Clinical trial NCT03952039
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
Sponsor: Celgene
Start date: 2019-09-09; Completion date: 2025-07-28
Enrollment: 202 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Arms: arm 1: Will include up to 128 subjects receiving fedratinib 400 mg self-administered Investigational Product (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. arm 2: Best-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.
Interventions: intervention 1: FEDRATINIB intervention 2: Best Available Therapy (BAT)
Intervention descriptions: intervention 1: A potent and selective inhibitor of JAK2 kinase activity intervention 2: Best available therapy (BAT)

Protocol documents:
Prot_SAP_000.pdf: 
Protocol for 
 
Official Title of Study 
A PHASE 3, MULTICENTER, OPEN-LABEL, 
RANDOMIZED STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF FEDRATINIB COMPARED TO BEST 
AVAILABLE THERAPY IN SUBJECTS WITH DIPSSINTERMEDIATE 
OR HIGH-RISK PRIMARY 
MYELOFIBROSIS, POST-POLYCYTHEMIA VERA 
MYELOFIBROSIS, OR POST-ESSENTIAL 
THROMBOCYTHEMIA MYELOFIBROSIS AND 
PREVIOUSLY TREATED WITH RUXOLITINIB 
NCT03952039 
 
April  23, 2021 


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
1
FEDR-MF-002 Amendment 4 Final:  23 April 2021
 
A PHASE 3, 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
The “FREEDOM 2” trial
PROTOCOL NUMBER:
FEDR-MF-002 
DATE FINAL:
26-Sep-2018
AMENDMENT No. 1 DATE:
01-Feb-2019
AMENDMENT No. 2 DATE:
08 Oct 2019
AMENDMENT No. 3 DATE:
15 Jan 2021
AMENDMENT No. 4 DATE:
23 Apr 2021
EudraCT NUMBER:
2018-003411-21
IND NUMBER:
078286 
SPONSOR NAME/ ADDRESS:
Impact Biomedicines, Inc., a Wholly Owned 
Subsidiary of Celgene Corporation (hereafter 
referred to as Celgene-Impact)
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address: 
Phone:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
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Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
See appended electronic signature page
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
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a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name: _______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene-Impact representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
8
FEDR-MF-002 Amendment 4 Final:  23 April 2021
The End of Trial is defined as the date of the last visit of the last subject to complete the Survival 
Follow-up or the date of receipt of the last data point from the last subject that is required for 
primary, secondary
 analysis, as prespecified in the protocol, whichever is the 
later date. End of trial is expected approximately 3 years after the last subject is randomized. 
Refer to Section 3.3 for more information.
Study Treatments
Subjects satisfying the eligibility criteria will be randomized 2:1 to one of these two arms:
•
Arm 1 (Fedratinib) will include up to 128 subjects receiving fedratinib 400 mg
OR
•
Arm 2 (BAT) will include up to 64 subjects receiving best available therapy
Fedratinib will be orally self-administered 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 may be taken with or without regard to food.
The most common adverse events associated with fedratinib are hematological and 
gastrointestinal. Hematological adverse events associated with Janus kinase (JAK) inhibitors are 
dose dependent, mechanism-based and managed through dose reductions, dose interruptions and 
transfusions.
The fedratinib dose in this study is 400 mg/day. If a subject experiences a drug toxicity as 
specified in the Fedratinib Dose Modification Schedule table (Table 4), the dosing should be 
interrupted and the dose may need to be modified (Section 7).
If a subject does not tolerate fedratinib therapy after 2 dose level reductions from the starting 
dose, he/she must be withdrawn from the study treatment. If the toxicity does not resolve in the 
time period as specified in the Fedratinib Dose Modification Schedule table (Table 4), subjects 
must be withdrawn from the study treatment. Reescalation of doses is possible in certain cases as 
defined in the Fedratinib Dose Modification Schedule table (Table 4). The daily dose of 
fedratinib cannot exceed 400 mg/day.
Subjects may continue treatment with fedratinib or BAT until unacceptable toxicity, lack of 
therapeutic effect, progression of disease according to the IWG-MRT 2013 criteria or until a 
subject is not compliant with treatment or withdraws consent.
Best available therapy (BAT) regimen may include any Investigator-selected treatment. 
Investigational agents, fedratinib (if approved during the course of the study) and hematopoietic 
stem cell transplantation are not regarded to be BAT.
Overview of Key Efficacy Assessments
Assessment of Spleen Size 
Spleen volume will be assessed at the study site (MRI or CT Scan if MRI is contraindicated) 
during screening and at the end of cycle 3, 6, 12, 18, 24, every sixth (6th) cycle after Cycle 24
and at End of Treatment Visit. MRI/CT scans will be reviewed centrally. The central review will 
be blinded for arm assignment and treatment.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
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a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................18
1.1.
Disease Background ...............................................................................................18
1.1.1.
Myeloproliferative Neoplasm (MPN) Associated Myelofibrosis .............................18
1.1.2.
Treatment Options for MPN-Associated Myelofibrosis...........................................19
1.1.3.
Approved Therapies ...............................................................................................19
1.1.4.
Medical Need .........................................................................................................20
1.2.
Fedratinib ...............................................................................................................21
1.3.
Wernicke Encephalopathy (WE) in Patients Treated with Fedratinib ......................23
1.4.
Rationale ................................................................................................................24
1.4.1.
Study Rationale and Purpose ..................................................................................24
1.4.2.
Rationale for the Study Design ...............................................................................24
1.4.3.
Rationale for Dose, Schedule and Regimen Selection .............................................25
1.4.4.
Rationale for Patient-Reported Outcomes ...............................................................26
1.4.5.
27
1.4.6.
27
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................29
3.
OVERALL STUDY DESIGN ................................................................................34
3.1.
Study Design ..........................................................................................................34
3.2.
Study Duration for Subjects....................................................................................35
3.3.
End of Trial ............................................................................................................36
4.
STUDY POPULATION.........................................................................................37
4.1.
Number of Subjects ................................................................................................37
4.2.
Inclusion Criteria....................................................................................................37
4.3.
Exclusion Criteria...................................................................................................39
5.
TABLE OF EVENTS.............................................................................................41
6.
PROCEDURES......................................................................................................44
6.1.
Screening Period.....................................................................................................44
6.2.
Randomization of a Subject to the Study.................................................................48
6.3.
Treatment Period ....................................................................................................49
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a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
6.3.1.
Symptoms Response Assessment using MFSAF version 4.0...................................50
6.3.2.
Health-related Quality of Life Assessments and Patient-Reported Outcomes ..........51
6.3.2.1.
EORTC QLQ-C30 questionnaire ............................................................................51
6.3.2.2.
EQ-5D-5L ..............................................................................................................51
6.3.2.3.
52
6.3.3.
53
6.4.
Response Assessment .............................................................................................54
6.5.
Crossover ...............................................................................................................54
6.6.
End of Treatment Visit ...........................................................................................55
6.7.
30-Day Follow-up After Last Dose Visit.................................................................57
6.8.
Survival Follow-up.................................................................................................57
6.9.
Unscheduled Assessments or Visits ........................................................................58
7.
DESCRIPTION OF STUDY TREATMENT..........................................................59
7.1.
Description of Investigational Product ....................................................................59
7.2.
Best Available Therapy Regimens ..........................................................................59
7.3.
Treatment Administration and Schedule .................................................................59
7.3.1.
Dose Modification for Toxicity...............................................................................59
7.3.2.
Dose Adjustment for Co-administration of Fedratinib with Strong CYP3A4 
Inhibitors................................................................................................................62
7.3.3.
Dose Adjustment for Renal Impairment..................................................................63
7.4.
Overview on Management of Gastrointestinal Adverse Events ...............................63
7.4.1.
Management of Nausea and Vomiting ....................................................................63
7.4.2.
Management of Diarrhea ........................................................................................64
7.5.
Management of Encephalopathy, including Wernicke’s..........................................64
7.5.1.
Clinical and Cognitive Assessment .........................................................................64
7.5.2.
Management of Encephalopathy, including Wernicke’s..........................................65
7.5.3.
Thiamine, Supplementation, Monitoring and Correction.........................................65
7.6.
Method of Treatment Assignment...........................................................................66
7.7.
Packaging and Labeling..........................................................................................66
7.8.
Investigational Product Accountability and Disposal ..............................................67
7.9.
Investigational Product Compliance........................................................................67
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................68
8.1.
Permitted Concomitant Medications and Procedures...............................................68
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a Wholly Owned Subsidiary of Celgene Corporation
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
8.2.
Prohibited Concomitant Medications ......................................................................69
8.3.
Clinically Relevant Cytochrome P450 Inducers, Inhibitors, Substrates, and 
Transporter Substrates ............................................................................................69
9.
STATISTICAL CONSIDERATIONS ....................................................................71
9.1.
Overview................................................................................................................71
9.2.
Study Population Definitions ..................................................................................71
9.3.
Sample Size Consideration .....................................................................................72
9.4.
Background and Demographic Characteristics........................................................73
9.4.1.
Demographic and Baseline Characteristics..............................................................73
9.4.2.
Prior or Concomitant Medications ..........................................................................73
9.5.
Subject Disposition.................................................................................................73
9.6.
Extent of Study Treatment Exposure and Compliance.............................................73
9.7.
Efficacy Analysis....................................................................................................74
9.7.1.
Spleen Volume Response Rate (35%) by MRI / CT (RR) .......................................74
9.7.2.
Symptom Response Rate (SRR)..............................................................................74
9.7.3.
Spleen Volume Response Rate (25%) by MRI / CT (RR25) ...................................75
9.7.4.
Spleen Response Rate by Palpation (RRP)..............................................................75
9.7.5.
Durability of Spleen Volume Response by MRI/CT (DR).......................................75
9.7.6.
Spleen and Disease Progression Free Survival (SDPFS) .........................................76
9.7.7.
Durability of Spleen Response by Palpation (DRP).................................................76
9.7.8.
Overall Survival .....................................................................................................76
9.7.9.
Crossover Efficacy Analysis...................................................................................76
9.8.
Safety Analysis.......................................................................................................77
9.8.1.
Adverse Events.......................................................................................................77
9.8.2.
Assessment of Risk Mitigation Strategy for Gastrointestinal Adverse Events 
and Encephalopathy, including Wernicke’s.............................................................77
9.8.3.
Laboratory Results..................................................................................................77
9.8.4.
Electrocardiograms.................................................................................................78
9.8.5.
Vital Signs..............................................................................................................78
9.9.
Patient-reported Outcomes / Health Economics ......................................................78
9.9.1.
Symptoms Response Assessment Using MFSAF V.4.0...........................................78
9.9.2.
EORTC QLQ-C30 Version 3.0...............................................................................79
9.9.3.
EQ-5D-5L ..............................................................................................................79
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Fedratinib 
Impact Biomedicines, Inc.,
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a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
9.10.
79
9.11.
Interim Analysis .....................................................................................................80
9.12.
Other Topics...........................................................................................................80
9.12.1.
Steering Committee ................................................................................................80
10.
ADVERSE EVENTS..............................................................................................81
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................81
10.2.
Evaluation of Adverse Events.................................................................................82
10.2.1.
Seriousness.............................................................................................................82
10.2.2.
Severity/Intensity....................................................................................................83
10.2.3.
Causality ................................................................................................................84
10.2.4.
Duration .................................................................................................................84
10.2.5.
Action Taken..........................................................................................................84
10.2.6.
Outcome.................................................................................................................84
10.3.
Abnormal Laboratory Values..................................................................................84
10.4.
Pregnancy...............................................................................................................85
10.4.1.
Females of Childbearing Potential: .........................................................................85
10.4.2.
Male Subjects.........................................................................................................86
10.5.
Reporting of Serious Adverse Events......................................................................86
10.5.1.
Safety Queries ........................................................................................................86
10.6.
Expedited Reporting of Adverse Events..................................................................86
10.7.
Adverse Events of Special Interest..........................................................................87
11.
DISCONTINUATIONS .........................................................................................89
11.1.
Treatment Discontinuation......................................................................................89
11.2.
Study Discontinuation ............................................................................................89
12.
EMERGENCY PROCEDURES.............................................................................90
12.1.
Emergency Contact.................................................................................................90
12.2.
Emergency Identification of Investigational Products .............................................90
13.
REGULATORY CONSIDERATIONS...................................................................91
13.1.
Good Clinical Practice............................................................................................91
13.2.
Investigator Responsibilities ...................................................................................91
13.3.
Subject Information and Informed Consent.............................................................92
13.4.
Confidentiality........................................................................................................92
13.5.
Protocol Amendments.............................................................................................92
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Impact Biomedicines, Inc.,
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a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................92
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................93
13.8.
Termination of the Study ........................................................................................93
14.
DATA HANDLING AND RECORDKEEPING.....................................................94
14.1.
Data/Documents.....................................................................................................94
14.2.
Data Management...................................................................................................94
14.3.
Record Retention....................................................................................................94
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................96
15.1.
Study Monitoring and Source Data Verification......................................................96
15.2.
Audits and Inspections............................................................................................96
15.3.
Product Quality Complaint .....................................................................................96
16.
PUBLICATIONS ...................................................................................................98
17.
REFERENCES.......................................................................................................99
18.
APPENDICES......................................................................................................105
APPENDIX A.
TABLE OF ABBREVIATIONS AND SPECIAL TERMS ..........................105
APPENDIX B.
MYELOFIBROSIS SYMPTOM ASSESSMENT FORM (MFSAF) 
VERSION 4.0.......................................................................................................109
APPENDIX C.
QUALITY OF LIFE ASSESSMENT: EORTC QLQ-C30 
QUESTIONNAIRE..............................................................................................110
APPENDIX D.
PATIENT-REPORTED OUTCOMES: EQ-5D-5L QUESTIONNAIRE ......112
APPENDIX E.
NATIONAL CANCER INSTITUTE (NCI) COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) 
VERSION 5.0.......................................................................................................114
APPENDIX F.
DYNAMIC INTERNATIONAL PROGNOSTIC SCORING SYSTEM 
(DIPSS)................................................................................................................115
APPENDIX G.
IWG-MRT: INTERNATIONAL WORKING GROUP-
MYELOPROLIFERATIVE NEOPLASMS RESEARCH AND 
TREATMENT (IWG-MRT).................................................................................116
APPENDIX H.
2016 WORLD HEALTH ORGANIZATION (WHO) DIAGNOSTIC 
CRITERIA FOR PRIMARY MYELOFIBROSIS (PMF)......................................117
APPENDIX I.
PROPOSED CRITERIA FOR THE DIAGNOSIS OF POST-
POLYCYTHEMIA VERA AND POST-ESSENTIAL 
THROMBOCYTHEMIA MYELOFIBROSIS......................................................119
APPENDIX J.
ECOG PERFORMANCE STATUS SCALE.................................................120
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a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
APPENDIX K.
ESTIMATION OF THE GLOMERULAR FILTRATION RATE BY 
THE MDRD FORMULA .....................................................................................121
APPENDIX L.
CLINICALLY RELEVANT P450 INDUCERS, INHIBITORS, 
SUBSTRATES, AND TRANSPORTER SUBSTRATES .....................................122
APPENDIX M.
NEW YORK HEART ASSOCIATION CLASSIFICATION FOR 
CONGESTIVE HEART FAILURE......................................................................124
125
APPENDIX O.
REVISED RESPONSE CRITERIA FOR MYELOFIBROSIS: 
INTERNATIONAL WORKING GROUP-MYELOPROLIFERATIVE 
NEOPLASMS RESEARCH AND TREATMENT (IWG-MRT) AND 
EUROPEAN LEUKEMIANET (ELN) CONSENSUS REPORT (2013)...............126
APPENDIX P.
MINI-MENTAL STATE EXAMINATION-2 ..............................................128
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a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................29
Table 2:
Study Endpoints .....................................................................................................31
Table 3:
Table of Events.......................................................................................................41
Table 4:
Fedratinib Dose Modification Schedule ..................................................................61
Table 5:
PCSA Criteria for Vital Signs and Weight ..............................................................78
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................35
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FEDR-MF-002 Amendment 4 Final:  23 April 2021
1.
INTRODUCTION
1.1.
Disease Background
1.1.1.
Myeloproliferative Neoplasm (MPN) Associated Myelofibrosis
Myeloproliferative neoplasm-associated myelofibrosis (MF) is a serious and life-threatening 
disease that can present as a de novo or primary myelofibrosis (PMF) or evolve from previous 
polycythemia vera (post PV-MF) or essential thrombocythemia (post ET-MF) (Swerdlow, 2008). 
The disease is characterized by clonal myeloproliferation, ineffective erythropoiesis, bone 
marrow stromal changes, hepatosplenic extramedullary hematopoiesis, and aberrant cytokine 
expression (Tefferi, 2011). Patients typically present with splenomegaly, constitutional 
symptoms, moderate to severe anemia, thrombocytopenia, and leukocytosis.
Primary myelofibrosis is a member of a group of Philadelphia chromosome (Ph1)-negative 
myeloproliferative neoplasms (MPN) which also includes PV and ET (Tefferi, 2007). Almost all 
patients with PV and about one-half of patients with ET and PMF have a Janus Kinase 2 (JAK2)
mutation, typically JAK2V617F. Other mutations in patients with PMF include calreticulin 
(CALR) and myeloproliferative leukemia virus (MPL). About 20% of patients with PMF have 
no detectable mutation in JAK2, CALR, or MPL and are termed triple negative (Levine, 2005; 
Wernig, 2006). Mutations in JAK2, CALR, and MPL result in activation of the JAK/STAT 
signaling pathway resulting in cell proliferation and inhibiting cell death. The result is clonal 
expansion (Ihle, 2007). Thus, a JAK2 inhibitor that can down regulate the JAK/STAT pathway is 
expected to be helpful in reducing cell proliferation.
Polycythemia vera (PV) and essential thrombocythemia (ET) are characterized by increased 
levels of red blood cells (RBCs) and platelets. However, about 10% of affected patients develop 
bone marrow fibrosis morphologically indistinguishable from PMF. These conditions are termed 
post-PV-MF and post-ET-MF (Campbell, 2005), and are clinically named MPN-associated 
myelofibrosis. Patients with MPN-associated myelofibrosis have similar survival prognoses to 
that of the PMF and about a 10% cumulative risk of transformation to acute myeloid leukemia 
(AML).
There are several prognostic scoring systems predicting survival of patients with PMF. The 
International Prognostic Scoring System (IPSS) is used to predict survival at diagnosis and the 
Dynamic International Prognostic Scoring System (DIPSS) at any time in the disease 
course (Cervantes, 2009; Passamonti, 2010). Variables included in the IPSS are age > 65 years, 
constitutional symptoms, hemoglobin level < 10 g/dL, and white blood cell (WBC) counts. 
Additional recent prognostic scoring systems include the Dynamic International Prognostic 
Scoring System Plus (DIPSS Plus) and scoring systems incorporating data from mutation 
analyses. There is a strong association between overall survival for MF patients and the DIPSS 
risk category for patients with low, intermediate risk 1, intermediate risk 2, or high risk with 
median survival of 15.4, 6.5, 2.9, and 1.3 years, respectively (Tefferi, 2016).
