A Phase 2 Study of Fedratinib in Myelodysplastic /Myeloproliferative Neoplasms (MDS/MPNs) and Chronic Neutrophilic Leukemia (CNL)
Phase: PHASE2
Conditions: Myeloproliferative Neoplasm, Chronic Neutrophilic Leukemia, MDS
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
i 
 
 
 
A Phase 2 Study of Fedratinib in Myelodysplastic /Myeloproliferative 
Neoplasms (MDS/MPNs) and Chronic Neutrophilic Leukemia (CNL)  
Protocol Identifying Number: MCC 20963 / 
FEDR-CL-MF-PI-13910 
IND Number: 154485 
Principal Investigator: Andrew T. Kuykendall, MD 
 
 IND/IDE Sponsor: Andrew T. Kuykendall/Moffitt Cancer Center 
 
Funded by:  
Bristol-Myers Squibb (BMS) 
 
 
v. 1.7 
 
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ii 
Table of Contents 
LIST OF ABBREVIATIONS ..................................................................................................................... vi 
STATEMENT OF COMPLIANCE ........................................................................................................... viii 
STUDY SUMMARY .............................................................................................................................. ix 
SCHEMATIC OF STUDY DESIGN .......................................................................................................... 1 
1 
KEY ROLES ............................................................................................................................ 2 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................... 2 
2.1 
BACKGROUND INFORMATION .................................................................................................. 2 
2.2 
RATIONALE ................................................................................................................................... 3 
2.3 
POTENTIAL RISKS AND BENEFITS .............................................................................................. 4 
2.3.1 
KNOWN POTENTIAL RISKS ..................................................................................................... 4 
2.3.2 KNOWN POTENTIAL BENEFITS ............................................................................................ 5 
3 
OBJECTIVES AND PURPOSE ................................................................................................ 5 
4 
STUDY DESIGN AND ENDPOINTS ...................................................................................... 6 
4.1 
DESCRIPTION OF THE STUDY DESIGN ...................................................................................... 6 
4.2 
STUDY ENDPOINTS ....................................................................................................................... 6 
4.2.1 PRIMARY ENDPOINT ............................................................................................................. 6 
4.2.2 SECONDARY ENDPOINTS ....................................................................................................... 6 
4.2.3 EXPLORATORY ENDPOINTS ................................................................................................... 6 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................... 7 
5.1 
PARTICIPANT INCLUSION CRITERIA ............................................................................................. 7 
5.2 
PARTICIPANT EXCLUSION CRITERIA ............................................................................................ 8 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................................. 9 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION ........................................................................ 9 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION .......................................................... 9 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION .................................. 10 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ....................................................... 11 
6 
STUDY AGENT .................................................................................................................... 11 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION ..................................................................... 11 
6.1.1 ACQUISITION ....................................................................................................................... 11 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING ........................................ 11 
6.1.3 PRODUCT STORAGE AND STABILITY ................................................................................ 11 
6.1.4 PREPARATION ...................................................................................................................... 12 
6.1.5 DOSING AND ADMINISTRATION ....................................................................................... 12 
6.1.6 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS ................................................................ 12 
6.1.7 DURATION OF THERAPY ..................................................................................................... 16 
6.1.8 
TRACKING OF DOSE ............................................................................................................. 16 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ................................................................... 16 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................................. 17 

 
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7.1 
STUDY PROCEDURES/EVALUATIONS ........................................................................................ 17 
7.1.1 
STUDY-SPECIFIC PROCEDURES ......................................................................................... 17 
7.1.2 STANDARD OF CARE STUDY PROCEDURES ..................................................................... 17 
7.1.3 Informed Consent ............................................................................................................ 17 
7.1.4 Inclusion/Exclusion Criteria ................................................................................................. 17 
7.1.5 
Demographics and Medical History .................................................................................... 17 
7.1.6 
Baseline Symptoms ............................................................................................................. 18 
7.1.7 
Eastern Cooperative Oncology Group (ECOG) Performance Status ................................... 18 
7.1.8     Concomitant Medications Review ....................................................................................... 18 
7.1.9 
Adverse Event Review ......................................................................................................... 18 
7.1.10  Physical Exam ...................................................................................................................... 18 
7.1.11 Vital Signs  ........................................................................................................................... 18 
7.1.12 Laboratory Procedures ........................................................................................................ 18 
7.1.13 Bone Marrow Biopsy ........................................................................................................... 18 
7.1.14 Correlative Studies .............................................................................................................. 19 
7.1.15 Spleen Imaging .................................................................................................................... 19 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ............................................................................ 20 
7.2.1 CLINICAL LABORATORY EVALUATIONS ............................................................................ 20 
7.2.2 SPECIMEN PREPARATION, HANDLING, AND STORAGE ....................................................... 20 
7.2.3 SPECIMEN SHIPMENT ......................................................................................................... 21 
7.3 
STUDY SCHEDULE ...................................................................................................................... 23 
7.3.1 SCREENING .......................................................................................................................... 23 
7.3.2 Cycle 1 Day 1 (Cycle length = 28 days) ................................................................................ 24 
7.3.3 ON-TREATMENT VISITS ........................................................................................................ 25 
7.3.4 
FINAL STUDY VISIT ............................................................................................................ 27 
7.3.5 
EARLY TERMINATION VISIT ............................................................................................. 27 
7.3.6 
UNSCHEDULED VISIT ........................................................................................................ 27 
7.3.7 
SCHEDULE OF EVENTS TABLE ........................................................................................... 28 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................... 29 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES .......................................... 29 
7.6 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ...................................... 30 
7.7 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................. 30 
8 
ASSESSMENT OF SAFETY .................................................................................................. 30 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ................................................................................ 30 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) ......................................................................... 30 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) ....................................................... 31 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS ................................................................. 32 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT .............................................................................. 33 
8.2.1 
SEVERITY OF EVENT ............................................................................................................ 33 

 
iv 
8.2.2 RELATIONSHIP TO STUDY AGENT ..................................................................................... 33 
8.2.3 EXPECTEDNESS/DURATION/ACTION TAKEN/OUTCOME .................................................... 34 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ................ 34 
8.4 
REPORTING PROCEDURES ......................................................................................................... 35 
8.4.1 
ADVERSE EVENT REPORTING .......................................................................................... 35 
8.4.2 SERIOUS ADVERSE EVENT REPORTING ............................................................................. 36 
8.4.3 UNANTICIPATED PROBLEM REPORTING ............................................................................ 36 
8.4.4 
EVENTS OF SPECIAL INTEREST ......................................................................................... 37 
8.4.5 REPORTING OF PREGNANCY ............................................................................................ 37 
8.5 
STUDY HALTING RULES ............................................................................................................. 38 
8.6 
SAFETY OVERSIGHT ................................................................................................................... 38 
9 
CLINICAL MONITORING ..................................................................................................... 39 
10 
STATISTICAL CONSIDERATIONS .......................................................................................... 41 
10.1 STATISTICAL AND ANALYTICAL PLANS .................................................................................. 41 
10.2 STATISTICAL HYPOTHESES ....................................................................................................... 41 
10.3 ANALYSIS DATASETS .................................................................................................................. 41 
10.4 DESCRIPTION OF STATISTICAL METHODS .............................................................................. 41 
10.4.1 GENERAL APPROACH......................................................................................................... 41 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) .................................................... 42 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) ................................................................. 42 
10.4.4 SAFETY ANALYSES .............................................................................................................. 44 
10.4.5 ADHERENCE AND RETENTION ANALYSES ........................................................................ 45 
10.4.6 BASELINE DESCRIPTIVE STATISTICS .................................................................................. 45 
10.4.7 PLANNED INTERIM ANALYSES .......................................................................................... 45 
10.4.11 EXPLORATORY ANALYSES .................................................................................................. 45 
10.5 
SAMPLE SIZE ............................................................................................................................. 46 
10.6 MEASURES TO MINIMIZE BIAS ................................................................................................ 46 
10.6.1 ENROLLMENT .................................................................................................................... 46 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ......................... 47 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................................... 47 
13 
ETHICS/PROTECTION OF HUMAN PATIENTS .................................................................... 47 
13.1 ETHICAL STANDARD ................................................................................................................. 47 
13.2 INSTITUTIONAL REVIEW BOARD ............................................................................................. 47 
13.3 INFORMED CONSENT PROCESS ............................................................................................... 48 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS ...................................................................................................................... 48 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION ............................................................ 48 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY ........................................................................... 48 
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA .......................... 49 

 
v 
above................................................................................................................................................. 49 
13.5 FUTURE USE OF STORED SPECIMENS .................................................................................... 49 
14 
DATA HANDLING AND RECORD KEEPING ......................................................................... 49 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ............................................... 49 
14.2 STUDY RECORDS RETENTION ................................................................................................... 50 
14.3 PROTOCOL DEVIATIONS ............................................................................................................ 50 
14.4 PUBLICATION AND DATA SHARING POLICY .......................................................................... 50 
15 
CONFLICT OF INTEREST POLICY ........................................................................................ 50 
16 
LITERATURE REFERENCES ........................................................................................................ 50 
APPENDICES ................................................................................................................................................ 50 
APPENDIX A. PATIENT CLOBAL IMPRESSION OF CHANGE (PGIC) ............................................................... 50 
APPENDIX B. ECOG PERFORMANCE STATUS .............................................................................................. 50 
APPENDIX C. MPN SYMPTOMS ASSESSMENT FORM .................................................................................. 51 
APPENDIX D. MODERATE/STRONG INDUCERS/INHIBITORS OF CYP3A4 .................................................... 51 
APPENDIX E. WHO DIAGNOSTIC CRITERIA FOR MDS/MPNs ...................................................................... 52 
APPENDIX F. PROPOSED MDS/MPN RESPONSE CRITERIA .......................................................................... 55 
APPENDIX G. CORRELATIVE WORKSHEET ................................................................................................... 56 
 
 
r 

 A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
 
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LIST OF ABBREVIATIONS 
 
 
 
vi 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
 
 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
 
 
CMML 
Chronic Myelomonocytic Leukemia 
CMP 
Clinical Metabolic Panel 
CNL 
Chronic Neutrophilic Leukemia 
CRF 
Case Report Form 
CRP 
C-reactive protein 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase 3 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICH E6 
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
ISO 
International Organization for Standardization 
IWG-MRT International Working Group – Myeloproliferative Neoplasms Research and Treatment 
JAK2 
Janus-associated kinase-2 
LDH 
 Lactate Dehydrogenase 
MDS/MPN Myelodysplastic Syndrome/Myeloproliferative Neoplasm 
MF 
Myelofibrosis 
MPN 
Myeloproliferative Neoplasm 
OHRP 
Office for Human Research Protections 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PET-MF 
Post-Essential Thrombocythemia Myelofibrosis 
PFS 
Progression Free Survival 
PGIC 
Patient Global Impression of Change 
PI 
Principal Investigator 
PMF 
Primary Myelofibrosis 
PPV-MF 
Post-Polycythemia Vera Myelofibrosis 
RR 
Response rate 
SAE 
Serious Adverse Event 
SAF 
Symptom Assessment Form 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SVR 
Spleen volume reduction 
TSS 
Total Symptom Score 
UP 
Unanticipated Problem 

 A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
 
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LIST OF ABBREVIATIONS 
 
 
 
vii 
 
US 
United States 

A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
MCC 20963 
 
STATEMENT OF COMPLIANCE 
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viii 
 
STATEMENT OF COMPLIANCE 
 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on 
the Protection of Human Patients (45 CFR Part 46). The Principal Investigator will assure that 
no deviation from, or changes to the protocol will take place without prior agreement from the 
sponsor and documented approval from the Institutional Review Board, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed of 
their obligation to meet the above commitments. 
 
