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A Safety Trial of Fedratinib in Subjects With DIPSS, Intermediate or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib With Concomitant Luspatercept for Subjects With Anemia

NCT03755518

Description:

This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib 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 including a Sub-study with concomitant Luspatercept for subjects with anemia. The primary objective of the main study is to evaluate the percentage of subjects with at least a 35% reduction in spleen size and one of the secondary objectives is to evaluate the safety of fedratinib. The primary objective of the sub-study is to evaluate the safety and tolerability of Luspatercept when administered concomitantly with Fedratinib.

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

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Safety Trial of Fedratinib in Subjects With DIPSS, Intermediate or High-Risk Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib With Concomitant Luspatercept for Subjects With Anemia
  • Official Title: A Phase 3b, Multicenter, Single-Arm, Open-Label Efficacy and Safety Study of Fedratinib 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 Including a Sub-study With Concomitant Luspatercept for Subjects With Anemia

Clinical Trial IDs

  • ORG STUDY ID: FEDR-MF-001
  • SECONDARY ID: U1111-1223-2862
  • SECONDARY ID: 2018-002237-38
  • NCT ID: NCT03755518

Conditions

  • Primary Myelofibrosis
  • Post-Polycythemia Vera
  • Myelofibrosis

Interventions

DrugSynonymsArms
FEDRATINIBAdministration of Fedratinib 400mg/day
LuspaterceptAdministration of Fedratinib 400mg/day

Purpose

This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib 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 including a Sub-study with concomitant Luspatercept for subjects with anemia. The primary objective of the main study is to evaluate the percentage of subjects with at least a 35% reduction in spleen size and one of the secondary objectives is to evaluate the safety of fedratinib. The primary objective of the sub-study is to evaluate the safety and tolerability of Luspatercept when administered concomitantly with Fedratinib.

Detailed Description

      This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib 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 including
      a Sub-study with concomitant Luspatercept for subjects with anemia.

      The spleen volume reduction at the end of Cycle 6 as the primary objective. The secondary
      objectives of the study are to further evaluate the safety and to assess and implement
      mitigation strategies for WE and for gastrointestinal (GI) adverse events.

      The study will be at multiple centers to provide access to a broad population and have
      assurance the results are likely to have general applicability.

      This is also conducted as an open-label study to collect efficacy and safety data with
      fedratinib use, no randomization or stratification will occur.

      The primary objective of the sub-study is to evaluate the safety and tolerability of
      Luspatercept when administered concomitantly with Fedratinib for the treatment of anemia in
      subjects with MF who are red blood cell (RBC) transfusion dependent (Group A) or
      non-transfusion dependent (Group B).
    

Trial Arms

NameTypeDescriptionInterventions
Administration of Fedratinib 400mg/dayExperimentalSelf-administered Investigational Product (IP) (400 mg/day) on an outpatient basis, once daily preferably with food during an evening meal at the same time each day in consecutive 4-week (28-day) cycles.
  • FEDRATINIB
  • Luspatercept
Administration of Luspatercept 1.33 mg/kgExperimentalAdministered as a subcutaneous injection concomitantly with Fedratinib at 3-week (21 day) cycles
  • Luspatercept

Eligibility Criteria

        Inclusion Criteria:

        Main Study 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 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 assessment or by palpable spleen
             measuring ≥ 5 cm below the left costal margin.

          6. Subject has been previously exposed to ruxolitinib, while diagnosed with MF (PMF,
             post-ET MF or post-PV MF), and must meet at least one of the following criteria (a or
             b)

               1. Treatment with ruxolitinib for ≥ 3 months

               2. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following:

                    -  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

          7. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1
             or pretreatment baseline before start of last therapy prior to 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. Participants must agree to use effective contraception

        Sub-Study Inclusion Criteria

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

          2. Subject must have been taking fedratinib for at least 32 weeks (~ 8 cycles)

          3. Subject must be on a stable dose of fedratinib for at least 16 weeks (~ 4 cycles) [no
             dose level changes] in the time immediately up to the projected date of enrollment
             (SC1D1)

          4. Subject has anemia defined as either:

               1. Group A - Transfusion dependent (TD) anemia

                    -  RBC-transfusion frequency: 4 to 12 RBC units/84 days immediately up to the
                       SC1D1 date (Sub-study Cycle 1 Day 1), with no interval of > 6 weeks (42
                       days) without an RBC transfusion.