Approximately 70% of individuals with MF are in the intermediate-2 or high-risk 
categories (Gangat, 2011), representing the greatest unmet medical need. Symptomatic 
enlargement of the spleen and liver, the necessity for RBC transfusions, cachexia, and the other 
MF-associated symptoms result in greatly compromised quality of life in these patients (Mesa, 
2007).
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
19
FEDR-MF-002 Amendment 4 Final:  23 April 2021
1.1.2.
Treatment Options for MPN-Associated Myelofibrosis
Allogeneic stem-cell transplantation (SCT) is currently the only treatment that can induce long-
term remission in patients with MF. The average age at diagnosis of MF is 65 years; thus, the 
majority of patients are not eligible for SCT. Therefore, the treatment options are primarily 
symptom-oriented, to help mitigate the clinical presentation of anemia, splenomegaly, 
constitutional symptoms and less commonly increased levels of platelets, and WBCs. So far, 
none of these symptom-oriented treatments have shown an anti-clonal effect, although 
alleviation in spleen size and splenic discomfort, symptoms, and anemia have been 
shown (Vannucchi, 2017).
Fortunately, the understanding of MPNs and the molecular mechanisms of the disease have been 
expanding. In 2005, the JAK2V617F mutation was discovered and observed in approximately 
50% to 60% of patients with PMF or ET and 90% to 95% of patients with PV. This discovery, 
along with the observation of other mutations in patients with MPNs found to activate the 
JAK/signal transducers and activators of transcription (STAT) pathway (JAK2 exon 12, 
myeloproliferative leukemia, and adaptor protein LNK) (Oh, 2010; Pikman, 2006; Scott, 2007), 
has established dysregulation of the JAK signaling pathway as the major contributor to the 
pathogenesis of MPNs. It has also translated into the development of small-molecule JAK 
inhibitors.
Until recently, the JAK1/2 inhibitor ruxolitinib was the only approved therapy for MF. On
August 16th, 2019, fedratinib was approved by the United States (US) Food and Drug 
Administration (FDA) for the treatment of MF. Ruxolitinib is indicated for treatment of patients 
with intermediate or high-risk MPN-associated myelofibrosis (MF), including primary MF, post-
polycythemia vera MF and post-essential thrombocythemia MF. The registration of ruxolitinib 
was based on 2 randomized, controlled studies (COMFORT-I and COMFORT-II) that compared 
ruxolitinib to placebo and to the best available therapy (BAT), respectively (Harrison, 2012; 
Verstovsek, 2012). The studies demonstrated benefit, with a higher proportion of subjects in the 
ruxolitinib arms exhibiting a ≥ 35% reduction in spleen volume as measured by magnetic 
resonance imaging (MRI) at 24 weeks in COMFORT-I (41.9% ruxolitinib versus 0.7% placebo) 
and at 48 weeks in COMFORT-II (28.5% ruxolitinib versus 0% BAT). In COMFORT-I, there 
was a > 50% improvement in the Myelofibrosis Symptom Assessment Form (MFSAF) Total 
Symptom Score (TSS) at 24 weeks in 45.9% of subjects on ruxolitinib compared with 5.3% of 
subjects on placebo. Improvement of survival in the ruxolitinib arm as compared with BAT was 
also demonstrated based on the recent 3-year follow-up data from the COMFORT-II study. The 
Kaplan-Meier estimated probability of survival at 144 weeks was 81% in the ruxolitinib arm and 
61% in the BAT arm (Cervantes, 2012). Improvement in bone marrow fibrosis was observed in 
15% of subjects receiving ruxolitinib at 24 months compared with 5% of subjects who received 
BAT; however, the improvements declined by 48 months in the small number of subjects who 
were available for follow-up. It is unclear if any of the subjects who were included in this study 
achieved clinical resolution of their spleen and symptoms (Kvasnicka, 2013).
1.1.3.
Approved Therapies 
Ruxolitinib is approved in the United States (US) and in the European Union (EU) for the 
treatment of MPN-associated myelofibrosis. 
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
20
FEDR-MF-002 Amendment 4 Final:  23 April 2021
In the US, ruxolitinib (Jakafi®) has been approved by the Food and Drug Administration (FDA)
in November 2011 for the treatment of patients with intermediate or high-risk myelofibrosis, 
including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential 
thrombocythemia myelofibrosis. On 16 August 2019, Inrebic® (fedratinib) was approved by the 
US FDA for the treatment of adult patients with intermediate-2 or high-risk primary or secondary 
(post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).
In the EU, ruxolitinib (Jakavi®) has been approved by the European Medicines Agency (EMA)
in August 2012 for the treatment of disease-related splenomegaly or symptoms in adult patients 
with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythemia 
vera myelofibrosis or post essential thrombocythemia myelofibrosis.
1.1.4.
Medical Need
MPN-associated myelofibrosis, particularly intermediate or high-risk disease, is a serious and 
fatal condition. Until recently, ruxolitinib, a JAK1/2 inhibitor, was the only drug approved for 
the treatment of patients with intermediate or high-risk MF. While the benefits of ruxolitinib 
therapy in terms of spleen response and improvement of constitutional symptoms are significant, 
ruxolitinib is also associated with the risks of treatment-associated anemia (40.4% vs 12.3% for 
BAT) and thrombocytopenia (44.5% vs 9.65% for BAT) (Harrison, 2012). The 1-, 2-, and 3-year 
discontinuation rates are 49%, 71% and 86%, respectively. Major reasons for ruxolitinib 
treatment discontinuation are loss of therapeutic effect, lack of response and drug-induced 
cytopenias (Tefferi, 2011). Additionally, responses to ruxolitinib are typically observed within 
the first 3–6 months after therapy initiation (Harrison, 2012; Verstovsek, 2012) and it has been 
suggested that for patients who have not had a reduction in spleen size or improvement in 
symptoms after that period, alternative therapies should be considered (Harrison, 2018a; 
Keohane, 2013). The effect of ruxolitinib on overall survival (OS) continues to be debated and 
the unclear limited effects on bone marrow fibrosis and driver mutation allele burden suggest 
that the disease-modifying activity of the drug is likely to be minor. Therefore, the unmet 
medical need for frontline MF patients remains high, despite the availability of ruxolitinib, 
especially for patients who have low baseline platelet counts and are susceptible to 
myelosuppression/thrombocytopenia.
For patients who have been previously treated with a JAK inhibitor, there is no approved therapy 
and the prognosis is poor (Newberry, 2017). Mechanisms of resistance to ruxolitinib remain 
unclear. It has been shown preclinically that MF is intrinsically more resistant to JAK2 inhibition 
than PV or ET and there continues to be a major unmet need for a JAK2 inhibitor that is 
effective after ruxolitinib treatment failure. Moreover, the median survival of relapsed and 
refractory patients who discontinued ruxolitinib has been reported to be 6 months (Jabbour, 
2013). Notably, after a median follow-up of 10 months from stopping ruxolitinib, only 34% of 
patients remained alive (Kantarjian, 2013). Only 27% of patients remained on therapy after 5 
years in the COMFORT-I trial. Outcomes for patients who discontinue ruxolitinib in this 
situation are poor. 
Two randomized studies assessed the use of JAK inhibitors for subjects with previous ruxolitinib 
treatment in comparison to BAT that included continuous or retreatment with ruxolitinib.
In the PERSIST-2 study subjects with a platelet count 100 × 109/L or less were randomized to 
receive either pacritinib 400 mg once daily, 200 mg twice daily or BAT. BAT included 
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
21
FEDR-MF-002 Amendment 4 Final:  23 April 2021
ruxolitinib and ruxolitinib was used in 44/98 (45%) subjects as BAT. In the subgroup of subjects 
(n=95) with prior ruxolitinib, a spleen volume response of 35% or more at week 24 was achieved 
at week 24 in 2 subjects (6%) and 4 subjects (13%) and in 1 subject on BAT (3%) 
respectively (Mascarenhas, 2018).
In the SIMPLIFY-2 study MF subjects (n=156) with previous ruxolitinib treatment for at least 28 
days who either required red blood cell transfusions while on ruxolitinib or ruxolitinib dose 
reduction to less than 20 mg twice a day with at least one of Grade 3 thrombocytopenia, anemia, 
or bleeding at Grade 3 or worse were randomized 2:1 to receive either momelotinib or BAT 
including ruxolitinib. 
A spleen volume response of 35% or more at week 24 was achieved at week 24 in 7 subjects 
(7%) and 3 subjects on BAT (6%) (Harrison, 2018b).
Currently, best available therapy (BAT) to treat patients with MF that have been previously 
treated ruxolitinib is limited. BAT may include retreatment with ruxolitinib, chemotherapy (eg, 
hydroxyurea), anagrelide, corticosteroids, hematopoietic growth factor, immunomodulating 
agents, androgens, interferon, and may also include “no treatment” and symptom directed 
treatment.
Therefore, there remains an unmet need for the patients who have been previously treated with a 
JAK inhibitor due to the low life expectancy, notably high discontinuation rate with ruxolitinib 
and the myelosuppression. 
1.2.
Fedratinib 
Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated 
Janus Kinase 2 (JAK2) and fibromyalgia syndrome (FMS)-like tyrosine kinase 3 (FLT3). 
Fedratinib is a JAK2-selective inhibitor with higher potency for JAK2 over family members 
JAK1, JAK3 and tyrosine kinase 2 (TYK2). In cell models expressing mutationally active JAK2 
or FLT3, fedratinib reduced phosphorylation of signal transducer and activator of transcription 
(STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse 
models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of 
STAT3/5, increased survival and improved disease-associated symptoms, including reduction of 
white blood cells, hematocrit, splenomegaly, and fibrosis.
Eighteen clinical studies were conducted with fedratinib. Fedratinib has been studied extensively 
in the treatment of patients with MPN-associated myelofibrosis. 
Fedratinib demonstrated clinical efficacy in a randomized, placebo-controlled, Phase 3 study 
(JAKARTA [EFC12153]) in patients with intermediate-2 or high-risk MF who were previously 
untreated. The primary endpoint was response rate, defined as the proportion of subjects who had 
a ≥ 35% reduction in spleen volume from baseline to the End of Cycle 6 and confirmed 4 weeks 
later by MRI. Analyses for spleen response were also performed at the end of Cycle 6 (eg,
regardless of confirmation), as recommended by the International Working Group-
Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria. Symptom 
response rate (SRR), based on a patient-reported outcome (PRO) tool, the modified 
Myelofibrosis Symptom Assessment Form (MFSAF) that assessed 6 key MF-associated 
symptoms (night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left 
side, and bone or muscle pain) was a key secondary endpoint. The SRR was defined as the 
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
22
FEDR-MF-002 Amendment 4 Final:  23 April 2021
proportion of subjects with a ≥ 50% reduction in the Total Symptom Score (TSS) of the modified 
MFSAF diary from baseline to the end of Cycle 6. Both endpoints are measures for 
demonstrating clinical benefit in the proposed population. The response rate per primary
endpoint was 36.5% and 40.2% at the 400 mg (proposed dose for this study) and 500 mg daily 
dose respectively vs 1% on the placebo arm. The response rate at Cycle 6 as recommended by 
IWG-MRT was of 46.9% and 49.5% in patients treated with the 400 mg and 500 mg daily doses 
respectively. A total of 36.3% and 34.1% of subjects at the dose of 400 mg and 500 mg doses 
respectively achieved a ≥ 50% reduction in TSS compared with 7.1% of subjects receiving 
placebo. Median duration of response (#35% reduction in spleen volume) was 10.4 months for 
responders from both active groups (400-mg and 500-mg groups). The most common treatment-
emergent adverse events (TEAEs) of all grades reported in the fedratinib 400-mg daily dose 
group were diarrhea 65.6%, nausea 63.5%, anemia (G3 and G4) 42.7%, vomiting 41.7%, fatigue 
15.6%, and peripheral edema 15.6%. The 400-mg dose was confirmed to be better tolerated than 
the 500-mg dose, in particular with fewer subjects reporting Grade 3 or 4 TEAEs (54.2% and 
70.1%, respectively), treatment-emergent serious adverse events (SAEs) (27.1 % and 30.9%, 
respectively) and TEAEs leading to permanent treatment discontinuation (13.5% and 24.7%, 
respectively) (Pardanani, 2015).
The single-arm Phase 2 JAKARTA2 study (ARD12181) enrolled patients with intermediate-1 
with symptoms, intermediate-2 or high-risk MPN-associated myelofibrosis who have been 
previously treated with ruxolitinib. The primary endpoint was response rate, which was defined 
as the proportion of subjects who have a ≥ 35% reduction from baseline in spleen volume to the 
End of Cycle 6 in the per protocol defined population. 
As in the Phase 3 JAKARTA study, one of the key secondary endpoints was symptom response 
rate (SRR), defined as the proportion of subjects with a ≥ 50% reduction in the TSS using the 
modified MFSAF diary from baseline to the end of Cycle 6.
Resistance to ruxolitinib was defined as any one of the following: a) lack of response: absence of 
response; b) disease progression: spleen size increase during ruxolitinib treatment; or c) loss of 
response at any time during ruxolitinib treatment. Intolerance to ruxolitinib was defined as any 
one of the following: a) hematologic toxicity (anemia, thrombocytopenia, others); b) non-
hematologic toxicity.
The overall spleen response rate (proportion of patients with ≥35% reduction from baseline in 
spleen volume to the End of Cycle 6) was 55.4%. A total of 25.6% of subjects achieved a ≥50% 
reduction in TSS.
All 97 patients had at least 1 TEAE (all grades); Grade 3 or 4 TEAEs were reported by 62.9% 
patients. The most common nonhematologic TEAEs (reported by ≥10% of patients) (all grades) 
were gastrointestinal disorders including diarrhea (61.9%), nausea (55.7%), and vomiting 
(41.2%). The most common hematologic TEAEs (reported by > 10 patients) (all grades) were 
anemia (48.5%) and thrombocytopenia (26.8%). Thirty-eight and one-tenth percent experienced 
Grade 3 or 4 anemia and 21.6% experienced Grade 3 or 4 thrombocytopenia. No Grade 5 
hematologic TEAEs were reported. Anti-infectives for systemic use were given to 55.7% 
patients in the study (Harrison, 2017).
The JAKARTA2 study was initiated shortly after ruxolitinib was approved and at the time, there 
were no well-established criteria to define resistance or intolerance. Therefore, subjects were 
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
23
FEDR-MF-002 Amendment 4 Final:  23 April 2021
classified as resistant or intolerant to ruxolitinib per the Investigators’ assessments and, to be 
eligible for the study, they were only required to have been treated with ruxolitinib for 14 days at 
a minimum.
Subsequently, analyses were performed on subjects enrolled in the JAKARTA2 study and 
determined to be relapsed/refractory or intolerant to ruxolitinib based on more stringent criteria 
recommended by MF experts. For 79/97 subjects that meet the more stringent definition for 
relapsed/refractory or intolerant to ruxolitinib, 24 subjects (30.4%) in the intent-to-treat (ITT)
population achieved ≥ 35% spleen volume reduction at the end of Cycle 6 and 20 out of 74 
subjects (27%) in the MFSAF analysis population achieved a ≥ 50% reduction in the symptom 
score relative to baseline.
Please refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of
fedratinib.
1.3.
Wernicke Encephalopathy (WE) in Patients Treated with Fedratinib
On 15 November 2013, all clinical studies ongoing at the time in the fedratinib clinical program 
were placed on clinical hold by the FDA. The hold decision was made based on provided 
preliminary data on fatal and serious cases of WE and heart failure that occurred in patients 
treated with fedratinib. Three days later, the fedratinib clinical program was terminated by the 
previous sponsor and all subjects were permanently discontinued from fedratinib treatment. 
Supplementation with thiamine (as well as monitoring of thiamine levels) and follow-up for 
safety for at least 90 days after the last dose of fedratinib were offered to all subjects in the 
ongoing studies including those who had previously been discontinued. No cases of WE were 
observed during this period. 
No subject has been treated with fedratinib in the clinical trial setting since December 2013. 
Independent central review of the data from all patients was performed to assess for potential 
cases of WE. Ultimately, 8 potential cases of WE were identified among 807 healthy subjects 
and patients who were enrolled and treated in the fedratinib clinical trials (193 healthy 
volunteers, 75 patients with solid tumors, and 539 patients with MF). No case of WE was 
observed at doses of 400 mg or lower.  Further analysis of the data surrounding these events 
suggest that while cases of WE did occur in subjects treated with fedratinib, the subjects had 
considerable predisposing factors that are known to lead to WE in any population. In addition, 
preclinical studies demonstrated that fedratinib does not have an effect on the thiamine receptor 
function (data on file), it does not actively cause WE. Taken together, the possible WE 
experienced by these patients is likely related to thiamine deficiency due to increased use in a 
hypermetabolic environment found in malignancies and decreased availability from underlying 
poor nutrition coupled with gastrointestinal adverse events experienced by these patients. 
The FDA removed the clinical hold on 18 August 2017. The agency required that risk mitigation 
for WE be implemented for further clinical studies.
This study includes routine thiamine monitoring and supplementation in order to mitigate the 
risk for WE in this study. Additionally, the use of fedratinib 400 mg daily dosing with proactive 
treatment of nausea, vomiting, and diarrhea will further help to prevent thiamine deficiency in 
the study patients.
Approved
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
24
FEDR-MF-002 Amendment 4 Final:  23 April 2021
1.4.
Rationale
1.4.1.
Study Rationale and Purpose
MPN-associated myelofibrosis (MF) is a serious and life-threatening disease. The only approved 
therapy currently available is the JAK1/2 inhibitor ruxolitinib.
For patients who have been previously treated with ruxolitinib and who failed first-line 
treatment, there is no approved therapy and prognosis for these patients is poor. 
Fedratinib is a potent and selective, orally available JAK2 inhibitor. 
The single-arm Phase 2 JAKARTA2 study of fedratinib enrolled patients with intermediate-1 
with symptoms, intermediate-2 or high-risk MPN-associated myelofibrosis who were previously 
treated with ruxolitinib. In that study, fedratinib at a starting dose of 400 mg daily, resulted in a 
reduction in splenomegaly at the end of cycle 6 (last observation carried forward) (response rate 
55.4%) and improvement in symptom burden (response rate: 25.6%).
The study was affected by the clinical hold mandated by the US FDA of the fedratinib 
development program in November 2013 due to reports of Wernicke encephalopathy (WE) and 
all subjects on treatment with fedratinib were discontinued from treatment. 
Based on the presentation of further analyses, the US FDA removed the clinical hold in August 
2017 and required that steps be implemented to mitigate the risk for Wernicke encephalopathy 
for future clinical studies.
The present study is a multicenter, randomized, open-label, Phase 3 study designed with the 
purpose to assess the efficacy of fedratinib administered at the dose of 400 mg daily orally in 
successive 28-day cycles as compared to BAT and to further evaluate the safety of fedratinib in 
subjects previously treated with ruxolitinib and with DIPSS-intermediate-2 or high-risk primary 
myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia 
myelofibrosis.
