject is willing and able to adhere to the study visit schedule and other protocol
             requirements.

         10. A female of childbearing potential (FCBP) must:

               1. Have 2 negative pregnancy tests as verified by the Investigator during screening
                  prior to starting fedratinib treatment. She must agree to ongoing pregnancy
                  testing during the course of the study, and after end of fedratinib 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 fedratinib treatment (including
                  dose interruptions), and for 30 days after discontinuation of fedratinib
                  treatment.

               3. If breastfeeding, agree to stop breastfeeding prior to the participation in the
                  study and not to resume breastfeeding for at least 30 days after treatment
                  discontinuation of the fedratinib 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 or
             amenorrhea due to other medical reasons 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).

         11. 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 fedratinib discontinuation, or longer if required by local regulations, even if
        he has undergone a successful vasectomy.

        True abstinence is acceptable when this is in line with the preferred and usual lifestyle
        of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation
        methods] and withdrawal are not acceptable methods of contraception).

        Agreement to use highly effective methods of contraception that alone or in combination
        resulting in a failure rate of a Pearl index of less than 1% per year when used
        consistently and correctly throughout the course of the study. Such methods include
        combined (estrogen and progestogen containing) hormonal contraception (oral),
        progestogen-only hormonal contraception associated with inhibition of ovulation (oral),
        placement of an intrauterine device, placement of an intrauterine hormone-releasing system,
        bilateral tubal occlusion, and vasectomized partner.

        Exclusion Criteria:

        The presence of any of the following will exclude a subject from enrollment:

          1. Any of the following laboratory abnormalities:

               1. Platelets < 50 x 109/L (without platelet transfusion)

               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 creatinine clearance < 30 mL/min (as estimated by Cockcroft-Gault
                  formula)

               6. Serum amylase or lipase > 1.5 x upper limit of normal

               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 breastfeeding female.

          3. Subject with previous splenectomy

          4. Subject with previous or planned hematopoietic Stem-cell transplantation (SCT)

          5. Subject with prior history of Encephalopathy, including Wernicke encephalopathy (WE)

          6. Subject with signs or symptoms of encephalopathy, including 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 starting the fedratinib treatment

          8. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or
             food known to be strong or moderate inducers of Cytochrome P450 (CYP) 3A4, and 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 starting the fedratinib treatment.

         10. Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating
             factor [G-CSF]) within 14 days prior to starting the fedratinib treatment

         11. Subject with previous exposure to JAK inhibitor(s) other than ruxolitinib treatment

         12. Subject has received ruxolitinib within 14 days prior to starting the fedratinib
             treatment

         13. Subject on treatment with aspirin with doses > 150 mg daily

         14. Subject with major surgery within 28 days prior to starting the fedratinib treatment

         15. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease,
             autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis,
             hemochromatosis, non-alcoholic steatohepatitis)

         16. 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 the start
             of fedratinib treatment. 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

         17. Subject with uncontrolled congestive heart failure (New York Heart Association
             Classification 3 or 4)

         18. Seropositive for and with evidence of active viral infection with hepatitis B virus
             (HBV)

               1. Subject who are hepatitis B surface antigen (HBsAg) negative but HB core
                  anti-body (HBcAb) positive or HBsAb positive are eligible in case HBV viral
                  deoxyribonucleoside (DNA) negative

               2. Subject who had HBsAg positive but show non-detectable viral DNA for at least 6
                  months prior to starting the fedratinib treatment where appropriate anti-viral
                  treatment should have been given/considered to prevent HBV reactivation based on
                  the standard practice are eligible

               3. Subject who are seropositive because of hepatitis B virus vaccine are eligible

         19. Seropositive for and with active viral infection with hepatitis C virus (HCV)

             • Subject who had hepatitis C but show no detectable HCV viral ribonucleotide (RNA)
             for at least 6 months prior to starting the fedratinib treatment are eligible.

         20. Evidence of human immunodeficiency virus (HIV) infection.

         21. Subject with serious active infection

         22. Subject with presence of any significant gastric or other disorder that would inhibit
             absorption of oral medication

         23. Subject is unable to swallow capsule

         24. Subject with any significant medical condition, laboratory abnormality, or psychiatric
             illness that would prevent the subject from participating in the study

         25. Subject has any condition including the presence of laboratory abnormalities, which
             places the subject at unacceptable risk if the subject were to participate in the
             study

         26. Subject has any condition that confounds the ability to interpret data from the study

         27. Subject with participation in any study of an investigational agent (drug, biologic,
             device) within 30 days prior to starting the fedratinib treatment

         28. Subject with a life expectancy of less than 6 months from the planned first dose of
             fedratinib.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:20 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:Up to Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:is the highest dose that causes DLTs in not more than 33% of the subjects treated with fedratinib in the first cycle with at least 3 evaluable subjects treated at this dose.

Secondary Outcome Measures

Measure:Adverse Events (AEs)
Time Frame:From ICF signature up until 30 days after last dose of IP
Safety Issue:
Description:An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.
Measure:Pharmacokinetics - Cmax
Time Frame:Up to Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Peak (maximum) plasma concentration of the drug
Measure:Pharmacokinetics - AUC
Time Frame:Up to Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Area under the plasma concentration curve
Measure:Pharmacokinetics - Tmax
Time Frame:Up to Cycle 1 (each cycle is 28 days)
Safety Issue:
Description:Time to maximum plasma concentration
Measure:Symptom response rate (SRR)
Time Frame:Up to Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Proportion of subjects with ≥ 50% reduction in total symptom scores measured by MFSAF version 2.0 (Appendix C) at end of Cycle 6
Measure:Spleen volume response rate 25 (RR25)
Time Frame:Up to Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Proportion of subjects who have ≥ 25% reduction in spleen volume at the end of Cycle 6
Measure:Spleen Response Rate by Palpation (RRP)
Time Frame:Up to Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Proportion of subjects who have ≥ 50% reduction in spleen size by palpation at end of Cycle 6
Measure:Duration of spleen volume response (DR)
Time Frame:Up to 4 years
Safety Issue:
Description:Duration of ≥ 35% SVR by MRI/CT
Measure:Duration of spleen response by palpation (DRP)
Time Frame:Up to 4 years
Safety Issue:
Description:Time from the first documented palpable spleen response, according to the IWGMRT 2013 to the time of the first documented loss of response according to the IWG-MRT 2013.
Measure:Duration of symptoms response (DSR)
Time Frame:Up to 4 years
Safety Issue:
Description:Duration of ≥ 50% reduction in total symptom scores measured by MFSAF version 2.0
Measure:Spleen and Disease Progression Free Survival (SDPFS)
Time Frame:Up to 4 years
Safety Issue:
Description:Time from the start of fedratinib treatment to death due to any reason or disease progression (modified IWGMRT 2013 including ≥ 25% increase in spleen volume by MRI/CT)
Measure:Gastrointestinal adverse events
Time Frame:From ICF signature to the 30-day follow-up after last dose of IP
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:From ICF signature to the 30-day follow-up after last dose of IP
Safety Issue:
Description:Occurrence of confirmed Wernicke encephalopathy events
Measure:Overall Survival (OS)
Time Frame:Up to 4 years
Safety Issue:
Description:Time from the start of fedratinib treatment to death due to any reason

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Fedratinib
  • Myelofibrosis
  • Japanese

Last Updated

February 18, 2021