 
Principal Investigator:   Andrew T. Kuykendall 
           
Print/Type Name 
 
 
Signed:    
 Date: 
 

A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
  MCC  20963 
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ix 
 
STUDY SUMMARY 
 
Title: 
A Phase 2 Study of Fedratinib in Myelodysplastic /Myeloproliferative 
Neoplasms (MDS/MPNs) and Chronic Neutrophilic Leukemia (CNL)  
 
Objectives: 
Primary Objective:  
1.) To evaluate the efficacy of fedratinib in patients with MDS/MPNs and 
CNL 
 
 
Important Secondary Objectives: 
1.) To evaluate the safety and tolerability of fedratinib in MDS/MPNs and 
CNL.  
2.) To evaluate the effect of fedratinib in MDS/MPNs and CNL on patient-
reported outcomes. 
 
Endpoint 
Primary Efficacy Endpoint 
1.) Proportion of patients achieving a clinical response from baseline to 
week 24 as defined as complete remission (CR), partial remission (PR), 
or clinical benefit (CB) per Modified MDS/MPN IWG Proposed 
Response Criteria1 
 
 
Safety and Tolerability Endpoints 
1.) Frequency, duration, and severity of adverse events (AE) will be 
determined by performing physical exams, and evaluating changes in 
vital signs, serum chemistry, hematology and urinalysis results using 
CTCAE version 5.0. 
2.) Proportion of patients experiencing grade ≥ 3 AE as defined by CTCAE 
v.5.0 
 
 
Important Secondary Efficacy Endpoints: 
a. Proportion of patients achieving spleen response at week 12 
in patients with baseline splenomegaly.  
b. Proportion of patients achieving spleen response at week 24 
in patients with baseline splenomegaly.  
c. Proportion of patients who have a 50% reduction in MPN-SAF 
TSS from baseline to week 12 in patients with baseline TSS ≥ 
10 
d. Proportion of patients who have a 50% reduction in MPN-SAF 
TSS from baseline to week 24 in patients with baseline TSS ≥ 
10 
e. Change in TSS from baseline to week 12 in patients with 
baseline TSS ≥ 10 
f. 
Change in TSS from baseline to week 24 in patients with 
baseline TSS ≥ 10 
g. Change in TSS from baseline to time of best response in 
patients with baseline TSS ≥ 10 
h. Patient’s global impression of change (PGIC) at week 12 
i. 
PGIC at week 24 

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x 
 
 
Sample Size: 
Total Patient Population: 25 
 
 
 
  
Population: 
Patients ≥ 18 years old with MDS/MPNs or CNL. 
Phase: 
2 
Number of Sites enrolling: 4 
Description of Study Agent: Fedratinib 400 mg PO daily 
 
Study Duration: 
36 months 
Participant Duration: 
24 months 
 
 
 

A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
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1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCHEMATIC OF STUDY DESIGN 
aCML, MDS/MPN-U, MDS/MPN-RS-T, CNL 
(n = 25) 
Fedratinib 400 mg daily 
Patient deemed to be experiencing clinical benefit 
will continue fedratinib until withdrawal criteria are 
met. 
Week 12 Assessment 
Interim Efficacy 
Analysis after 9 
patients evaluable 
for efficacy. If ≥ 3 
responses an 
additional 16 
patients will be 
enrolled  
End of Study 
Week 24 Assessment 

A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
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2 
 
 
 
 
Principal Investigator: 
Andrew T. Kuykendall, MD 
 
 
 
Moffitt Cancer Center 
 
 
12902 Magnolia Dr. FOB-3 
Tampa, FL 33612 
 
 
 
 
813-745-4639 
 
 
 
 
Andrew.Kuykendall@moffitt.org  
 
 
Statistician: 
Jongphil Kim, PhD 
Associate Member, Department of Biostatistics and Bioinformatics 
Moffitt Cancer Center 
12902 Magnolia Dr.  
Tampa, FL 33612 
Jongphil.Kim@moffitt.org 
                                  
 
 
 
 
 
 
Disease Background 
 
Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs) and chronic neutrophilic leukemia (CNL) are 
heterogeneous myeloid malignancies that are characterized by proliferative features, bone marrow 
dysfunction, complex molecular features, and poor outcomes.2 Clinically and genetically, these diseases 
have significant overlap and are better viewed as a continuum of disease rather than distinct disease 
entities.2 Treatment is typically symptom-directed and based on extrapolation from other, related disease 
entities. Therapeutic options have traditionally included cytoreductive agents such as hydroxyurea and 
hypomethylating agents such as azacitidine and decitabine.3-6 With the exception of azacitidine and 
decitabine for CMML, there are currently no FDA-approved therapies for these indications. Allogeneic 
hematopoietic cell transplant (AHCT) offers a curative option for some patients, but the majority of patients 
are not eligible for this procedure due to age, comorbidities, or lack of a suitable donor.7-13 Clinical trials 
represent a preferred option, but these diagnoses are often excluded from clinical trials that specifically 
enroll myelodysplastic syndrome (MDS) or MPN patients.14 
 
Upregulation of the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway is a 
hallmark of MPNs. This results in cell proliferation, inhibition of cell death and clonal expansion of 
myeloproliferative malignant cells.15 JAK2 inhibitors that downregulate the JAK/STAT pathway can be 
expected to reduce cell proliferation and induce malignant cell killing in MPN patients. To that end, JAK2 
inhibitors have been shown to improve disease-related symptoms and splenomegaly in patients with MF.16-
19  
Preclinical work has shown that MDS/MPNs feature GM-CSF hypersensitivity that can be abrogated with JAK 
1 
KEY ROLES 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
BACKGROUND INFORMATION 

A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
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inhibition.20 Additionally, driver mutations involving the JAK/STAT pathway are frequently present in 
MDS/MPNs and CNL.2 Several small studies assessing JAK inhibition in MDS/MPNs with ruxolitinib have 
shown activity in this setting.21-23 
 
Study Agent Background  
 
Fedratinib, an oral kinase inhibitor with activity against wild type and mutationally activated Janus 
Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3), was recently approved in the United 
States and is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or 
secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF). The 
registration of fedratinib was supported by data from Study EFC12153 (JAKARTA), a randomized, 
placebo-controlled, Phase 3 study in patients with intermediate-2 or high-risk PMF, post-PV MF, or post-ET 
MF with splenomegaly.  
 
JAKARTA met its primary endpoint, with 36.5% of patients in the 400 mg fedratinib arm compared with 
1.0% of patients in the placebo arm achieving ≥ 35% SVR at the end of cycle 6 confirmed 4 weeks later (p < 
0.0001). When response was assessed at the end of cycle 6, as per IWG MRT criteria, 46.9% of patients 
treated with fedratinib 400 mg achieved ≥ 35% spleen volume reduction (SVR); the rate remained at 1% for 
patients in the placebo arm (p < 0.0001). Kaplan-Meier estimate for median duration of spleen response 
was 18.2 months for patients in the fedratinib 400 mg arm and suggest durable response. The study also 
met its key secondary endpoint by demonstrating clinically meaningful and statistically significant 
superiority of fedratinib 400 mg over placebo for symptom response rate (RR). Symptom RR is defined as ≥ 
50% reduction in total symptoms score (TSS) and was 40.4% in the fedratinib 400 mg arm and 8.6% in the 
placebo arm; the difference was statistically significant (p < 0.0001). Further, reductions in all individual 
symptoms from the modified MF-SAF contributed to the improvement observed in patients treated with 
fedratinib. 
 
Based on these data, the author believes there is rationale for further study of fedratinib in MDS/MPNs and 
CNL.  
 
 
 
 
MDS/MPNs and CNL comprise a group of molecular complex, heterogenous, myeloid malignancies 
that have limited treatment options and poor prognoses. Patients frequently exhibit proliferative 
features of leukocytosis, splenomegaly, and constitutional symptoms that negatively impact quality of 
life. Moreover, these diseases frequently progress to acute myeloid leukemia and overall survival is 
estimated between 1-3 years.24-26 AHCT offers the only curative approach, but is associated with 
significant morbidity and mortality and most patients are not eligible due to comorbidities, functional 
status or lack of a suitable donor.  
 
JAK/STAT inhibition offers a promising therapeutic approach for patients with MDS/MPNs and CNL. 
Preclinical data in MDS/MPNs have shown these cells to exhibit GM-CSF hypersensitivity that signals 
through the JAK/STAT pathway and can be abrogated by JAK2 inhibition.20 Moreover, many of these 
patients harbor driver mutations that signal though the JAK/STAT pathway.2 Small studies using the 
JAK1/2 inhibitor ruxolitinib in CMML, aCML and CNL have demonstrated promising activity, and large 
studies using ruxolitinib and fedratinib in MF have led to regulatory approval based on the ability for 
these agents to improve disease-related symptoms and reduce spleen size.16-19,22,27  
 
2.2 
RATIONALE 

A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
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4 
 
Fedratinib is a selective JAK2 inhibitor with a unique kinase inhibition profile. In addition to inhibition 
JAK2 in its active and mutated form, fedratinib has activity against FLT3 – a protein implicated in 
proliferative myeloid malignancies. Fedratinib showed significant activity in MF patients who were 
intolerant or resistant to ruxolitinib – a group of patients known to have molecularly complex disease 
and extremely poor outcomes.17,28,29 
 
Based on this data, we believe that fedratinib will have significant activity in MDS/MPNs and CNL. To 
further investigate this, we are proposing an open-label, phase 2 study to evaluate the safety and 
efficacy of fedratinib in this setting. Fedratinib will be given orally at 400 mg daily which is the 
recommended dose based on its label for patients with higher-risk MF.  
 
Patients with a diagnosis of MDS/MPN-U, aCML, MDS-MPN-RS-T, and CNL will be enrolled. A modified 
Simon’s minimax 2-stage approach will be used, wherein an interim analysis will be performed after 
nine patients are evaluable for response to assess for futility. The primary endpoint of the study will 
be the proportion of patients achieving an objective clinical response at week 24. This endpoint is 
consistent with typical endpoints for early phase trials in MPN and MDS/MPN and the timeframe is 
consistent with that which has been utilized in prior studies of JAK inhibitors.  
 
 
 
 
According to the US fedratinib package insert, fedratinib has been used to treat 608 patients with either 
MPNs or solid tumors. The safety profile of the drug is consistent across studies with the most common 
adverse events (AEs) being hematologic and gastrointestinal (GI). The most common hematologic AEs are 
anemia and thrombocytopenia. These events can be managed by dose modification, including dose 
interruption and other supportive treatments. The most common GI events are diarrhea, nausea, and 
vomiting. Gastrointestinal events are generally Grade 1 to 2, but Grade 3 to 4 events have occurred and 
have led to discontinuation of treatment. These events commonly occur at the highest frequency in the first 
two cycles. Prophylactic anti-emetic therapy (e.g., 5-HT3 receptor antagonists) during fedratinib treatment 
should be considered. Diarrhea should be treated with anti-diarrheal medications promptly at the first 
onset of symptoms. Common laboratory findings include increased alanine aminotransferase (ALT), 
increased aspartate aminotransferase (AST), increased amylase, increased lipase, and creatinine increased. 
These events are primarily asymptomatic and Grade 1 to 2 in severity.  Recommendations for monitoring 
and dose modifications are included in the protocol.   
Serious and fatal encephalopathy, including Wernicke’s, was reported in patients taking fedratinib. Serious 
cases were reported in 1.3% (8/608) of patients treated with fedratinib in clinical trials and 0.16% (1/608) of 
cases were fatal.  
Seven out of the 8 patients were taking fedratinib at 500mg daily prior to the onset of neurologic findings 
and had predisposing factors such as malnutrition, gastrointestinal adverse events, and other risk factors 
that could lead to thiamine deficiency. This dose will not be assessed in the current study. Most events 
resolved with some residual neurological symptoms including memory loss, cognitive impairment, and 
dizziness. In a solid tumor study, one patient with head and neck cancer, brain metastasis, difficulty eating 
and weight loss had a fatal outcome. 
Despite these potential risks, we believe the investigation of fedratinib in patients with MDS/MPN and CNL 
is worth pursuing since these diseases have poor prognoses, lack treatment options, and the preclinical and 
clinical evidence suggests patients have a high potential to benefit.  
2.3 
POTENTIAL RISKS AND BENEFITS 
2.3.1 
KNOWN POTENTIAL RISKS 

A Phase 2 Study of Fedratinib in MDS/MPN and CNL 
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Fedratinib was approved in the US in 2019 and is indicated for the treatment of adult patients with 
intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential 
thrombocythemia) myelofibrosis (MF). The registration of fedratinib was supported by data from Study 
EFC12153 (JAKARTA), a randomized, placebo-controlled, Phase 3 study in patients with intermediate-2 or 
high-risk PMF, post-PV MF, or post-ET MF with splenomegaly.16  
In this study, fedratinib was shown to produce spleen responses in 36.5% of the patients treated with a 400 
mg daily dose compared to 1% of those patients in the placebo arm. Spleen response lasted for 18.2 months 
suggesting potential for durable responses. The study also met its key secondary endpoint by producing a 
symptom response (≥ 50% reduction in total symptoms score) in 40% of patients compared to only 9% of 
patients who achieved a symptom response on the placebo arm.  
In an exploratory analysis of two phase I studies of fedratinib in MF, improvement or stabilization of bone 
marrow fibrosis was seen in 83% of patients at cycle 6.30  
Based on the available data, patients treated with fedratinib have the potential to achieve reduction in 
spleen size, improvement in disease-related symptoms, patient-reported outcomes, and may experience 
stability or improvement in bone marrow fibrosis.  
 
 
 
 
The primary objective of this study is to evaluate the efficacy of fedratinib in patients with MDS/MPNs and 
CNL. Formal response assessment will be performed at week 24 using information from bone marrow 
biopsy, spleen imaging, hematologic laboratory values and physical exam. Responses will be determined 
based upon the Modified MDS/MPN IWG Proposed Response Criteria.1  
 
We will also evaluate the safety and tolerability of fedratinib in patients with MDS/MPNs and CNL. Safety 
and tolerability will be assessed in all patients receiving at least one dose of the study drug. CTCAE version 
5.0 will be used to detail the scope and severity of AEs. 
 
Secondary objectives will be to evaluate the efficacy of fedratinib in MDS/MPNs and CNL as it pertains to 
spleen size and patient-reported outcomes (PRO). Patients will have spleen size assessments performed at 
baseline, week 12, week 24 and every 24 weeks thereafter up to 96 weeks. To evaluate PROs, patients will 
complete validated questionnaires that assess disease-related symptoms and their global impression of 
change while on the study agent.  
 
From an exploratory state, we will further assess the efficacy of fedratinib in patients with MDS/MPN and 
CNL by measuring progression-free survival (PFS),overall survival (OS), and duration of response. Additional 
exploratory objectives will aim to correlate the presence or lack of a response with the presence and 
quantity of specific genetic mutations and, when feasible, with matched PDX mouse models. Serial single-
cell sequencing will also be used to analyze clonal dynamics at a single-cell level in response to JAK inhibition 
with fedratinib.  
 
 
 
2.3.2 
KNOWN POTENTIAL BENEFITS 
3 
OBJECTIVES AND PURPOSE 

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This is an open-label,multi-center, phase 2 study of fedratinib in MDS/MPN and CNL. Approximately 25 
patients will be enrolled at 4 US sites. The study will be enrolled via modified Simon’s minimax 2-stage 
approach wherein an interim efficacy analysis will be performed after 9 patients have either completed 24 
weeks of treatment or come off study treatmentto assess for futility. This will determine whether the 
remainder of the planned study population will be enrolled.   
 
 
 
 
 
• 
To estimate the response rate of fedratinib in MDS/MPN and CNL, we will measure the 
proportion of patients achieving a clinical response from baseline to week 24 as defined by CR, 
PR, or CB by Modified MDS/MPN IWG Proposed Response Criteria.1 This is a standard endpoint 
to measure drug activity in phase 2 MPN trials.   
 
 
 
 
 
 
• 
To evaluate the safety and tolerability of fedratinib in MDS/MPNs and CNL we will: 
o Measure the frequency, duration, and severity of AEs per CTCAE v.5.0 using information from 
physical exams, evaluation of changes in vital signs, serum chemistry, and hematology. 
o Determine the proportion of patients experiencing grade ≥ 3 AE as defined by CTCAE v.5.0 
• 
To evaluate the efficacy of fedratinib on splenomegaly in MDS/MPNs and CNL we will: 
o Determine the proportion of patients who have a spleen response at week 12 as per Modified 
MDS/MPN IWG Proposed Response Criteria or demonstration of ≥ 35% spleen volume 
reduction. 
o Determine the proportion of patients who have a spleen response at week 24 as per Modified 
MDS/MPN IWG Proposed Response Criteria or demonstration of ≥ 35% spleen volume 
reduction. 
• 
To evaluate the efficacy of fedratinib on patient-reported outcomes in MDS/MPNs and CNL we will: 
o Determine the proportion of patients who have a 50% reduction in MPN-SAF TSS from 
baseline to week 12 in patients with baseline TSS ≥ 10 
o Determine the proportion of patients who have a 50% reduction in MPN-SAF TSS from 
baseline to week 24 in patients with baseline TSS ≥ 10 
o Measure the change in TSS from baseline to week 12 in patients with baseline TSS ≥ 10 
o Measure the change in TSS from baseline to week 24 in patients with baseline TSS ≥ 10 
o Measure the change in TSS from baseline to time of best response in patients with 
baseline TSS ≥ 10 
o Measure patients’ global impression of change (PGIC) at week 12 
o Measure PGIC at week 24 
 
 
 
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
4.2 
STUDY ENDPOINTS 
4.2.1 
PRIMARY ENDPOINT 
4.2.2 
SECONDARY ENDPOINTS 
4.2.3 
EXPLORATORY ENDPOINTS 

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• 
OS defined as time from first treatment to death due to any cause. OS of patients with MDS/MPNs 
and CNL is estimated between 1-3 years. OS is a standard criterion for assessing therapeutic benefit 
in clinical trials. 
• 
PFS defined by Modified MDS/MPN IWG Proposed Criteria for Disease Progression in adult 
MDS/MPNs (Appendix H).1 PFS is a standard criterion for assessing therapeutic benefit in clinical 
trials and closely correlates with OS. 
• 
Response duration defined as time from initial response to disease progression or death.   
• 
Correlation between the presence of specific genetic mutations as determined by next generation 
sequencing (NGS) and the presence or lack of a response. 
• 
Correlation between the number of genetic mutations as determined by NGS and the presence or 
lack of a response. 
• 
Correlation of clinical responses with responses of individually-matched patient-derived xenograft 
(PDX) mouse models. Each patient will have primary cells transplanted into a matched PDX mouse 
model that will, in turn, be dosed with fedratinib to assess whether PDX modeling correlates with 
clinical outcomes on an individual scale.  
• 
Serial analysis of mutations at the single-cell level during treatment with fedratinib and correlation 
with clinical responses. Correlation of baseline c-myc staining on bone marrow core biopsy and 
change in c-myc staining on core biopsy and clinical response. 
 