This study will also implement and assess the effectiveness of risk mitigation strategies for 
Encephalopathy, including Wernicke’s, including routine thiamine monitoring and 
supplementation, monitoring for signs and symptoms of Encephalopathy, including WE, and 
proactive management of nausea, vomiting, and diarrhea to prevent thiamine deficiency.
The study will also provide additional data to specify population 
Patient-
Reported Outcomes and Health-related Quality of Life.
1.4.2.
Rationale for the Study Design
This is a multicenter, 2:1 randomized, Phase 3 study with 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 implement and to 
assess the effectiveness of risk mitigation strategies for Encephalopathy, including Wernicke’s
and for gastrointestinal (GI) adverse events.
The primary endpoint is the proportion of subjects who have a ≥ 35% reduction in spleen volume 
(response rate measured by MRI or computed tomography [CT] scan and assessed by central 
Approved
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
25
FEDR-MF-002 Amendment 4 Final:  23 April 2021
blinded review) at the end of Cycle 6. The primary endpoint follows the established response 
criteria by IWG-MRT (Tefferi, 2013).
With the assumption of a 20% drop-out rate and a true response rate (considering drop-outs) in 
the BAT arm of 10%, in the fedratinib arm of 28%, 192 subjects will yield approximately 90% 
power at a one-sided significance level of 0.025. (Refer to Section 9.3).
The assumption of a 28% spleen volume response rate is in line with the results of the 
JAKARTA-2 study and the assumption of a 10% spleen volume response rate for BAT is 
derived from similar studies, such as SIMPLIFY-2 and PERSIST-2 (Harrison, 2018b; 
Mascarenhas, 2018), considering the variability and limited predictably of BAT use in this study. 
Considering the potential lack of therapeutic effect of BAT the crossover will allow subjects
access to fedratinib and provide additional data on safety and efficacy of fedratinib without 
affecting assessment of the primary endpoint of the study. 
Safety will be assessed by evaluating adverse events and laboratory data. Adverse events and 
abnormal laboratory value severity will be graded using Version 5.0 of the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).
Efficacy in terms of spleen response will be objectively assessed by MRI/CT scans that will be 
reviewed centrally by an independent reviewer. Spleen response by palpation as well as 
symptom response will also be assessed.
Symptoms response rate (SRR) will be assessed by the change from baseline to end of cycle 6 of 
symptoms measured by the MFSAF version 4.0. SRR is a key secondary endpoint because 
symptoms are an important aspect of the disease, many of which are driven by splenomegaly.
An additional key secondary endpoint is a spleen response rate (RR25) for the subjects who 
have ≥25% reduction in spleen volume at the end of cycle 6. This addresses the situation in 
subjects previously treated with ruxolitinib that a 35% reduction of the spleen volume might be 
only achieved in a small proportion of subjects.
To ensure subjects are evaluable for the key secondary endpoints, the study will randomize 
subjects with measurable splenomegaly and symptoms score ≥ 1 at baseline. 
1.4.3.
Rationale for Dose, Schedule and Regimen Selection
Fedratinib capsules will be administered orally, once-daily at a dose of 400 mg. 
Dose finding (study TED12037) and dose ranging (study ARD11936) studies with fedratinib 
were performed, with the maximum tolerated dose (MTD) being 680 mg for patients with MPN-
associated myelofibrosis.
In the JAKARTA study, doses of 400 mg and 500 mg were used in separate study arms, and 
while the efficacy in terms of spleen response was similar, the 400-mg dose was better tolerated 
than the 500-mg dose, in particular with fewer subjects reporting Grade 3 or 4 treatment-
emergent adverse events (TEAEs) (70.8% and 78.4%, respectively) and TEAEs leading to 
permanent treatment discontinuation (27.1% and 36.1%, respectively).
Fedratinib dose modifications will be allowed based on observed toxicity to a 300 mg or 200 mg 
daily dose in this study. Provisions are in place to allow further dose reduction for subjects with 
co-medication with moderate or strong Cytochrome P450 3A4 (CYP3A4) inhibitors.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
26
FEDR-MF-002 Amendment 4 Final:  23 April 2021
Currently there is no established standard of care and no approved treatment option after 
previous ruxolitinib treatment. Best available therapy has been used as a comparator in studies 
with subjects previously exposed to ruxolitinib.
1.4.4.
Rationale for Patient-Reported Outcomes
Beyond the risk of progression to AML and reduced survival, patients with myelofibrosis
experience a variety of complications, such as symptomatic enlargement of the spleen and liver, 
anemia, cachexia, and the other MF-associated symptoms. These symptoms and the need to face 
the considerable burden from regular transfusions result in greatly compromised quality of life 
(QoL) in these patients (Mesa, 2007).
In the study protocol, Celgene has identified and prioritized the patient-reported MF-associated 
symptoms (night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left 
side, bone or muscle pain, and fatigue); they are assessed by a specific PRO measure, the 
MFSAF version 4.0. The MFSAF is a specific self-administered and validated PRO tool that has 
been developed to assess MF-associated symptoms and has been used in several prior studies in 
MF population (Harrison, 2012; Mesa, 2013). The MFSAF version 4.0. is the most recent 
version developed in collaboration with industry and the FDA, validated and recommended to be 
used in clinical trials to assess MF symptoms (Gwaltney, 2017).
The European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) version 
3.0 is a self-administered, well-known, and validated questionnaire developed to assess the QoL 
of cancer patients. It is the most commonly used PRO instrument in oncology studies and has 
been used to assess QoL in MF patients (Mesa, 2013).
Data from the registration trial COMFORT-I assessing ruxolitinib versus BAT indicate that both 
patient-assessed MF-symptoms using the MFSAF and Health-related Quality of Life (HRQoL)
assessed by the EORTC QLQ-C30 are improved in MF patients when clinical improvement in 
reduction of splenomegaly is achieved (Mesa, 2013).
These data suggest that patient-assessed MF symptoms and HRQoL should be considered as a 
key endpoint when assessing the efficacy of a novel treatment for this patient population. 
The SRR based on the total symptom score of the MFSAF version 4.0 (proportion of subjects 
with ≥ 50% reduction in MFSAF TSS at end of cycle 6) is assessed as the key secondary efficacy 
endpoint. A 50%-reduction in TSS is an accepted endpoint that has already supported label 
claims in drugs developed MF. The timepoint for its assessment (end of cycle 6) is aligned with 
the timepoint for assessing the primary endpoint (spleen volume response rate). This timeframe 
is considered sufficient to assess an effect of treatment on patient-reported MF-associated 
symptoms and to evaluate the durability of symptom response.
Other PROs assessed by the EORTC QLQ-C30 domains will be considered as secondary 
endpoints. They will be assessed on Day 1 of each treatment cycle, at the End of Treatment 
(EOT) and the 30-day follow-up visit after last dose of study treatment, before the subject 
undergoes any procedure to avoid bias. This schedule would allow to capture any change in 
subject-reported symptoms, functioning level or HRQoL. 
Approved
8.0
v
Approved
1.0
v


Approved
1.0
v


Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
29
FEDR-MF-002 Amendment 4 Final:  23 April 2021
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
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
Secondary Objective(s)
The secondary objectives are:
!
To evaluate the percentage of subjects with at least 50% reduction in myelofibrosis 
(MF)-associated symptoms as measured by the Myelofibrosis Symptom Assessment 
Form (MFSAF) (Appendix B)
!
To evaluate the percentage of subjects with at least 25% spleen volume reduction
(SVR)
!
To evaluate the safety of fedratinib
!
To evaluate the reduction of spleen size by palpation
!
To evaluate durability of spleen response by MRI/CT and by palpation
!
To evaluate the durability of symptoms response
!
To evaluate spleen and disease progression free survival
!
To assess the effectiveness of the risk mitigation strategy for gastrointestinal events 
and Encephalopathy, including Wernicke’s
!
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) (Appendix C)
!
To evaluate Patient-Reported Outcomes (PRO) as measured by the EQ-5D-5L
questionnaire (Appendix D)
!
To evaluate Overall Survival (OS)
Approved
8.0
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Approved
1.0
v


Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
31
FEDR-MF-002 Amendment 4 Final:  23 April 2021
Table 2:
Study Endpoints
Endpoint
Name
Description
Assessment Timeframe
Primary 
Spleen volume 
response rate (RR)
Proportion of subjects who have ≥ 
35% SVR at end of cycle 6 
From Screening to the 
end of Cycle 6
Key 
Secondary
Symptom response 
rate (SRR)
Proportion of subjects with ≥ 50% 
reduction in total symptom scores 
measured by MFSAF at end of cycle 
6
From C1D1 to the end 
of Cycle 6
Spleen volume 
response rate 
(RR25) 
Proportion of subjects who have ≥ 
25% reduction in spleen volume at the 
end of cycle 6
From Screening to the 
end of Cycle 6
Secondary
Safety profile of 
fedratinib
Incidence and severity of all Grade 
AEs per NCI CTCAE (Appendix E) 
Incidence and severity of Grade 3-4 
AEs as per the NCI CTCAE 
(Appendix E), including laboratory 
parameters
From ICF signature up 
until 30 days after last 
dose 
For fedratinib related 
AEs, anytime until the 
last study visit
Spleen response 
rate by palpation
(RRP)
Proportion of subjects who have ≥ 
50% reduction in spleen size by 
palpation at end of cycle 6
From C1D1 to the end 
of Cycle 6
Durability of 
spleen volume 
response (DR)
Duration of ≥ 35% SVR
From screening to the 
End of Treatment visit 
Durability of 
spleen response by 
palpation (DRP)
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
From C1D1 until the 30-
day follow-up after last 
dose visit 
Durability of 
symptoms 
response (DSR)
Duration of ≥ 50% reduction in total 
symptom scores measured by MFSAF
From C1D1 until the 30-
day follow-up after last 
dose visit
Spleen and disease 
progression free 
survival (SDPFS)
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) 
From randomization to 
the End of Survival 
Follow-up 
Approved
8.0
v
Approved
1.0
v


Approved
1.0
v


Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
34
FEDR-MF-002 Amendment 4 Final:  23 April 2021
3.
OVERALL STUDY DESIGN
3.1.
Study Design
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 3 multicenter, open-label, randomized, multinational study in subjects previously 
treated with ruxolitinib and with Dynamic International Prognostic Scoring System (DIPSS) 
(Appendix F) intermediate-2 or high risk PMF (Appendix G and Appendix H), post-PV or post-
ET MF (Appendix I).
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. The overall study design is 
described in Figure 1, with more detail for each period of the study design found in Section 6.
Screening Period
All enrolled subjects will undergo screening procedures during the screening period which must 
be completed within 28 days prior to the start of study treatment. This will serve to determine 
subject eligibility based on all inclusion and exclusion criteria defined in the protocol. For 
subjects that are receiving ruxolitinib during the screening period or that have potentially 
reversible laboratory abnormalities (or other criteria that excludes subjects from randomization) 
detected during screening, the screening period may be extended to 35 days (additional 7 days).
If needed, randomization will be preceded by a taper-off period for previous treatment according 
to the prescribing information and a washout period for previous treatment in line with the 
inclusion and exclusion criteria which is to be started at least 14 days before randomization.
When screening a subject, it is necessary to account for the required duration of the ruxolitinib 
washout period of 14 days and the need to perform the MRI or CT scan within 3 days before 
randomization.
Randomization
Upon confirmation of eligibility, subjects will be randomized 2:1 to receive treatment with 
fedratinib at a dose of 400 mg once daily orally continuously or treatment with BAT.
Treatment Period
Cycles are defined for administrative purposes as 4-week (28 day) periods irrespective of the 
assigned treatment arm. Unless otherwise noted, visit windows are ± 3 days except for MRI/CT 
scan procedures which have a visit window of ± 7 days. For the first 3 cycles, site visits will be 
performed on Day 1 and Day 15 and thereafter on Day 1 for the subsequent cycles. At Cycle 1 
Day 8 the site will contact the subject by telephone to assess occurrence and discuss management 
of nausea, vomiting and diarrhea. Subjects may continue treatment with study treatment until 
unacceptable toxicity, lack of therapeutic effect, progression of disease according to the IWG-
MRT 2013 criteria or until consent is withdrawn.
Subjects may crossover from the BAT arm to the fedratinib arm at any time before the Cycle 6 
response assessment in the event of a confirmed progression of splenomegaly (by MRI/CT scan) 
or after the Cycle 6 response assessment. 
Approved
8.0
v
Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
35
FEDR-MF-002 Amendment 4 Final:  23 April 2021
Subjects on the BAT arm that discontinue treatment before cycle 6 response assessment without 
confirmed progression of splenomegaly are allowed to stay on study and eventually cross-over at 
cycle 6 response assessment. 
All subjects will be monitored for adverse events during the study.
All subjects discontinued from protocol-prescribed therapy for any reason will be followed for a 
period of 30 days following the last dose of study drug to collect safety data. 
Survival Follow-up Period
All subjects discontinued from protocol-prescribed therapy for any reason will be followed for 
survival, subsequent therapies, new malignancy and progression of myelofibrosis to acute 
myeloid leukemia (AML) every 3 months until death, lost to follow-up, withdrawal of consent
for further data collection, or study closure, whichever comes first.
Figure 1:
Overall Study Design
AML = acute myeloid leukemia; AE = adverse events; ANC = absolute neutrophil count; DIPSS = Dynamic International 
Prognostic Scoring System; GI = gastrointestinal; Int = intermediate; LCM = left costal margin; MF = myelofibrosis; MPN = 
myeloproliferative neoplasm; MRI = magnetic resonance imaging; PB = peripheral blood; PO = oral; QoL/PRO = quality of 
life/patient-reported outcomes; SVR = spleen volume reduction; WE = Wernicke encephalopathy.
3.2.
Study Duration for Subjects 
The average treatment period for each subject in the fedratinib arm is expected to be 
approximately 12 months. Subjects receiving BAT may crossover to fedratinib treatment as 
Approved
8.0
v
Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
36
FEDR-MF-002 Amendment 4 Final:  23 April 2021
specified in Section 6.5. The actual study duration for an individual subject will be dependent 
upon the actual treatment duration and survival Follow-up duration and is expected not to exceed 
5 years. This duration includes at least 36 months for treatment and follow-up, or until death, lost 
to follow-up, withdrawal of consent for further data collection, or study closure whichever comes 
first.
3.3.
End of Trial
The End of Trial is defined as the date of the last visit of the last subject to complete the Survival 
Follow-up or the date of receipt of the last data point from the last subject that is required for 
primary, secondary
, as prespecified in the protocol, whichever is the 
later date. 
End of trial is expected approximately 3 years after the last subject is randomized.
The trial completes when all key endpoints and objectives of the study have been analyzed. The 
subjects who remain on active treatment and are continuing to derive benefit may have available 
to them either a roll-over protocol, or alternative means for providing study drug to them after 
study closure.
Approved
8.0
v
Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
37
FEDR-MF-002 Amendment 4 Final:  23 April 2021
4.
STUDY POPULATION
4.1.
Number of Subjects 
The multinational study will enroll approximately 192 subjects previously treated with 
ruxolitinib (as per the definition below) and with DIPSS-intermediate-2 or high risk PMF, post-
PV MF or post-ET MF.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
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) (Appendix J) 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 (Appendix G and Appendix H), or diagnosis of post-
ET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria (Appendix I), 
confirmed by the most recent local pathology report 
4. Subject has a DIPSS Risk score of Intermediate-2 or High (Appendix F)
5. Subject has a measurable splenomegaly during the screening period as demonstrated by 
spleen volume of ≥ 450 cm3 by MRI or CT-scan (refer to Section 6.1) 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) 
a.
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
b. 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
Approved
8.0
v
Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
38
FEDR-MF-002 Amendment 4 Final:  23 April 2021
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:
a.
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.
b. 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.
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation 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; Intravaginal; Transdermal; Progestogen-only hormonal contraception associated with 
inhibition of ovulation:  Oral; Injectable hormonal contraception; Implantable hormonal contraception; 
Placement of an intrauterine device; Placement of an intrauterine hormone-releasing system; Bilateral tubal 
occlusion; Vasectomized partner.
Approved
8.0
v
Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
39
FEDR-MF-002 Amendment 4 Final:  23 April 2021
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from randomization:
1. Any of the following laboratory abnormalities:
a.
Platelets < 50 x 109/L
b. Absolute neutrophil count (ANC) < 1.0 x 109/L
c.
White blood count (WBC) > 100 x 109/L
d. Myeloblasts ≥ 5 % in peripheral blood
e.
Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification 
of Diet in Renal Disease [MDRD] formula) (Appendix K)
f.
Serum amylase or lipase > 1.5 x upper limit of normal (ULN)
g. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper 
limit of normal (ULN)
h. 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 (refer to Section 8 and Appendix L)
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
Approved
8.0
v
Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib 
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
40
FEDR-MF-002 Amendment 4 Final:  23 April 2021
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) (Appendix M)
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
Approved
8.0
v
Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
41
FEDR-MF-002 Amendment 4 Final:  23 April 2021
5.
TABLE OF EVENTS
Table 3:
Table of Events
Visits 
Screen-
ing 
Treatment Period
a
30-Day 
Follow-
up after 
last dose
(+ 7 
days)
Survival 
Follow-up 
every 3 
months 
(± 14 days)
Cycle 1
Cycle 2
Cycle 3 b
Cycle 4 Cycle 5 Cycle 6
b
Cycle ≥ 7
Response 
Assessment
c
End of 
Treatment 
(EOT)
Days
-28 to -1 Day 1 Day 8 Day 15 Day 1 Day 15 Day 1 Day 15 Day 1
Day 1
Day 1
Day 1
End of C3, 6, 
12, 18, 24 (±7D)
-
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion / Exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Myelofibrosis disease history
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior therapies for disease 
under study
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
IRT subject registration
X
X
-
-
-
-
-
-
-
-
-
-
-
X
-
-
Height 
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Treatment 
Fedratinib dispensing to 
subject 
-
X
-
-
X
-
X
-
X
X
X
X
-
-
-
-
Fedratinib accountability
-
-
-
-
X
-
X
-
X
X
X
X
-
X
-
-
Fedratinib administration
-
Once daily with an evening meal including daily dose of thiamine
-
-
Safety assessments 
Pregnancy test for FCBP only
X
X
-
-
X
-
X
-
X
X
X
X
-
-
X
-
Adverse events
From ICF signature until 30 days after last dose of study treatment and anytime thereafter if suspected to be related
Risk mitigation for GI & 
Encephalopathy including WE
From ICF signature until 30 days after last dose of study treatment
-
Prior/concomitant medications
From 28 days prior to C1D1 until 30 days after last dose of study treatment
-
Approved
8.0
v
Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
42
FEDR-MF-002 Amendment 4 Final:  23 April 2021
Table 3:
Table of Events (Continued)
Visits 
Screen
-ing 
Treatment Period 
a
30-Day 
Follow-
up after 
last dose
(+ 7 
days)
Survival 
Follow-up 
every 3 
months 
(± 14 days)
Cycle 1
Cycle 2
Cycle 3 b
Cycle 4 Cycle 5 Cycle 6
b
Cycle ≥ 7
Response 
Assessment 
c
End of 
Treatment
(EOT)
Days
-28 to -1 Day 1 Day 8 Day 15 Day 1 Day 15 Day 1 Day 15 Day 1
Day 1
Day 1
Day 1
End of C3, 6, 
12, 18, 24 (±7D)
-
Prior/concomitant procedures
From 28 days prior to C1D1 until 30 days after last dose of study treatment 
-
Phone call for management of 
nausea, vomiting, diarrhea
-
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
Vital signs including weight
X
X
-
-
X
-
X
-
X
X
X
X
-
X
X
-
Physical exam
X
X
-
-
X
-
X
-
X
X
X
X
-
X
X
-
Transfusion burden
assessment
From 84 days prior to C1D1 until 30 days after last dose of study treatment
-
Local 12-lead ECG
X
At any time if clinically indicated
-
Hematology 
X
X
-
X
X
X
X
X
X
X
X
X
-
X
X
-
Serum Chemistry 
X
X
-
X
X
X
X
X
X
X
X
X
-
X
X
-
Lipid panel
X
X
X (every 
3rd cycle)
X
Urinalysis & Coagulation
X
At any time if clinically indicated
-
Thiamine (whole blood 
sample) d
X
X
-
-
X
-
X
-
-
-
X (every 
3rd cycle)
-
-
X
-
-
Cognitive assessments 
(MMSE) d
X
-
-
-
X
-
X
-
-
-
X (every 
3rd cycle)
-
-
X
-
-
Assessment for survival 
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
X
Progression of MF to AML 
assessment
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
X
Subsequent therapies for 
disease under study
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
X
ECOG PS 
X
X
-
-
X
-
X
-
X
X
X
X
-
X
X
-
Approved
8.0
v
Approved
1.0
v


Approved
1.0
v


EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
44
FEDR-MF-002 Amendment 4 Final:  23 April 2021
6.
PROCEDURES
Any questions regarding the protocol should be directed to the Celgene-Impact Medical Monitor
or designee. All data obtained from these assessments must be recorded in the subject’s source 
documentation. Refer to the eCRF (electronic Case Report Form) completion guidelines for 
additional information related to data entry requirements. Procedures will be performed as stated 
in the sections below. Detailed instructions for sample collection, processing, storage, shipping 
and handling will be contained in a separate laboratory manual provided to the sites. Waivers or 
deviations to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
In the event that immediate hematology / biochemistry / urinalysis / coagulation / thiamine 
values are needed for clinical decisions, local laboratory results may be used pending the 
outcome of the central laboratory assessment. However, matching samples must always be sent 
to the central laboratory and clinical decisions and assessments must be reconciled with the 
results of the central laboratory. The results of these additional analyses will be recorded in the 
subjects’ CRF as applicable as described in Section 10.
Procedures and assessments are described in detail below. The timing of all the below 
assessments / procedures is specified in the Table of Events, Table 3.
6.1.
Screening Period
All screening procedures and assessments are performed during a subject’s screening period in 
order to establish eligibility and to document relevant medical and demographic data (eg, 
medical history and prior/concomitant medications). The written informed consent form must be 
signed before any study-specific procedures are performed and any samples are collected for 
study-specific analysis. Subject eligibility is established by the Investigator by confirming all 
inclusion and exclusion criteria are satisfied. The MRI or CT scan for spleen volume assessment 
should be performed within 3 days before randomization. Inclusion of a subject can be based on 
a local MRI or CT scan assessment demonstrating a spleen volume of ≥ 450 cm3. Documentation
used to establish eligibility should be forwarded to the Sponsor to ensure documentation is 
sufficient from a regulatory and quality perspective. The Sponsor may contact the study site for 
additional information if there is any deficiency in the documentation provided. Failure to satisfy 
any entry criterion will preclude a subject from receiving the first study treatment dose.
The following will be performed during the 28-day Screening Period as specified in the Table of 
Events (Table 3) after informed consent has been obtained:
!
Interactive Response Technology (IRT) Subject Registration:
Registration of the subject into the IRT system.
!
Assessment of inclusion/exclusion criteria for study eligibility 
Screening evaluations will be performed for all subjects to determine eligibility. 
Screening laboratory values must demonstrate subject eligibility, but may be repeated 
within the screening window, if necessary. 
Approved
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
45
FEDR-MF-002 Amendment 4 Final:  23 April 2021
!
Demographics
Information about the subject’s demographics (if allowed per local country 
regulations; including, but not limited to: date of birth, sex, race, and ethnicity).
!
Medical history (including Disease History)
Relevant medical history, including potential alcohol abuse, and current medical 
conditions, including MF signs and symptoms, must be recorded on the appropriate 
Case Report Form (CRF) pages at screening. History of myelofibrosis disease
including its prior treatments, response to prior therapy with ruxolitinib and current 
DIPSS (Dynamic International Prognostic Scoring System) Score, other prior 
malignancies will also be recorded on the appropriate CRF pages. This may include 
relevant information related to original MF diagnosis and/or other past malignancies 
as applicable.
Review of historical bone marrow biopsy information will be used to confirm MPN-
associated myelofibrosis diagnosis.  The report should come from the most recent 
local bone marrow biopsy performed and should contain the mutational status of the 
disease (eg, JAK2, MPL, and CALR). 
Information regarding transfusion history (at least 84 days prior to and including the 
randomization date), including pretransfusion hemoglobin (Hgb) levels, number of 
units transfused and dates of transfusions, will be collected and reported in the 
appropriate eCRF. Any transfusions given at outside institutions must also be 
collected. 
!
Pregnancy testing
Pregnancy testing is required for all female subjects of childbearing potential. The 
Investigator will appraise a female subject as a FCBP according to the definition 
included in the eligibility criteria (Section 4.2). Justification must be recorded in the 
eCRF and the source document. Pregnancy testing is not required for non-FCBP 
subjects. Two urine (or serum) pregnancy tests will be performed to assess subject 
eligibility during screening with one test within 72 hours prior to the first 
administration of study treatment, if the initial pregnancy test did not already occur 
within 72 hours of dosing (negative results required for IP administration).
!
Adverse events
All subjects will be monitored for AEs including AESIs (AE of Special Interest) 
during the study as described in Section 10.
Information about common side effects already known about fedratinib will be 
included in the subject informed consent form and should be discussed with the 
subject as needed during the study. This information can also be found in the IB or 
will be communicated between IB updates in the form of Investigator notifications.
!
Risk mitigation for Gastrointestinal toxicity & Encephalopathy, including 
Wernicke’s
Refer to Section 7.4 and Section 7.5. 
Approved
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Approved
1.0
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
46
FEDR-MF-002 Amendment 4 Final:  23 April 2021
!
Height
Height will be measured only during the screening period.
!
Symptoms Response Assessment using MFSAF version 4.0 
Refer to Section 6.3.1 for more information.
!
Prior/concomitant medications 
Information relating to prior/concomitant medications are to be reported on the 
appropriate eCRF pages.  Refer to Section 8 for more information. The details of 
prior treatment by ruxolitinib with outcomes will be recorded in the subject’s eCRF.
!
Prior/concomitant procedures
Information relating to prior/concomitant procedures are to be reported on the 
appropriate eCRF pages.  Refer to Section 8 for more information.
!
Physical exam 
Information about the physical examination for clinically significant findings 
including assessment of abnormal eye movements, assessment for cerebellar 
abnormalities, spleen palpation, as well as spleen size assessment are to be captured 
in the eCRF.
!
Vital signs including weight
Information regarding vital signs including seated blood pressure (systolic and 
diastolic), body temperature, heart rate and weight are measured and reported on the 
appropriate eCRF.
!
Electrocardiogram (ECG)
A 12-lead ECG is to be performed locally at the site.  The following ECG parameters 
will be recorded on the respective eCRF(s):  Heart rate (HR), PR interval, QRS 
duration, QT, QTc.  The Investigator will review the results and assess as normal, 
abnormal – not clinically significant, or abnormal – clinically significant, and report 
the abnormal finding(s) on the appropriate eCRF.  If the ECG is abnormal, the 
Investigator should consult a cardiologist if deemed appropriate. An ECG will be 
performed at screening and if clinically indicated thereafter.
!
Hematology 
This assessment may include the following: red blood cells (RBC) count, 
hemoglobin, hematocrit, mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), mean corpuscular volume (MCV), platelet 
count, white blood cell (WBC) count, RBC morphology, and differential cell count 
including myeloblasts. Detailed instructions for sample collection, processing, 
storage, shipping and handling will be contained in a separate laboratory manual 
provided to the sites.  
Approved
8.0
v
Approved
1.0
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
47
FEDR-MF-002 Amendment 4 Final:  23 April 2021
!
Serum Chemistry
This assessment may include the following: total bilirubin, direct bilirubin, gamma-
glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), bicarbonate, alkaline phosphatase (AP), lactate 
dehydrogenase (LDH) amylase, lipase, total protein, albumin, globulin, sodium, 
potassium, chloride, calcium, phosphate, magnesium, glucose, urea, creatinine and 
creatinine clearance as per the Modification of Diet in Renal Disease (MDRD) 
formula, blood urea nitrogen (BUN) and uric acid. Detailed instructions for sample 
collection, processing, storage, shipping and handling will be contained in a separate 
laboratory manual provided to the sites.
!
Lipid panel
This assessment may include the following: cholesterol, high-density lipoprotein 
cholesterol (HDL), low-density lipoprotein cholesterol (LDL), very low-density 
lipoprotein cholesterol (VLDL) and triglycerides.
!
Coagulation
This assessment may include the following: prothrombin time/international 
normalized ratio and activated partial thromboplastin time. Coagulation testing will 
be performed at screening and if clinically indicated thereafter.
!
Urinalysis
This assessment may include the following: macroscopic (eg, color, blood, glucose, 
ketones, leukocyte esterase, nitrite, pH, protein, specific gravity and bilirubin), 
microscopic (eg, RBC, WBC, casts, crystals, bacteria and epithelial cells). Urinalysis 
testing will be performed at screening and if clinically indicated thereafter.
!
Thiamine level
Information regarding thiamine level in whole blood will be tested according to the 
Table of Events (Section 5) and as clinically indicated.
!
Cognitive assessment - Mini-Mental State Examination
Information regarding the cognitive status will be performed using the Mini-Mental 
State Examination (MMSE): to objectively assess for signs/symptoms of 
encephalopathy.
If the MMSE-2 SV (standard version) questionnaire (Appendix P) is unavailable at 
the time of study start, the original version of the MMSE questionnaire may be used. 
This questionnaire is to be completed as specified in the Table of Events (Table 3)
and as clinically indicated.
!
Spleen volume by MRI/CT scan 
Spleen volume will be assessed at the study site (MRI or CT Scan if MRI is 
contraindicated) during screening. The screening MRI/CT scan needs to be performed 
within 3 days prior to randomization. The locally assessed spleen volume will be 
recorded in the appropriate CRF pages. The same method MRI or CT scan should be 
Approved
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v
Approved
1.0
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
48
FEDR-MF-002 Amendment 4 Final:  23 April 2021
used consistently throughout the study. MRI/CTs will be reviewed centrally. The 
central review will be blinded for arm assignment, treatment and dose levels.
!
Spleen size by palpation
Spleen size palpation in cm below left costal margin (LCM) will be assessed at the 
study site. 
!
Eastern Cooperative Oncology Group (ECOG) performance status
Performance status will be assessed by the Investigator using the ECOG criteria 
provided in Appendix J.
!
Biomarker assessments 
Blood and saliva (saliva sample taken at screening only) for evaluation of biomarkers, 
such as, but not limited to, mutational analysis, cytogenetics, signaling pathways,
gene expression profiling, inflammatory and fibrogenic circulating proteins, including 
cytokines, circulating cells such as blasts (CD34+ cells) and immune cells.  If 
collection is required on fedratinib dosing days, samples should be obtained prior to 
administration of fedratinib. 
Evaluation of some of the samples may require blood samples to be collected and 
processed as multiple samples to allow for the possibility of future analyses. 
A blood and saliva sample will be drawn for biomarker assessments. 
Specified screening assessments must take place within 28 days after the date of the informed 
consent form signature. For subjects that are on ruxolitinib at the start of the screening period or 
who have a laboratory abnormality detected during screening, the screening period may be 
extended to 35 days to allow for retesting to demonstrate resolution of the laboratory 
abnormality. In case a subject has a laboratory parameter related to an exclusion criterion that 
was under the influence of a treatment or medication (eg, platelet transfusion in the last 7 days,
granulocyte-colony stimulating factor (G-CSF) in last 14 days) retesting needs to be performed 
before randomization after an appropriate washout period (refer to Section 4.3). 
Subjects who fail screening for study entry may be rescreened if it is reasonable to believe they 
will meet eligibility criteria during rescreening. If screening assessments are not within the 
allowed screening period, the rescreened subject must reconsent to participation in the study by 
signing a new and current informed consent form.
6.2.
Randomization of a Subject to the Study 
All the screening evaluations must be completed, and eligibility criteria must be verified by the 
responsible Investigator. The appropriate documentation may be reviewed by the Sponsor prior 
to a subject receiving the first study treatment dose. Information needed to stratify a subject must 
be available at randomization.
Subjects will be randomized 2:1 to fedratinib or best available therapy (BAT). 
Stratification at Randomization will be done according to:
!
Spleen size by palpation: < 15 cm below LCM versus ≥15 cm below LCM
Approved
8.0
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Approved
1.0
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
49
FEDR-MF-002 Amendment 4 Final:  23 April 2021
!
Platelets ≥ 50 to < 100 x 109/L versus platelets ≥ 100 x 109/L
!
Refractory or relapsed to ruxolitinib treatment versus intolerance to ruxolitinib 
treatment
See inclusion criteria #7 (a versus b). In case both apply, the criteria for 
refractory/relapsed will be used for stratification.
Randomization of the subject (inclusion in the Treatment Period) will occur via Interactive 
Response Technology (IRT) to enable automated tracking and replenishment of fedratinib study 
treatment. Specific contact information and instructions will be provided to each study site.
The IRT randomization should be performed as close as possible to the planned first dose of 
study treatment to avoid enrolling a subject who ultimately does not receive study treatment for 
any reason. The first dose of study treatment should be administered at the site on the day of 
randomization but may be delayed for up to 3 days if necessary, for logistical reasons.
If screening assessments are performed within 7 days of the C1D1 date, safety laboratory and 
physical examinations will not need to be repeated during the C1D1 visit except for hematology 
laboratory assessments.
The BAT assigned will be documented as study treatment on the appropriate pages of the 
electronic case report form (eCRF).
6.3.
Treatment Period 
The following procedures/evaluations will be performed at the frequency specified in the Table 
of Events (Table 3) during the Treatment Period.  
Unless otherwise specified, all study visits during the Treatment Period must occur within ± 3 
days of the scheduled day except for MRI/CT scan procedures which have a visit window of ±7 
days. For the first 3 cycles, site visits will be performed on Day 1 and Day 15 and thereafter on 
Day 1 for the subsequent cycles. At Cycle 1 Day 8 the site will contact the subject by telephone 
to assess management of nausea, vomiting and diarrhea.
The procedures/evaluations should be performed prior to dosing on the visit day, unless 
otherwise specified. The following will be performed at treatment visits as specified in the Table 
of Events (Section 5):
!
Pregnancy testing: As detailed in Section 6.1
!
Prior/concomitant medications and procedures: As detailed in Section 6.1
!
Phone call for management of nausea, vomiting, diarrhea: will be assessed and 
managed by telephone contact
!
Vital signs, Physical exam and weight: As detailed in Section 6.1
!
Electrocardiogram (ECG): As clinically indicated (detailed in Section 6.1)
!
Hematology: As detailed in Section 6.1
Before starting each treatment cycle, a hematology lab results including ANC, 
platelet (PLT) and RBC must be available
Approved
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Approved
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Approved
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Approved
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Approved
1.0
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
54
FEDR-MF-002 Amendment 4 Final:  23 April 2021
6.4.
Response Assessment
Response assessments should occur at the end of C3, C6, C12, C18, C24 and at the end of every 
sixth (6th) cycle as applicable afterwards. The response assessment can be combined with the 
Day 1 visit of the subsequent cycle or End of Treatment visit. The following assessments will be 
performed:
!
Symptoms response assessment: Refer to Section 6.1
!
Spleen volume by MRI/CT scan: Refer to Section 6.1
!
Spleen size by palpation: Refer to Section 6.1
In case there are signs of progression of the splenomegaly (eg, by palpation) an MRI/CT scan 
can be performed to confirm at any time during the study. 
If a bone marrow assessment is performed as per standard of care, in addition to the assessments 
described above, the Investigator will assess response, for example, in terms of complete 
response (CR),partial response (PR), relapse, cytogenetic and molecular response as per IWG-
MRT 2013 (Tefferi, 2013).
6.5.
Crossover
Subjects in the BAT arm may crossover to receive fedratinib treatment. 
One of the following criteria must be fulfilled: 
1. Subject has completed the End of Cycle 6 response assessment including MRI/CT scan 
within 28 days before crossover
2. Subject has not completed the End of Cycle 6 response assessment but has demonstrated 
confirmed progression of splenomegaly.
Confirmed progression of splenomegaly is defined as enlargement of spleen volume by 
MRI/CT scan (within 28 days before crossover) of ≥ 25% compared to the subject’s 
baseline as assessed by the central imaging laboratory.
Note: In case of suspected progression of splenomegaly, a response assessment can be 
performed (refer to the Section 6.4) for confirmation of progression at any time. MRI/CT 
scans must be sent to the designated central imaging review laboratory and marked for 
expedited processing. 
The presence of any of the following will exclude a subject from crossover to fedratinib 
treatment:
1. Any of the following laboratory abnormalities assessed within 28 days before cross-over: 
!
Platelets < 25 x 109/L or Platelets < 50 x 109/L if associated with major bleeding
Approved
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Approved
1.0
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
55
FEDR-MF-002 Amendment 4 Final:  23 April 2021
!
Absolute neutrophil count (ANC) < 0.5 x 109/L
!
Myeloblasts ≥ 5 % in peripheral blood
!
Estimated glomerular filtration rate < 30 mL/min/1.73 m² (as per the Modification of 
Diet in Renal Disease [MDRD] formula) (Appendix K) 
!
Serum amylase or lipase > 2.0 x ULN 
!
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN 
!
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 with signs indicating transformation/progression to blast phase of myelofibrosis
3. Subject has received ruxolitinib any other JAK inhibitor or hydroxyurea within 14 days 
prior to crossover 
4. 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 crossover
5. 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 
6. 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 (refer to Section 7 and Appendix L)
7. Subject with serious active infection
Eligibility criteria for crossover must be verified by the responsible Investigator. The appropriate 
documentation may be reviewed by the Sponsor prior to a subject receiving the first fedratinib 
dose treatment dose.
If the criteria are met, subjects are eligible for assignment to fedratinib treatment via IRT.
Depending on laboratory results, an adjustment of the fedratinib starting dose (eg, for a low 
glomerular filtration rate [GFR]) may be required. 
After crossover subjects will continue in the study following the schedule of assessments
beginning with the C1D1 assessments with the exception of PK samples that will not be 
collected for subject after crossover.
