Clinical trial NCT03755518: A 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
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Primary Myelofibrosis
Post-Polycythemia Vera Myelofibrosis
Myelofibrosis
Post-essential Thrombocythemia Myelofibrosis
Keywords: Myelofibrosis (MF)
Primary Myelofibrosis (PMF)
Post-Polycythemia Vera Myelofibrosis (Post-PV)
Post-essential thrombocythemia Myelofibrosis (Post-ET)
Myeloproliferative neoplasms (MPN)
Lead sponsor: Celgene
Sponsor class: INDUSTRY
Collaborators: name: Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation
First posted: 2018-11-28
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

The primary objective of the 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.

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.

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.

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

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.

Primary outcomes:
measure: Percentage of Participants Who Have a ≥ 35% Spleen Volume Reduction (SVR) at End of Cycle 6
timeFrame: From First Dose to end of Cycle 6 (approximately 168 days)
Secondary outcomes:
measure: Number of Participants of All Grade Adverse Events (AEs) and Grade 3/4 AEs
timeFrame: From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 128 weeks)
measure: Number of Participants and Severity of Treatment Related All Grade Adverse Events (AEs) and Grade 3/4 AEs
timeFrame: From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks)
measure: Mean Change From Baseline in Hematology Laboratory Analysis - Hemoglobin
timeFrame: at Cycle 4 Day 1 and Cycle 7 Day 1
measure: Mean Change From Baseline in Hematology Laboratory Analysis - Erythrocytes
timeFrame: at Cycle 4 Day 1 and Cycle 7 Day 1
measure: Mean Change From Baseline in Hematology Laboratory Analysis - Platelets, Leukocytes and Neutrophils
timeFrame: at Cycle 4 Day 1 and Cycle 7 Day 1
measure: Mean Change From Baseline in the Percentage of Blasts/Leukocytes in Hematology Laboratory Analysis
timeFrame: at Cycle 4 Day 1 and Cycle 7 Day 1
measure: Mean Change From Baseline in Chemistry Parameters Analysis - ALT, AST, Amylase, Lipase
timeFrame: at Cycle 4 Day 1 and Cycle 7 Day 1
measure: Mean Change From Baseline in Chemistry Parameters Analysis - Creatinine
timeFrame: at Cycle 4 Day 1 and Cycle 7 Day 1
measure: Spleen Response Rate by Palpation
timeFrame: From First Dose to end of Cycle 6 (approximately 168 days)
measure: Symptom Response Rate
timeFrame: From First Dose to end of Cycle 6 (approximately 168 days)
measure: Durability of Spleen Volume Response by MRI/CT (DR)
timeFrame: From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 59.40 Weeks)
measure: Durability of Spleen Response by Palpation (DRP)
timeFrame: From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 59.32 Weeks)
measure: Durability of Symptom Response (DSR)
timeFrame: From Cycle 1 Day 1 up to 30 days after last dose (Approximately an average of 31.33 Weeks)
measure: Number of Participants With Grade 3 or Higher AEs: Nausea, Vomiting, Diarrhea and Encephalopathy Including Wernicke's.
timeFrame: From first dose to end of treatment (an average of 50.3 weeks up to a maximum of 124 weeks)
measure: Number of Participants With Thiamine Levels < Lower Limit of Normal (LLN).
timeFrame: At Cycle 1, 2, 3, and every 3 cycles afterwards till End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks)
measure: Number of Participants With Thiamine Levels > Upper Limit of Normal (ULN).
timeFrame: At Cycle 1, 2, 3, and every 3 cycles afterwards till End of Treatment (an average of 50.3 weeks up to a maximum of 124 weeks)
measure: Number of Participants With Clinically Notable Laboratory Results, Grade 3 or 4
timeFrame: From first dose up to 30 days post last dose. (an average of 50.3 weeks up to a maximum of 124 weeks)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Local Institution - 117
state: Colorado
city: Miami
country: United States
facility: Local Institution - 126
state: Florida
city: Augusta
country: United States
facility: Local Institution - 113
state: Georgia
city: Chicago
country: United States
facility: Local Institution - 112
state: Illinois
city: Chicago
country: United States
facility: Local Institution - 109
state: Illinois
city: Park Ridge
country: United States
facility: Local Institution - 121
state: Illinois
city: Kansas City
country: United States
facility: Local Institution - 100
state: Kansas
city: Baltimore
country: United States
facility: Local Institution - 123
state: Maryland
city: Bethesda
country: United States
facility: Local Institution - 118
state: Maryland
city: Columbia
country: United States
facility: Local Institution - 127
state: Maryland
city: Ann Arbor
country: United States
facility: Local Institution - 103
state: Michigan
city: Saint Louis
country: United States
facility: Local Institution - 101
state: Missouri
city: Newark
country: United States
facility: Local Institution - 128
state: New Jersey
city: Brooklyn
country: United States
facility: Local Institution - 130
state: New York
city: New York
country: United States
facility: Local Institution - 115
state: New York
city: New York
country: United States
facility: Local Institution - 124
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: Local Institution - 105
state: North Carolina
city: Durham
country: United States
facility: Local Institution - 114
state: North Carolina
city: Cincinnati
country: United States
facility: Local Institution - 111
state: Ohio
city: Pittsburgh
country: United States
facility: Local Institution - 106
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Local Institution - 108
state: South Dakota
city: Dallas
country: United States
facility: Local Institution - 119
state: Texas
city: Fort Worth
country: United States
facility: Local Institution - 132
state: Texas
city: Houston
country: United States
facility: Local Institution - 110
state: Texas
city: San Antonio
country: United States
facility: Local Institution - 120
state: Texas
city: Seattle
country: United States
facility: Local Institution - 116
state: Washington
city: Madison
country: United States
facility: Local Institution - 129
state: Wisconsin
city: Vancouver
country: Canada
facility: Local Institution - 203
state: British Columbia
city: London
country: Canada
facility: Local Institution - 207
state: Ontario
city: Ottawa
country: Canada
facility: Local Institution - 205
state: Ontario
city: Toronto
country: Canada
facility: Local Institution - 200
state: Ontario
city: Montreal
country: Canada
facility: Local Institution - 201
state: Quebec
city: Montreal
country: Canada
facility: Local Institution - 202
state: Quebec
city: Sherbrooke
country: Canada
facility: Local Institution - 204
state: Quebec
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: