Clinical trial NCT03755518
Conditions: Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Myelofibrosis Post-essential Thrombocythemia Myelofibrosis
Keywords: Myelofibrosis (MF) Primary Myelofibrosis (PMF) Post-Polycythemia Vera Myelofibrosis (Post-PV) Post-essential thrombocythemia Myelofibrosis (Post-ET) Myeloproliferative neoplasms (MPN)
Sponsor: Celgene
Start date: 2019-03-27; Completion date: 2023-11-08
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib in Subjects with DIPSS (Dynamic International Prognostic Scoring System)-Intermediate or High- Risk Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF), or Post-Essential Thrombocythemia Myelofibrosis (post-ET MF) and Previously Treated with Ruxolitinib.

The primary objective of the study is to evaluate the percentage of subjects with at least a 35% reduction in spleen size and one of the secondary objectives is to evaluate the safety of fedratinib.

Detailed description:
This is Single-Arm, Open-Label Efficacy and Safety Trial of Fedratinib in Subjects with DIPSS (Dynamic International Prognostic Scoring System)-Intermediate or High- Risk Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF), or Post-Essential Thrombocythemia Myelofibrosis (post-ET MF) and Previously Treated with Ruxolitinib.

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

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

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

Arms: arm 1: Self-administered Investigational Product (IP) (400 mg/day) on an outpatient basis, once daily preferably with food during an evening meal at the same time each day in consecutive 4-week (28-day) cycles.
Interventions: intervention 1: FEDRATINIB
Intervention descriptions: intervention 1: A potent and selective inhibitor of JAK2 kinase activity

Protocol documents:
Prot_SAP_000.pdf: 
Protocol for 
 
Official Title of Study 
A PHASE 3B, MULTICENTER, SINGLE-ARM, OPENLABEL 
EFFICACY AND SAFETY STUDY OF 
FEDRATINIB IN SUBJECTS WITH DIPSSINTERMEDIATE 
OR HIGH-RISK PRIMARY 
MYELOFIBROSIS, POST-POLYCYTHEMIA VERA 
MYELOFIBROSIS, OR POST-ESSENTIAL 
THROMBOCYTHEMIA MYELOFIBROSIS AND 
PREVIOUSLY TREATED WITH RUXOLITINIB 
NCT03755518 
April 21, 2021 


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
1
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
TITLE PAGE
A PHASE 3B, MULTICENTER, SINGLE-ARM, OPEN-
LABEL EFFICACY AND SAFETY STUDY OF 
FEDRATINIB IN SUBJECTS WITH DIPSS-
INTERMEDIATE OR HIGH-RISK PRIMARY 
MYELOFIBROSIS, POST-POLYCYTHEMIA VERA 
MYELOFIBROSIS, OR POST-ESSENTIAL 
THROMBOCYTHEMIA MYELOFIBROSIS AND 
PREVIOUSLY TREATED WITH RUXOLITINIB
The “FREEDOM” Trial
PROTOCOL NUMBER:
FEDR-MF-001
DATE FINAL:
26-Sep-2018
DATE AMENDMENT No. 1 FINAL:
12-Feb-2020
DATE AMENDMENT No. 2 FINAL:
21 Apr 2021
EudraCT NUMBER:
2018-002237-38
IND NUMBER:
078286
SPONSOR NAME/ ADDRESS:
Impact Biomedicines, Inc., a wholly owned 
subsidiary of Celgene Corporation
(hereafter referred to as Celgene-Impact)
86 Morris Avenue, Summit, NJ 07901
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: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
2
FEDR-MF-001 Amendment 2.0 Final:  21 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.
Back-up 24-hour Global Emergency Contact Call Center:
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
3
FEDR-MF-001 Amendment 2.0 Final:  21 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: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
4
FEDR-MF-001 Amendment 2.0 Final:  21 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: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
5
FEDR-MF-001 Amendment 2.0 Final:  21 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: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
6
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
PROTOCOL SUMMARY
Study Title
A Phase 3b, Multicenter, Single-Arm, Open-Label Efficacy and Safety Study of Fedratinib in 
Subjects with DIPSS (Dynamic International Prognostic Scoring System)-Intermediate or High-
Risk Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF), or 
Post-Essential Thrombocythemia Myelofibrosis (post-ET MF) and Previously Treated with 
Ruxolitinib.
Objectives
The primary objective of the study is to evaluate the percentage of subjects with at least a 35% 
spleen volume reduction with fedratinib.
The secondary objectives are:
!
To evaluate the safety of fedratinib
!
To evaluate the reduction of spleen size by palpation
!
To evaluate the symptom response rate in myelofibrosis (MF)-associated symptoms 
as measured by the Myelofibrosis Symptom Assessment Form (MFSAF)
!
To evaluate durability of spleen response by MRI (magnetic resonance imaging)/CT 
(computed tomography) and by palpation 
!
To evaluate the durability of symptoms response 
!
To assess the effectiveness of the risk mitigation strategy for gastrointestinal (GI) 
events 
!
To assess the effectiveness of the risk mitigation strategy for encephalopathy 
including Wernicke’s
Study Design
The study will consist of the following 3 periods:
!
A 28-day Screening Period
!
Fedratinib Treatment Period including a 30-Day Follow-up after last dose visit
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
7
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
A 12 month Survival Follow-up Period
This study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
The study will enroll approximately 110 subjects internationally. 
Study population consists of subjects with intermediate or high-risk primary myelofibrosis 
(PMF), post-polycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia 
myelofibrosis (post-ET MF).
Length of Study
The expected duration of the study is approximately 4 years, which includes approximately 
18 months to fully enroll, and 24 months for treatment and follow-up. Actual duration of the trial 
will be dependent upon the median treatment duration for subjects. 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
Survival Follow-up (or Long-term 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.
Study Treatments
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. However, fedratinib may be taken with or without regard to food.
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 until unacceptable toxicity, lack of therapeutic 
effect, progression of disease, or until a subject is not compliant with treatment or withdraws 
consent.
Overview of Key Efficacy Assessments
Assessment of Spleen Size 
Spleen volume will be assessed (MRI or CT Scan if MRI is contraindicated) during screening 
and at the end of Cycle 3, 6, 12, 18, 24, and End of Treatment (EOT). The same method (MRI or 
CT scan) should be used throughout the study. An MRI or CT scan (if MRI is contraindicated)
needs to be performed within 5 days of starting study treatment and after previous treatments 
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
8
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
have been discontinued for ≥14 days according to exclusion criteria #9 and #10 (Section 4.3).
The MRI/CT scans will be reviewed centrally. 
Spleen size will also be assessed by palpation at screening and on Day 1 of each treatment cycle, 
at the end of treatment visit and at the 30-Day Follow-up visit after last dose of fedratinib.
Assessment of MF-associated symptoms
The MF-related symptoms evaluation will be performed using the MFSAF version 4.0 using a 
7-day recall period (Gwaltney, 2017).
Overview of Key Safety Assessments
Safety of fedratinib is evaluated based on the incidence of treatment-emergent adverse events 
(TEAEs) and changes in clinical laboratory parameters, Eastern Cooperative Oncology Group 
(ECOG) Performance Status (PS), electrocardiogram (ECG), and vital signs. 
Safety assessments will be comprised of: 
!
Record of adverse events (AEs) and serious adverse events (SAEs) at each study visit 
!
Physical examination including assessment of abnormal eye movements, cerebellar 
abnormalities, body weight
!
Vital signs
!
Cognitive assessment: Mini-Mental State Examination (MMSE)
!
Laboratory assessments: hematology, serum chemistry, lipid profile, thiamine level, 
coagulation, urinalysis, serum/urine pregnancy tests 
!
Electrocardiogram (ECG)
!
Risk mitigation strategies for gastrointestinal events and encephalopathy including 
Wernicke’s
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
9
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................17
1.1.
Disease Background ...............................................................................................17
1.1.1.
Myeloproliferative Neoplasm (MPN) Associated Myelofibrosis .............................17
1.1.2.
Treatment Options for MPN-Associated Myelofibrosis...........................................18
1.1.3.
Approved Therapies ...............................................................................................19
1.1.4.
Medical Need .........................................................................................................19
1.2.
Fedratinib ...............................................................................................................20
1.2.1.
Encephalopathy including Wernicke’s in Patients Treated with Fedratinib..............21
1.3.
Rationale ................................................................................................................22
1.3.1.
Study Rationale and Purpose ..................................................................................22
1.3.2.
Rationale for the Study Design ...............................................................................23
1.3.3.
Rationale for Dose, Schedule and Regimen Selection in the Study..........................24
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................25
3.
OVERALL STUDY DESIGN ................................................................................28
3.1.
Study Design ..........................................................................................................28
3.1.1.
Study Periods..........................................................................................................28
3.2.
Study Duration for Subjects....................................................................................29
3.3.
End of Trial ............................................................................................................29
4.
STUDY POPULATION.........................................................................................31
4.1.
Number of Subjects ................................................................................................31
4.2.
Inclusion Criteria....................................................................................................31
4.3.
Exclusion Criteria...................................................................................................32
5.
TABLE OF EVENTS.............................................................................................35
5.1.
Table of Events.......................................................................................................35
6.
PROCEDURES......................................................................................................39
6.1.
Screening Period.....................................................................................................39
6.1.1.
Enrollment of a Subject in the Study.......................................................................43
6.2.
Treatment Period ....................................................................................................44
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
10
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
6.2.1.
End of Treatment Visit ...........................................................................................45
6.3.
Follow-up Period....................................................................................................46
6.3.1.
30-Day Follow-up After Last Dose Visit (+ 7 days)................................................46
6.3.2.
Survival Follow-up.................................................................................................47
6.4.
Unscheduled Assessments or Visits ........................................................................47
6.5.
Response Assessment .............................................................................................48
6.7.1.
Symptoms Response Assessment............................................................................48
7.
DESCRIPTION OF STUDY TREATMENTS........................................................50
7.1.
Description of Investigational Products...................................................................50
7.1.1.
Fedratinib ...............................................................................................................50
7.2.
Treatment Administration and Schedule .................................................................50
7.2.1.
Fedratinib Dose Modification for Toxicity..............................................................50
7.2.2.
Fedratinib Dose Adjustment for Co-administration with Strong CYP3A4 
Inhibitors................................................................................................................52
7.2.3.
Fedratinib Dose Adjustment for Renal Impairment .................................................53
7.2.4.
Overdose ................................................................................................................53
7.3.
Overview on Management of Gastrointestinal Adverse Events (Fedratinib)............53
7.3.1.
Management of Nausea and Vomiting ....................................................................54
7.3.2.
Management of Diarrhea ........................................................................................54
7.4.
Management of Encephalopathy, including Wernicke’s..........................................55
7.4.1.
Clinical and Cognitive Assessment .........................................................................55
7.4.2.
Management of Encephalopathy Including Wernicke’s...........................................55
7.4.3.
Thiamine Supplementation, Monitoring, and Correction.........................................55
7.5.
Method of Treatment Assignment...........................................................................57
7.6.
Packaging and Labeling..........................................................................................57
7.7.
Investigational Product Accountability and Disposal ..............................................57
7.8.
Investigational Product Compliance........................................................................57
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................58
8.1.
Permitted Concomitant Medications and Procedures...............................................58
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
11
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
8.2.
Prohibited Concomitant Medications ......................................................................58
8.3.
Clinically Relevant Cytochrome P450 Inducers, Inhibitors, Substrates, and 
Transporter Substrates ............................................................................................59
8.3.1.
CYP3A4 Inducers and Inhibitors ............................................................................59
8.3.2.
Dual CYP2C19 and CYP3A4 Inhibitors .................................................................59
8.3.3.
Sensitive Substrates: Effect of Fedratinib on Plasma Levels of Other Co-
administered Drugs (Drugs Metabolized by CYP3A4, CYP2C19, and 
CYP2D6):...............................................................................................................59
8.3.4.
Transporters: Effect of Fedratinib on Plasma Levels of Other Co-
administered Drugs (Drugs Transported by P-gp, BCRP, MATE1, MATE2-
K, OATP1B1/1B3, and OCT1/2):...........................................................................60
9.
STATISTICAL CONSIDERATIONS ....................................................................61
9.1.
Overview................................................................................................................61
9.2.
Study Population Definitions ..................................................................................61
9.3.
Sample Size Consideration .....................................................................................61
9.4.
Background and Demographic Characteristics........................................................62
9.4.1.
Demographic and Baseline Characteristics..............................................................62
9.4.2.
Prior or Concomitant Medications ..........................................................................62
9.5.
Subject Disposition.................................................................................................62
9.6.
Efficacy Analysis....................................................................................................62
9.6.1.
Spleen Volume Response Rate (RR) by MRI/CT:...................................................62
9.6.2.
Spleen Response Rate by Palpation (RRP)..............................................................62
9.6.3.
Symptom Response Rate (SRR)..............................................................................63
9.6.4.
Durability of Spleen Volume Response by MRI/CT (DR).......................................63
9.6.5.
Durability of Spleen Response by Palpation (DRP).................................................63
9.6.6.
Durability of Symptoms Response (DSR)...............................................................64
9.7.
Safety Analysis.......................................................................................................64
9.7.1.
Extent of Study Treatment Exposure and Compliance.............................................64
9.7.2.
Adverse Events.......................................................................................................65
9.7.3.
Assessment of Risk Mitigation Strategy for Gastrointestinal Adverse Events 
and Potential Encephalopathy including Wernicke’s...............................................65
9.7.4.
Laboratory Results..................................................................................................65
9.7.5.
Electrocardiogram (ECG) .......................................................................................65
9.7.6.
Vital Signs..............................................................................................................65
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
9.9.
Interim Analysis .....................................................................................................66
9.10.
Steering Committee ................................................................................................67
10.
ADVERSE EVENTS..............................................................................................68
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................68
10.2.
Evaluation of Adverse Events.................................................................................68
10.2.1.
Seriousness.............................................................................................................68
10.2.2.
Severity/Intensity....................................................................................................70
10.2.3.
Causality ................................................................................................................70
10.2.4.
Duration .................................................................................................................71
10.2.5.
Action Taken..........................................................................................................71
10.2.6.
Outcome.................................................................................................................71
10.3.
Abnormal Laboratory Values..................................................................................71
10.4.
Pregnancy...............................................................................................................71
10.4.1.
Females of Childbearing Potential ..........................................................................71
10.4.2.
Male Subjects.........................................................................................................72
10.5.
Reporting of Serious Adverse Events......................................................................72
10.6.
Expedited Reporting of Adverse Events..................................................................73
10.7.
Adverse Events of Special Interest..........................................................................73
10.7.1.
Fedratinib AESI......................................................................................................74
11.
DISCONTINUATIONS .........................................................................................75
11.1.
Study Treatment Discontinuation............................................................................75
11.2.
Study Discontinuation ............................................................................................75
12.
EMERGENCY PROCEDURES.............................................................................77
12.1.
Emergency Contact.................................................................................................77
12.2.
Emergency Identification of Investigational Products .............................................77
13.
REGULATORY CONSIDERATIONS...................................................................78
13.1.
Good Clinical Practice............................................................................................78
13.2.
Investigator Responsibilities ...................................................................................78
13.3.
Subject Information and Informed Consent.............................................................79
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
13
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
13.4.
Confidentiality........................................................................................................79
13.5.
Protocol Amendments.............................................................................................79
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................79
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................80
13.8.
Termination of the Study ........................................................................................80
14.
DATA HANDLING AND RECORDKEEPING.....................................................81
14.1.
Data/Documents.....................................................................................................81
14.2.
Data Management...................................................................................................81
14.3.
Record Retention....................................................................................................81
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................83
15.1.
Study Monitoring and Source Data Verification......................................................83
15.2.
Audits and Inspections............................................................................................83
15.3.
Product Quality Complaint .....................................................................................84
16.
PUBLICATIONS ...................................................................................................85
17.
REFERENCES.......................................................................................................86
18.
APPENDICES........................................................................................................91
APPENDIX A.
TABLE OF ABBREVIATIONS....................................................................91
APPENDIX B.
MYELOFIBROSIS SYMPTOM ASSESSMENT FORM (MFSAF) 
VERSION 4.0.........................................................................................................96
APPENDIX D.
REVISED RESPONSE CRITERIA FOR MYELOFIBROSIS: 
INTERNATIONAL WORKING GROUP-MYELOPROLIFERATIVE 
NEOPLASMS RESEARCH AND TREATMENT (IWG-MRT) AND 
EUROPEAN LEUKEMIANET (ELN) CONSENSUS REPORT (2013).................98
APPENDIX E.
NATIONAL CANCER INSTITUTE (NCI) COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) 
VERSION 5.0.......................................................................................................100
APPENDIX F.
DYNAMIC INTERNATIONAL PROGNOSTIC SCORING SYSTEM 
(DIPSS)................................................................................................................101
APPENDIX G.
IWG-MRT: INTERNATIONAL WORKING GROUP-
MYELOPROLIFERATIVE NEOPLASMS RESEARCH AND 
TREATMENT (IWG-MRT).................................................................................102
APPENDIX H.
2016 WORLD HEALTH ORGANIZATION (WHO) DIAGNOSTIC 
CRITERIA FOR PRIMARY MYELOFIBROSIS (PMF)......................................103
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
APPENDIX I.
PROPOSED CRITERIA FOR THE DIAGNOSIS OF POST-
POLYCYTHEMIA VERA AND POST-ESSENTIAL 
THROMBOCYTHEMIA MYELOFIBROSIS......................................................105
APPENDIX J.
ECOG PERFORMANCE STATUS SCALE.................................................106
APPENDIX K.
ESTIMATION OF THE GLOMERULAR FILTRATION RATE BY 
THE MDRD FORMULA .....................................................................................107
APPENDIX L.
CLINICALLY RELEVANT P450 INDUCERS, INHIBITORS, 
SUBSTRATES, AND TRANSPORTER SUBSTRATES .....................................108
APPENDIX M.
NEW YORK HEART ASSOCIATION CLASSIFICATION FOR 
CONGESTIVE HEART FAILURE......................................................................110
APPENDIX N.
MINI-MENTAL STATE EXAMINATION (MMSE)..................................111
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................25
Table 2:
Study Endpoints .....................................................................................................26
Table 3:
Study Table of Events.............................................................................................35
Table 4:
Fedratinib Dose Modification Schedule ..................................................................51
Table 5:
PCSA Criteria for Vital Signs and Weight ..............................................................66
Table 6:
Abbreviations and Specialist Terms........................................................................91
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
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FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................29
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
17
FEDR-MF-001 Amendment 2.0 Final:  21 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
 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 neoplasm (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
 
. Mutations in JAK2, CALR, and MPL result in activation of the JAK/ signal 
transducers and activators of transcription (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 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
18
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
MF-associated symptoms result in greatly compromised quality of life in these patients (Mesa, 
2007).
1.1.2.
Treatment Options for MPN-Associated Myelofibrosis
Allogeneic stem-cell transplantation (SCT) is 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 has 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/STAT pathway (JAK2 exon 12, myeloproliferative leukemia, and adaptor protein 
LNK) (Oh, 2010; Pikman, 2006; 
), 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 MPN-
associated MF in the United States (US). On 16 Aug 2019, fedratinib (INREBIC®) was approved 
by the US Food and Drug Administration (FDA) for the treatment of adult patients with 
intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential 
thrombocythemia) myelofibrosis. Ruxolitinib is indicated for treatment of patients with 
intermediate or high-risk MPN-associated 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 (vs) 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).
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
19
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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. 
In the US ruxolitinib (Jakafi™1) 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.
In the EU ruxolitinib (Jakavi™2) 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.
In Canada, ruxolitinib is approved for the treatment of splenomegaly and/or its associated 
symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic 
myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia 
myelofibrosis. 
On 16 Aug 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.
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 in the US. 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
. 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, 2018; 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.
                                                            
1 Jakafi is a registered trademark of Incyte Corporation.
2 Jakavi is a registered trademark of Novartis AG in countries outside of the US.
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
20
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
For patients who have been previously treated with a JAK2 inhibitor, there is no approved 
therapy and the prognosis is very poor. 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. 
Therefore, there remains an unmet need for the patients who have been previously treated with a 
JAK2 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 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 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 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
21
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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 (Grade 3 and Grade 4) 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)
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).
On 16 Aug 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.
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.
1.2.1.
Encephalopathy including Wernicke’s in Patients Treated with Fedratinib
Following the submission of cases with potential events of Wernicke’s encephalopathy (WE) in 
subjects treated with fedratinib across the fedratinib clinical development program, the Food and 
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
22
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
Drug Administration (FDA) placed the fedratinib Investigational New Drug (IND) application 
(IND 078286) on full clinical hold on 15 Nov 2013.
Consequently, Sanofi terminated the development of fedratinib on 18 Nov 2013. All subjects 
worldwide were permanently discontinued from fedratinib treatment, offered thiamine 
supplementation for ≥ 90 days, and followed for safety. The FDA removed the clinical hold on 
18 Aug 2017, following additional data being provided to the FDA by a new sponsor.
Eight subjects with potential Wernicke’s encephalopathy (WE) were identified in 608 patients 
treated with multiple doses of fedratinib in the clinical program. One subject was determined to 
have hepatic encephalopathy. Of the remaining 7 subjects, all were taking fedratinib 500 mg 
daily prior to the onset of neurological symptoms. One of these subjects had a confirmed 
diagnosis of WE based upon review by 5 independent experts. These subjects had predisposing 
factors (including baseline malnutrition and/or treatment emergent GI AEs) that are known to 
lead to thiamine deficiency and increase the risk of WE in any population. Preclinical studies in 
rats have demonstrated that, under clinically relevant doses, fedratinib does not inhibit thiamine 
transport in the gastrointestinal tract or the brain. 
Recommendations for the use of fedratinib with adequate supportive treatment of nausea, 
vomiting, and diarrhea, as well as for increased clinical awareness of the signs and symptoms of 
encephalopathy, including Wernicke’s and routine thiamine monitoring with thiamine 
supplementation, are included in this study protocol.
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
Myeloproliferative neoplasm-associated MF is a serious and life-threatening disease. The only 
approved therapy currently available worldwide is the JAK1/2 inhibitor ruxolitinib.
While many JAK1/2 inhibitors are in development, only ruxolitinib was approved in the US and 
EU for the treatment of MPN-associated myelofibrosis. Recently, fedratinib was approved on 
16 Aug 2019 in the US for the treatment of MPN-associated myelofibrosis.
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. 
The Phase 3 JAKARTA study of fedratinib enrolled patients with intermediate-2 or high risk 
MPN -associated myelofibrosis. Fedratinib was given at 400 mg daily or 500 mg daily versus 
placebo evaluating the proportion who had ≥35% reduction in spleen volume determined by 
CT/MRI at the end of Cycle 6 with a confirmation 4 weeks later. The proportion of patients with 
this reduction were 1.0% in placebo, 36.5% in fedratinib 400 mg and 40.2% in fedratinib 500
mg.
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%).
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
23
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
The studies were affected by the clinical hold mandated by the US FDA of the fedratinib 
development program in November 2013 due to reports of potential Wernicke’s encephalopathy 
(WE) and all subjects on treatment with fedratinib were discontinued from treatment. 
Based on the presentation of further analyses of the potential WE cases, the US FDA removed 
the clinical hold in August 2017 and required that steps be implemented to mitigate the risk for 
encephalopathy including Wernicke’s for future clinical studies.
The present study is a multicenter, single-arm, open-label, Phase 3b 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 and implement mitigation strategies to address US FDA request and to 
further evaluate the safety of fedratinib in subjects with DIPSS-intermediate or high-risk primary 
myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia 
myelofibrosis.
To mitigate the risk for encephalopathies including Wernicke’s, routine thiamine monitoring and 
supplementation, monitoring for signs and symptoms of encephalopathy including Wernicke’s, 
and proactive management of nausea, vomiting, and diarrhea to prevent thiamine deficiency have 
all been implemented in the present study.
The study will also provide additional data for Patient Reported Outcomes. 
1.3.2.
Rationale for the Study Design
This is a multicenter, single-arm, Phase 3b 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 assess and 
implement mitigation strategies for encephalopathy including Wernicke’s and for gastrointestinal 
(GI) adverse events.
The study will be at multiple centers to provide access to a broad population and have assurance 
the results are likely to have general applicability. 
This is also conducted as an open-label study to collect efficacy and safety data with fedratinib 
use, no randomization or stratification will occur. 
The sample size of approximately 110 subjects and accounting for approximately 10 subjects 
that are not evaluable for evaluation will approximately yield 90% power to detect a lower bound 
of the 95% confidence interval for primary endpoint response rate excludes 20% under the 
assumption of a 35% response rate (Refer to Section 9.3).
The primary endpoint is the proportion of subjects who have a ≥ 35% reduction in spleen volume 
(measured by MRI or CT scan and assessed by central review) at the end of Cycle 6.
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 data will be 
assessed using symptoms response assessment and palpation as well as MRI/CT imaging 
collected for the first year.
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
24
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
1.3.3.
Rationale for Dose, Schedule and Regimen Selection in the Study
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 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: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
25
FEDR-MF-001 Amendment 2.0 Final:  21 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 with
fedratinib
Secondary Objective(s)
The secondary objectives are:
!
To evaluate the safety of fedratinib
!
To evaluate the reduction of spleen size by palpation
!
To evaluate the symptom response rate in myelofibrosis (MF)-associated symptoms as 
measured by the Myelofibrosis Symptom Assessment Form (MFSAF) (Appendix B)
!
To evaluate the durability of spleen response by magnetic resonance imaging 
(MRI)/computer tomography (CT)-scan and by palpation
!
To evaluate the durability of symptoms response 
!
To assess the effectiveness of the risk mitigation strategy for gastrointestinal events 
!
To assess the effectiveness of the risk mitigation strategy for encephalopathy including 
Wernicke’s
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
26
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
Table 2:
Study Endpoints
Endpoint
Name
Description
Assessment Timeframe
Primary 
Spleen volume 
response rate (RR)
Proportion of subjects who have a 
≥35% SVR at 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 post 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 
From C1D1 to the end of 
Cycle 6
Symptom response 
rate (SRR)
Proportion of subjects with ≥ 50% 
reduction in total symptom scores 
measured by MFSAF
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 C1D1
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
Assessment of the 
effectiveness of the 
risk mitigation 
strategy for 
gastrointestinal 
adverse events and 
encephalopathy 
including Wernicke’s
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).
Assessment of thiamine levels at 
screening, on Day 1 of the first 3 
cycles and every third cycle 
thereafter, and at the End of 
Treatment visit
From ICF signature to 
the 30-Day Follow-up 
after last dose visit
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
27
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Assessment Timeframe
AEs = adverse events; C1D1 = Cycle 1 Day 1; CTC = Common Terminology Criteria for Adverse Events;
ICF = informed consent form; MFSAF = Myelofibrosis Symptom Assessment Form; MRI = magnetic resonance 
imaging; NCI = National Cancer Institute; 
 
; SVR = spleen volume reduction.
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
28
FEDR-MF-001 Amendment 2.0 Final:  21 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 3b, multicenter, single-arm, open-label study in subjects with Dynamic 
International Prognostic Scoring System (DIPSS) (Appendix F) intermediate or high-risk PMF
(Appendix G, 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. Further details are provided in 
Section 3.1.1.
The overall study design is described in Figure 1, with more detail for each phase of the study 
design found in Section 6.
3.1.1.
Study Periods
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 the subject from enrollment) 
detected during screening, the screening period may be extended to 35 days (additional 7 days).
If needed, enrollment 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 for the study which is to be started at least 14 days before 
enrollment. Specifically, ruxolitinib should be gradually tapered before the 14-day washout and 
supportive care provided to mitigate potential ruxolitinib withdrawal syndrome with close 
physician supervision. 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 5 days prior to enrollment. 
Treatment Period
Upon confirmation of eligibility, subjects will be enrolled and receive treatment with fedratinib 
at a dose of 400 mg once daily orally continuously. Cycles are defined for administrative 
purposes as 4-week (28-day) periods. 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 fedratinib until unacceptable toxicity, lack of therapeutic 
effect, progression of disease, or until consent is withdrawn. 
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
29
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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 at 
least a period of 30 days following the last dose of fedratinib. 
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 or up to 12 months after End of Treatment 
(EOT), lost to follow-up, withdrawal of consent for further data collection, or study closure 
whichever comes first.
Figure 1:
Overall Study Design
AE = adverse events; ANC = absolute neutrophil count; DIPSS = Dynamic International Prognostic Scoring 
System; GI = gastrointestinal; Int = intermediate; LCM = left costal margin; MPN = myeloproliferative neoplasm; 
MRI = magnetic resonance imaging; PB = peripheral blood; po = orally; 
 
; WE = Wernicke’s encephalopathy. 
3.2.
Study Duration for Subjects
The average treatment period for each subject enrolled in the Study is expected to be 
approximately 12 months. The Survival Follow-up period will last up to 12 months. The total 
expected study duration for enrolled subjects, including the Survival Follow-up period, will be 
approximately 2 years. Actual study duration will be dependent upon actual treatment duration 
for individual subjects.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
Survival follow-up (or Long-term Follow-up), or the date of receipt of the last data point from 
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
30
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
the last subject that is required for primary, secondary, 
analysis, as 
prespecified in the protocol, whichever is the later date.
The End of Trial is expected approximately 2 years after last patient has enrolled.
The trial completes when the 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
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
31
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
4.
STUDY POPULATION
4.1.
Number of Subjects 
The study will enroll a maximum of 110 subjects previously treated with ruxolitinib (as per the 
definition below) and with DIPSS-intermediate 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, 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 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 assessment or by palpable spleen 
measuring ≥ 5 cm below the left costal margin
6. Subject has been previously exposed to ruxolitinib while diagnosed with MF (PMF, post-
ET MF or post-PV MF), and must meet at least one of the following criteria (a or b) 
a.
Treatment with ruxolitinib for ≥ 3 months
b. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following:
#
Development of a red blood cell transfusion requirement (at least 2 units/month 
for 2 months) or
#
Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage 
while on treatment with ruxolitinib 
7. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or 
pretreatment baseline before start of last therapy prior to fedratinib treatment.
8. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted
9. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements
10. A female of childbearing potential (FCBP) must:
a.
Have two negative pregnancy tests as verified by the Investigator prior to starting 
study therapy. She must agree to ongoing pregnancy testing during the course of the 
study, and after end of study therapy. This applies even if the subject practices true 
abstinence* from heterosexual contact.
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
32
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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 therapy (including dose 
interruptions), and for 30 days after discontinuation of study therapy. 
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).
11. Male subjects must:
a.
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 result 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.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Any of the following laboratory abnormalities:
a.
Platelets < 50,000/μL
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 ULN (upper limit of normal)
g. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x 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
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
33
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
6. Subject with signs or symptoms of encephalopathy including Wernicke’s (eg, severe 
ataxia, ocular paralysis or cerebellar signs) 
7. Subject with thiamine deficiency, defined as thiamine levels in whole blood below 
normal range according to institutional standard and not corrected prior to enrollment on 
the study
8. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food 
known to be strong or moderate inducers of Cytochrome P450 3A4 (CYP3A4), or dual 
CYP2C19 and CYP3A4 inhibitors (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 the start of fedratinib treatment
10. Subject has received ruxolitinib within 14 days prior to the start of fedratinib
11. Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating 
factor [G-CSF]) within 14 days prior to the start of fedratinib treatment
12. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) for more than 1 cycle 
other than ruxolitinib treatment
13. Subject on treatment with aspirin with doses > 150 mg daily
14. Subject with major surgery within 28 days before starting fedratinib treatment
15. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, 
autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, 
non-alcoholic steatohepatitis)  
16. Subject with prior malignancy other than the disease under study unless the subject has 
not required treatment for the malignancy for at least 3 years prior to enrollment. 
However, subject with the following history/concurrent conditions provided successfully 
treated may enroll: non-invasive skin cancer, in situ cervical cancer, carcinoma in situ of 
the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, 
nodes, metastasis [TNM] clinical staging system), or is free of disease and on hormonal 
treatment only
17. Subject with uncontrolled congestive heart failure (New York Heart Association 
Classification 3 or 4) (Appendix M)
18. Subject with known human immunodeficiency virus (HIV), known active infectious 
Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
19. Subject with serious active infection
20. Subject with presence of any significant gastric or other disorder that would inhibit 
absorption of oral medication
21. Subject is unable to swallow capsule
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
34
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study
23. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study
24. Subject has any condition that confounds the ability to interpret data from the study
25. Subject with participation in any study of an investigational agent (drug, biologic, device) 
within 30 days prior to start of fedratinib treatment
26. Subject with life expectancy of less than 6 months.
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
35
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
5.
TABLE OF EVENTS
5.1.
Table of Events
Table 3:
Study Table of Events
Visits 
Screening d
Treatment Period
a
30-Day 
Follow-
up after 
last dose
Visit
(+ 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 (±7 
Days)
-
Informed consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion / Exclusion criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Myelofibrosis disease history
(local confirmation)
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
X
-
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
36
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
Table 3:
Study Table of Events (Continued)
Visits 
Screening d
Treatment Period
a
30-Day 
Follow-
up after 
last dose 
Visit
(+ 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 (±7 
Days)
-
Adverse events
From ICF signature until 30 days after last dose of fedratinib taken by subject
-
Risk mitigation for GI & 
encephalopathy including 
Wernicke’s
From ICF signature until 30 days after last dose of fedratinib taken by subject
-
Prior/concomitant 
medications
From 28 days prior to C1D1 until 30 days after last dose of fedratinib taken by subject
-
Prior/concomitant procedures
From 28 days prior to C1D1 until 30 days after last dose of fedratinib taken by subject 
-
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 fedratinib taken by subject
-
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) e
X
X
-
-
X
-
X
-
-
-
X (every 
3rd cycle)
-
-
X
-
-
Cognitive assessments 
(MMSE) e
X
-
-
-
X
-
X
-
-
-
X (every 
3rd cycle)
-
-
X
-
-
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number:
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
37
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
Table 3:
Study Table of Events (Continued)
Visits 
Screening d
Treatment Period
a
30-Day 
Follow-
up after 
last dose 
Visit
(+ 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 (±7 
Days)
-
Survival Follow-up
-
-
-
-
-
-
-
-
-
-
-
-
-
X
X
Assessment of progression of 
MF to AML
After signing ICF and until death, lost to follow-up, withdrawal of consent for further data collection, or study closure
Subsequent therapies for 
disease under study
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
X
ECOG PS 
X
X
-
-
X
-
X
-
X
X
X
X
-
X
X
-
Efficacy Assessments 
MRI measurements (or CT-
Scan if MRI contraindicated) f
X
-
-
-
-
-
-
-
-
-
-
-
X
X
-
-
Spleen size by palpation 
X
X
-
-
X
-
X
-
X
X
X
X
X
X
X
-
MFSAF v.4.0
X
X
-
-
X
-
X
-
X
X
X
X
X
X
X
-
AML = acute myeloid leukemia; C1D1 = Cycle 1 Day 1; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of 
Treatment; FCBP = female of childbearing potential: GI = gastrointestinal; ICF = informed consent form; IRT = Interactive Response Technology; MF = myelofibrosis; MFSAF = 
Myelofibrosis Symptom Assessment Form; MMSE = Mini-mental state examination; MRI = magnetic resonance imaging; 
 
; PS = Performance Status.
a
A visit window of ± 3 days is allowed.
b
Subjects that discontinue study treatment prior to Cycle 4 or prior to Cycle 7 will complete the response assessments in the End of Treatment visit.
c
Response assessments can be done at the same time as the Day 1 of the following Cycle. 
d
For subjects that are on ruxolitinib during the screening period or that have potentially reversible laboratory abnormalities (or other criteria that excludes the subject from 
enrollment) detected during screening, the screening period may be extended to 35 days (additional 7 days).
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
38
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
e
And at any time if clinically indicated.
f
A window of ± 7 days is allowed for MRI/CT scan procedures. The screening MRI needs to be performed within 5 days before the start of study treatment and after previous 
treatments have been discontinued for ≥ 14 days according to exclusion criteria #9 and #10. MRI/CT scans may be performed at any time during the study if clinical progression of 
splenomegaly is suspected.
.
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
39
FEDR-MF-001 Amendment 2.0 Final:  21 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.
Procedures and assessments are described in detail below. The timing of all the below Study 
assessments / procedures is specified in Sections 6.1, 6.2, 6.3.
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. 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. 
!
Demographics:
Information about the subject’s demographics (if allowed per local country 
regulations; including, but not limited to: initials, date of birth, sex, race, and 
ethnicity).
Approved
6.0
v
Approved
1.0
v


EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
40
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
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 eCRF pages. This should 
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). 
!
Transfusion history:
Transfusion history for at least 84 days prior to C1D1 including pretransfusion 
hemoglobin (Hgb) or platelet 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 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 pregnancy test occurring within 72 hours prior to the first 
administration of investigational product (IP) (negative results required for IP 
administration).
!
Adverse events:
All subjects will be monitored for AEs including Adverse Events of Special Interest 
(AESIs) 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 7.3 and Section 7.4. 
!
Height:
Height will be measured only during the screening period.
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
41
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
Prior/concomitant medications:
Information relating to prior/concomitant medications (including those taken ≤28 
days before screening) 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 (including all procedures 
occurring ≤28 days before screening) 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 site.  The following ECG parameters will 
be recorded on the respective eCRF(s):  Heart rate, 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. ECG will be performed at screening and 
if clinically indicated thereafter.  
!
Hematology:
This assessment may include the following: red blood cell (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.  
!
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, blood urea nitrogen or 
urea, creatinine and creatinine clearance as per the Modification of Diet in Renal 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
42
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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. Lipid testing will be performed at 
screening and at every 3 cycles starting with Cycle 3 Day 1 (then C6D1, C9D1, etc).
!
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, bilirubin, blood, 
glucose, ketones, leukocyte esterase, nitrite, pH, protein, specific gravity and 
urobilirubin), 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 5.1) which is every cycle for the first 3 cycles, then every 
3rd cycle thereafter or 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 Standard Version (SV) questionnaire (Appendix N) is unavailable at 
the time of study start, the original version of the MMSE questionnaire may be used. 
This is questionnaire is to be completed as specified in the Table of Events (Table 3).
!
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 5 days before the start of treatment and after previous treatments have been 
discontinued for ≥14 days according to exclusion criteria #9 and #10 (see 
Section 4.3). The locally assessed spleen volume will be recorded in the appropriate 
eCRF pages. The same method MRI or CT scan should be used consistently 
throughout the study. The MRI/CTs will be reviewed centrally. 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
43
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
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.
!
Symptoms response assessment: Myelofibrosis Symptom Assessment Form 
(MFSAF) Refer to Section 6.7.1
!
Progression of myelofibrosis to AML assessment: Refer to Section 10.7
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, 
the dose of ruxolitinib should be gradually tapered (refer to prescribing information) before the 
14-day washout and supportive care provided to mitigate potential ruxolitinib withdrawal 
syndrome with close physician supervision. In some cases, restarting of ruxolitinib may be 
indicated and the subject should be screen failed. Future rescreening may occur after resolution 
of ruxolitinib withdrawal syndrome. In addition, 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, G-CSF in last 14 days) retesting needs to be performed before enrollment after an 
appropriate washout period (refer to Section 4.3).
Subjects who screen fail 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.
6.1.1.
Enrollment of a Subject in 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. Enrollment of the subject (inclusion in the 
Treatment Period) will occur via Interactive Response Technology (IRT) to enable automated 
tracking and replenishment of study treatment. Specific contact information and instructions will 
be provided to each study site.
The IRT enrollment 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 
enrollment, 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 except for hematology 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
44
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
laboratory. Note: A negative pregnancy result is required for FCBP within 72 hours of the first 
dose of study treatment.
6.2.
Treatment Period 
The following procedures/evaluations will be performed at the frequency specified in the Table 
of Events (Table 3) during Treatment Period.  
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 5.1):
!
IRT subject registration (at Cycle 1 Day 1)
!
Pregnancy testing: As detailed in Section 6.1
!
Prior/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
Before starting each treatment cycle, local hematology lab results including ANC, 
platelet (PLT) and RBC must be available 
!
Serum Chemistry: As detailed in Section 6.1
!
Lipid Panel: Every 3rd cycle thereafter (starting from C3D1) (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
As clinically indicated and at C1D1, C2D1, C3D1, C6D1 and every 3rd cycle 
thereafter
!
Transfusion burden assessment: 
Information regarding RBC and PLT transfusions including pretransfusion Hgb or 
PLT 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. 
!
Cognitive assessment - Mini-Mental State Examination: As detailed in Section 6.1
As clinically indicated and at C2D1, C3D1, C6D1 and every 3rd cycle thereafter
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
45
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
Response assessments: As detailed in Section 6.5
!
Spleen volume by MRI/CT scan: As detailed in Section 6.5
!
Spleen size by palpation: As detailed in Section 6.1  
!
Eastern Cooperative Oncology Group (ECOG) performance status: As detailed 
in Section 6.1
!
Administration/accountability of fedratinib: Refer to Section 7 for details
!
Adverse events: Refer to Section 6.1
!
Risk mitigation for Gastrointestinal toxicity & Encephalopathy including 
Wernicke’s: Refer to Section 7.3 and Section 7.4
!
Symptoms response assessment: Myelofibrosis Symptom Assessment Form 
(MFSAF) Refer to Section 6.7.1
!
 
!
Progression of myelofibrosis to AML assessment: Refer to Section 10.7  
6.2.1.
End of Treatment Visit
The treatment period will be concluded by an End of Treatment (EOT) visit performed for 
subjects who are withdrawn from treatment for any reason as soon as possible after the decision 
to permanently discontinue treatment has been made.  
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 5.1):
!
IRT subject registration for treatment discontinuation
!
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
!
Lipid Panel: As detailed in Section 6.1
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
46
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
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 6.2
!
Cognitive assessment - Mini-Mental State Examination: As detailed in Section 6.1
!
Spleen volume by MRI/CT scan: As detailed in Section 6.5
!
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
!
Accountability of fedratinib treatment 
!
Risk mitigation for Gastrointestinal toxicity & Encephalopathy including 
Wernicke’s: Refer to Section 7.3 and Section 7.4. 
!
Symptoms response assessment: as detailed in Section 6.7.1
!
!
Progression of myelofibrosis to AML assessment: Refer to Section 10.7
6.3.
Follow-up Period
6.3.1.
30-Day Follow-up After Last Dose Visit (+ 7 days)
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 5.1, Table 3):
!
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)
!
Pregnancy testing: As 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)
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
47
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
Thiamine level: As clinically indicated (detailed in Section 6.1)
!
Transfusion burden assessment: As detailed in Section 6.2
!
Cognitive assessment - Mini-Mental State Examination: As clinically indicated 
(detailed in Section 6.1)
!
Survival: Refer to Section 6.3.2
!
Progression of myelofibrosis to acute myeloid leukemia (AML) assessment: Refer 
to Section 6.3.2 and Section 10.7
!
Subsequent therapies for disease under study: Refer to Section 6.3.2
!
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: Refer to Section 7.3 and Section 7.4. 
!
Symptoms response assessment: as detailed in Section 6.7.1
!
6.3.2.
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 
myeloid leukemia (AML) every 3 months until death, up to 12 months after EOT, lost to follow-
up, withdrawal of consent for further data collection, or study closure whichever comes first. See 
Section 10.7 for additional details on reporting. 
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.  
6.4.
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 eCRF 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/lipid 
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 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
48
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
results of the central laboratory. The results of these additional analyses will be recorded in the 
subjects’ eCRF as applicable as described in Section 10.
6.5.
Response Assessment
Response assessments should occur at the end of C3, C6, C12, C18, C24, and EOT (and at the 
end of every 6th cycle [24 weeks]) 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 6.7.1
!
Spleen volume by MRI/CT scan: Refer to Section 6.1
!
Spleen size by palpation: Refer to Section 6.1
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 CR, PR, relapse, 
cytogenic and molecular response as per IWG-MRT 2013 (Tefferi, 2013).
!
 
6.7.
Subject Reported Outcomes
All PRO evaluations will be performed on an electronic tablet at the site. These assessments 
should be performed before any other assessments are performed by the Investigator or designee 
during the visit.
6.7.1.
Symptoms Response Assessment 
The MF-related symptoms evaluation will be performed using the MFSAF v.4.0 version using a 
7-day recall period (Gwaltney, 2017).
This questionnaire assesses 7 key MF-associated symptoms (night sweats, pruritus, abdominal 
discomfort, early satiety, pain under ribs on left side, bone or muscle pain, and fatigue). Due to 
the number of different questionnaires used in clinical trials for patient-reported MF symptoms, 
this version was developed following harmonization work conducted in collaboration with 
industry and the FDA with the aim to create a publicly available, consensus -based and 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
49
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
harmonized version of MF symptoms questionnaire (Gwaltney, 2017). The MFSAF version 4.0. 
was validated and recommended to be used in clinical trials to assess MF symptoms.
The Total Symptom Score is a composite score defined as the sum of each of the 7 symptom 
scores. To allow indirect comparison with previous MF studies, a modified Total Symptom 
Score (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).
The MF-related symptoms evaluation will be performed at the site at screening, on Day 1 of each 
treatment cycle (and for Response Assessments), at the EOT and the 30-Day Follow-up after last 
dose visit. If exceptional circumstances preclude the continued administration of measures using 
planned modalities, then alternate administration methods may be required.
A copy of the questionnaire is presented in Appendix B.
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
50
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Products
7.1.1.
Fedratinib
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 
site. Celgene will not provide these medications.
7.2.
Treatment Administration and Schedule
Fedratinib
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. However, fedratinib 
may be taken with or without regard to food. 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 100 mg, 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 7.2.2 and Section 7.2.3).
For administrative purposes cycles are defined as 4-week (28-day) periods.  Subjects may 
continue treatment with fedratinib until one of the conditions described in the “Treatment 
Period” section of Section 3.1 occurs.
All study subjects will receive thiamine supplementation (Refer to Section 7.4.3). 
7.2.1.
Fedratinib Dose Modification for Toxicity 
The most common adverse events associated with fedratinib are hematological and 
gastrointestinal events. Hematological adverse events associated with JAK2 inhibitors are dose 
dependent, mechanism-based and are managed through dose reductions, dose interruptions and 
transfusions.
The Fedratinib Dose Modification table (Table 4) should only be used for events attributed to 
fedratinib treatment or if the AE cannot be attributed by the investigator 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 severe impairment of renal 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
51
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
function and co-administration of strong or moderate CYP3A4 inhibitors the fedratinib dose is 
adjusted (Refer to Section 7.2.2 and Section 7.2.3). 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 the subject must be withdrawn from the study
treatment. Reescalation of doses is possible in certain cases. The daily dose of fedratinib cannot 
exceed 400 mg/day.
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 
Non-hematological 
Grade 4 or unmanageable 
Grade 3 toxicity after 
already dose reducing in 
the previous cycle 
-
-
Subsequent upward dose titration 
not permitted 
Consider fedratinib 
discontinuation as per the 
Investigator’s discretion 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
52
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
Table 4:
Fedratinib Dose Modification Schedule (Continued)
Adverse Event 
Fedratinib 
Management 
Recovery
Fedratinib Dose After Recovery
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 
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 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 7.4, Management of 
encephalopathy, including Wernicke’s.
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; 
LFT = liver function test.
7.2.2.
Fedratinib Dose Adjustment for Co-administration with Strong CYP3A4 
Inhibitors
Concomitant administration of fedratinib with strong CYP3A4 inhibitors increases fedratinib 
exposure. Increased fedratinib exposure may increase the risk of AEs. In place of strong 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
53
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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 (Section 7.3) 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 2 weeks after discontinuation of the 
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. 
7.2.3.
Fedratinib 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 2 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.
7.2.4.
Overdose
Overdose, as defined in this protocol, refers to fedratinib dosing only. On a per dose basis, an 
overdose is defined as any amount over the protocol-specified dose of fedratinib, regardless of 
any associated adverse events or sequelae.  
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. Complete data about drug administration, including any 
overdose, regardless of whether the overdose was accidental or intentional, should be reported in 
the case report form. See Section 10.1 for the reporting of adverse events associated with 
overdose.
7.3.
Overview on Management of Gastrointestinal Adverse Events
(Fedratinib)
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 to 8 weeks on fedratinib 
treatment.
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
54
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
7.3.1.
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. 
!
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
!
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
7.3.2.
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 in the study on Day 1 of every following 28-day cycle, at Day 15 of the first 3 
cycles and by a mandatory telephone contact at Day 8 of the first cycle.
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
55
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
7.4.
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 potential cases during treatment with 
fedratinib will be done according the following steps:
7.4.1.
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 
subject history) during screening and Day 1 of every treatment cycle, at the End of 
Treatment (EOT), and the 30-Day Follow-up visit during the study.
!
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, and at the EOT visit for the study.
7.4.2.
Management of Encephalopathy Including Wernicke’s
In case of signs or symptoms that may indicate encephalopathy including Wernicke’s:
!
Hold fedratinib until Encephalopathy, including WE is ruled out
!
Obtain sample for thiamine level
!
Start parenteral thiamine supplementation, as described in Section 7.4.3 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 
Medical Monitor. 
7.4.3.
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) 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
56
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
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 instruction in Section 7.4.2
#
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.
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.
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
57
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
#
If thiamine levels are low, ensure that magnesium levels are normal or corrected if 
low
7.5.
Method of Treatment Assignment
The treatment assignment will occur at the end of the Screening Period, once all the required 
screening procedures have been completed, the investigator has verified the subject meets all 
eligibility criteria, 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.  
7.6.
Packaging and Labeling
The label(s) for fedratinib will include Sponsor name, address and telephone number, the 
protocol number, fedratinib, dosage form and strength (where applicable), amount of fedratinib
per container, lot number, expiry date (where applicable), medication 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.
7.7.
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).
7.8.
Investigational Product Compliance
Subjects will self-administer all fedratinib doses in the treatment phase. 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: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
58
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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 enrollment until 30 days after 
the last dose of fedratinib 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 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 enrollment
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 7.3)
Subjects are required to take daily thiamine supplementation (Refer to Section 7.4) 
Blood product support (RBCs and platelets 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.
The details of the prior treatment and its outcomes will also be recorded in the subject’s eCRF
regardless of treatment discontinuation/procedure date. 
For information regarding clinically relevant P450 inducers, inhibitors, substrates, and 
Transporter Substrates refer to Section 8.3. 
8.2.
Prohibited Concomitant Medications
The following concomitant medications are specifically excluded during the course of the study:
!
Cytotoxic, chemotherapeutic, targeted or investigational agents/therapies
!
Immunomodulatory drug therapy (eg, thalidomide)
!
Immunosuppressive therapy
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
59
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
!
Systemic corticosteroids >10 mg/day prednisone or equivalent
!
Hydroxyurea
!
Interferon-alpha
!
Anagrelide
!
JAK inhibitors other than fedratinib
!
Aspirin at doses of > 150 mg daily
!
Any investigational agent
For information regarding clinically relevant P450 inducers, inhibitors, substrates, and 
Transporter Substrates refer to Section 8.3.
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.
8.3.1.
CYP3A4 Inducers and Inhibitors
Strong and moderate CYP3A4 inducers (Appendix L) that may decrease fedratinib plasma 
concentrations are not permitted while receiving fedratinib. 
Strong CYP3A4 inhibitors (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 7.2.2).
8.3.2.
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.
8.3.3.
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 plasma concentration 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 (Appendix L) as necessary when co-administering with fedratinib.
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
60
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
8.3.4.
Transporters: Effect of Fedratinib on Plasma Levels of Other Co-administered 
Drugs (Drugs Transported by P-gp, BCRP, MATE1, MATE2-K, OATP1B1/1B3, 
and OCT1/2):
Fedratinib inhibits transporters P-gp, BCRP, MATE1, MATE2-K, OATP1B1/1B3, and OCT2, 
which may increase the concentration of drugs that are substrates of these transporters. Monitor 
for adverse reactions and adjust the dose of drugs that are substrates of these transporters 
(Appendix L) as necessary when coadministered with fedratinib.
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: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
61
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a multicenter, single-arm, open-label efficacy and safety study of fedratinib in subjects 
previously treated with ruxolitinib and with DIPSS-intermediate 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
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 
75% 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.
9.2.
Study Population Definitions
Enrolled Population: this population includes all subjects enrolled into the study.
Safety population: this population will consist of all subjects who were administered at least 
one dose of fedratinib.
Efficacy evaluable population: this population includes subjects treated with fedratinib with 
evaluable spleen volume measurements based on MRI/CT scan at baseline and at least one post 
baseline response assessment by MRI/CT scan. This population will be used for analyses of 
spleen volume changes.
MFSAF population: For symptoms response (MFSAF version 4.0), fedratinib treated subjects 
with a Total Symptom Score (TSS) at baseline (eg, symptom score) > 0 and at least 1 post 
baseline TSS assessment will be included in the analysis.
9.3.
Sample Size Consideration
Assuming the primary endpoint response rate is 35%, 100 evaluable subjects will approximately 
yield 90% power to detect the lower bound of 95% confidence interval (calculated by Pearson-
Klopper method) for primary endpoint response rate excludes 20%. 
The study will enroll approximately 110 subjects by accounting for a 10% drop-out rate.
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
62
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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 screening as a 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.
For quantitative variables, the summary using descriptive statistics will be provided, while 
frequency tabulations will be given for categorical variables. 
9.4.2.
Prior or Concomitant Medications
The prior and concomitant medications will be presented for the safety population.
Medications will be summarized according to the World Health Organization (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 for the study.
9.6.
Efficacy Analysis
Unless otherwise specified, analysis of spleen volume response will be performed on the efficacy 
evaluable population, myelofibrosis symptom response analyses will be performed on the 
MFSAF population and spleen size response analyses will be performed on the safety 
population.
9.6.1.
Spleen Volume Response Rate (RR) by MRI/CT: 
Response rate of reduction in spleen volume is defined as proportion of subjects who have a ≥ 
35% reduction in spleen volume at the end of Cycle 6 as compared to baseline. The response rate 
and 95% confidence interval will be provided. In addition, a descriptive summary of spleen 
volumes measurements and percentage change from baseline will be provided. 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.
A sensitivity analysis will be conducted for response rate of subjects who have a ≥ 25% 
reduction in spleen volume at the end of Cycle 6 as compared to baseline. 
9.6.2.
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 D) at the end of Cycle 6 as compared to baseline. This will be 
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
63
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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 the end of Cycle 6 will be considered not to be 
responders. The response rate and 95% confidence interval will be provided. 
9.6.3.
Symptom Response Rate (SRR)
Symptom response rate (SRR) 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. The SRR and 95% confidence interval will be provided. The TSS will be 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. 
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 
for baseline scores, postbaseline scores and change from baseline for TSS, modified TSS and 
symptom scores.
Subjects without a baseline TSS > 0 will be considered non-evaluable (due to no place for 
symptom reduction) for the SRR analysis. 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.
Details of the statistical analysis will be provided in a separate Health-related Quality of Life 
(HRQoL) SAP and will be reported under a separate cover.
9.6.4.
Durability of Spleen Volume Response by MRI/CT (DR)
Durability of spleen volume response (DR) by MRI/CT is defined as time from the first 
documented spleen response (ie, ≥ 35% reduction in spleen volume) to the date of subsequent 
progressive disease (PD) (ie, ≥ 25% increase in spleen volume from baseline) or death, 
whichever is earlier. In the absence an event (ie, subsequent spleen volume reduction < 35% 
before the analysis is performed), the DR will be censored at the date of the last valid assessment 
performed before the analysis performed date. 
Durability of spleen volume response by MRI/CT scan will be analyzed using Kaplan-Meier 
method. The K-M estimates of the 25th, 50th, and 75th percentiles and the 95% confidence 
interval of median will be provided, and the K-M curves will be plotted.
9.6.5.
Durability of Spleen Response by Palpation (DRP)
Durability of spleen response by palpation (DRP) is defined as time from the date of first 
documented palpable spleen response, according to the IWG-MRT 2013 (Appendix D) to the 
date of subsequent PD 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 (ie, no loss of spleen response by 
palpation) before the analysis is performed, the DRP will be censored at the date of the last valid 
assessment performed before the analysis performed date. 
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
64
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
Durability of spleen response by palpation will be analyzed using Kaplan-Meier (K-M) method. 
The K-M estimates of the 25th, 50th, and 75th percentiles and the 95% confidence interval of 
median will be provided, and K-M curves will be plotted.
9.6.6.
Durability of Symptoms Response (DSR)
Durability of symptoms response is defined as time from the first documented response in TSS 
(ie, reduction in TSS ≥ 50%) measured by MFSAF version 4.0 to the first documented TSS 
reduction < 50%. In the absence of TSS reduction < 50% before the analysis performed, the DSR 
will be censored at the date of the last valid assessment performed before the analysis performed 
date. The DSR will be analyzed using K-M method. The K-M estimates of the 25th, 50th, and 
75th percentiles and the 95% confidence intervals of median will be provided, and K-M curves 
will be plotted.
9.7.
Safety Analysis
All safety analyses will be conducted based on the safety population for the study.
Literature “book” values and normal ranges from local laboratory results will be utilized for this 
study.
9.7.1.
Extent of Study Treatment Exposure and Compliance
Extent of exposure will be assessed within the safety population for the study.
Dose information will be assessed by the following variables:
!
Duration of treatment exposure is defined as: last dose date - first dose date regardless of 
unplanned intermittent discontinuations
!
The cumulative dose is the sum of all doses from Cycle 1 to the last dose
!
The actual dose intensity is defined as the cumulative dose divided by the duration of 
treatment 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 dose for each 
cycle divided by planned cycle length in weeks
!
Dose reduction and reason for dose reduction
!
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 for fedratinib in the study.
Dose interruption, delays and dose reductions will also be analyzed for study IPs within the 
study.
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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9.7.2.
Adverse Events
The endpoints of this study are type, frequency, seriousness and severity of AEs, and relationship 
of AEs to study treatment. The safety population, which includes all enrolled subjects who 
received at least 1 dose of fedratinib, will be the analysis population for all safety analyses.
Adverse events will be analyzed in terms of TEAEs that are defined to be any event that begins 
or worsens in grade after the start of fedratinib through 30 days after the last dose. AEs 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.
9.7.3.
Assessment of Risk Mitigation Strategy for Gastrointestinal Adverse Events and 
Potential 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 and at the EOT during the study.
9.7.4.
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. For each of the parameters, a baseline value is defined as the last value 
or measurement taken up to the first dose of fedratinib.
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.
9.7.5.
Electrocardiogram (ECG)
All ECG data will be provided in a listing.
9.7.6.
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.
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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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.
Interim Analysis
A formal interim analysis is not planned in this study.
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Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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9.10.
Steering Committee 
The conduct of this trial will be overseen by a steering committee (SC), presided over by a
coordinating Principal Investigator, and if possible, the representative Regional Investigators 
from countries participating in this study.
The SC will serve in an advisory capacity to the Sponsor.  Operational details for the SC will be 
detailed in a separate SC charter.
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 7.2.4 for the definition of overdose.) Any sequela of 
an accidental or intentional overdose of an investigational product which meets the definition of 
an adverse event should be reported as an AE on the CRF. If the sequela of an overdose meets 
serious criteria, then it must be marked as serious on the CRF. The overdose itself should not be 
reported as an SAE.
 
Complete data about drug administration, including any overdose, 
regardless of whether the overdose was accidental or intentional, should be reported in the case 
report form.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for fedratinib overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 30 days after the last dose of fedratinib, as well as those SAEs made known to the 
investigator at any time thereafter that are suspected of being related to fedratinib AE and SAEs. 
All adverse events (serious/non-serious) will be recorded on the CRF and in the subject’s source 
documents. Refer to Section 10.5 for instructions on how to report SAEs to Drug Safety.  
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;
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Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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!
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.
!
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 the IP, action taken regarding the IP, and outcome.
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Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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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
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.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of fedratinib 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
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 caused the adverse event.  ‘Reasonable possibility’ 
means there is evidence to suggest a causal relationship between 
fedratinib 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.
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Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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If an event is assessed as suspected of being related to a comparator, ancillary or additional IP
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 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 fedratinib dose administration, or any 
other therapeutic intervention; or
!
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 [β-hCG] or positive pregnancy test in a female subject of childbearing potential 
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Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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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 30 days of birth should be reported, without regard to 
causality, as an SAE.  In addition, any infant death after 30 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.
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.  
Males will be advised to use a latex condom during any sexual contact with FCBP prior to study 
entry and continue for 30 days following the last dose of fedratinib, even if he has undergone a 
successful vasectomy.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any serious 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 IP) 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.
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Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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The SAE is recorded within the CRF, and the data is transmitted electronically to Celgene Drug 
Safety. 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.
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
electronic data capture (EDC) or other appropriate method.
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 IB, 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 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) 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.  
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. All 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, 
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Protocol FEDR-MF-001
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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.
10.7.1.
Fedratinib AESI
The following are considered to be Adverse Events of Special Interest (AESIs) for Fedratinib:
!
Encephalopathy, including Wernicke’s 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
!
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
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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11.
DISCONTINUATIONS
11.1.
Study 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.
11.2.
Study Discontinuation
Subjects who discontinue from treatment for any reason will be followed via telephone contact 
by the site for collection of data on survival including: cause(s) of death, disease progression, 
and posttreatment therapies for MPN-associated MF; until death, lost to follow up, or withdrawal 
of consent from the study.
Every attempt should be made to contact subjects during follow up unless subjects discontinue 
from the study.  Every attempt should be made to collect all data on discontinued subjects.
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
#
The following information is to be captured in the subject’s source documents and 
eCRF page(s): the date the informed consent forms (ICFs) were signed, 
demographics, prior ruxolitinib history, the reason a subject did not qualify for the 
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Protocol FEDR-MF-001
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study, and the investigator’s signature for the eCRF pages. Any adverse events 
experienced by a screen failure subject will be collected from the date of signing 
the ICF to the day the subject is confirmed as a screen failure. Serious adverse 
events occurring prior to treatment (after signing the ICF) are to be recorded 
within the eCRF, but do not require reporting to Celgene Drug Safety. Relevant 
information will also be recorded on the Screening Log.
!
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.
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Protocol FEDR-MF-001
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-001
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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 Council for 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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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
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.
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 
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Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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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.
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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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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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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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.
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Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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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.
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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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. Product Quality Complaints 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 patient.  Examples of PQCs include (but are not limited to): mixed product, 
mislabeling, lack of effect, seal/packaging breach, product missing/short/overage, contamination, 
suspected falsified, tampered, diverted or stolen material, and general product/packaging 
damage. If you become aware of a suspected PQC, you are obligated to report the issue 
immediately.  You can do so by emailing 
 or by contacting the 
Celgene Customer Care Center 
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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17.
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to the World Health Organization classification of myeloid neoplasms and acute leukemia. 
Blood. 2016 May 19;127(20):2391-405.
Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, et al. Proposed criteria 
for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a 
consensus statement from the International Working Group for Myelofibrosis Research and 
Treatment. Leukemia. 2008 Feb;22(2):437-8.
Barosi G, Magrini U, Gale RP. Does auto-immunity contribute to anemia in myeloproliferative 
neoplasms (MPN)-associated myelofibrosis? Leuk Res. 2010 Sep;34(9):1119-20. 
Campbell PJ, Green AR. Management of polycythemia vera and essential thrombocythemia. 
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Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, et al. New prognostic 
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Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing 
Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF). Blood. 
2012;120(21):801.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical 
application and proposal for modification of the International Working Group (IWG) response 
criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25.
Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J, et al. An activin receptor IIA 
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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Elena C, Passamonti F, Rumi E, Malcovati L, Arcaini L, Boveri E, et al. Red blood cell 
transfusion-dependency implies a poor survival in primary myelofibrosis irrespective of IPSS 
and DIPSS. Haematologica. 2011 Jan;96(1):167-70. 
Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a 
refined Dynamic International Prognostic Scoring System for primary myelofibrosis that 
incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin 
Oncol. 2011 Feb 1;29(4):392-7.
Gerds A, Vannucchi A, Passamonti F, Kremyanskaya M, Gotlib J, Palmer J, et al. A Phase 2 
study of luspatercept in patients with myelofibrosis-associated anemia [abstract]. Presented at: 
The 61st Annual Meeting of the American Society of Hematology (ASH) and Exposition: 2019; 
Orlando, FL; USA. Abstract 557.
Gwaltney C, Paty J, Kwitkowski VE, Mesa RA, Dueck AC, Papadopoulos EJ, et al. 
Development of a harmonized patient-reported outcome questionnaire to assess myelofibrosis 
symptoms in clinical trials. Leuk Res. 2017 Aug;59:26-31.
Harrison C, Vannucchi AM. Ruxolitinib: a potent and selective Janus kinase 1 and 2 inhibitor in 
patients with myelofibrosis. An update for clinicians. Ther Adv Hematol. 2012 Dec;3(6):341-54.
Harrison CN, McLornan DP. Current treatment algorithm for the management of patients with 
myelofibrosis, JAK inhibitors, and beyond. Hematology Am Soc Hematol Educ Program. 2017 
Dec 8;2017(1):489-97.
Harrison CN, Mesa RA, Jamieson C, Hood J, Bykowski J, Zuccoli G, et al. Case Series of 
Potential Wernicke's Encephalopathy in Patients Treated with Fedratinib. Blood. 2018;130(Suppl 
1):4197.
Ihle JN, Gilliland DD. Jak2: normal function and role in hematopoietic disorders. Curr Opin 
Genet Dev. 2007 Feb;17(1):8-14.
Jabbour E, Kantarjian HM, Garcia-Manero G, Quintas-Cardama A, Cardena-Turanzas M, 
O'Brien S, et al. Outcome Of Patients (pts) With Myelofibrosis (MF) After Ruxolutinib (Rux) 
Therapy [abstract]. Blood. 2013;122(21):1584;.
Kantarjian HM, Silver RT, Komrokji RS, Mesa RA, Tacke R, Harrison CN. Ruxolitinib for 
myelofibrosis--an update of its clinical effects. Clin Lymphoma Myeloma Leuk. 2013 
Dec;13(6):638-45.
Keohane C, Radia DH, Harrison CN. Treatment and management of myelofibrosis in the era of 
JAK inhibitors. Biologics. 2013;7(1):189-98.
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
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Kvasnicka HM. WHO classification of myeloproliferative neoplasms (MPN): A critical update. 
Curr Hematol Malig Rep. 2013 Dec;8(4):333-41.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized 
serum creatinine values in the modification of diet in renal disease study equation for estimating 
glomerular filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247-54.
Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753-91. 
Mesa RA, Camoriano JK, Geyer SM, Wu W, Kaufmann SH, Rivera CE, et al. A phase II trial of 
tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential 
thrombocythemia. Leukemia. 2007 Sep;21(9):1964-70.
Mesa RA, Gotlib J, Gupta V, Catalano JV, Deininger MW, Shields AL, et al. Effect of 
ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in 
COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2013 Apr 
1;31(10):1285-92.
Oh ST, Simonds EF, Jones C, Hale MB, Goltsev Y, Gibbs KD, Jr., et al. Novel mutations in the 
inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative 
neoplasms. Blood. 2010 Aug 12;116(6):988-92.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic 
prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT 
(International Working Group for Myeloproliferative Neoplasms Research and Treatment). 
Blood. 2010 Mar 4;115(9):1703-8.
 
Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel 
somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006 
Jul;3(7):e270.
Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, et al. Luspatercept for the 
treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a 
multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet 
Oncol. 2017 Oct;18(10):1338-47. 
Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, et al. Transforming growth 
factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage 
erythropoiesis. Nat Med. 2014 Apr;20(4):408-14. 
Swerdlow SH. Editors. WHO classification of tumours of haematopoietic and lymphoid tissues. 
Lyon, France: IARC Press, 2008.
Tefferi A. Primary myelofibrosis: 2017 update on diagnosis, risk-stratification, and management. 
Am J Hematol. 2016 Dec;91(12):1262-71.
Tefferi A. Recent advances in classic BCR-ABL-negative myeloproliferative disorders. Clin Adv 
Hematol Oncol. 2007;5:113-5
Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi AM, et al. Revised 
response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms 
Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. 
Blood. 2013 Aug 22;122(8):1395-8. Epub 2013 Jul 9.
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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Vannucchi AM, Harrison CN. Emerging treatments for classical myeloproliferative neoplasms. 
Blood. 2017 Feb 9;129(6):693-703.
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, 
placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):799-
807.
Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, et al. Long-term treatment 
with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-
blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017 Feb 22;10(1):55.
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Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
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18.
APPENDICES
APPENDIX A. TABLE OF ABBREVIATIONS
Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ActRIIB
Human activin receptor type IIB
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
β-hCG
β-subunit of human chorionic gonadotropin
BAT
Best available therapy
BM
Bone marrow 
BUN
Blood urea nitrogen
CALR
Calreticulin
CRF
Case report form
CRP
C-reactive Protein
CSR
Clinical Study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP2C19
Cytochrome P450 2C19
CYP2D6
Cytochrome P450 2D6
CYP3A4
Cytochrome P450 3A4
DIPSS
Dynamic International Prognostic Scoring System
DR 
Durability of spleen volume response
DRP
Durability of spleen response by palpation 
DSR 
Durability of symptoms response
EC
Ethics Committee
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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
ECD
Extracellular domain
ECG
Electrocardiogram
ECOG 
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
EMA
European Medicine Agency
EOT
End of treatment
EPO
Erythropoietin
ESA
Erythropoietin-stimulating agent
ET 
Essential Thrombocythemia
EU
European Union 
FCBP
Female of childbearing potential 
FDA
Food and Drug Administration
FLT3
Fibromyalgia syndrome (FMS)-like tyrosine kinase 3
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony stimulating factor
GDF
Growth differentiation factor
GI
Gastrointestinal 
HDPE
High density polyethylene
Hgb
Haemoglobin
HI-E
Hematological Improvement – Erythroid
HIV
Human immunodeficiency virus
HRQoL
Health-related Quality of Life 
IB
Investigator Brochure 
ICF
Informed consent form
ICH
International Council for Harmonisation
IM
Intramuscular
IND
Investigational new drug
IP
Investigational product
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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
IPSS
International Prognostic Scoring System 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
IWG-MRT
International Working Group-Myeloproliferative Neoplasms Research and 
Treatment
JAK
Janus kinase
K-M
Kaplan-Meier 
LCM
Left costal margin
LFT
Liver function test
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
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
NTD
Non-transfusion dependent
OS
Overall survival
PB
Peripheral blood
PBPK
Physiologically based pharmacokinetics
PCSA
Potentially clinically significant abnormality
PK
Pharmacokinetics
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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
PLT
Platelet
PMF
Primary myelofibrosis 
PQC
Product Quality Complaint
PRO
Patient-reported outcomes 
PS
Performance Status
PV 
Polycythemia vera
QD
Once a day 
RBC
Red blood cell
RR
Spleen volume response rate
SAE
Serious adverse event
SAP
Statistical analysis plan
SCT
Stem-cell transplantation 
SOP
Standard Operating Procedure
SRR
Symptom response rate 
STAT 
Signal transducers and activators of transcription
SUSAR
Suspected unexpected serious adverse reaction
SV
Standard version
SVR
Spleen volume reduction
TD
Transfusion dependent
TEAE
Treatment emergent adverse event 
TGF-β
Transforming growth factor - beta
TNF
Tumor necrosis factor
TSS
Total Symptom Score
ULN
Upper limit of normal
US
United States
vs
Versus
WBC
White blood cell 
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Table 6:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
WE
Wernicke’s 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 D. 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 109/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 109/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 study enrollment, but have received transfusions within the previous month, 
the pretransfusion hemoglobin level should be used as the baseline.
{ Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood 
cells (PRBC), in the 12 weeks prior to study enrollment, 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 study enrollment. 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 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
Prognostic variables
Value
0
1
2
Age, years
≤ 65
> 65
White blood cell count, 
x109/L
≤ 25
> 25
Hemoglobin, g/dL
≥ 10
< 10
Peripheral blood blast, 
%
< 1
≥ 1
Constitutional 
symptoms, Y/N
N
Y
The risk category is obtained 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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APPENDIX H. 2016 WORLD HEALTH ORGANIZATION (WHO) 
DIAGNOSTIC CRITERIA FOR PRIMARY 
MYELOFIBROSIS (PMF)
2016 WHO diagnostic criteria for prePMF and overt PMF
PrePMFa
Overt PMFb
Major criteria 
1. Megakaryocytic proliferation and atypia, 
without reticulin fibrosis > grade 1*, 
accompanied by increased age-adjusted BM 
cellularity, granulocytic proliferation, and
often decreased erythropoiesis
1. Presence of megakaryocytic proliferation and atypia, 
accompanied by either reticulin and/or collagen fibrosis 
grades 2 or 3*
2. Not meeting the WHO criteria for BCR-
ABL1+ CML, PV, ET, myelodysplastic 
syndromes, or other myeloid neoplasms 
2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, 
myelodysplastic syndromes, or other myeloid neoplasms
3. Presence of JAK2, CALR, or MPL mutation or 
in the absence of these mutations, presence of 
another clonal markerc, or absence of minor 
reactive BM reticulin fibrosisd
3. Presence of JAK2, CALR, or MPL mutation or in the 
absence of these mutations, presence of another clonal 
markerc, or absence of reactive myelofibrosisd
Minor criteria
Presence of at least 1 of the following, 
confirmed in 2 consecutive determinations:
Presence of at least 1 of the following, confirmed in 2 
consecutive determinations:
a. Anemia not attributed to a comorbid 
condition
a. Anemia not attributed to a comorbid condition
b. Leukocytosis ≥ 11 x 109/L
b. Leukocytosis ≥ 11 x 109/L
c. Palpable splenomegaly
c. Palpable splenomegaly
d. LDH increased to above upper normal 
limit of institutional reference range
d. LDH increased to above upper normal limit of 
institutional reference range
e. Leukoerythroblastosis
* More than 25% above mean normal predicted value.
a Diagnosis of prePMF requires meeting all 3 major criteria, and at least 1 minor criterion
b Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criterion. 
c In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations 
(eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the 
disease.
d Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory 
conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) 
myelopathies.
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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)3
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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APPENDIX L. CLINICALLY RELEVANT P450 INDUCERS, 
INHIBITORS, SUBSTRATES, AND TRANSPORTER 
SUBSTRATES
A list of clinically relevant P450 inducers and inhibitors as well as substrates, and transporter 
substrates can be found in this appendix This is not an exhaustive list. It is periodically updated 
at the following link:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm
Examples of clinical inducers for P450-mediated metabolisms
Strong CYP3A inducers
Moderate CYP3A inducers
carbamazepine, enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s wort
bosentan, efavirenz, etravirine, modafinil
Examples of clinical inhibitors for P450-mediated metabolisms
Strong CYP3A inhibitors
Dual CYP2C19 and CYP3A4 inhibitors
boceprevir, cobicistat, conivaptan, danoprevir and 
ritonavir, elvitegravir and ritonavir, grapefruit juice, 
indinavir and ritonavir, itraconazole, ketoconazole, 
lopinavir and ritonavir, paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir), posaconazole, ritonavir, 
saquinavir and ritonavir, telaprevir, tipranavir and 
ritonavir, troleandomycin, voriconazole
fluconazole, fluvoxamine
clarithromycin, diltiazem, idelalisib, nefazodone, 
nelfinavir
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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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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
110
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
111
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
APPENDIX N. MINI-MENTAL STATE EXAMINATION (MMSE)
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
112
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
113
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
114
FEDR-MF-001 Amendment 2.0 Final:  21 April 2021
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EDMS Doc. Number: 
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
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1.0
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
3
FEDR-MF-001 Amendment 2.0 Final: 21 April 2021
1.
JUSTIFICATION FOR AMENDMENT
As of 12 Nov 2020, BMS – Celgene has made the decision to not implement the sub-study due 
to the coronavirus disease 2019 (COVID-19) pandemic’s impact on the sub-study start-up 
activities. 
In the ongoing clinical program, BMS has observed events of low thiamine and one case of 
Wernicke’s encephalopathy which was discussed with the Scientific Steering Committee. The 
Steering Committee made the recommendation to implement prophylactic thiamine 
supplementation for all study subjects. 
This amendment will therefore include updated language to reflect the mandatory thiamine 
supplementation and updated guidelines for thiamine deficiency as well as the removal of all 
sub-study language.
The protocol has been revised to remove this optional sub-study throughout the protocol from the 
Cover page through Sections 11, including figures and tables. The subsections added in Protocol 
Amendment 1; which separated sections referred to as the “Main Study” and “Sub-Study” have 
been amended to only reflect the original protocol design.
The following changes were made to the protocol with the removal of the sub-study: 
!
Title updated to remove the sub-study – Cover page and Protocol Summary
!
The following sections, tables, and figures from Protocol Amendment 1 were deleted
and subsequent sections have therefore been renumbered, as applicable: Sections
1.1.5, 1.3, 1.3.1, 1.4.5, 1.4.5.2-1.4.5.4, 2.1, 3.1.2, 4.4-4.4.3, 5.2, 6.8-6.8.5, 7.1.2,
7.2.4-7.2.4.3, 8.4-8.4.2, 9.2.1, 9.3.2, 9.6.7-9.6.7.2, 10.7.2-10.7.2.2, and 11.3. Tables 3,
4, 6, and 8-10. Figures 1 and 3.
!
The following sections and figure have been updated to remove all references to the
sub-study: Protocol Summary, Sections 3.1-3.3, 4.1, 6.5, 7.2, 7.2.4, 7.4.3, 7.5-7.6, 7.8,
9.1, 9.5, 9.7-9.7.2, 
 10.1, 10.2.3, 10.2.5, 10.3, and 10.4.1-10.6. Figure 2.
!
References to “Main study” have been removed or revised to “study” throughout.
1.1.
Additional Clarifications and Corrections
Other changes included in this amendment are summarized below. These changes are based on 
recommendations received from internal discussions and expert opinions. 
!
Updated language in Section 6.7.1. Symptoms Response Assessment
∀
To ensure every possible attempt to collect symptom response information is
made, wording has been updated to include alternate modalities.
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
4
FEDR-MF-001 Amendment 2.0 Final: 21 April 2021
!
Updated language in Section 6.5 Response Assessment 
∀
Revised language regarding the time point frequency and assessments to be 
completed. Aligned frequency of all “response assessments” to occur every six (6) 
cycles after Cycle 24 which includes spleen imaging (in addition to spleen size by 
palpation and Myelofibrosis Symptom Assessment Form [MFSAF])
!
Updated language in Sections 7.4.2 Management of Encephalopathy Including 
Wernicke’s 
o
Updated Section 7.4.3- Management of Encephalopathy including Wernicke’s
language to empirically start parenteral thiamine supplementation for subjects 
with thiamine levels < 30 nM/L
!
Updated language in Section 7.4.2 Thiamine Supplementation, Monitoring, and 
Correction
o
Updated Section 7.4.3 title from “Thiamine Monitoring and Correction” to 
“Thiamine Supplementation, Monitoring, and Correction” to reflect updated 
language for required thiamine supplementation 
o
Revised language to state that oral thiamine supplementation of 100 mg or 
equivalent is mandatory for all subjects throughout the treatment period until 
study medication is discontinued and though the 30-Day Follow-Up visit
o
Revised language to reflect thiamine level monitoring to be taken in a fasting state 
at the start of Cycles 1, 2, 3 and every third cycle thereafter, including end of 
treatment (EOT) visits
o
Revised language to include new monitoring parameters and thiamine level 
thresholds for encephalopathy including Werneck’s Encephalopathy (WE) 
monitoring

Updated guidance to site if subject develops signs or symptoms suggestive 
of WE, to follow instructions updated in Section 7.4.2

For thiamine levels below normal range but > 30 nM/L without signs or
symptoms of WE – updated language to increase thiamine 
supplementation to twice the daily dose (100 mg to 200 mg)

Updated guidance to site to contact Medical Monitor regarding low 
thiamine level 

For thiamine levels < 30 nM/L without signs or symptoms of WE –
updated language to stop oral thiamine supplementation and start 
intravenous (IV) thiamine at therapeutic dosages 
!
Updated guidance to follow IV thiamine therapy with 250 mg to 
500 mg IV thiamine infused once daily for 3 to 5 days (or via 
intramuscular [IM] injection)
!
Updated guidance to increase subjects daily dose to twice the 
previous daily dose post event 
Approved
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Fedratinib
Impact Biomedicines, Inc.,
Protocol FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
5
FEDR-MF-001 Amendment 2.0 Final: 21 April 2021
!
Updated guidance to monitor thiamine levels monthly 
!
Updated guidance to hold study medication until thiamine levels 
are restored

Updated Table 3 – Table of events to include daily dose of thiamine 

Updated language in Section 8.1 to reflect the mandatory thiamine 
supplementation 
!
Updated safety language in Section 10.6 to reflect changes in the heritage Celgene 
(hCelgene) protocol template to alleviate the confusion resulting from reporting pre-
treatment events 
1.2.
Minor Corrections, Clarifications and Administrative Changes 
!
Other clarifications, corrections of minor typographical errors and incidental 
formatting changes were made throughout the document
!
Clarified Section 11.1 Study Treatment Discontinuation to include International 
Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
2013 criteria 
!
New Medical Monitor on “Medical Monitor / Contact Information” page 
Approved
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Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Summary of Changes FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
3
FEDR-MF-001 Amendment 1.0 Final: 12 Feb 2020
1.
JUSTIFICATION FOR AMENDMENT
As of 12 Feb 2020, approximately 20 subjects have been enrolled into the main study of FEDR-
MF-001 of which ~2 have completed at least 8 cycles of treatment with fedratinib.
Approved
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Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Summary of Changes FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
4
FEDR-MF-001 Amendment 1.0 Final: 12 Feb 2020
Other significant changes included in this amendment are summarized below. These changes are
based on recommendations received from the 
 expert opinion, and internal 
discussions.
!
Modifications to the eligibility criteria
∀
To ensure subjects are evaluable for the primary and key secondary endpoints in 
the study, an additional exclusion criterion is added requiring subjects to have a 
minimum life expectancy of 6 months. Subjects with a white blood cell count > 
100 x 109/L are not eligible to participate in the study.
Revised section: Section 4.3;
!
Surveillance of suspected encephalopathy, including Wernicke's encephalopathy, in 
patients receiving or who have received fedratinib from any source
∀
The objective, endpoint, and further reference in the protocol to assess the 
effectiveness of the risk mitigation strategy for Wernicke encephalopathy is 
updated to include Encephalopathy, including Wernicke's.
Revised sections: Protocol Summary, Section 1.2.1, Section 1.4.1, Section 1.4.2,
Section 4.3, Table 5, Section 6, Section 7.4, Section 9.7.3 and Section 10.7.1;
∀
Language is revised to clarify that platelet and red blood cell transfusion history 
will be collected 84 days prior to enrollment. This will establish the subject’s 
baseline transfusion status information.
Revised sections: Table 5, Section 6.1 and Section 8;
!
Lipid testing is included in the study 
∀
Lipid profile monitoring is added
 
 since lipid profile changes have been observed in patients treated with 
ruxolitinib. This request is to better understand if the lipid profile changes are 
specific to ruxolitinib or if changes could possibly be a Janus kinase inhibitor
class effect. 
Revised sections: Table 5, Section 6.1, Section 6.2, Section 6.2.1, and Section 6.4;
!
The language is updated throughout the protocol for concomitant administration of 
fedratinib with clinically relevant cytochrome P450 inducers, inhibitors, substrates, 
and transporter substrates to align with the information included in the Inrebic® label 
recently approved by the FDA
∀
The eligibility criteria are updated to exclude subjects receiving concomitant
treatment with or use of pharmaceutical, herbal agents or food known to be strong 
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Summary of Changes FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
5
FEDR-MF-001 Amendment 1.0 Final: 12 Feb 2020
or moderate inducers of Cytochrome P450 3A4 (CYP3A4) or dual CYP2C19 and 
CYP3A4 inhibitors.
Revised section: Section 4.3;
∀
Clarifying language is added for the recommended dose adjustment for co-
administration of fedratinib with CYP3A4 inhibitors and for subjects with renal 
impairment. 
Revised section: Section 7.2.2 and 7.2.3;
∀
Clarification is made to the cytochrome P450 inducers, inhibitors, substrates, and 
transporter substrates section and associated appendix information for consistency 
with the previously stated updates.
Revised section: Section 8.3 and Appendix L;
!
Statistical sections were updated to ensure accurate population and durability of 
response definitions.
∀
Addition of an “Enrolled population” added for the main study – Section 9.2;
∀
Durability of spleen volume response revised from loss of response to disease 
progression or death – Section 9.6.4;
∀
Durability of spleen response by palpation revised from loss of response to 
disease progression or death – Section 9.6.5;
!
A Steering Committee was formed during study start-up but language was missing 
from the protocol.
∀
Provided details on the study Steering Committee – Section 9.10;
!
Extended the duration of response assessment capture during the main study and 
provided clarity on assessment timeframe beyond End of Cycle 24
∀
Revised the Response Assessment duration to include End of Cycles 18 and 24 to 
align with FEDR-MF-002. In addition, adding language on every 6 cycles 
thereafter for spleen size by palpation and symptom response – Protocol 
Summary, Section 6.5;
!
 
!
Language and sections related to fedratinib dose modification were aligned and 
clarified to avoid potential confusion and duplication
∀
Provided clarification regarding the Fedratinib Dose Modification table is for 
related events. Also added details on the duration for fedratinib treatment 
interruption – Section 7.2.1;
∀
Updated table to clarify repeating toxicities and “Other AE” definition - Table 7;
∀
Updated definition changing cardiomegaly to cardiomyopathy – Section 10.7.1;
Approved
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Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Summary of Changes FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
6
FEDR-MF-001 Amendment 1.0 Final: 12 Feb 2020
1.1.
Additional Clarifications and Corrections
This amendment also includes the following clarifications and corrections:
!
Language is added to the key secondary objective to evaluate MF-associated 
symptoms by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0 to 
further describe the secondary objective to evaluate the percentage of subjects with at 
least 50% reduction in MF-associated symptoms as measured by the MFSAF –
Protocol Summary and Table 1 in Section 2;
!
Added clarification regarding ruxolitinib washout timing during screening – Section 
3.1.1;
!
Clarified previous exposure with ruxolitinib must be when the subject is diagnosed 
with primary MF (PMF), post-essential thrombocythemia MF (post-ET MF) or post-
polycythemia MF (post-PV MF) – Section 4.2;
!
Added clarification on prior JAK inhibitor excluding ruxolitinib – Section 4.3;
!
Added criteria to ensure subjects have a life expectancy of at least 6 months – Section 
4.3
!
Clarification that all patient reported outcomes (PRO) evaluations will be performed 
on an electronic tablet – Section 6.7;
!
Language is added to provide more detail for the mechanism of action of fedratinib 
and to provide additional background as to how resistance and intolerance to 
ruxolitinib was defined for subjects in previous clinical studies – Section 1.2;
!
Modified the units of measure for the hematology laboratory key eligibility criteria 
for platelets to maintain consistency throughout the protocol – Figure 2;
!
Modified language to accurately describe the units of measure for results reporting 
and the formula to calculate the estimated glomerular filtration rate using the 
Modification of Diet in Renal Disease Study (MDRD) formula – Section 4.3 and 
Appendix K;
!
Language is revised to include reference to the recent new drug approval of fedratinib 
by US FDA – Section 1.1.2, Section 1.1.3 and Section 1.4.1;
!
Added an additional timepoint for pregnancy testing at End of Treatment to align 
with program standards – Section 6.2.1 and Table 5;
!
Language is added providing high level guidance for when fedratinib retreatment may 
be considered after encephalopathy is resolved – Section 7.4.2;
!
Language is added providing high level guidance for when thiamine supplementation 
may be discontinued – Section 7.4.3;
!
Language is removed to record dose reduction or titration in the Interactive Response 
Technology (IRT) system as titration data will not be included in the IRT system 
functionality – Section 7.5;
Approved
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EDMS Doc. Number: 
Fedratinib
Impact Biomedicines, Inc.,
Summary of Changes FEDR-MF-001 
a Wholly Owned Subsidiary of Celgene Corporation
Confidential and Proprietary
7
FEDR-MF-001 Amendment 1.0 Final: 12 Feb 2020
!
Moved and clarified the definition of Study Treatment Overdose – Section 7.2.5 and 
Section 10.1;
!
The requirements for monitoring, recording and reporting adverse events and serious 
adverse events are clarified– Section 10.1, Section 10.2.1, Section 10.2.2, Section 
10.2.3, Section 10.2.4, Section 10.2.5, Section 10.2.6, Section 10.3, Section 10.4.1,
Section 10.5, Section 10.6 and Section 10.7;
!
Added collection of prior ruxolitinib history for screen failures – Section 11.2;
1.2.
Minor Corrections, Clarifications and Administrative Changes 
!
Added clarification on the trademark and availability of ruxolitinib – Section 1.1.3 
and Section 1.4.1;
!
Revised JAKARTA adverse event percentages to align with the citation – Section 
1.2;
!
The Table of Events screening range is clarified to -28 to -1 days. The visit 
description in the Table of Events for Risk mitigation for GI & WE is updated to Risk 
mitigation for GI & Encephalopathy including Wernicke’s – Table 5;
!
Described the physical exam requirements further to include clinically significant 
findings – Section 6.1;
!
Clarified sections of management of gastrointestinal (GI) AEs and Encephalopathy 
including Wernicke’s is for fedratinib – Section 7.3 and Section 7.4;
!
Added language for clinical guidance on the minimum required thiamine dosing for 
treating subjects with thiamine levels below normal to maintain a consistent treatment 
approach as was used in the JAKARTA Phase 3 study – Section 7.4.3;
!
Included a recent change to the standard protocol template language stating that 
literature “book” values and normal ranges will be utilized for local laboratory results 
– Section 9.7;
!
Updated details on Study discontinuation and SAE reporting to align with other 
sections – Section 11.2;
!
Added a clarifying note to ensure reference to the author’s definition of constitutional 
symptoms for Dynamic International Prognostic Scoring System (DIPSS) calculation 
– Appendix F;
!
Corrected typo in the Progressive disease criteria and added response categories for 
stable disease and relapse – Appendix O;
!
Other clarifications, corrections of minor typographical errors and incidental 
formatting changes were made throughout the document;
!
References were updated based on updated details throughout the document – Section 
17.
Approved
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Approved
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