6.6.
End of Treatment Visit
The treatment period will be concluded by an End of Treatment (EOT) visit performed for 
subjects who are withdrawn from the assigned study treatment (except for those subjects 
crossing over from the BAT arm to the fedratinib treatment) for any reason as soon as possible 
after the decision to permanently discontinue treatment has been made. 
Approved
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
56
FEDR-MF-002 Amendment 4 Final:  23 April 2021
If clinically justified, a subject that needs to discontinue BAT treatment can stay on “no 
treatment” or symptom directed treatment, until a crossover as described above or at latest till 
completion of Cycle 6.
At the time study treatment is discontinued all subjects will undergo the End of Treatment 
assessment.  End of Treatment Visit procedures/assessments may not need to be repeated if 
previously performed within ±7 days of EOT visit. If a subject is discontinued during a regular 
scheduled visit, all EOT procedures should be completed at that visit. 
The following assessments will be performed at the EOT visit as specified in the Table of 
Events (Section 5):
!
IRT subject registration for treatment discontinuation
!
Concomitant medications and procedures: As detailed in Section 6.1
!
Vital signs, Physical exam and weight: As detailed in Section 6.1
!
Electrocardiogram (ECG): As clinically indicated (detailed in Section 6.1)  
!
Hematology: As detailed in Section 6.1
!
Serum chemistry: As detailed in Section 6.1
!
Lipid panel: As detailed in Section 6.1
!
Coagulation: As clinically indicated (detailed in Section 6.1)  
!
Urinalysis: As clinically indicated (detailed in Section 6.1)
!
Thiamine level: As detailed in Section 6.1
!
Transfusion burden assessment: As detailed in Section 6.3
!
Cognitive assessment - Mini-Mental State Examination: As clinical indicated 
(detailed in Section 6.1)
!
Response Assessment: As detailed in Section 6.4
!
Spleen size by palpation: As detailed in Section 6.1
!
Spleen volume by MRI/CT scan: Refer to Section 6.1
!
Eastern Cooperative Oncology Group (ECOG) performance status: As detailed 
in Section 6.1
!
Adverse events: Refer to Section 6.1
!
Accountability of fedratinib treatment 
!
Risk mitigation for gastrointestinal toxicity & Encephalopathy, including 
Wernicke’s: Refer to Section 7.4 and Section 7.5. 
!
Symptoms response assessment: as detailed in Section 6.3
Approved
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v
Approved
1.0
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
57
FEDR-MF-002 Amendment 4 Final:  23 April 2021
!
Health-related Quality of Life Assessments and Patient-Reported Outcomes: as 
detailed in Section 6.3
6.7.
30-Day Follow-up After Last Dose Visit
All subjects will be followed for 30 days after the last dose of study treatment for AE reporting, 
as well as any SAEs made known to the Investigator at any time thereafter that are suspected of 
being related to study treatment, as described in Section 10.1.
The following will be performed as specified in the Table of Events (Section 5, Table 3):
!
Pregnancy testing: As detailed in Section 6.1
!
Concomitant medications and procedures: As detailed in Section 6.1
!
Vital signs, Physical exam and weight: As detailed in Section 6.1
!
Electrocardiogram (ECG): As clinically indicated (detailed in Section 6.1)
!
Hematology: As detailed in Section 6.1
!
Serum chemistry: As detailed in Section 6.1
!
Coagulation: As clinically indicated (detailed in Section 6.1)  
!
Urinalysis: As clinically indicated (detailed in Section 6.1)
!
Thiamine level: As clinically indicated (detailed in Section 6.1)
!
Transfusion burden assessment: As detailed in Section 6.3
!
Survival: Refer to Section 6.8
!
Progression of myelofibrosis to acute myeloid leukemia (AML) assessment: Refer 
to Section 6.8
!
Subsequent therapies for disease under study: Refer to Section 6.8
!
Spleen size by palpation: As detailed in Section 6.1
!
Eastern Cooperative Oncology Group (ECOG) performance status: As detailed 
in Section 6.1
!
Adverse events: Refer to Section 6.1
!
Risk mitigation for gastrointestinal toxicity & Encephalopathy, including 
Wernicke’s: Refer to Section 7.4 and Section 7.5. 
!
Symptoms response: as detailed in Section 6.3
!
Health-related Quality of Life Assessments and Patient-Reported Outcomes: as 
detailed in Section 6.3
6.8.
Survival Follow-up
All subjects discontinued from protocol-prescribed therapy for any reason will be followed for 
survival, subsequent therapies, new malignancy and progression of myelofibrosis to acute 
Approved
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
58
FEDR-MF-002 Amendment 4 Final:  23 April 2021
myeloid leukemia (AML) every 3 months for at least 36 months from the first dose of study 
medication, or until death, lost to follow-up, withdrawal of consent for further data collection, or 
study closure, whichever comes first.
A window of ± 14 days is allowed for post treatment survival follow-up assessments; the visits 
should be performed every 3 months ± 14 days and can be done by a documented telephone 
contact between site and subject.  
6.9.
Unscheduled Assessments or Visits
Should it become necessary to repeat an evaluation (eg, laboratory tests, vital signs, etc.) outside 
of scheduled study visits, or to perform additional evaluations than the ones described in the 
current protocol, the results of these additional evaluations should be recorded in an unscheduled 
visit CRF pages(s). These evaluations should also appear in the subject’s chart and/or other 
source documentation.
In the event that immediate hematology / biochemistry / urinalysis / coagulation / thiamine
values are needed for clinical decisions, local laboratory results may be used pending the 
outcome of the central laboratory assessment. However, matching samples must always be sent 
to the central laboratory and clinical decisions and assessments must be reconciled with the 
results of the central laboratory. The results of these additional analyses will be recorded in the 
subjects’ CRF as applicable as described in Section 10.
Approved
8.0
v
Approved
1.0
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
59
FEDR-MF-002 Amendment 4 Final:  23 April 2021
7.
DESCRIPTION OF STUDY TREATMENT
7.1.
Description of Investigational Product
The Sponsor will supply fedratinib 100 mg capsules in high density polyethylene (HDPE) bottles 
for oral administration and will be labeled appropriately as Investigational Product for this study.
The study drug must be kept at the temperature condition as specified on the label. Fedratinib 
must be stored at temperatures below 30°C.
Other recommended/required concomitant medications per the protocol will be provided by the 
local site. The Sponsor will not provide these medications.
7.2.
Best Available Therapy Regimens
BAT will be provided by the local site. 
Best available therapy regimen (BAT) may include any Investigator-selected treatment and is not 
limited to approved JAK inhibitors (used according to the prescribing information), 
chemotherapy (eg, hydroxyurea), anagrelide, corticosteroid, hematopoietic growth factor, 
immunomodulating agent, androgens, interferon, and may also include “no treatment” and 
symptom directed treatment. BAT may not include investigational agents, fedratinib (if 
approved during the course of the study) and hematopoietic stem cell transplantation.
7.3.
Treatment Administration and Schedule
Fedratinib will be dispensed to subjects using the IRT system. The fedratinib dose is 400 mg/day 
PO (4 x 100 mg capsules) to be self-administered orally once daily continuously on an outpatient 
basis, preferably together with an evening meal, the same time each day.  In case a dose is 
missed, the next dose should be taken the following day at the same time of day as previously 
taken before the dose was missed.
A flexible dose modification regimen may be employed to minimize drug toxicity for individual 
subjects, with possible daily doses of 200 mg, 300 mg, or 400 mg. For subjects with severe 
impairment of renal function and co-administration of strong or moderate CYP3A4 inhibitors,
the fedratinib dose is adjusted (Refer to Section 7.3.2 and Section 7.3.3).
For administrative purposes cycles are defined as 4-week (28-day) periods irrespective of the 
assigned treatment arm.  Subjects may continue treatment with fedratinib or BAT until one of the 
conditions described in the “Treatment Period” section of Section 3.1 occurs.
Subjects treated on the BAT arm will be treated according to local prescribing information.
7.3.1.
Dose Modification for Toxicity 
Management of the BAT will be performed in line with prescribing information and as per the 
Investigator’s discretion as per the local standard of care. 
The section below describes the dose management for fedratinib only.
The most common adverse events associated with fedratinib are hematological and 
gastrointestinal events. Hematological adverse events associated with JAK inhibitors are dose 
Approved
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dependent, mechanism-based and are managed through dose reductions, dose interruptions and 
transfusions.
The Fedratinib Dose Modification Schedule (Table 4) should only be used for adverse events 
considered drug-related by the investigator and cannot be attributed to an identifiable cause such 
as underlying illness or disease progression, other concurrent illness, or concomitant medication.
If a subject experiences a drug toxicity as specified in the table below, the dosing must be 
interrupted; in some cases (ie, when it is not a liver function test (LFT) abnormality) the dose can 
be titrated by a 100 mg/day decrement during the study, depending upon the Investigator’s
judgment, down to a minimum dose of 200 mg/day. For subjects with co-administration of 
strong or moderate CYP3A4 inhibitors and severe impairment of renal function the fedratinib 
dose is adjusted (Refer to Section 7.3.2 and Section 7.3.3). In addition, if a subject experiences a 
dose interruption of fedratinib for more than 28 consecutive days, consultation with the medical 
monitor is required to determine if study treatment may resume.
If a subject does not tolerate fedratinib therapy after 2 dose level reductions from the starting 
dose, he/she must be withdrawn from the study treatment. If the toxicity does not resolve in the 
time period as specified in the table below subjects must be withdrawn from the study treatment. 
Re-escalation of doses is possible in certain cases. The daily dose of fedratinib cannot exceed 
400 mg/day.
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Table 4:
Fedratinib Dose Modification Schedule
Adverse Event 
Fedratinib 
Management 
Recovery
Fedratinib Dose After 
Recovery
Hematological
Grade 4 or Grade 3 
thrombocytopenia 
with major bleeding
Hold fedratinib up 
to 28 days
Grade ≤ 3 
thrombocytopenia 
without bleeding
Dose decrement by 1 dose 
level: 100 mg daily decrease
Grade 4 neutropenia 
Hold fedratinib up 
to 28 days
Grade ≤ 2 neutropenia 
Dose decrement by 1 dose 
level: 100 mg daily decrease 
Grade 4 hematological 
toxicity with dose 
reduction in 
subsequent cycle
-
Toxicity resolves for at 
least 1 cycle 
Subsequent upward dose 
titration possible of 1 dose 
level (100 mg daily) per cycle 
as per the Investigator’s 
discretion
Recurrence of a Grade 
4 hematological 
toxicity
-
-
Subsequent upward dose 
titration not permitted 
Fedratinib discontinuation as 
per the Investigator’s 
discretion
Non-hematological 
Drug-related non-
hematological Grade 4 
or unmanageable 
Grade 3 toxicity with 
dose reduction in 
subsequent cycle 
-
-
Subsequent upward dose 
titration not permitted 
Fedratinib discontinuation as 
per the Investigator’s 
discretion 
Hepatic (LFT abnormalities) 
Grade ≥ 3 AST or 
ALT or total bilirubin
Hold fedratinib 
Weekly 
monitoring of 
LFTs, until 
resolution
After fedratinib 
resumed, LFT 
monitoring every 
2 weeks for the 3 
subsequent cycles 
at a minimum 
Grade ≤ 1
Fedratinib Hold ≤ 14 days:
Dose decrement by 1 dose 
level: 100 mg daily decrease, 
Subsequent upward dose 
titration not permitted 
Fedratinib Hold > 14 days
(AE did not return to Grade ≤ 
1): Fedratinib permanently 
discontinued
Grade 4 in the absence of 
demonstrable cause: 
permanently discontinue 
fedratinib 
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EDMS Doc. Number: 25557463 - 23009667
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Table 4:
Fedratinib Dose Modification Schedule (Continued)
Adverse Event 
Fedratinib 
Management
Recovery
Fedratinib Dose After 
Recovery
Recurrence of LFT abnormality 
(ie, ≥ Grade 3 toxicity) after dose 
reduction
Discontinue 
fedratinib 
permanently 
-
-
Gastrointestinal 
Grade 2 nausea, vomiting, 
diarrhea, or constipation that does 
not respond to adequate 
therapeutic or supportive measures 
within 48 hours
Hold fedratinib 
up to 14 days
Toxicity
resolves to 
Grade ≤ 1
Consider resuming the dose 
at the same level after 
resolution of adverse event 
(see section on management 
of GI toxicity) 
Grade ≥ 3 or recurrence of Grade 2 
nausea vomiting, diarrhea, or 
constipation that does not respond 
to adequate therapeutic or 
supportive measures within 48 
hours
Hold fedratinib 
up to 14 days
Toxicity 
resolves to 
Grade ≤ 1
Consider reducing one dose 
level after resolution of 
adverse event (see section on 
management of GI toxicity 
below)
Other Adverse Events Not Described Above
Grade ≥ 3 or recurrence of Grade 2 
that does not respond to adequate 
therapeutic or supportive measures 
within 48 hours
Hold fedratinib 
up to 14 days
Toxicity 
resolves to 
Grade ≤ 1
Consider reducing one dose 
level after resolution of 
adverse event
Grade ≥ 3 non-hematological 
toxicity, non-gastrointestinal 
toxicity or Grade ≥ 2 peripheral 
neuropathies 
Hold fedratinib 
up to 14 days
Toxicity 
resolved to 
Grade ≤ 1
Dose decrement by 1 dose 
level: 100 mg daily decrease
In case of a potential case of Encephalopathy, including Wernicke’s refer to Section 7.5, Management of 
Encephalopathy, including Wernicke’s.
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; 
LFT = liver function test.
7.3.2.
Dose Adjustment for Co-administration of Fedratinib with Strong CYP3A4 
Inhibitors
Concomitant administration of fedratinib with strong CYP3A4 inhibitors increase fedratinib 
exposure. Increased fedratinib exposure may increase the risk of AEs. In place of strong 
CYP3A4 inhibitors, consider alternative therapies that do not strongly inhibit CYP3A4 activity. 
If strong CYP3A4 inhibitors cannot be replaced, reduce fedratinib dose to 200 mg when 
administering with strong CYP3A4 inhibitors, (eg, ketoconazole, ritonavir; refer to Appendix L).
Additional dose adjustments (decrease or increase of the daily dose) should be made with 
monitoring of fedratinib-related safety (see Section 7.3.1) and efficacy.
In cases where co-administration with a strong CYP3A4 inhibitor is discontinued, the fedratinib 
dose should be increased to 300 mg daily during the first two weeks after discontinuation of the 
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CYP3A4 inhibitor, and then to 400 mg daily thereafter as tolerated. Additional dose adjustments 
should be made as needed based upon frequent monitoring of safety.  
In all the situations above, please contact the Sponsor medical monitor for any question or 
guidance. 
7.3.3.
Dose Adjustment for Renal Impairment
No modification of the starting dose is recommended for patients with mild to moderate renal 
impairment. Due to potential increase of fedratinib exposure, patients with pre-existing moderate 
renal impairment require more intensive safety monitoring, and if necessary, dose modifications 
based on adverse reactions. 
In subjects that develop severe renal impairment during the study the fedratinib dose should be 
adjusted by two dose decrement levels (eg, from 400 mg to 200 mg once a day [QD]). 
Clinical signs and symptoms for efficacy and fedratinib-related AEs should be monitored and the 
dose of fedratinib should be further adjusted as necessary.
7.4.
Overview on Management of Gastrointestinal Adverse Events
Gastrointestinal adverse events, specifically nausea, vomiting and diarrhea, are commonly 
associated with fedratinib treatment and require multifaceted management using dose 
adjustment, active treatment or prophylaxis with anti-emetics, and monitoring. GI symptoms 
generally start in the first treatment cycle but typically improve within 6-8 weeks on fedratinib 
treatment.
7.4.1.
Management of Nausea and Vomiting
Management of nausea and vomiting during treatment with fedratinib will be done according to 
the following steps:
!
Subjects will be provided management instructions (including when to contact the 
study site) before the start of treatment
!
In order to mitigate for nausea and vomiting events, it is recommended to take 
fedratinib with food during an evening meal. Specific instructions for fedratinib 
administration will be provided for PK sampling days (C1D1, the day before C2D1 
and C2D1)
!
It is highly recommended to use anti-nausea/vomiting treatment prophylactically 
according to local practice for the first 8 weeks of treatment (eg, ondansetron). If 
dimenhydrinate or other muscarinic receptor antagonists are used for nausea and 
vomiting, administer these agents in the evening to minimize drowsiness and other 
potential neurological AEs
!
Hold / reduce the dose of fedratinib according to Table 4
!
Hospitalization may be indicated for Grade 3 or higher nausea or vomiting or events 
that persist
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EDMS Doc. Number: 25557463 - 23009667
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Confidential and Proprietary
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!
For medications that are administered for prophylactic use of nausea and vomiting, if 
no clinically significant nausea and vomiting occurs during the first 8 weeks of 
fedratinib treatment, consider weaning the subject off these medications
7.4.2.
Management of Diarrhea
Management of diarrhea during treatment with fedratinib will be done according to the following 
steps:
!
Subjects should have loperamide available at home and should be provided with 
diarrhea management instructions (including when to contact the study site) before 
the start of treatment
!
Loperamide should not be given as prevention in case the subject does not experience 
diarrhea
!
Treat with loperamide as per local practice at the onset of diarrhea. Consider starting 
loperamide at a 4 mg loading dose and then 2 mg after each diarrheal bowel 
movement without exceeding 16 mg/24 hours
!
Dietary modifications including adequate hydration, avoidance of lactose-containing 
foods and alcohol, small meals with rice, bananas, bread, etc
!
Hold / reduce the dose of fedratinib according to Table 4
!
Hospitalization may be indicated for Grade 3 or higher persisting diarrhea.
!
Management of nausea, vomiting and diarrhea will be assessed during the subject’s
visit on Day 1 of every following 28-day cycle, at Day 15 of the first three cycles and 
by a mandatory telephone contact at Day 8 of the first cycle.
7.5.
Management of Encephalopathy, including Wernicke’s
A potential case of Encephalopathy, including Wernicke’s is a medical emergency. Screening for 
Encephalopathy, including Wernicke’s and management of cases during treatment with 
fedratinib will be done according the following steps:
7.5.1.
Clinical and Cognitive Assessment
Interval history: including a review of the subject’s history for confusion, memory problems, 
vision problems (eg, double vision) as well as poor nutrition, signs and symptoms of 
malabsorption, and alcohol use 
!
Physical examination: including assessment for abnormal eye movements, cerebellar 
abnormalities and body weight (weight loss compared to previous examination or 
patient history) during screening and Day 1 of every treatment cycle, at the End of 
Treatment (EOT), and the 30-Day Follow-up visit
!
Mini-Mental State Examination (MMSE): to objectively assess for signs/symptoms of 
encephalopathy during screening, on Day 1 of Cycles 2 and 3 and every third cycle 
thereafter, at the End of Treatment Visit and more frequently as clinically indicated
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
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Confidential and Proprietary
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7.5.2.
Management of Encephalopathy, including Wernicke’s
In case of signs or symptoms that may indicate Encephalopathy, including Wernicke’s:
!
Hold study medication until Encephalopathy, including Wernicke’s is ruled out
!
Obtain sample for thiamine level
!
Start parenteral thiamine as described in Section 7.5.3 for subjects with thiamine 
levels < 30 nM/L regardless of thiamine level
!
Report the event as an AESI to the Sponsor
!
Obtain a neurological consult
!
Perform a brain MRI
!
If WE is confirmed, discontinue fedratinib permanently
!
If WE is ruled out, assess for other causes of encephalopathy and treat accordingly.
Once resolved, consider restarting treatment with fedratinib after discussion with 
study monitor.
7.5.3.
Thiamine, Supplementation, Monitoring and Correction
All subjects receiving study medication will receive thiamine supplementation. Start oral 
thiamine supplementation at a minimum daily dose of 100 mg (or equivalent) at Cycle 1 Day 1. 
Continue supplementation throughout the treatment period until study medication is 
discontinued, and through the 30-day follow-up visits.
Thiamine levels (for whole blood) will be monitored in all subjects.
!
Thiamine levels are assessed at screening and need to be corrected and retested before 
starting fedratinib treatment (see inclusion criteria) 
!
While on treatment with study medication, thiamine levels are assessed in a fasting 
state at start of Cycles 1, 2, 3 and every third cycle thereafter, at the End of Treatment 
Visit and as clinically indicated 
!
In case of documented thiamine deficiency and a subject is receiving thiamine 
supplementation, while on study:
∀
Thiamine levels should be assessed in a fasting state and thiamine 
supplementation should be given after the blood draw
∀
If the subject develops signs or symptoms suggestive of encephalopathy including 
Wernicke’s, please follow instructions in Section 7.5.2
∀
For thiamine levels below normal range but > 30 nM/L without signs or 
symptoms of WE while receiving thiamine supplementation:
o
The site should contact the Medical Monitor regarding the low thiamine level 
as soon as possible
o
Report the event as an Adverse Event of Special Interest (AESI) to the 
Sponsor.
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EDMS Doc. Number: 25557463 - 23009667
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o
Consider increasing the dose of oral thiamine supplementation to twice the 
daily dose (if the subject is taking 100 mg, increase to 200 mg)
o
Monitor thiamine level closely (monthly at least) and adjust dose as needed
∀
For thiamine level < 30 nM/L without signs or symptoms of WE while receiving 
thiamine supplementation:
o
The site should contact the Medical Monitor regarding the low thiamine level 
as soon as possible
o
Report the event as an Adverse Event of Special Interest (AESI) to the 
Sponsor.
o
Study medication must be held until thiamine levels are restored to normal 
range.
o
Immediate treatment with IV thiamine (stop oral thiamine), at therapeutic 
dosages eg, 500 mg IV infused over 30 minutes 3 times daily for 2 to 3 days
or alternatively IM in equivalent doses according to local standard of care
o
This will be followed by 250 mg to 500 mg IV thiamine infused once a day 
for 3 to 5 days or alternatively IM in equivalent doses according to local 
standard of care
o
And then consider increasing the dose of oral thiamine supplementation to 
twice the previous daily dose (for example if the subject is taking 100 mg, 
increase the dose to 200 mg) 
o
Monitor thiamine levels closely (at least monthly) and adjust the dose as 
needed
∀
Thiamine supplementation should be administered as a thiamine only formulation.
∀
If thiamine levels are low, ensure that magnesium levels are normal or corrected if 
low
7.6.
Method of Treatment Assignment
Randomization and treatment assignment will occur at the end of the Screening Period, once all 
the required screening procedures have been completed and all required data have been 
submitted to the Sponsor or its authorized representative.  Upon receiving acknowledgment of 
subject’s eligibility review from the Sponsor or its authorized representative, the subject can be 
assigned fedratinib treatment using an IRT built for this study. 
Designated research personnel at each investigational site will be assigned unique, password-
protected user accounts which give them the authorization to utilize the IRT to enroll subjects. 
7.7.
Packaging and Labeling
Sections 7.7, 7.8 and 7.9, only apply to fedratinib.
The label(s) for fedratinib will include Sponsor name, address and telephone number, the 
protocol number, fedratinib name, dosage form and strength (where applicable), amount of 
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EDMS Doc. Number: 25557463 - 23009667
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Confidential and Proprietary
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fedratinib per container, lot number, expiry date (where applicable), fedratinib identification/kit 
number, dosing instructions, storage conditions, and required caution statements and/or 
regulatory statements as applicable. Additional information may be included on the label as 
applicable per local regulations.
7.8.
Investigational Product Accountability and Disposal 
Sponsor (or designee) will review with the Investigator and relevant site personnel the process 
for Investigational Product return, disposal, and/or destruction including responsibilities for the 
site versus Sponsor (or designee).
7.9.
Investigational Product Compliance
Fedratinib will be administered by the study site personnel in the clinic on PK sampling days.  
Subjects will self-administer all other fedratinib doses in the treatment period. Study site 
personnel will review the dosing information with the subject (or legally authorized 
representative) on scheduled clinic visit days. Subjects (or legally authorized representative) will 
be asked to bring all unused capsules with them to scheduled clinic visits (ie, prior to the start of 
the next treatment cycle).  Study site personnel will perform a fedratinib administration 
compliance check and record this information in the subject’s source documentation.
Administration of all fedratinib will be recorded including dispensing, dosing and any changes in 
dosage administration such as interruption or reduction in dosing due to an AE.
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EDMS Doc. Number: 25557463 - 23009667
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Confidential and Proprietary
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression. 
Supportive care, such as anti-emetic medications, may be administered at the discretion of the 
Investigator.
All prior/concomitant medications including, prescription, over-the-counter, and herbal 
preparations taken for any indication used from 28 days prior to randomization until 30 days 
after the last dose of fedratinib/BAT during the study must be reported on the eCRF. The type, 
dose route, start and end date of administration must be documented on the appropriate pages of 
the electronic case report form (eCRF).
BAT is regarded to be the study treatment and not a concomitant treatment and will be 
documented separately on the appropriate pages of the eCRF.
The details of the prior treatment with ruxolitinib and its outcomes will also be recorded in the 
subject’s eCRF regardless of treatment discontinuation/procedure date.
Information regarding transfusion history (at least 84 days prior to and including the 
randomization date), including pretransfusion hemoglobin (Hgb) levels, number of units 
transfused and dates of transfusions, will be collected and reported in the appropriate eCRF
For information regarding other drugs that may interact with fedratinib and affect its metabolism, 
pharmacokinetics, or excretion, please also see the Investigator’s Brochure.
8.1.
Permitted Concomitant Medications and Procedures
Prophylaxis and/or treatment of gastrointestinal adverse events, specifically nausea, vomiting 
and diarrhea (eg, loperamide) is an essential part of management of potential fedratinib toxicity. 
(Refer to Section 7.4).
Subjects are required to take daily thiamine supplementation (Refer to Section 7.5).
Blood product support (RBCs and platelet transfusions) may be administered according to 
institutional standards.
Subjects may be administered supportive and palliative care (eg, pain control) as clinically 
indicated throughout the study.
Prior anticancer treatments should be recorded on the appropriate eCRF(s) regardless of 
treatment discontinuation/procedure date.
For information regarding clinically relevant P450 inducers, inhibitors, substrates, and
transporter substrates refer to Section 8.3.
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8.2.
Prohibited Concomitant Medications
The following concomitant medications are specifically excluded during the course of the study
for subjects randomized to the fedratinib arm or for subjects that crossover to fedratinib 
treatment:
!
Cytotoxic, chemotherapeutic, targeted or investigational agents/therapies
!
Immunomodulatory drug therapy (eg, thalidomide)
!
Immunosuppressive therapy
!
Systemic corticosteroids > 10 mg/day prednisone or equivalent
!
Hydroxyurea
!
Interferon-alpha
!
Anagrelide
!
JAK inhibitors other than fedratinib
!
Aspirin at doses > 150 mg daily
!
Any investigational agent
For information regarding clinically relevant P450 inducers, inhibitors, substrates, and 
transporter substrates refer to Section 8.3.
For subjects on the BAT arm not crossing over to fedratinib, fedratinib is specifically excluded 
during the study. Additional treatments might be prohibited according to BAT prescribing 
information.
If a subject requires treatment with any new medications that are specifically excluded, the 
subject may need to be discontinued from treatment. The Investigator should consult the medical 
monitor regarding any questions about whether a new medication or dosage of existing 
medication would require the subject to discontinue from the study.
8.3.
Clinically Relevant Cytochrome P450 Inducers, Inhibitors, 
Substrates, and Transporter Substrates
Fedratinib is metabolized by multiple cytochrome P450 enzymes (CYPs) in vitro, with 
prominent contribution from CYP3A4 and with a lesser contribution from CYP2C19.
CYP3A4 inducers and inhibitors
Strong and moderate CYP3A4 inducers (see Appendix L) that may decrease fedratinib plasma 
concentrations are not permitted while receiving fedratinib. 
Strong CYP3A4 inhibitors (see Appendix L) increase fedratinib plasma concentrations. In place 
of strong CYP3A4 inhibitors, alternative therapies that do not inhibit CYP3A4 need to be 
considered. If strong CYP3A4 inhibitors cannot be replaced, the strong CYP3A4 inhibitor needs
to be used with caution and the fedratinib dose needs to be adjusted (refer to Section 7.3.2).
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EDMS Doc. Number: 25557463 - 23009667
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Confidential and Proprietary
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Dual CYP2C19 and CYP3A4 inhibitors 
Dual inhibitors of CYP2C19 and CYP3A4 (eg, fluconazole, fluvoxamine) that may increase 
fedratinib plasma concentrations are not permitted while receiving fedratinib.
Sensitive Substrates: Effect of fedratinib on plasma levels of other co-administered drugs 
(drugs metabolized by CYP3A4, CYP2C19, and CYP2D6):
Co-administration of fedratinib with drugs that are CYP3A4 substrates (eg, midazolam), 
CYP2C19 substrates (eg, omeprazole), or CYP2D6 substrates (eg, metoprolol) increase the area 
under the curve from time zero to infinity (AUCinf) of these drugs by 4-, 3-, and 2-fold, 
respectively, which may increase the risk of adverse reactions of these drugs. Monitor for 
adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 
substrates (see Appendix L) as necessary when co-administering with fedratinib.
Transporters: Effect of fedratinib on plasma levels of other co-administered drugs (drugs 
transported by P-gp, BCRP, MATE-1, MATE-2K, OATP1B1/1B3, and OCT1/2):
Fedratinib can increase plasma levels of drugs that are substrates of transporters, P-gp, BCRP, 
MATE-1, MATE-2K, OATP1B1/1B3, and OCT1/2. Fedratinib should be used with caution with 
drugs that are substrates of these transporters (see Appendix L), and dose modifications of 
substrates of these transporters should be made, as necessary, with monitoring of safety and 
efficacy.
A list of clinically relevant P450 inducers and inhibitors as well as substrates, and transporter 
substrates can be found in Appendix L. 
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EDMS Doc. Number: 25557463 - 23009667
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a multicenter, open-label, randomized study to evaluate the efficacy and safety of 
fedratinib compared to best available therapy in subjects previously treated with ruxolitinib and 
with DIPSS-intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera 
myelofibrosis, or post-essential thrombocythemia myelofibrosis. 
The sections below provide an overview of the proposed statistical considerations and analyses. 
The final statistical analysis methods will be documented in detail in the statistical analysis plan 
(SAP).
General Considerations
A descriptive summary for continuous data will include the number of non-missing observations 
(n), mean, standard deviation, median, minimum and maximum. In addition, 25% percentile and 
75th percentile may be provided if needed.
Categorical data will be summarized using counts (n) and percentages (%). The number of 
subjects with missing data may be displayed but will not be included in the denominator for the 
calculation of percentages unless otherwise specified.
Unless otherwise specified, baseline value is defined as the last value or measurement taken prior 
to the first dose in the study. For crossover subjects, baseline for records after crossover is 
defined as last value prior to or on the same day of crossover.
For crossover subjects in BAT arm, only data before crossover will be included in the analysis 
where comparison between fedratinib and BAT is intended. The data after crossover will be 
summarized separately.
Hierarchical Testing on Key Efficacy Endpoints
The primary and key secondary efficacy endpoints are listed in Section 2. This study employs 
multiple testing. A fixed sequence procedure with the following sequence order is planned to 
maintain a familywise error rate of 2.5% (1-sided):
1. Spleen volume response rate by MRI or CT scan ≥ 35% reduction (RR), 
2. Symptoms response rate (SRR), 
3. Spleen volume response rate by MRI or CT scan ≥ 25% reduction (RR25).
9.2.
Study Population Definitions
Intent to Treat (ITT) population: this population will consist of all subjects who were 
randomized. This is the primary analysis population for efficacy variables. All analyses using 
this population will be based on the treatment assigned by Interactive Response Technology 
(IRT).
Per Protocol population: this population consists of all randomized subjects who received at 
least one dose of study medication, had no important violation to the inclusion/exclusion criteria 
and had no other important protocol deviation that could have an impact on efficacy outcome. A 
list of important protocol deviations which could have an impact on efficacy outcome will be 
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(Harrison, 2018b; Mascarenhas, 2018). Assuming the response rate at end of cycle 6 is 10% in 
the BAT arm (average of historical information) and 27% in the fedratinib arm, 192 subjects will 
provide 88% power at a one-sided significance level of 0.025.
9.4.
Background and Demographic Characteristics
9.4.1.
Demographic and Baseline Characteristics
Standard demographic and baseline characteristics (including age and race), medical history, 
cancer diagnosis and prior anti-cancer therapy will be collected at baseline. Baseline efficacy 
variables and other prognostic variables will be assessed as well. The details of previous 
ruxolitinib treatment (eg, dose, best response, duration of response) will be summarized.
These parameters will be summarized on the ITT population and will be analyzed in the 
treatment group to which they were randomized. Analyses for the safety population will be 
included if the size of any treatment group in the safety population differs (>10%) from the size 
of that in the ITT population.
9.4.2.
Prior or Concomitant Medications
The prior and concomitant medications will be presented for the ITT population.
Medications will be summarized by treatment group according to the WHO drug dictionary, 
considering the first digit of the anatomical therapeutic chemical (ATC) class (anatomic 
category) and the first three digits of the ATC class (therapeutic category). All ATC codes 
corresponding to a medication will be summarized. Subjects will be counted for each of the ATC 
categories (anatomic or therapeutic) linked to the medication.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary
reason for discontinuation) will be summarized using frequency and percentage.
9.6.
Extent of Study Treatment Exposure and Compliance
Extent of exposure will be assessed within the safety population. Summary of dose information 
will be separated for the fedratinib arm and the BAT arm.
Dose information for fedratinib arm will be assessed by the following variables:
!
Duration of treatment exposure is defined as: last fedratinib dose date - first fedratinib 
dose date regardless of unplanned intermittent discontinuations
!
The cumulative dose is the sum of all fedratinib doses
!
The actual dose intensity is defined as the cumulative dose divided by the duration of 
fedratinib exposure in terms of the number of weeks on study
!
The relative dose intensity is defined as the ratio of the actual dose intensity to the 
planned dose intensity. The planned dose intensity is defined as the planned fedratinib 
dose for each cycle divided by planned cycle length in weeks
!
Dose reduction and reason for dose reduction
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
74
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!
Dose interruption / delays
The number of subjects treated, number of cycles administered, duration of dosing (weeks), 
cumulative dose (mg), dose intensity (mg/week), and relative dose intensity (%) will be 
summarized. Dose interruption / delays and dose reductions will also be analyzed.
Given determination of BAT for a subject will be made by the Investigator, summary of dose 
information for BAT arm will be limited to type and frequency of medications in BAT arm. If 
one medication is prevalent in BAT arm (eg, 50% subjects in BAT arm take the same 
medication), a detailed summary for that medication will be conducted using the same variables 
listed above. For crossover subjects, only exposure data prior to crossover will be included.
For subjects in BAT arm who crossover to fedratinib, dose information for fedratinib after 
crossover will be summarized in the same way as in fedratinib arm, based on crossover safety 
population.
9.7.
Efficacy Analysis
9.7.1.
Spleen Volume Response Rate (35%) by MRI / CT (RR)
The primary analysis for spleen volume response rate by MRI/CT will be based on ITT 
population. The data cut-off for RR will occur when the last randomized subject has completed 6 
cycles of fedratinib or BAT. Subjects with a missing MRI/CT spleen volume at the end of cycle 
6, including those who meet the criteria for progression of splenomegaly before end of cycle 6,
will be considered non-responders. For crossover subjects, only data before crossover will be 
included.
A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size 
by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment) will 
be performed to compare fedratinib to BAT at a one-sided 2.5% alpha level. The RRs and 95% 
confidence intervals (CI) will be provided for each arm as well as for the difference in RRs and 
95% confidence interval of the difference for fedratinib to BAT. In addition, a descriptive 
summary of spleen volume measurements and percentage change from baseline will be provided.
Sensitivity analyses for RR will be pre-planned and details will be documented in the SAP.
9.7.2.
Symptom Response Rate (SRR)
The SRR is a key secondary endpoint and 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. (Total symptom score is defined in Section 9.9.1). Subjects with a missing TSS at 
the end of cycle 6 or who had disease progression before the end of the cycle 6 will be 
considered non-responders. The primary analysis of SRR will be conducted using ITT 
population with non-zero baseline TSS, and sensitivity analyses will be performed using 
symptom evaluable population.
For subjects crossing over before the End of Cycle 6 assessment, only data before the crossover 
date will be included for the comparison with the fedratinib arm. 
A CMH test to adjust for planned stratification factors (spleen size by palpation, platelet counts 
and refractory/relapsed or intolerance to ruxolitinib treatment) will be performed to compare 
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
75
FEDR-MF-002 Amendment 4 Final:  23 April 2021
fedratinib to BAT at a one-sided 2.5% alpha level. The proportions and 95% CIs will be 
provided for each arm as well as for the difference in proportions and 95% CI of the difference 
for fedratinib to BAT.
Additional sensitivity analyses will be pre-planned for SRR and will be documented in the SAP.
For crossover subjects, the SRR during the fedratinib period will be summarized separately using 
the same method as described above. No formal statistical testing will be conducted to compare 
with BAT. The analysis will be based on the crossover efficacy population with evaluable TSS at 
the time of crossover.
9.7.3.
Spleen Volume Response Rate (25%) by MRI / CT (RR25)
The proportion of subjects who have ≥25% reduction in spleen volume at the end of cycle 6 
(RR25) is a key secondary endpoint and will be summarized using the same method as RR. 
Subjects with a missing MRI/CT spleen volume at the end of cycle 6 including those who meet 
the criteria for progression of splenomegaly before the end of cycle 6 will be considered non-
responders. For crossover subjects, only data before crossover will be included.
The analysis will be conducted using ITT and Per Protocol population.
9.7.4.
Spleen Response Rate by Palpation (RRP)
Spleen response rate by palpation is the proportion of subjects with a spleen response according 
to the IWG-MRT 2013 (Appendix O) at the end of cycle 6 as compared to baseline. This will be 
calculated for subjects that have an enlarged spleen (≥5 cm below LCM) at baseline. Subjects
with a missing spleen size assessment at the end of cycle 6 including those who meet the criteria 
for progression of splenomegaly before end of cycle 6 will be considered not to be responders.  
The RR by palpation and 95% CI will be provided for each arm as well as for the difference and 
95% CI of the difference for fedratinib to BAT.
The analysis will be conducted based on a subgroup of the ITT population where subjects with 
baseline spleen size < 5 cm below LCM are excluded (ie, not eligible for spleen response).
9.7.5.
Durability of Spleen Volume Response by MRI/CT (DR)
Durability of spleen volume response (DR) by MRI/CT is defined as the date from the first 
documented spleen response (ie, ≥ 35% reduction in spleen volume) to the date of subsequent 
progressive disease (PD) in spleen volume per the IWG-MRT 2013 criteria or death, whichever 
is earlier. In the absence of an event before the analysis is performed, the DR will be censored at 
the date of the last valid assessment performed before the analysis performed date.
Duration of spleen volume response by MRI/CT scan will be analyzed using the Kaplan-Meier
(K-M) method. Kaplan-Meier estimates of the 25th, 50th, and 75th percentiles and the 95% 
confidence interval of median will be provided for both fedratinib and BAT arms. Kaplan-Meier
curves will be plotted.
The analysis will be conducted based on a subgroup of the ITT population where subjects have 
achieved ≥ 35% SVR at any time during treatment. An additional analysis will be performed on 
a population including subjects who have ≥ 35% SVR at end of cycle 6 only.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
76
FEDR-MF-002 Amendment 4 Final:  23 April 2021
9.7.6.
Spleen and Disease Progression Free Survival (SDPFS)
Spleen and disease progression free survival is defined as the 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). In the absence of an event before the analysis is performed, the 
SDPFS will be censored at the date of the last valid assessment.
SDPFS will be analyzed using the Kaplan-Meier method. Kaplan-Meier estimates of the 25th, 
50th, and 75th percentiles and the 95% confidence interval of median will be provided for both 
fedratinib and BAT arms. Kaplan-Meier curves will be plotted.
The analysis will be conducted based on ITT population.
9.7.7.
Durability of Spleen Response by Palpation (DRP)
Durability of spleen response by palpation (DRP) is defined as time from the date of the first 
documented palpable spleen response, according to the IWG-MRT 2013 (Appendix O) to the 
date of the subsequent PD in spleen size according to the IWG-MRT 2013 or death, whichever is
earlier. Durability of spleen response by palpation according to the IWG-MRT 2013 criteria will 
be calculated for subjects that have an enlarged spleen at baseline (≥ 5 cm below LCM), and that 
have a spleen response by palpation. In the absence of an event before the analysis is performed, 
the DRP will be censored at the date of the last valid assessment performed before the analysis 
performed date.
Duration of spleen response by palpation will be analyzed using Kaplan-Meier method (K-M). 
Kaplan-Meier estimates of the 25th, 50th, and 75th percentiles and the 95% confidence interval 
of median will be provided for both fedratinib and BAT arms. Kaplan-Meier curves will be 
plotted.
The analysis will be conducted based on ITT population.
9.7.8.
Overall Survival
Overall survival (OS) is defined as the time interval from the date of randomization to the date of 
death due to any cause. In the absence of the confirmation of death before the analysis 
performed, OS will be censored at the last date of subjects was known to be alive or at the study 
cut-off date (if applicable), whichever is earlier. OS will be analyzed based on the ITT 
population using the Kaplan-Meier method. Kaplan-Meier estimates of the 25th, 50th, and 75th 
percentiles and the 95% confidence intervals of median will be provided for both fedratinib and 
BAT arms. Kaplan-Meier curves will be plotted based on ITT population.
9.7.9.
Crossover Efficacy Analysis
For crossover subjects, the visit cycles will be recounted from cycle 1 for fedratinib exposure
period. The analyses during the fedratinib period will be summarized separately using the same 
method as described above. No formal statistical testing will be conducted to compare with BAT.
The analysis will be based on crossover efficacy population.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
77
FEDR-MF-002 Amendment 4 Final:  23 April 2021
9.8.
Safety Analysis
All safety analyses will be conducted based on the safety population or crossover safety 
population for crossover subjects.
Literature “book” values and normal ranges from local laboratory results will be utilized for this 
study.
9.8.1.
Adverse Events
The type, frequency, seriousness and severity of AEs, and relationship of AEs to study treatment 
will be summarized. 
Adverse events will be analyzed in terms of TEAEs. TEAE is defined as any event that begins or 
worsens in grade after the start of study medication (or start of fedratinib for crossover subjects) 
through 30 days after the last dose of study treatment.
Adverse events will be summarized by severity/grade based on the NCI CTCAE. If a subject 
experiences the same AE multiple times during the treatment, the event will be counted only 
once by the worst grade / greatest severity.
Treatment emergent adverse events, Grade 3 or higher TEAEs, serious AEs, TEAEs leading to 
dose reduction, and dose interruption, TEAEs leading to treatment discontinuation, and TEAEs 
with an outcome of death will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred terms. Adverse events of special interest of 
fedratinib identified in previous trials in a similar population will be summarized in the same 
manner. If data warranted, additional analyses on fedratinib safety profile may be performed (eg, 
incidence of nausea, vomiting and diarrhea in relationship to prophylaxis and treatment, etc.) and 
will be specified in the statistical analysis plan.
9.8.2.
Assessment of Risk Mitigation Strategy for Gastrointestinal Adverse Events and 
Encephalopathy, including Wernicke’s
Assessment of risk mitigation strategy will include an analysis of incidence of subjects with a 
CTCAE Grade ≥3 of nausea, diarrhea, or vomiting, or occurrence of Encephalopathy, including 
Wernicke’s (confirmed by brain MRI or autopsy). Analysis of thiamine levels will be at 
screening, on Day 1 of the first 3 cycles, every third cycle thereafter, and at the EOT during the 
study.
9.8.3.
Laboratory Results
Analysis of laboratory data will be descriptive and conducted on the safety population. Summary 
of laboratory data (including thiamine levels) and change from baseline will also be performed 
by subject and by cycle.
Hematological toxicities will be assessed from laboratory parameters. Worst NCI CTCAE grades 
of leukopenia, neutropenia, thrombocytopenia, and anemia will be calculated according to the 
NCI common terminology criteria.
Qualitative and quantitative results will be summarized for hematological toxicities. Qualitative 
data (worst NCI CTCAE grade) will be summarized by cycle and by subject.
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EDMS Doc. Number: 25557463 - 23009667
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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9.8.4.
Electrocardiograms
All ECG data will be provided in a listing.
9.8.5.
Vital Signs
Vital signs will be summarized based on the number of subjects with at least one potentially 
clinically significant abnormality (PCSA) occurring during the observation period according to 
baseline status. The PCSA criteria are provided in Table 5.
Table 5:
PCSA Criteria for Vital Signs and Weight
Parameter
PCSA
Heart (bpm)
≤50 bpm and decrease from baseline ≥20 bpm
≥120 bpm and increase from baseline ≥20 bpm
SBP (mmHg)
≤95 mmHg and decrease from baseline ≥20 mmHg
≥160 mmHg and increase from baseline ≥20 mmHg
DBP (mmHg)
≤45 mmHg and decrease from baseline ≥10 mmHg
≥110 mmHg and increase from baseline ≥10 mmHg
Weight (kg)
≥5 % increase from baseline
≥5 % decrease from baseline
DBP = diastolic blood pressure; kg = kilograms; mmHg = millimeters of mercury; PCSA = potentially clinically 
significant abnormalities; SBP = systolic blood pressure.
9.9.
Patient-reported Outcomes / Health Economics
Patient-Reported Outcomes and Health economics will be assessed using validated instruments 
(MFSAF version 4.0, EORTC QLQ-C30 version 3.0, EQ-5D-5L and 
 The 
analysis of MFSAF will be based on the ITT population with non-zero baseline TSS, and the 
analysis of EORTC QLQ-C30, EQ-5D-5L, and 
data will be based on the HRQoL-
evaluable population.
9.9.1.
Symptoms Response Assessment Using MFSAF V.4.0
The compliance profile over time will be summarized (number and percentage of forms received 
versus expected, and number of percentage of forms evaluable versus expected). A descriptive 
summary of each of the individual symptoms at each visit and change from baseline will be 
provided.
Total symptom score (TSS)
The TSS is defined as the sum of each of the 7 symptom scores (Gwaltney, 2017). To allow 
indirect comparison with previous MF studies, a modified TSS (Mesa, 2013) will also be 
derived from the 6 symptoms considered (night sweats, pruritus, abdominal discomfort, early 
satiety, pain under ribs on left side, bone or muscle pain) and analysis of SRR will be also 
performed. Fatigue will be assessed as part of the EORTC QLQ-C30.
At each timepoint, the TSS (based on 7 symptoms) and the modified TSS will be calculated. 
Descriptive summary statistics (size, mean, standard deviation, median, range) will be provided 
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
82
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10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
!
a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
!
routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.
!
hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
83
FEDR-MF-002 Amendment 4 Final:  23 April 2021
!
an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 
!
emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
For each AE, the Investigator will provide information on severity, start and stop dates, 
relationship to fedratinib or comparator, action taken regarding the fedratinib or comparator, and 
outcome.
10.2.2.
Severity/Intensity
For each AE, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE
Version 5.0);
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
Approved
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
84
FEDR-MF-002 Amendment 4 Final:  23 April 2021
10.2.3.
Causality
The Investigator must determine the relationship between the administration of fedratinib or 
comparator and the occurrence of an AE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to fedratinib or 
comparator administration is unlikely or remote, or other 
medications, therapeutic interventions, or underlying conditions 
provide a sufficient explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of
fedratinib or comparator caused the adverse event.  ‘Reasonable 
possibility’ means there is evidence to suggest a causal 
relationship between fedratinib or comparator and the adverse 
event.
Causality should be assessed and provided for each AE based on currently available information.  
Causality is to be reassessed and provided as additional information becomes available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional
fedratinib that has not been manufactured or provided by Celgene-Impact, please provide the 
name of the manufacturer when reporting the event.
10.2.4.
Duration
For each AE, the Investigator will provide a record of the start and stop dates of the event.
10.2.5.
Action Taken
The Investigator will report the action taken with fedratinib or comparator as a result of each AE, 
as applicable (eg, discontinuation, interruption, or dose reduction of IP, as appropriate) and 
report if concomitant and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for each AE.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of study treatment, or any other 
therapeutic intervention; or
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
85
FEDR-MF-002 Amendment 4 Final:  23 April 2021
!
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded as the AE.  If the abnormality was not a part of a diagnosis or 
syndrome, then the laboratory abnormality should be recorded as the AE. If possible, the 
laboratory abnormality should be recorded as a medical term and not simply as an abnormal 
laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.  
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated β-subunit of human chorionic 
gonadotropin [βhCG] or positive pregnancy test in a female subject of childbearing potential 
regardless of disease state) occurring while the subject is on fedratinib treatment, or within 30
days of the subject’s last dose of fedratinib, are considered immediately reportable events.  
Investigational Product is to be discontinued immediately and the subject instructed to return any 
unused portion of the fedratinib to the Investigator. The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to Celgene Drug Safety immediately by email, phone or 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form.
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
The Investigator will follow the female subject until completion of the pregnancy and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the event.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as an SAE.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in-utero exposure to the fedratinib should also be reported as an SAE to Celgene 
Drug Safety within 24 hours of the Investigator’s knowledge of the event.
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
86
FEDR-MF-002 Amendment 4 Final:  23 April 2021
10.4.2.
Male Subjects
If a female partner of a male subject taking fedratinib becomes pregnant, the male subject taking
fedratinib should notify the Investigator, and the pregnant female partner should be advised to 
call their healthcare provider immediately.  
10.5.
Reporting of Serious Adverse Events
Any AE that meets any seriousness criterion requires reporting as an SAE within 24 hours of the 
Investigator’s knowledge of the event. This instruction pertains to initial SAE reports as well as 
any follow-up reports.
This requirement applies to all SAEs (regardless of relationship to fedratinib) that occur during 
the study (from the time the subject signs informed consent until 30 days after the last dose of IP) 
or any SAE made known to the Investigator at any time thereafter that are suspected of being 
related to IP.  Serious adverse events occurring prior to treatment (after signing the ICF) are to be 
recorded within the CRF, but do not require reporting to Celgene Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
source documents and all correspondence with the IRB/EC.
The SAE is recorded within the CRF, and the data is transmitted electronically to Celgene Drug 
Safety within 24 hours of the Investigator’s knowledge of the event. In the event electronic 
transmission is not available, a paper SAE Report Form will be completed and sent directly to 
Celgene Drug Safety, ensuring the event is recorded on the CRF as well.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via
electronic data capture (EDC) or other appropriate method.  The response time is expected to be 
no more than five (5) business days.  Urgent queries (eg, missing causality assessment) may be 
handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to fedratinib based on the Investigator Brochure.
In the United States, expedited reports sent to the FDA by the sponsor based on the reasonable 
possibility threshold are known as “IND safety reports” and will be reported in accordance with 
21 CFR 312.32.
For reporting to the FDA, events that are not suspected to be causally related to fedratinib by the 
sponsor will not be considered adverse reactions. As per FDA regulations, events that are 
anticipated in the study population, listed in the fedratinib IB Reference Safety Information, will 
not be considered adverse reactions on individual assessment and will be reviewed on an 
aggregate basis for assessment of frequency.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
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EDMS Doc. Number: 25557463 - 23009667
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
87
FEDR-MF-002 Amendment 4 Final:  23 April 2021
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) with 
fedratinib in accordance with Directive 2001/20/EC and the Detailed Guidance on collection, 
verification and presentation of adverse reaction reports arising from clinical trials on 
investigational products for human use (ENTR/CT3) and also in accordance with country-
specific requirements.  
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the comparator, based on the UK or EU 
Summary of Product Characteristics (SmPC).
For the purpose of regulatory reporting in the EEA, Celgene non-investigational medicinal 
product (when the comparator is a Celgene product such as thalidomide) serious adverse 
reactions and nonserious adverse reactions will be reported to the Regulatory Authorities, in 
accordance with Regulation (EC) No. 726/2004 and/or Directive 2001/83/EC as amended, and 
also in accordance with country-specific requirements for countries within the EEA.
Celgene or its authorized representative shall notify the Investigator of the following information
!
Any AE suspected of being related to the use of fedratinib in this study or in other 
studies that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC. (See Section 14.3 for record retention 
information).
10.7.
Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. AESI (serious and non-serious) are to be 
recorded within the CRF and the data transmitted electronically to Celgene Drug Safety within 
24 hours of the Investigator’s knowledge of the event. In the event electronic transmission is not 
available, a paper SAE Report Form will be completed and sent directly to Celgene Drug Safety, 
ensuring the event is recorded on the CRF as well. The rapid reporting of AESIs allows ongoing 
surveillance of these events to characterize and understand them in association with the use of 
this Investigational Product. Events of special interest may be referred to external experts for 
review as needed.
The following are considered to be Adverse Events of Special Interest (AESIs):
!
Encephalopathy, including Wernicke’s (WE) or suspected cases of WE associated 
with thiamine levels below normal range.
!
Thiamine levels below normal range with or without signs or symptoms of WE
!
New malignancy after start of study treatment
Approved
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Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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!
Progression of myelofibrosis to acute myeloid leukemia (AML)
!
Cardiac failure or cardiomyopathy
!
Grade 3 or 4 hyperlipasemia or Grade 3 or 4 hyperamylasemia according to CTCAE 
criteria, v 5.0 or events of pancreatitis
!
Grade 3 or 4 alanine transaminase (ALT), aspartate transaminase (AST), or total 
bilirubin elevation or events of hepatotoxicity
Approved
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EDMS Doc. Number: 25557463 - 23009667
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from 
fedratinib
!
Lack of efficacy
!
Adverse event
!
Progression of disease according to the IWG-MRT 2013 criteria
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Pregnancy
!
Protocol deviation
!
Study terminated by Sponsor
!
Treatment discontinuation guidance related to the Dose Modification Schedule table 
(Table 4)
!
Other (to be specified on the CRF)
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents. The decision to discontinue a subject from treatment remains the responsibility of the 
treating physician, which will not be delayed or refused by the Sponsor.  However, prior to 
discontinuing a subject, the Investigator may contact the Medical Monitor and forward 
appropriate supporting documents for review and discussion.
Subjects that discontinue treatment will complete the 30-Day follow-up visit and enter the 
Survival Follow-up.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Protocol deviation
!
Study terminated by Sponsor
!
Other (to be specified on the CRF)
The reason for study discontinuation should be recorded in the CRF and in the source 
documents.
Approved
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene-
Impact/contract research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, fedratinib will be identified on the package labeling.
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Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene-Impact, its authorized 
representative, and Investigator abide by Good Clinical Practice (GCP), as described in 
International Counsel on Harmonisation (ICH) Guideline E6 and in accordance with the general 
ethical principles outlined in the Declaration of Helsinki. The study will receive approval from 
an IRB/EC prior to commencement. The Investigator will conduct all aspects of this study in 
accordance with applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations. Celgene-Impact staff or an authorized representative will evaluate and 
approve all Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene-Impact information. The Investigator should 
maintain a list of Sub-investigators and other appropriately qualified persons to whom he or she 
has delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene-Impact on public registry websites) is considered Celgene-
Impact confidential information.  Only information that is previously disclosed by Celgene-
Impact on a public registry website may be freely disclosed by the Investigator or its institution, 
or as outlined in the Clinical Trial Agreement.  Celgene-Impact protocol, amendment and IB 
information is not to be made publicly available (for example on the Investigator’s or their 
institution’s website) without express written approval from Celgene-Impact.  Information 
proposed for posting on the Investigator’s or their institution’s website must be submitted to 
Celgene-Impact for review and approval, providing at least 5 business days for review.
At the time results of this study are made available to the public, Celgene-Impact will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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EDMS Doc. Number: 25557463 - 23009667
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Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene-Impact affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene-Impact
requires the Investigator to permit Celgene-Impact's representatives and, when necessary, 
representatives from regulatory authorities, to review and/or copy any medical records relevant 
to the study in accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene-Impact Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
Approved
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EDMS Doc. Number: 25557463 - 23009667
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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Fedratinib can only be supplied to an Investigator by Celgene-Impact or its authorized 
representative after documentation on all ethical and legal requirements for starting the study has 
been received by Celgene-Impact or its authorized representative. This documentation must also 
include a list of the members of the IRB/EC and their occupation and qualifications. If the 
IRB/EC will not disclose the names, occupations and qualifications of the committee members, it 
should be asked to issue a statement confirming that the composition of the committee is in 
accordance with GCP. For example, the IRB General Assurance Number may be accepted as a 
substitute for this list. Formal approval by the IRB/EC should mention the protocol title, number, 
amendment number (if applicable), study site (or region or area of jurisdiction, as applicable), 
and any other documents reviewed. It must mention the date on which the decision was made 
and must be officially signed by a committee member. Before the first subject is enrolled in the 
study, all ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene-Impact
and the IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene-Impact reserves the right to terminate this study prematurely at any time for reasonable 
medical or administrative reasons. Any premature discontinuation will be appropriately 
documented according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Celgene-Impact has the right to discontinue a single site at any 
time during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
Approved
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene Standard 
Operating Procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:
!
Signed ICFs for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the Investigator and the IRB/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the Investigator, Celgene-Impact, and their 
authorized representative(s);
!
List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
Fedratinib accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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EDMS Doc. Number: 25557463 - 23009667
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene-Impact if he/she wishes to assign the essential documents 
to someone else, remove them to another location or is unable to retain them for a specified 
period.  The Investigator must obtain approval in writing from Celgene-Impact prior to 
destruction of any records. If the Investigator is unable to meet this obligation, the Investigator 
must ask Celgene-Impact for permission to make alternative arrangements. Details of these 
arrangements should be documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
Approved
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EDMS Doc. Number: 25557463 - 23009667
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene-Impact or its authorized 
representative for compliance with applicable government regulations with respect to current 
GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene-Impact ensures that appropriate monitoring procedures are performed before, during 
and after the study.  All aspects of the study are reviewed with the Investigator and the staff at a 
study initiation visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the 
study, a Celgene-Impact representative will review the protocol, CRFs, procedures for obtaining 
informed consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring 
will include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene-Impact representative in accordance 
with the Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene-Impact.  Representatives of this unit will conduct audits of clinical 
research activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical 
Practice guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives.  The Investigator should make every effort to be available 
for the audits and/or inspections.  If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene-Impact immediately.
15.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene-Impact
after it is released for distribution. PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the subject.  
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
Approved
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EDMS Doc. Number: 25557463 - 23009667
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-002
a Wholly Owned Subsidiary of Celgene Corporation
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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene-Impact on public registry websites, is 
considered Celgene-Impact confidential information and is not to be used in any publications.  
Celgene-Impact protocol-related information proposed for use in a publication must be submitted 
to Celgene-Impact for review and approval and should not be utilized in a publication without 
express written approval from Celgene-Impact, or as described in the Clinical Trial Agreement.
Celgene-Impact will ensure Celgene-Impact-sponsored studies are considered for publication in 
the scientific literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this 
applies to results from all Phase 3 clinical studies, and any other study results of significant 
medical importance.  This also includes results relating to investigational medicines whose 
development programs have been discontinued.
Study results may also be presented at one or more medical congresses and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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EDMS Doc. Number: 25557463 - 23009667
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Protocol FEDR-MF-002
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18.
APPENDICES
APPENDIX A. TABLE OF ABBREVIATIONS AND SPECIAL TERMS
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
AESI
Adverse event of special interest 
ALT
Alanine aminotransferase 
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase 
ATC
Anatomical therapeutic chemical
AUC
Area under the curve
BAT
Best available therapy 
BM
Bone marrow 
BUN
Blood urea nitrogen
CALR
Calreticulin
CI
Confidence interval
CRF
Case report form
CSR
Clinical Study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP2C19
Cytochrome P450 2C19
CYP3A4
Cytochrome P450 3A4
CYP2D6
Cytochrome P450 2D6
DIPSS
Dynamic International Prognostic Scoring System
DR 
Duration of spleen volume response
DRP
Duration of spleen response by palpation 
DSR 
Duration of symptoms response
EC
Ethics Committee
ECG
Electrocardiogram
ECOG 
Eastern Cooperative Oncology Group
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a Wholly Owned Subsidiary of Celgene Corporation
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Abbreviation or 
Specialist Term
Explanation
EEA
European Economic Area
EORTC 
European Organization for Research and Treatment of Cancer
EMA
European Medicine Agency
EOT
End of treatment
ET 
Essential thrombocythemia
EU
European Union 
FCBP
Female of childbearing potential 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony stimulating factor
GI
Gastrointestinal 
GVHD
Graft-versus-host-disease 
Hgb
Haemoglobin
HIV
Human immunodeficiency virus
HRQoL
Health-related Quality of Life 
IB
Investigator Brochure 
ICF
Informed consent form
ICH
International Council for Harmonisation
IL-
Interleukin-
IPSS
International Prognostic Scoring System 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IWG-MRT
International Working Group-Myeloproliferative Neoplasms Research and 
Treatment
JAK
Janus kinase
K-M
Kaplan-Meier 
LCM
Left costal margin
LDH
Lactate dehydrogenase
LFT
Liver function test
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation or 
Specialist Term
Explanation
MF
Myelofibrosis (in terms of this protocol, myeloproliferative neoplasm 
associated myelofibrosis)
MFSAF 
Myelofibrosis Symptom Assessment Form
MMSE
Mini-Mental State Examination 
MPL
Myeloproliferative leukemia virus
MPN
Myeloproliferative neoplasms 
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
OS
Overall survival
PB
Peripheral blood
PD
 progressive disease
PD-L1
Program death-ligand 1
PK
Pharmacokinetics
PLT
Platelet
PMF
Primary myelofibrosis 
PQC
Product Quality Complaint
PRO
Patient-reported outcomes 
PS
Performance Status
PV 
Polycythemia vera
QD
Once a day 
QoL
Quality of Life 
RBC
Red blood cell
RR
Response rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Steering committee
SCT
Stem-cell transplantation 
SDPFS
Spleen and disease progression free survival
SOP
Standard Operating Procedure
SRR
Symptom response rate 
STAT 
Signal transducers and activators of transcription
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Abbreviation or 
Specialist Term
Explanation
SUSAR
Suspected unexpected serious adverse reaction
SVR
Spleen volume reduction
TEAE
Treatment Emergent Adverse Event 
TGF-β
Transforming growth factor-β
Tmax 
Time to maximum plasma concentration
TNF-a 
Tumor necrosis factor-a
TSS
Total Symptom Score
 
ULN
Upper limit of normal
US
United States
VAS
Visual analog scale 
WBC
White blood cell 
WE
Wernicke Encephalopathy 
WHO
World Health Organization 
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APPENDIX B. MYELOFIBROSIS SYMPTOM ASSESSMENT FORM 
(MFSAF) VERSION 4.0
Source: (Gwaltney, 2017).
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APPENDIX C. QUALITY OF LIFE ASSESSMENT: EORTC QLQ-C30 
QUESTIONNAIRE 
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Source: (Aaronson, 1993)
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APPENDIX D. PATIENT-REPORTED OUTCOMES: EQ-5D-5L 
QUESTIONNAIRE 
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APPENDIX E. NATIONAL CANCER INSTITUTE (NCI) COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) VERSION 5.0
Currently active version of NCI CTCAE, Version 5.0:
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50
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APPENDIX F.
DYNAMIC INTERNATIONAL PROGNOSTIC SCORING
SYSTEM (DIPSS)
DIPSS Risk Score
Value
Prognostic variable 
0
1
2
Age, years 
≤ 65
> 65
White blood cell count, x 109/L
≤ 25
> 25
Hemoglobin, g/dL
≥ 10
< 10
Peripheral blood blast, %
< 1
≥ 1
Constitutional symptoms, Y/N
N
Y
The risk category is obtained by adding up the values of each prognostic variable. 
Risk categories are defined as low: 0; intermediate-1: 1 or 2; intermediate-2: 3 or 4; and high: 5 
or 6.
Constitutional symptoms are defined as >10% weight loss in 6 months, night sweats, 
unexplained fever higher than 37.5°C.
Sources: (Passamonti, 2010).
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APPENDIX G. IWG-MRT: INTERNATIONAL WORKING GROUP-
MYELOPROLIFERATIVE NEOPLASMS RESEARCH 
AND TREATMENT (IWG-MRT)
Proposed nomenclature by the International Working Group for Myelofibrosis Research and 
Treatment (IWG-MRT)
de novo presenting disease
Primary myelofibrosis (PMF)
Myelofibrosis transformation from prior polycythemia vera
(PV) or essential thrombocythemia (ET)
Post PV myelofibrosis (post-PV MF)
Post ET myelofibrosis (post-ET MF)
Transformation to acute leukemia 
Primary myelofibrosis in blast phase (PMF-BP)
Post PV/ET MF in blast phase
Source: (Mesa, 2007).
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Grading of myelofibrosis 
Myelofibrosis 
grading 
MF-0
Scattered linear reticulin with no intersections (crossovers) corresponding to normal 
BM
MF-1
Loose network of reticulin with many intersections, especially in perivascular areas
MF-2
Diffuse and dense increase in reticulin with extensive intersections, occasionally with 
focal bundles of thick fibers mostly consistent with collagen, and/or focal 
osteosclerosis*
MF-3 
Diffuse and dense increase in reticulin with extensive intersections and coarse bundles 
of thick fibers consistent with collagen, usually associated with osteosclerosis*
Semiquantitative grading of BM fibrosis (MF) with minor modifications concerning collagen and osteosclerosis. 
Fiber density should be assessed only in hematopoietic areas.
*In grades MF-2 or MF-3 an additional trichrome stain is recommended.
Source: (Arber, 2016).
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APPENDIX I.
PROPOSED CRITERIA FOR THE DIAGNOSIS OF POST-
POLYCYTHEMIA VERA AND POST-ESSENTIAL 
THROMBOCYTHEMIA MYELOFIBROSIS 
International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) 
recommended criteria for post-PV MF and post-ET MF
Criteria for post-polycythemia vera 
myelofibrosis
Criteria for post-essential thrombocythemia 
myelofibrosis
Required criteria:
1. Documentation of a previous diagnosis of 
polycythemia vera as defined by the WHO 
criteria
1. Documentation of a previous diagnosis of 
essential thrombocythemia as defined by the 
WHO criteria
2. Bone marrow fibrosis grade 2–3 (on 0–3 
scale) or grade 3–4 (on 0–4 scale) a
2. Bone marrow fibrosis grade 2–3 (on 0–3 
scale)3 or grade 3–4 (on 0–4 scale) a
Additional criteria (two are required):
1. Anemiab or sustained loss of requirement of 
either phlebotomy (in absence of cytoreductive 
therapy) or cytoreductive treatment for 
erythrocytosis
1. Anemiab and a ≥ 2 mgml-1 decrease from 
baseline hemoglobin level 
2. A leukoerythroblastic peripheral blood picture
2. A leukoerythroblastic peripheral blood picture
3. Increasing splenomegaly defined as either an 
increase in palpable splenomegaly of ≥ 5 cm 
(distance of the tip of the spleen from the left 
costal margin) or the appearance of a newly 
palpable splenomegaly
3. Increasing splenomegaly defined as either an 
increase in palpable splenomegaly of ≥ 5 cm 
(distance of the tip of the spleen from the left 
costal margin) or the appearance of a newly 
palpable splenomegaly
4. Development of ≥ 1 of three constitutional 
symptoms: > 10% weight loss in 6 months, night 
sweats, unexplained fever (> 37.5°C)
4. Increased LDH (above reference level)
5. Development of ≥ 1 of three constitutional 
symptoms: > 10% weight loss in 6 months, night 
sweats, unexplained fever (> 37.5°C)
a Grade 2–3 according to the European classification:3 diffuse, often coarse fiber network with no evidence of 
collagenization (negative trichrome stain) or diffuse, coarse fiber network with areas of collagenization (positive 
trichrome stain). Grade 3–4 according to the standard classification:4 diffuse and dense increase in reticulin with 
extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and 
dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with 
significant osteosclerosis.
b Below the reference range for appropriate age, sex, gender and altitude considerations.
Source: (Barosi, 2008).
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APPENDIX J.
ECOG PERFORMANCE STATUS SCALE
The ECOG Performance Status Scale is used to score a subject’s quality of life through 
evaluation, by a health professional, of daily activities and how those activities are affected by 
the disease of the subject.
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead
Source: (Oken, 1982).
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APPENDIX K. ESTIMATION OF THE GLOMERULAR FILTRATION 
RATE BY THE MDRD FORMULA
GFR Estimation
GFR is estimated using the MDRD formula below: 
GFR (mL/min/1.73 m2) = 175 x (Scr)–1.154 x (age)–0.203 x 1.212 (if African American) x 0.742 (if 
female) 
Where Scr (standardized serum creatinine) = mg/dL; age = years
Source: (Levey, 2006).
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Examples of clinical substrates for P450-mediated metabolism
Sensitive substrates
Substrates with 
narrow therapeutic 
range
CYP2C19
S-mephenytoin, omeprazole
S-mephenytoin
CYP2D6
atomoxetine, dextromethorphan, eliglustat, nebivolol, 
nortriptyline, perphenazine, tolterodine, venlafaxine
desipramine
CYP3A
alfentanil, avanafil, buspirone, conivaptan, darifenacin, 
darunavir, ebastine, everolimus, ibrutinib, lomitapide, 
lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, 
simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, 
vardenafil
Alfentanil, cyclosporin, 
diergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus, tacrolimus
budesonide, dasatinib, dronedarone, eletriptan, eplerenone, 
felodipine, indinavir, lurasidone, maraviroc, quetiapine, 
sildenafil, ticagrelor, tolvaptan
Examples of clinical substrates for transporters 
Transporter
Substrate
P-gp
dabigatran, digoxin, fexofenadine
BCRP
rosuvastatin, sulfasalazine
OATP1B1
OATP1B3
asunaprevir, atorvastatin, bosentan, cerivastatin, danoprevir, docetaxel, 
fexofenadine, glyburide, nateglinide, paclitaxel, pitavastatin, pravastatin, 
repaglinide, rosuvastatin, simvastatin acid
MATE1,
MATE-2K, 
OCT2
dofetilide, metformin
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APPENDIX M. NEW YORK HEART ASSOCIATION CLASSIFICATION 
FOR CONGESTIVE HEART FAILURE
Classification of Heart Failure
Class
Functional Capacity
Class I
Subjects with cardiac disease but without resulting limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain.
Class II
Subjects with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, 
or anginal pain.
Class III
Subjects with cardiac disease resulting in marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, 
or anginal pain.
Class IV
Subjects with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort is increased.
Source: AHA Medical/Scientific Statement (1994).
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APPENDIX O. REVISED RESPONSE CRITERIA FOR 
MYELOFIBROSIS: INTERNATIONAL WORKING 
GROUP-MYELOPROLIFERATIVE NEOPLASMS 
RESEARCH AND TREATMENT (IWG-MRT) AND 
EUROPEAN LEUKEMIANET (ELN) CONSENSUS 
REPORT (2013)
Response 
Categories
Required Criteria (For All Response Categories, Benefit Must Last For ≥ 12 
Weeks To Qualify As A Response) 
CR 
Bone marrow:* Age-adjusted normocellularity; < 5% blasts; ≤ grade 1 MF† and
Peripheral blood: Hemoglobin ≥ 100 g/L and < UNL; neutrophil count ≥ 1 x 109/L and < UNL;
Platelet count ≥ 100 x 109/L and < UNL; < 2% immature myeloid cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH
PR 
Peripheral blood: Hemoglobin ≥ 100 g/L and < UNL; neutrophil count ≥ 1 x 109/L and < UNL; platelet 
count ≥ 100 x 109/L and < UNL; < 2% immature myeloid cells‡ and
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH or 
Bone marrow:* Age-adjusted normocellularity; < 5% blasts; ≤ grade 1 MF†, and peripheral blood: 
Hemoglobin ≥ 85 but < 100 g/L and < UNL; neutrophil count ≥ 1 x 109/L and < UNL; platelet count ≥50, 
but < 100 x 109/L and < UNL; < 2% immature myeloid cells‡ and
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH
Clinical 
improvement 
(CI)
The achievement of anemia, spleen or symptoms response without progressive disease or increase in 
severity of anemia, thrombocytopenia, or neutropenia§
Anemia 
response 
Transfusion-independent patients: a ≥ 20 g/L increase in hemoglobin level||
Transfusion-dependent patients: becoming transfusion-independent {
Spleen response 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable** or
A baseline splenomegaly that is palpable at > 10 cm, below the LCM, decreases by ≥50%**
A baseline splenomegaly that is palpable at < 5 cm, below the LCM, is not eligible for spleen response
A spleen response requires confirmation by MRI or computed tomography showing ≥35% spleen volume 
reduction
Symptoms 
response#
A ≥50% reduction in the MPN-SAF TSS††
Progressive 
disease‡‡
Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or
A ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 cm or
A 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm or
Leukemic transformation confirmed by a bone marrow blast count of ≥ 20% or
A peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1 x 10(9)/L that 
lasts for at least 2 weeks
Stable disease
Belonging to none of the above-listed response categories
Relapse
No longer meeting criteria for at least CI after achieving CR, PR, or CI,
or Loss of anemia response persisting for at least 1 month
or Loss of spleen response persisting for at least 1 month
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or imaging study-proven non-
hepatosplenic EMH); LCM, left costal margin; UNL, upper normal limit.
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* Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review process. Cytogenetic and 
molecular responses are not required for CR assignment.
† Grading of MF is according to the European classification Thiele et al. European consensus on grading bone marrow fibrosis 
and assessment of cellularity. Haematologica. 2005;90:1128.
‡ Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood cells. In 
splenectomized patients, < 5% immature myeloid cells is allowed.
§ Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥ 20 g/L decrease in hemoglobin 
level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is
defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according to the 
CTCAE version 4.0. In addition, assignment to CI requires a minimum platelet count of ≥ 25 000 x 10(9)/L and absolute 
neutrophil count of ≥ 0.5 x 10(9)/L.
|| Applicable only to patients with baseline hemoglobin of < 100 g/L. In patients not meeting the strict criteria for transfusion 
dependency at the time of randomization, but have received transfusions within the previous month, the pretransfusion 
hemoglobin level should be used as the baseline.
{ Transfusion dependency before randomization is defined as transfusions of at least 6 units of packed red blood cells (PRBC), in 
the 12 weeks prior to study randomization, for a hemoglobin level of < 85 g/L, in the absence of bleeding or treatment-induced 
anemia. In addition, the most recent transfusion episode must have occurred in the 28 days prior to randomization. Response in 
transfusion-dependent patients requires absence of any PRBC transfusions during any consecutive “rolling” 12-week interval 
during the treatment phase, capped by a hemoglobin level of ≥ 85 g/L.
# In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy.
**Spleen or liver responses must be confirmed by imaging studies where a ≥35% reduction in spleen volume, as assessed by 
MRI or CT, is required. Furthermore, a ≥35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response 
regardless of what is reported with physical examination.
†† Symptoms are evaluated by the MPN-SAF TSS.17 The MPN-SAF TSS is assessed by the patients themselves and this 
includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, 
and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-
SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires ≥ 50% reduction in the 
MPN-SAF TSS.
‡‡ Progressive disease assignment for splenomegaly requires confirmation by MRI or computed tomography showing a ≥ 25% 
increase in spleen volume from baseline. Baseline values for both physical examination and imaging studies refer to 
pretreatment baseline and not to posttreatment measurements.
Source: (Tefferi, 2013).
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APPENDIX P.
MINI-MENTAL STATE EXAMINATION-2
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