                    -  Subjects must have a Hgb value of < 11.5 g/dL on SC1D1 prior to luspatercept
                       administration.

               2. Group B - Non-transfusion dependent (NTD) anemia

                    -  RBC-transfusion frequency: < 4 RBC units/84 days immediately up to the SC1D1
                       date.

             OR

               -  At least 3 Hgb levels of ≤ 9.5 g/dL recorded on ≥ 3 different days, including the
                  day of dosing, in the 84-day period immediately up to Sub-study C1D1 date. There
                  must be ≥ 14 days in between each Hgb measurement. No subjects with an interval ≥
                  42 days between hemoglobin measurements will be enrolled.

             Baseline is defined as the 84-day rolling period (3 cycles at 28 days each) prior to
             Sub-study Cycle 1 Day 1. Any transfusions given either at a Hgb ≤ 7 or for a Hgb ≤ 9.5
             g/dL with symptoms will be counted towards baseline transfusion needs. Transfusions
             given only for bleeding or infections will not be counted towards eligibility baseline
             transfusion requirements.

          5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

        Exclusion Criteria:

        Main Study Exclusion Criteria

          1. Any of the following laboratory abnormalities:

               1. Platelets < 50,000/μL

               2. Absolute neutrophil count (ANC) < 1.0 x 109/L

               3. White blood count (WBC) > 100 x 10^9/L

               4. Myeloblasts > 5 % in peripheral blood

               5. Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 (as per the
                  Modification of Diet in Renal Disease [MDRD] formula)

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

               7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x 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

          6. Subject with signs or symptoms of encephalopathy including Wernicke's (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 institutional standard and not corrected prior to enrollment
             on the study

          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 the start of fedratinib treatment

         10. Subject has received ruxolitinib within 14 days prior to the start of fedratinib

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

         12. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) for more than 1
             cycle other than ruxolitinib treatment

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

         14. Subject with major surgery within 28 days before starting 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
             enrollment.

             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. Subject with known human immunodeficiency virus (HIV), known active infectious
             Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)

         19. Subject with serious active infection

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

         21. Subject is unable to swallow capsule

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

         23. 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

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

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

         26. Subject with life expectancy of less than 6 months.

        Sub- Study Exclusion Criteria

          1. Subject with anemia from causes other than MPN-associated MF or JAK2 inhibitor therapy
             (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic
             anemia, infection, or any type of known clinically significant bleeding or
             sequestration).

          2. Subject with any of the following laboratory abnormalities at SC1D1:

               1. Neutrophils < 1 x 10^9/L

               2. White blood count (WBC) > 100 x 10^9/L

               3. Platelets < 50 x 10^9/L or > 1000 x 10^9/L

               4. Peripheral blood myeloblasts > 5%.

               5. Estimated glomerular filtration rate < 40 mL/min/1.73 m^2 (via the 4-variable
                  modification of diet in renal disease [MDRD] formula)

               6. Aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3.0 x upper
                  limit of normal (ULN)

               7. Direct bilirubin ≥ 2 x ULN (higher levels are acceptable if these can be
                  attributed to active red blood cell precursor destruction within the bone marrow
                  (ie, ineffective erythropoiesis))

          3. Subject with diastolic blood pressure ≥ 90 mmHg or systolic blood pressure ≥ 140 mmHg
             before SC1D1 despite appropriate treatment.

          4. 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
             enrollment.

             However, subject with the following history/concurrent conditions is allowed:

               1. Basal or squamous cell carcinoma of the skin

               2. Carcinoma in situ of the cervix

               3. Carcinoma in situ of the breast

               4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
                  nodes, metastasis [TNM] clinical staging system)

          5. Subject with stroke, deep venous thrombosis, pulmonary or arterial embolism within 6
             months immediately up to SC1D1.

          6. Subject with major surgery within 2 months up to the enrollment date. Subject must
             have completely recovered from any previous surgery immediately up to the enrollment
             date.

          7. Subject with inadequately controlled heart disease and/or have a known left
             ventricular ejection fraction < 35%.

          8. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as
             ongoing signs/symptoms related to the infection without improvement despite
             appropriate antibiotics, antiviral therapy, and/or other treatment).

          9. Subject with prior therapy of luspatercept or sotatercept.

         10. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity
             to recombinant proteins or excipients in the investigational products (see
             luspatercept IB).

         11. Subject with a major bleeding event (defined as symptomatic bleeding in a critical
             area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to
             transfusion of

             ≥ 2 units of packed red cells) in the last 6 months prior to enrollment.

         12. Subject use of erythropoietin-stimulating agents (ESA) ≤ 56 days prior to SC1D1.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Main study - Adverse Event(s)
Time Frame:Up to 12 months post last dose
Safety Issue:
Description:Number of participants with adverse event
Measure:Main study - Proportion of subjects who have ≥ 50% reduction in spleen size by palpation
Time Frame:At the end of Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Spleen response rate by palpation (RRP)
Measure:Main study - Symptom response rate (SRR)
Time Frame:At the end of Cycle 6 (each cycle is 28 days)
Safety Issue:
Description:Is defined as the proportion of subjects with ≥ 50% reduction from baseline to the end of Cycle 6 in total symptom score (TSS) measured by MFSAF version 4.0.
Measure:Main study - To evaluate durability of spleen volume response (DR)
Time Frame:From enrollment until treatment discontinuation (estimation of 12 months)
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:Main study - To evaluate the durability of spleen response by palpation (DRP)
Time Frame:From enrollment until treatment discontinuation (estimation of 12 months)
Safety Issue:
Description:Is defined as time from the first documented palpable spleen response, according to the IWG-MRT 2013 to the time of the first documented loss of response according to the IWG-MRT 2013.
Measure:Main study - Durability of symptoms response (DSR)
Time Frame:Up to 30 days post last dose
Safety Issue:
Description: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%.
Measure:Main study - Gastrointestinal Adverse Events
Time Frame:Up to 30 days post last dose
Safety Issue:
Description:Incidence of subjects with Grade 3 or higher Gastrointestinal events (nausea, diarrhea, or vomiting) according to CTCAE v5.0
Measure:Main study - Wernicke encephalopathy (WE)
Time Frame:Up to 30 days post last dose
Safety Issue:
Description:Occurrence of confirmed Wernicke encephalopathy events
Measure:Main study - Wernicke encephalopathy (WE) thiamine monitoring
Time Frame:Up to 30 days post last dose
Safety Issue:
Description:Monitoring and correction of thiamine levels as appropriate
Measure:Sub study - Anemia response related to modified Hematological Improvement - Erythroid Response (HI-E)
Time Frame:From SC1D1 through and including Sub-study Week 24 (Day 169) Also from SC1D1 through EOT
Safety Issue:
Description:it is defined as the proportion of subjects with hemoglobin increase by ≥ 1.5 g/dL OR reduction of units of RBC transfusion by an absolute number of at least 4 RBC transfusions over any consecutive 56-day (8 weeks) period compared with sub-study baseline.
Measure:Sub study - Anemia Response related to Reduction in Transfusion Burden
Time Frame:From SC1D1 through and including Sub-study Week 24 (Day 169) Also from SC1D1 through EOT
Safety Issue:
Description:it is defined as the proportion of RBC transfusion dependent subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks over any consecutive 12-week period compared with sub-study baseline.
Measure:Sub study - Anemia Response related to Mean Hemoglobin Increase
Time Frame:From SC1D1 through and including Sub-study Week 24 (Day 169) Also from SC1D1 through EOT
Safety Issue:
Description:it is defined as the proportion of subjects achieving a mean ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion.
Measure:Sub study - Anemia response related to RBC-transfusion independence
Time Frame:From SC1D1 through and including Sub-study Week 24 (Day 169) Also from SC1D1 through EOT
Safety Issue:
Description:it is defined as the proportion of subjects who become RBC-transfusion free over any consecutive 84- day period. The response rate will be calculated using the number of responders divided by number of subjects in the sub-study Safety population.
Measure:Sub study - Duration of anemia response
Time Frame:Up to 12 months post last dose
Safety Issue:
Description:Maximum duration of anemia response in each of the endpoints and groups

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Myelofibrosis (MF)
  • Primary Myelofibrosis (PMF)
  • Post-Polycythemia vera (Post-PV)
  • Post-essential thrombocythemia (Post-ET)
  • Myeloproliferative neoplasms (MPN)

Last Updated

July 7, 2020