 
 
 
 
      Patients must meet all of the following criteria to be eligible for study entry: 
 
1. Patient must understand and voluntarily sign an ICF prior to any study-related assessments/ 
procedures being conducted 
2. Be ≥ 18 years of age on day of signing informed consent.  
3. Morphologically confirmed diagnosis of one of the following in accordance with WHO (2016) diagnostic 
criteria:  
a. Atypical Chronic Myeloid Leukemia (aCML), BCR-ABL1 negative 
b. Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable (MDS/MPN-U) 
c. Myelodysplastic Syndrome/Myeloproliferative Neoplasm with ring sideroblasts and 
thrombocytosis (MDS/MPN-RS-T)  
d. Chronic Neutrophilic Leukemia (CNL).  
4. Palpable splenomegaly ≥ 5 cm below left costal margin (LCM), spleen volume ≥ 450 cc, AND/OR MPN-
SAF TSS > 10.   
5. Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2  
6. Able to adhere to the study visit schedule and other protocol requirements.  
7. Females of childbearing potential (FCBP) must have a negative serum pregnancy test at screening. A 
FCBP is considered when a sexually mature female: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months. 
8. A FCBP must agree to use of two methods of highly effective contraception, be surgically sterile, or 
abstain from heterosexual activity for the course of the study through 30 days after the last dose of 
study treatment. 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 

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9. Male patients must agree to use an adequate method of contraception starting with the first dose of 
study therapy through 90 days after the last dose of study therapy. Men must agree to not donate 
sperm during study therapy and for 30 days after the last dose of study therapy.  
 
 
 
 
Any of the following is a criterion for exclusion from the study: 
1. Any of the following laboratory abnormalities:  
a. Platelets , < 35 x 109/L  
b. Absolute neutrophil count (ANC) < 1.0 x 109/L (independent of growth factor for 7 days)  
c. Creatinine clearance < 30 ml/min  
d. Serum amylase and lipase > 1.5 x ULN  
e. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5xULN,  
f. 
Total bilirubin > 1.5 x ULN, Patients with a total bilirubin between 1.5 –3.0 x ULN are eligible if 
the direct bilirubin fraction is < 25% of the total bilirubin 
2. Accelerated phase or blast phase disease as defined by peripheral or bone marrow blast percentage > 
10%  
3. Patient is pregnant or lactating female  
4. Patient is a woman of childbearing potential as previously defined in inclusion #7, unless using 
effective contraception while on study treatment  
5. Patient is a man who is a partner with of a woman of childbearing potential, unless they agree to use 
effective contraception while on study treatment as previously defined in inclusion #9. 
6. Patient with prior history of encephalopathy, including Wernicke’s Encephalopathy (WE)  
7. Patient has signs or symptoms of encephalopathy, including Wernicke’s Encephalopathy (e.g. severe 
ataxia, ocular paralysis or cerebellar signs) in which case thiamine deficiency needs to be excluded 
and a brain MRI might be required to exclude possible Wernicke’s encephalopathy  
8. Patient has thiamine deficiency if not corrected before enrollment on the study  
9. Patient with concomitant treatment with or use of pharmaceutical or herbal agents known to be 
moderate or strong inducers of CYP3A4 or dual CYP3A4 and CYP2C19 inhibitors.  For a list of 
moderate or strong inhibitors or inducers of CYP3A4, see table 3-2 and 3-3 at 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers.   
10. Patient on any chemotherapy, immunomodulatory drug therapy (e.g., lenalidomide, pomalidomide, 
thalidomide, interferon-alpha), ruxolitinib, anagrelide, corticosteroids >10 mg/day prednisone or 
equivalent. Patients may remain on hydroxyurea (e.g., hydrea) if it is being employed to control 
leukocytosis as long as the patient has been on a stable dose for > 14 days prior to initiation of 
fedratinib.  
11. Prior treatment with fedratinib 
12. Patient on treatment with myeloid growth (e.g. G-CSF) factor within 14 days prior to initiation of 
fedratinib  
13. Patient on treatment with aspirin with doses > 150 mg daily.  
14. Patient with diagnosis of chronic liver disease (e.g., chronic alcoholic liver disease, autoimmune 
hepatitis, sclerosing cholangitis, primary biliary cirrhosis).  
15. Patients with active (uncontrolled, metastatic) second malignancies are excluded. 
16. Patient with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 
4). 
17. Patient with known human immunodeficiency virus (HIV), active infectious Hepatitis B (Hep B), 
and/or active Hepatitis C (Hep C).  
5.2 
PARTICIPANT EXCLUSION CRITERIA 

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a. Patients with known HIV are eligible if the following criteria are met: 
i. Patient has CD4+ T-cell count ≥ 350 cells/µL  
ii. Patient is on established anti-retroviral therapy (ART) (with medications that are not 
specifically excluded due to potential interactions within this study) for at least four 
weeks prior to study enrollment and have an HIV viral load less than 400 copies/mL 
prior to enrollment.  
b. Patients with a history of Hep C infection are eligible if: 
i. Pt has completed curative antiviral treatment and has hepatitis C viral load below the 
limit of quantification 
ii. Pt has Hep C antibody positive but Hep C RNA negative due to prior treatment or 
natural resolution. 
18. Patient with serious active infection requiring IV anti-microbials.  
19. Patient with presence of any significant gastric or other disorder that would inhibit absorption of oral 
medication. 
20. Patient is unable to swallow capsules. 
21. Patient with participation in any study of an investigational agent (drug, biologic, device) within 30 
days prior to start of fedratinib. 
22. Patient has any condition including the presence of laboratory abnormalities, which places the 
patient at unacceptable risk if he/she were to participate in the study.  
23. Patient has any condition that confounds the ability to interpret data from the study. 
24. Any major surgery or radiation therapy within four weeks.  
 
 
 
Recruitment of the 25 participants for this trial will occur from new or established patients treated at 
one of the participating sites. Screen failure is anticipated to be less than 10%. The target accrual is 
expected to be reached in 12-18 months. All faculty members in the myeloid sections of participating 
sites will be trained on the trial design, study agents, and eligibility criteria and will be offered the 
opportunity to be sub-investigators. This will equip each investigator to discuss the trial with potential 
participants as appropriate. The trial will be listed on the websites of the participating centers for the 
availability of local physicians to refer patients who could be eligible for the trial.  
 
All investigators will be made aware of the emphasis to enroll women and minorities. The design of the trial 
and eligibility criteria are not restrictive relative to women and minorities.  
 
Potential participants will be assessed prior to screening for any perceived barriers related to the clinical 
trial process. Referrals will be made to a social worker, supportive care services, financial services, or the 
research nurse to address barriers prior to consent.  
 
 
 
 
 
Patients may withdraw consent at any time for any reason or be dropped from the trial at the discretion of 
the investigator should any untoward effect occur that may jeopardize participant safety.  In addition, a 
patient may be withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons.   
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION 

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A patient must be discontinued from the trial for any of the following reasons: 
• 
The patient or legal representative (such as a parent or legal guardian) withdraws consent 
• 
Unacceptable adverse events 
• 
Dose delay lasting > 12 consecutive weeks 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the patient 
• 
The patient has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The patient is lost to follow-up 
• 
Administrative reasons 
• 
Disease progression by proposed IWG response criteria for MDS/MPN1 (Appendix H) 
• 
Lack of response (including clinical benefit, marrow response, partial remission, complete remission) 
at week 24 assessment as defined by proposed IWG response criteria for MDS/MPN1  
a. In cases where the investigator believes a patient is clinically deriving a benefit from fedratinib 
despite not meeting pre-specified criteria for clinical benefit, continuation of fedratinib will  
need to be approved by the study PI.  
• 
Requiring a medication/procedure on the prohibited medication/procedure list (refer to section 7.6) 
• 
≥ 3 dose reductions due to AE suspected to be related to study drug 
 
The End of Treatment and Follow-up visit procedures are listed in the Schedule of Events and Section 7.3 
(Visit Requirements).  After the end of treatment, each patient will be followed for 30 days for adverse event 
monitoring. Patients who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status and toxicity up to 30 days.  Follow-up rules will apply unless participant initiates 
a non-study cancer treatment, withdraws consent, or becomes lost to follow-up (unsuccessful attempts to 
contact for 3 months).  After documented disease progression, each patient will be followed 104 weeks for 
overall survival until death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
 
 
 
Every effort will be made to maintain contact with a patient who withdraws early. If the patient remains at 
MCC for further care, clinic visits may be tracked and the condition of the patient followed. If the patient is 
not continuing care at MCC, contact information will be updated at the end of treatment visit, including 
accurate phone numbers, and email address. The importance of the follow-up period for AEs and SAEs will 
be stressed to the patient. 
 
Replacement of participants is permitted for those who fail to meet the eligibility requirements of the study.  
 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 

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This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to investigator, funding agency, the IND/IDE sponsor 
and regulatory authorities.  If the study is prematurely terminated or suspended, the PI will promptly 
inform the IRB and will provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard 
to patients 
4. Plans to modify or discontinue the development of the study drug 
5. Determination of futility 
In the event Bristol-Myers Squibb decides to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to patient treatment can be made. 
 
 
 
 
 
 
 
Study agent will be supplied by the manufacturer, Bristol-Myers Squibb to the Moffitt Investigational 
Pharmacy.  
 
 
 
The dosage form labeled for clinical trials is a hard gelatin capsule Reddish brown, opaque, size 0 capsule, 
printed with “FEDR 100 mg” in white ink for oral administration. Each capsule contains 100 mg fedratinib 
(equivalent to 117.30 mg fedratinib dihydrochloride monohydrate) with the following excipients: silicified 
microcrystalline cellulose and sodium stearyl fumarate.  
Bristol-Myers Squibb will supply fedratinib 100 mg capsules for oral administration in high density 
polyethylene (HDPE) bottles with heat induction seal (tamper-resistant) and polypropylene child-resistant 
closures,  labeled appropriately as Investigational Product. 
 
 
Store as directed on the package label: fedratinib must be stored at temperatures below 86○F (30○°C). 
 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
6 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 
ACQUISITION 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
6.1.3 
PRODUCT STORAGE AND STABILITY 

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Bristol Myers Squibb will supply fedratinib 100 mg capsules for oral administration in high density 
polyethylene (HDPE) bottles with heat induction seal (tamper-resistant) and polypropylene child-resistant 
closures, labeled appropriately as Investigational Product. 
 
 
 
Fedratinib will be given at a dose of 400 mg PO once daily (4-100 mg capsules). Fedratinib can be given at 
any time during the day, but patients are advised to take the dose at the same approximate time every day. 
Patients are further advised to take their dose with a high fat meal as this may reduce the incidence of 
nausea and vomiting.  
 
In patients taking concomitant strong CYP3A4 inhibitors that are deemed necessary by study PI (see section 
7.6), fedratinib dose should be reduced to 200 mg once daily. In cases where co-administration with a 
strong CYP3A4 inhibitor is discontinued, fedratinib dose should be increased to 300 mg once daily during 
the first two weeks after discontinuation of the CYP3A4 inhibitor, and then to 400 mg once daily thereafter.  
 
If a daily dose of fedratinib is missed, the next scheduled dose should be taken the following day. A dose will 
be considered “missed” if it is not administered within 8 hours of the typical time of administration. Missed 
doses do not need to be made up.  
 
 
 
 
 
Patients will be treated at a starting dose of fedratinib 400 mg PO daily, unless they require co-
administration with a strong CYP3A4 inhibitor, in which case, fedratinib dose will be reduced to 200 mg PO 
daily (see section 7.5). There will be no dose escalation above the 400 mg PO daily dose. Dose interruptions 
and modifications should occur according to the US Package Insert and protocol-defined guidelines and, 
when feasible, this decision should be after discussion with the study PI. Adverse events that have a clear 
alternative explanation or transient (≤ 72 hours) abnormal laboratory values without associated clinically 
significant signs or symptoms may be exempt from dose reduction rules. Hematologic AEs that precipitate 
dose interruptions should be monitored for recovery for at least every 7 days, if feasible.  
 
Guidelines for Management of Gastrointestinal Adverse Events: 
 
Gastrointestinal adverse events, specifically nausea, vomiting and diarrhea, are commonly associated with 
fedratinib treatment and require multifaceted management using dose adjustment, active treatment or 
prophylaxis with anti-emetics, and monitoring. GI symptoms generally start in the first treatment cycle but 
typically improve within 6-8 weeks on fedratinib treatment. 
 
Management of Nausea and Vomiting 
Management of nausea and vomiting during treatment with fedratinib will be done according to the 
following steps: 
• 
Patients will be provided management instructions (including when to contact the study site) 
before the start of treatment. 
6.1.4 
PREPARATION 
6.1.5 
DOSING AND ADMINISTRATION 
6.1.6 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 

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• 
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  
• 
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 patient off these medications 
 
Management of Diarrhea 
Management of diarrhea during treatment with fedratinib will be done according to the following 
steps: 
• 
Patients 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 patient 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.  
• 
Hospitalization may be indicated for Grade 3 or higher persisting diarrhea. 
• 
Management of nausea, vomiting and diarrhea will be assessed during the patients visit. 
 
 
Guidelines for Management of Encephalopathy:  
 
A potential case of WE is a medical emergency. Screening for WE and management of potential cases of WE 
during treatment with fedratinib will be done according the following steps: 
 
Clinical and Cognitive Assessment 
Interval history: including a review of the patient’s history for confusion, memory problems, vision 
problems (e.g., double vision) as well as poor nutrition, signs and symptoms of malabsorption, and 
alcohol use 
• 
Physical examination: including assessment for abnormal eye movements, cerebellar 
abnormalities and body weight (weight loss compared to previous examination or patient history)  
 
Management of Potential WE 
In case of signs or symptoms that may indicate WE: 
• 
Hold fedratinib until WE is ruled out 
• 
Obtain sample for thiamine level 
• 
Empirically start thiamine supplementation 
• 
Report the event as an AESI to the Sponsor 
• 
Obtain a neurological consult 

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• 
Perform a brain MRI 
• 
If WE is confirmed, discontinue fedratinib permanently 
 
Thiamine Monitoring and Correction 
Thiamine levels (for whole blood) will be monitored and thiamine supplementation will be 
administered to all patients with thiamine levels below the normal range. 
• 
Thiamine levels are assessed at screening and need to be corrected and retested before starting 
fedratinib treatment (see inclusion criteria) 
• 
While on treatment with fedratinib, thiamine levels are assessed as clinically indicated 
• 
In case a patient is on thiamine supplementation, thiamine levels should be assessed in a fasting 
state for thiamine supplementation and thiamine given after the blood draw 
• 
In case a thiamine level result is below normal, the site will contact the patient as soon as 
possible to start supplementation as described below. 
• 
For thiamine levels below the normal range but ≥ 30 nM/L without signs or symptoms of WE: 
• 
Supplementation with a minimum daily dose of 100 mg of oral thiamine must be started 
• 
In case the results were obtained by a local laboratory, report the event as an Adverse Event of 
Special Interest (AESI). 
• 
For thiamine level < 30 nM/L with or without signs or symptoms of WE: 
• 
Immediate treatment with thiamine (preferably IV) at therapeutic dosages eg, 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 
• 
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 
• 
And then continue at an oral minimum daily dose of 100 mg thiamine for at least 90 days 
• 
Fedratinib must be held until thiamine levels are restored to normal range. 
• 
Thiamine supplementation should be administered as a thiamine only formulation. 
• 
If thiamine levels are low, ensure that magnesium levels are normal or corrected if low 
 
 
Guidelines for Interruption and Restarting of Study Drug 
 
Chemistry 
Adverse Event 
Trigger 
Action Taken 
ALT and/or AST 
elevation 
Grade 2 
• 
Continue study drug 
• 
Monitor LFTs at least weekly until ≤ Grade 1 or baseline 
• 
If Grade 2 elevation lasts ≤ 14 days, no action required. 
• 
If Grade 2 elevation lasts > 14 days, interrupt drug, monitor LFTs at 
least weekly, and: 
o If resolved within 14 days after interruption, resume study drug 
at the same dose, monitor LFTs at least weekly during the next 
month and according to the protocol schedule thereafter 
o If LFTs do not resolve to ≤ Grade 1 or baseline within 14 days 
after interruption lasts, discuss with study PI. 
Grade 3 
or 4 
• 
Complete a coagulation profile on the patient. 
• 
Interrupt study drug and monitor LFTs at least weekly until ≤ Grade 1 or 
baseline: 
o If resolved within 14 days after interruption, patient may 
resume study drug at next lower dose. 

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o If LFTs do not resolve to ≤ Grade 1 or baseline within 14 days 
after interruption, discuss with study PI. 
• 
Carefully examine patient’s concomitant medications for those that 
may contribute to LFT elevations. Hold those medications or switch to 
an alternative; consult study PI if needed.  
• 
In the case of recurrent grade ≥ 3 ALT and/or AST elevation, study drug 
should be discontinued. 
Amylase/Lipase 
Elevation 
Grade 2 
• 
Continue study drug 
• 
If Grade 2 elevation lasts > 14 days, interrupt drug, monitor 
amylase/lipase at least weekly, and: 
o If resolved within 14 days after interruption, resume study drug 
at the same dose, monitor amylase/lipase at least weekly 
during the next month and according to the protocol schedule 
thereafter 
• 
If amylase/lipase does not resolve to ≤ Grade 1 or baseline within 14 
days after interruption lasts, discuss with study PI. 
Grade 3 
or 4 
• 
Interrupt study drug and monitor amylase/lipase at least weekly until ≤ 
Grade 1 or baseline: 
o If resolved within 14 days after interruption, patient may 
resume study drug at next lower dose. 
o If amylase/lipase do not resolve to ≤ Grade 1 or baseline within 
14 days after interruption, discuss with study PI. 
• 
Carefully examine patient’s concomitant medications for those that 
may contribute to amylase/lipase elevations. Hold those medications or 
switch to an alternative; consult study PI if needed. 
Creatinine 
elevation 
Grade 3 
or 4 
• 
Interrupt study drug for up to 2 weeks (≤ 14 days) and monitor 
creatinine at least weekly until ≤ Grade 1 or baseline.  
• 
Carefully examine patient’s concomitant medications for those that 
may contribute to creatinine elevation. Hold those medications or 
switch to an alternative; consult study PI if needed 
o If deemed unrelated to study drug, resume study drug at same 
dose 
o If assessed as at least possibly related to study drug, resume at 
next lower dose; monitor as clinically indicated.  
• 
If creatinine does not resolve to ≤ grade 1 or baseline within 14 days 
after interruption, discuss with study PI. Dose reduction to 200 mg 
daily should be considered in patients with severe renal impairment 
(creatinine clearance of 15 mL/min to 29 ml/min).  
 
Hematology 
Thrombocytopenia 
Grade 4 or Grade 3 
with bleeding 
• 
Hold until resolved to > 50 x 109/L or baseline, 
if baseline was lower than 50 x 109/L. 
• 
Restart dose at 100 mg daily below last given 
dose.  
• 
If grade 4 thrombocytopenia persists for > 14 
days, then discontinue study drug.  
Neutropenia 
Grade 4 
• 
Interrupt dose until ANC > 1.0 x 109/L. Restart 
dose at 100 mg daily below the last given 

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dose.  
• 
If grade 4 neutropenia persists for > 14 days, 
discontinue study drug.  
 
 
Other Toxicities 
Any Grade 1 or Grade 2  
Continue study drug treatment and treat the 
toxicity; monitor as clinically indicated 
Any grade 3 toxicity, if clinically significant and not 
manageable by supportive care 
• 
Interrupt study drug up to 2 weeks (14 
days); until toxicity resolves to ≤ Grade 1 
or baseline. 
• 
Resume study drug at same dose. If 
assessed as at least possibly related to 
study drug, resume at next lower dose; 
monitor as clinically indicated 
Any recurrent Grade 3 toxicity at 100 mg daily dose 
(lowest dose allowed on study) that is at least possibly 
related to study drug  
• 
Discontinue study drug and follow-up 
per Protocol. Exceptions require 
approval of study PI.  
Any other non-hematologic Grade 4 toxicity 
• 
Discontinue study drug and follow-up 
per protocol 
New red blood cell (RBC) transfusion requirement 
• 
Dose reduction should be considered in 
patients who become newly dependent 
upon RBC transfusions. 
 
Dose reductions will be made in increments of 100 mg with 100 mg daily being the lowest dose to be 
administered on study. Any toxicity that occurs at a dose level of 100 mg daily that would require a dose 
reduction will result in discontinuation of study drug unless otherwise approved by the study PI.   
 
Dose increases can occur after a dose reduction if toxicity has remained ≤ 1 or at baseline for ≥ 28 days. 
Dose increases will be made in increments of 100 mg daily may only occur once per cycle. Dose levels can 
only be tried on three occasions.  
 
 
 
All patients receiving at least 1 dose of study drug will evaluable for safety and efficacy. Patients may 
continue on study drug until withdrawal criteria are met (section 5.4.1). Treatment duration will vary 
significantly between patients but is expected to average approximately 12-24 months.  
 
 
 
All patients will be given a study drug diary to document compliance with daily dosing schedule. This diary 
will also provide an opportunity for the patient to document missed/skipped doses, new or discontinued 
concomitant medications and adverse events.  
 
 
 
The study drugs will be stored in the Moffitt Investigational Pharmacy Department. There will be an 
accountability log for the drug. Any unused study drug will be destroyed on site per Investigational Pharmacy 
6.1.7 
DURATION OF THERAPY 
6.1.8 
TRACKING OF DOSE 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 

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standard procedures. 
 
 
 
 
 
 
The Schedule of Events - Section 7.3.7 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the PI and/or Bristol-Myers 
Squibb for reasons related to patient safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional 
consent be obtained from the patient.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations. 
 
 
 
The majority of procedures and laboratory tests on this trial will be performed per standard of care for 
MDS/MPNs and CNL. Standard of care screening testing will include CBC with differential, serum chemistry, 
amylase, lipase, thiamine level, vital signs, physical exam, bone marrow biopsy/aspirate, serum pregnancy 
test (in women of childbearing age).  
 
During routine follow-up, CBC with differential, serum chemistry, vital signs, and supportive care measures 
will be following standard of care for any other MDS/MPN or CNL patient.   
 
 
 
Prior to any study procedure, informed consent must be obtained and documented by the patient’s 
dated signature or by the patient’s legally acceptable representative’s dated signature on a consent 
form. The dated signature of the person conducting the consent discussion must also appear on the 
consent form.  
 
 
 
Prior to any trial treatment, all inclusion and exclusion criteria will be reviewed and signed by the PI or 
Sub-Investigator to ensure the patient qualifies for the trial. For collaborating sites, eligibility will be 
reviewed by study PI prior to enrollment. 
 
 
Demographical information collected will include birth date, age, sex, race, and ethnicity. A medical history 
will be obtained by the investigator or qualified designee.  Medical history will include all active conditions 
and any condition diagnosed that is considered to be clinically significant by the Investigator.  Details 
regarding the disease for which the patient has enrolled in this study will be recorded separately and not 
listed as medical history.   
7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 
STUDY-SPECIFIC PROCEDURES 
7.1.2 
STANDARD OF CARE STUDY PROCEDURES 
7.1.3 
Informed Consent 
7.1.4 
Inclusion/Exclusion Criteria 
7.1.5 
Demographics and Medical History 

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Baseline symptoms are defined as those present at the closest time before the start of study drug 
administration.  
 
 
The investigator or qualified designee will assess ECOG status (see Appendix) as specified in the 
Schedule of Events.   
 
      
 
 
The investigator or qualified designee will record medication, if any, taken by the patient starting at the 
screening visit until the last dose of study drug.  All medications related to reportable SAEs should be 
recorded as defined in the SAE section of the protocol. 
 
 
The investigator or qualified designee will assess each patient to evaluate for  
potential new or worsening AEs as specified in the Schedule of Events and more frequently if clinically 
indicated.  Adverse events will be collected from the time of consent until 30 days after last dose.  
 
 
The investigator or qualified designee will perform a complete physical exam during the screening period.  
Clinically significant abnormal findings should be recorded as medical history.  Physical exam must include 
assessment of spleen size on Cycle 4 Day 1 and Cycle 7 Day 1. Problem-focused physical exams will suffice 
for other time points. 
 
 
The investigator or qualified designee will take vital signs at screening andon day 1 of cycles 1-6. Vital 
signs should include temperature, pulse, respiratory rate, and blood pressure. Weight is required to be 
measured 
on 
cycle 
1 
day 
1.  
 
At screening, laboratory procedures will include a CBC with differential, CMP (albumin, BUN, creatinine, 
alkaline phosphatase, ALT, AST, CO2, calcium, chloride, glucose, potassium, sodium, total bilirubin, total 
protein), LDH, uric acid, magnesium, phosphorous, thiamine (vitamin B1) level, vitamin B12 level, folic 
acid, C-reactive protein (CRP), amylase and lipase. Standard follow-up visits (Day 1, 8,15, and 22 of cycle 1, 
Day 1 and 15 of Cycle 2 and Day 1 of 3,5,6,8+) will include CBC with differential, CMP, LDH, amylase, and 
lipase. Disease assessment visits on day 1 of cycle 4 and 7 will include CBC with differential, CMP, LDH, 
thiamine level, and CRP. Thiamine level will also be checked on Day 1 of Cycle 2. 
 
 
 
A bone marrow biopsy will be performed during screening and after cycle 6 (day 168 +/- 14 days). If a 
7.1.6 
Baseline Symptoms 
7.1.7 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
7.1. 8        Concomitant Medications Review 
7.1.9 
Adverse Event Review 
7.1.10  
Physical Exam 
7.1.11 
Vital Signs 
7.1.12 
Laboratory Procedures 
7.1.13 
Bone Marrow Biopsy 

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patient discontinues treatment early or progression of disease is suspected, a bone marrow biopsy will be 
done at the discretion of the investigator. During follow-up, bone marrow biopsies will be performed per 
investigator discretion.  
 
 
 
Next-generation sequencing (NGS) will be performed on a bone marrow aspirate or peripheral blood 
sample during screening and after cycle 6. NGS will be performed per institutional standards. Acceptable 
NGS platforms must include testing for the following genes with sensitivity of at least 5%: JAK2, MPL, CALR, 
TET2, DNMT3A, ASXL1, EZH2, SRSF2, U2AF1, ZRSR2, SF3B1, RUNX1, CSF3R, KRAS, NRAS, CBL, PTPN11, TP53, 
PHF6, IDH1, IDH2, ETV6, SETBP1. If NGS has been performed within 12 months of screening, this may be 
used as baseline NGS if approved by PI.  
 
Mononuclear cells from bone marrow aspirate will be collected at screening and used to develop PDX 
mouse models for each enrolled patient. Samples will be under the care of Dr. Eric Padron’s lab.  
 
To determine whether PDX models recapitulate responses to study drug in patients with MDS/MPN and 
CNL, we will obtain purified hCD34+ cells from each primary pre-treatment patient sample. These cells will 
be sent to the lab of Dr. Eric Padron at Moffitt Cancer Center where they will be xenografted into 6 NSGS 
vehicle- and 6 fedratinib-treated mice. After 7 days of transplantation and peripheral blood analysis to 
assess for hCD45 cell engraftment, we will treat NSGS mice with fedratinib at pharmacologically comparable 
doses to that exposed to the patient on clinical study. Treatment would occur until the animal becomes 
moribund. PDX response assessment would be measured in three categories compared to vehicle: 1.) 
Reduction in splenomegaly as measured by spleen weight at necropsy and MRI at baseline and at the time 
that the first mouse becomes moribund. MRI experiments will be done on a 7T horizontal magnet (Agilent 
Technologies) using a 35 mm 1H birdcage coil (Doty Scientific). 2) Improvement in hematologic parameters 
(to include anemia, thrombocytopenia, WBC count, monocyte count). 3) Improvement in BM pathology to 
include decreases in bone marrow myeloblasts (hCD34+) and resolution of dysplasia/fibrosis. We will also 
measure survival of each treatment cohort of mice. These responses will then be compared to those seen in 
the clinical trial to determine the ability for the NSGS PDX to recapitulate drug response.  
 
Patients enrolled after the interim analysis of nine patients will have purified hCD34+ cells from primary pre-
treatment samples xenografted into an additional 6 NSGS mice that will be treated with ruxolitinib. These 
mice will be subjected to the same procedures as the vehicle- and fedratinib-treated mice in an effort to 
directly compare the efficacy of ruxolitinib and fedratinib in PDX mouse models of MDS/MPN and CNL.  
 
 
 
 
Spleen imaging will be performed during screening (day -30 – 0), at week 12 assessment (day 84 +/- 7 
days), at week 24 assessment (day 168 +/- 14 days) and every 24 weeks thereafter (+/- 28 days) while on 
study drug up to week 96. Preferred spleen imaging is ultrasound; however, CT without contrast or MRI 
without contrast can be used in patients whom ultrasound is not feasible/sufficient per the discretion of 
the investigator. Spleen length on three axes (anteroposterior [AP] length, craniocaudal [CC] height, 
transverse [TR] width at the hilum) should be documented with emphasis to the spleen length in longest 
dimension. The imaging modality for each patient should be kept consistent throughout the study (i.e. 
always use ultrasounds for patients with screening ultrasound and always use CT for patients with 
screening CT). When possible, spleen volume should be calculated using the following formula: 
7.1.14 
Correlative Studies 
7.1.15 
Spleen Imaging 

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AP x TR (at the hilum) x CC x 0.524 = Spleen Volume (cc)   
 
If spleen imaging has been performed within 90 days of fedratinib initiation, this can be substituted for a 
screening spleen imaging as long as, in the opinion of the treating physician, the spleen has not undergone 
substantial change in size during that period of time and required spleen measurements have been 
performed. If any treatment-directed medications (i.e. ruxolitinib, hydroxyurea, interferon, lenalidomide, 
thalidomide, pomalidomide, corticosteroids, azacitidine, decitabine) have been started, stopped, or had 
dose modifications since the last spleen imaging test, then new spleen imaging must be obtained during 
the screening period.  
 
 
 
 
• 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet 
count. 
• 
To be performed at screening and at each protocol-defined follow-up 
visit. 
• 
Metabolic Panel: albumin, BUN, alkaline phosphatase, CO2, calcium, chloride, 
glucose, potassium, sodium, total proteincreatinine, total bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST). 
• 
To be performed at screening and at each protocol-defined follow-up 
visit. 
• 
Additional electrolytes/labs: lactate dehydrogenase (LDH), uric acid, magnesium, 
phosphorous, amylase, lipase 
• 
Uric acid, magnesium, and phosphorous are to be drawn during 
screening and as clinically indicated afterward. 
• 
LDH is to be drawn during screening and on day 1 of cycle 1-7 and every 
3 cycles thereafter.  
• 
Amylase and lipase are to be drawn during screening, day 1, 8, 15, 22 of 
cycle 1, day 1 of cycle 2-4 and day 1 of cycle 7.   
 
• 
Nutritional Labs: Vitamin B12, vitamin B1 (thiamine), folic acid  
• 
To be performed during screening period. Thiamine level to be assessed 
on day 1 of cycle 1, 2, 4 and 7.  
• 
Inflammatory Labs: CRP  
• 
To be performed on day 1 of cycles 1, 4, and 7 and at disease assessment 
visits thereafter. 
 
Laboratory testing to be performed as stated above or at the discretion of the treating 
physician. Laboratory tests will be performed at the respective treating institution. 
 
 
 
 
 
At screening (day -30 to 0), week 12 assessment, week 24 assessment peripheral blood will be collected. 
Designated study personnel will collect the sample from the laboratory draw area. Peripheral blood will be 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 
7.2.2 
SPECIMEN PREPARATION, HANDLING, AND STORAGE 
S
CI
A A IO
HA
LI G A
S O AG

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collected in six green top (heparinized) 10 ml tubes and one red top (clot activator or no additive) 10 ml 
tube for a total of seven tubes and 70 cc of peripheral blood. At screening and week 24 assessment (see 
study calendar), bone marrow aspirate will be collected in three lavender (EDTA) 10 ml tubes or a 60 ml 
heparinized syringe for a total of 30 cc. These will be shipped to the H. Lee Moffitt Cancer Center laboratory 
as directed in section 7.2.4 and will be processed first by centrifugation (530 rcf for 20 minutes) with density 
gradient medium to collect the mononuclear cellular layer, followed by the addition of RBC lysis buffer to 
remove RBCs and debris. The mononuclear cells will be cryopreserved as previously described and stored in 
liquid nitrogen for later use labeled with a unique identifier that corresponds to each patient known only to 
the investigator and study personnel. The plasma and serum will be cryopreserved for later use and labeled 
with a unique identifier that corresponds to each patient known only to the investigator and study 
personnel.  
 
 
 
Contact Information:  
 
For general shipping concerns:  
 
Eric Padron, MD  
e-mail: eric.padron@moffitt.org, 
Phone: 8137458264 (office) 
 
Maria Balasis 
e-mail: Maria.Balasis@moffitt.org 
Phone: 813-745-6458 
 
 
 
For detailed specimen processing concerns: 
 
Maria Balasis 
e-mail: Maria.Balasis@moffitt.org 
Phone: 813-745-6458 
 
 
Site Requirements: 
o Green Top (heparinized) Vacutainer (6 per peripheral blood sample shipment) 
o Red Top Vacutainer (1 per peripheral blood sample shipment) 
o Lavender Top (EDTA) Vacutainer (3 per bone marrow sample shipment) or 60 ml heparinized 
syringe  
o Biohazard bags, coolers 
o Bio-mailer boxes, IATA placards, etc. 
 
Collection Procedures: 
o Peripheral Blood.  
 
Peripheral blood will be collected at time points as described in study protocol. 
 
At time of phlebotomy, 6 green tops (10 ml each) and 1 red top (10 ml) will be 
collected for a total of 70 cc. 
 
Please label each vacutainer as follows: 
• 
Abbreviate site name –Subject ID #-PB-mm/dd/yyyy 
• 
Please fill out accompanying correlative worksheet (see below) 
Bone Marrow. 
7.2.3 
SPECIMEN SHIPMENT 

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 
The bone marrow aspirate will be collected at time points as described in study 
protocol. 
 
At time of aspirate, 3 lavender tops (10 ml) or one 60 ml heparinized syringe will be 
collected for a total of 30 cc. 
 
Please label each vacutainer as follows: 
• 
Abbreviate site name –Subject ID #-BM-mm/dd/yyyy 
• 
Please fill out accompanying worksheet (see below) 
Packaging and Shipment  
o Shipping Timelines and General Guidelines 
 
Ship samples overnight on Monday through Thursday ONLY.  Do not ship samples 
to arrive on weekends or holidays. 
 
All samples are to be sent at room temperature in biohazard bags, bio mailer boxes. 
 
Ensure all tubes are tightly capped when packaging. 
 
Shipments should be performed by personnel who have completed IATA 1.5 training 
for transportation of dangerous goods. 
 
Notify the Cancer Center at least 24 hours prior to arrival of shipment. 
 
Email the details along with the patient # and courier tracking # to: 
• 
Maria Balasis: maria.balasis@moffitt.org and 
• 
Eric Padron: eric.padron@moffitt.org 
• 
Andrew Kuykendall: Andrew.Kuykendall@moffitt.org 
o Sample Packaging  
 
All samples from one patient should have been able to fit in one bio mailer box. 
 
Be sure to fill the internal cooler with ambient packing to keep all samples near room 
temperature during transit. 
 
Ship samples to: 
Maria Balasis 
12902 Magnolia Drive 
Stabile Research Building (SRB) Room #23234 
Tampa, FL 33612 
813-745-6458 
 
Label appropriately as in section 4 
 
Use FedEx mailing 3rd party billing as the billing option on the label and include this 
account number: 156056111 
o Transportation and Record Keeping 
 
Schedule the samples for pickup and next day delivery with FedEx. 
 
Retain a copy of the shipment’s waybill with the photocopy of the patient’s 
correlative worksheet sampling document. The original should be sent with the 
sample. 
 
 
Correlative worksheet (see Appendix G) 
 
 Site name: ___________________     
Patient's Initials:_________    Pt. Study ID #:__________  
 
Blood or Bone Marrow (circle) Collections – all times must be recorded in military time  

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Cycle/Day 
Date of Collection 
(mm-dd-yyyy) 
Collection Time 
 
 
 
 
 
 
Comments 
 
 
Please photocopy this for your records and maintain with a copy of the shipping waybill.   
Return the original to Moffitt with the specimens.  This source document stands as a custodial 
record.    
 
Ship all the above samples to: 
Maria Balasis 
12902 Magnolia Drive 
Stabile Research Building (SRB) Room #23234 
Tampa, FL 33612 
813-745-6458 
Please email (maria.balasis@moffitt.org, eric.padron@moffitt.org, Andrew.Kuykendall@moffitt.org)  
on the day of shipment with courier tracking information.       
 
Ship Monday through Thursday ONLY! 
 
______________________________Do not write below this line_____________________________ 
 
Condition received:  ________________________________________________   Initials: ________ 
 
Comments: _______________________________________________________   Initials: ________ 
 
 
 
 
 
  
 
 
 
Screening Visit (Day -30 to 0)  
 
• 
Obtain and review medical history to determine eligibility based on inclusion/exclusion 
criteria. 
• 
Written informed consent to be obtained prior to any screening procedures 
7.3 
STUDY SCHEDULE 
7.3.1 
SCREENING 

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• 
Review medications history (including over-the-counter drugs, vitamins, herbs, alcohol) to 
determine eligibility based on inclusion/exclusion criteria.  
• 
Perform physical examination needed to determine eligibility based on inclusion/exclusion 
criteria 
• 
Vital signs measurements  
• 
Evaluation of ECOG performance status 
• 
Spleen imaging needed to determine eligibility based on inclusion/exclusion criteria 
• 
Symptom assessment needed to determine eligibility based on inclusion/exclusion criteria 
• 
Serum beta-human chorionic gonadotropin (β-hCG) pregnancy test for women of 
childbearing potential 
• 
Clinical laboratory testing including serum chemistry, hematology, thiamine level, folic acid, 
vitamin B12,amylase, lipase, magnesium, phosphorous, uric acid, LDH. Clinical assessments 
(laboratory tests, spleen imaging) performed as part of the subject’s routine clinical 
evaluation and not specifically for this study need not be repeated after signed informed 
consent has been obtained provided the assessments fulfill the study requirements and are 
performed within 30 days of starting study treatment.  
• 
Bone marrow biopsy and aspirate and peripheral blood sample will be performed in order to 
collect correlative samples. Biopsy must include reticulin stain. 
• 
Cytogenetics  
• 
Next-generation sequencing to assess for mutation involving the following genes: JAK2, MPL, 
CALR, TET2, DNMT3A, ASXL1, EZH2, SRSF2, U2AF1, ZRSR2, SF3B1, RUNX1, CSF3R, KRAS, 
NRAS, CBL, PTPN11, TP53, PHF6, IDH1, IDH2, ETV6, SETBP1  
 
 
 
7.3.2.1 Baseline Visit (Cycle 1; Day 1) 
 
• 
Verify patient still meets inclusion/exclusion criteria 
• 
Review results of serum pregnancy test, if applicable 
• 
Assess and record baseline symptoms prior to study drug administration 
• 
Administer MPN symptom assessment form (SAF). This will serve as baseline symptom score.  
• 
Physical exam with documentation of spleen size measured as extent below the left costal 
margin (LCM) at the mid-clavicular line (measured in centimeters) (e.g. 10 cm below the LCM).  
• 
ECOG performance status assessment 
• 
Record vitals 
• 
Weight 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH, amylase, lipase 
• 
Thiamine level 
• 
C-reactive protein (CRP) 
• 
Administer study treatment and provide medication supply sufficient to reach next protocol-
defined visit.  
• 
Provide patient pill and adverse event diary 
 
 
 
7.3.2 
Cycle 1 Day 1 (Cycle length = 28 days) 

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7.3.3.1 Cycle 1; Day 8, 15, 22 and Cycle 2, Day 15) 
 
• 
Focused physical exam 
• 
Assess and record symptoms 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH, amylase, lipase 
 
7.3.3.2 Cycle 2-3; Day 1 
 
• 
Record vitals 
• 
Focused physical exam 
• 
Assess and record symptoms 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH, amylase, lipase 
• 
Thiamine level to be checked on Cycle 2, Day 1 
• 
Assess TSS with MPN SAF 
• 
Assess PGIC 
 
 
7.3.3.3 Week 12 Assessment – Performed at day 84 +/- 7 days 
 
• 
Record vitals 
• 
Physical exam with documentation of spleen size measured as extent below the left costal 
margin (LCM) at the mid-clavicular line (measured in centimeters) (e.g. 10 cm below the 
LCM)Assess and record symptoms 
• 
Peripheral blood drawn for correlatives 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH, amylase, lipase 
• 
Thiamine level 
• 
CRP 
• 
Assess TSS with MPN SAF 
• 
Assess PGIC 
• 
Spleen imaging with documentation of spleen length on three axes (length, height, width at 
the hilum) and volume (when feasible).   
• 
MDS/MPN Response Assessment 
 
7.3.3.4 Cycle 4-6; Day 1 (Assessments here can contribute to week 12 assessment) 
 
• 
Record vitals 
• 
Focused physical exam 
7.3.3 
ON-TREATMENT VISITS 

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• 
Assess and record symptoms 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH 
• 
Assess TSS with MPN SAF 
• 
Assess PGIC 
 
 
7.3.3.5 Week 24 Assessment – Performed at day 168 +/- 14 days 
• 
Record vitals 
• 
Physical exam with documentation of spleen size measured as extent below the left costal 
margin (LCM) at the mid-clavicular line (measured in centimeters) (e.g. 10 cm below the 
LCM)Assess and record symptomsBone marrow biopsy and aspirate (with correlative samples 
sent from aspirate) 
• 
Peripheral blood drawn for correlatives 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH, amylase, lipase 
• 
Thiamine level 
• 
CRP 
• 
Assess TSS with MPN SAF 
• 
Assess PGIC 
• 
Spleen imaging with documentation of spleen length on three axes (length, height, width at 
the hilum) and volume (when feasible).Bone marrow biopsy and/aspirate with reticulin stain 
• 
MDS/MPN Response Assessment 
 
7.3.3.6 Cycle 7; Day 1 (Assessments here can contribute to week 24 assessment) 
 
• 
Record vitals 
• 
Focused physical exam 
• 
Assess and record symptoms 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH 
• 
Assess TSS with MPN SAF 
• 
Assess PGIC 
 
7.3.3.7 Post-Week 24 On Treatment Visits (To occur every 3 cycles while on study drug) 
 
• 
Record vitals 
• 
Focused physical exam 
• 
Assess and record symptoms 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 

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• 
LDH 
• 
Assess TSS with MPN SAF 
• 
Assess PGIC 
 
7.3.3.8 Post-Week 24 Disease Assessment(s) (To occur on day 336 +/- 14 days and every 168 +/- 
14 days thereafter while on study drug) 
 
• 
Record vitals 
• 
Physical exam with documentation of spleen size measured as extent below the left costal 
margin (LCM) at the mid-clavicular line (measured in centimeters) (e.g. 10 cm below the 
LCM)Assess and record symptoms 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH 
• 
Thiamine level 
• 
CRP 
• 
Assess TSS with MPN SAF 
• 
Assess PGIC 
• 
Spleen imaging with documentation of spleen length on three axes (length, height, width at 
the hilum) and volume (when feasible).MDS/MPN Response Assessment 
• 
MDS/MPN Response Assessment  
 
 
 
 
7.3.4.1 End of Treatment Visit (28 +/- 7 days from study drug completion) 
 
• 
Record vitals 
• 
Peripheral blood drawn for correlativesPhysical exam 
• 
Assess and record symptoms 
• 
CBC with differential 
• 
Chemistry profile (sodium, potassium, chloride, creatinine, BUN, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, calcium, CO2) 
• 
LDH 
 
Final instructions will be provided to the patient and the patient will be informed if results will be 
available or any planned presentation or publication of the study data.  
 
 
 
 
If a patient terminates study participation for any reason prior to completion of the protocol treatment 
plan, any subsequent procedures or evaluation will be per physician discretion as part of standard of 
care. Evaluation of AEs will continue as outlined in Section 7.1.9.  
 
 
 
7.3.4 
FINAL STUDY VISIT 
7.3.5 
EARLY TERMINATION VISIT 
7.3.6 
UNSCHEDULED VISIT 

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Any visit not include on the Schedule of Events Table that includes examination in the Moffitt 
hematology clinic, inpatient hospitalization, or any unexpected extended hospitalization, laboratory 
evaluation or management of adverse events, will be considered an Unscheduled Visit. It will be 
documented in the subject’s medical record and included on the adverse event log. Adverse event or 
serious adverse event data will be collected in OnCore. No separate OnCore form for an unscheduled 
visit will be used to collect additional data.  
 
 
 
 
 
Procedures 
Screening 
Enrollment/Baseline 
Cycle 1, Day 1 
Cycle 1*, Day 8,15 , 22 (+/- 5 
days) 
Cycle  2, Day  1 (+/- 7 days) 
Cycle 2, Day 15 (+/- 5 days) 
Cycle 3, Day 1 ((+/- 7 days) 
Cycle 4, Day 1 
Week 12  Assessment (+/- 7 
days) 
Cycle 5, Day  1 (+/- 7 days) 
Cycle 6, Day 1 (+/- 7 days) 
Cycle 7, Day 1 
Week 24 Assessment (+/- 14 
days) 
Subsequent Visits (Every 3 
cycles) (+/- 14 days) 
End of Treatment Visit            
(+/- 7 days from study drug 
completion)e 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
     X  -------------------------------------------------------------------------------------------------------- X 
Fedratinib dispensedd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Investigational Drug Diary Provided 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
Performance status (ECOG) 
X 
X 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Metabolic panel a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Uric acid, magnesium, phosphorous 
X 
 
 
 
 
 
 
 
 
 
 
 
Amylase, lipase 
X 
X 
X 
X 
 
X 
X 
 
 
X 
 
 
LDH 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Folic acid, Vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
Thiamine 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
 
CRP 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
Serum Pregnancy test b 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
      X  ---------------------------------------------------------------------------------------------------------- X 
Spleen Imaging 
X 
 
 
 
 
 
X 
 
 
X 
Xc 
 
MPN SAF TSS 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PGIC 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
MDS/MPN Response Assessment 
 
 
 
 
 
 
X 
 
 
X 
Xc 
 
Bone Marrow Biopsy/Aspirate 
X 
 
 
 
 
 
 
 
 
X 
 
 
Bone marrow aspirate for 
correlatives 
X 
 
 
 
 
 
 
 
 
X 
 
 
7.3.7 
SCHEDULE OF EVENTS TABLE 

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Peripheral Blood Draw for 
correlatives 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Cytogenetics 
X 
 
 
 
 
 
 
 
 
 
 
 
Next Generation Sequencing 
X 
 
 
 
 
 
 
 
 
 
 
 
a: 
Albumin, alkaline phosphatase, total bilirubin, CO2, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, AST,ALT, 
sodium,  
b: 
Serum pregnancy test (women of childbearing potential). 
c:       Spleen imaging and MDS/MPN response criteria to be performed every 24 weeks +/- 28 days (6 cycles) after week 24 
 d.      See section 7.2.3 and 7.2.4 for details regarding specimen preparation, handling, and storage 
 *       Cycle length = 28 days 
 
 
 
 
All concomitant prescription medications taken during study participation will be reviewed in the 
electronic medical record. For this protocol, a prescription medication is defined as a medication 
that can be prescribed only by a properly authorized/licensed clinician.  
 
 
 
Treatment with the following drugs will not be permitted unless discussed with, and approved by, the 
primary investigator: 
• 
Moderate and strong CYP3A4 Inducers (should be avoided in all cases) 
o Phenytoin 
o Rifampicin 
o Enzalutamide 
o Apalutamide 
o Carbamazepine 
o Bosentan 
o Efavirenz 
o Phenobarbital 
o Primidone 
o St. John’s Wort 
Treatment with the following drugs is cautioned against; however, if absolutely necessary, necessitates 
dose reduction. 
• 
CYP3A4 Inhibitors  
o Diltiazem 
o Erythromycin 
o Clarithromycin 
o Ketoconazole 
o Itraconazole 
o Voriconazole 
o Posaconazole 
o Fluconazole 
o Ritonavir 
o Aprepitant 
o Ciprofloxacin 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 

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o Cyclosporine 
o Dronedarone 
o Fluconazole 
o Imatinib 
o Fluovaxaomine 
o Verapamil 
 
 
 
Prophylactic anti-emetics (e.g. ondansetron) are highly recommended during the first 8 weeks of 
treatment with fedratinib. See section 6.1.6 for detailed guidance.  
 
 
 
 
• 
In the setting of leukocytosis > 50,000/µL, hydroxyurea can be provided up to a dose of 
2,000 mg per day per the discretion of the treating physician. For hydroxyurea use outside of 
these parameters, use will be determined after discussion with the PI.   
• 
In the setting of anemia (Hgb < 11 g/dL) and EPO level < 500, erythropoiesis-stimulating 
agent (ESA) can be provided at the discretion of the treating physician. Patients who start 
ESA within 2 months of study enrollment or while on study will not be eligible for anemia 
response.  
• 
Growth factor support with granulocyte stimulating factor may be administered for patients 
with an absolute neutrophil count (ANC) < 500/µL per the discretion of the treating 
physician.  
• 
The use of transfusion support (RBCs and platelets) will be according to standard of care as 
rescue therapy for anemia or thrombocytopenia. 
• 
Corticosteroids and antihistamines may be administered per institutional protocol for the 
treatment of hypersensitivity reactions should they emerge.  
• 
Loperamide should be available at home for each patient enrolled on the study. Treatment 
with loperamide should be directed by the treating physician based on local practices. 
Consider starting loperamide at a 4 mg loading dose at the onset of diarrhea and giving 2 mg 
after each diarrheal bowel movement without exceeding 16 mg/24 hours.  
• 
See section 6.1.6 for detailed guidance on management of expected toxicities. 
 
 
 
 
 
 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear 
or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values, regardless of etiology.  Any worsening (i.e., any clinically significant adverse 
change in the frequency or intensity of a pre-existing condition) should be considered an AE. A 
7.6 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES 
7.7 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES 
8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) 

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diagnosis or syndrome should be recorded 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.  An overdose, accidental or intentional, whether or not it is associated with an AE, should be 
reported. Any sequela of an accidental or intentional overdose of an investigational product should 
be reported as an AE.  If the sequela of an overdose is an SAE, then the sequela must be reported on 
an SAE report form and as an AE.   
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Schedule of Events and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period. The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
Toxicities will be characterized in terms regarding seriousness, causality, severity, duration, action 
taken, and outcome with regard to trial treatment.  
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 IP dose, or any other therapeutic 
intervention; or 
 
• 
Is judged to be of significant clinical importance, e.g., one that indicates a new disease process 
and/or organ toxicity, or is an exacerbation or worsening of an existing condition. 
 
Regardless of severity of 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 on the AE page/screen of the CRF.  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 (e.g. record thrombocytopenia rather than decreased platelets). 
 
 
 
 
A qualified Investigator will evaluate all adverse events as to their seriousness. A serious adverse 
event (SAE) is any AE occurring at any dose that: 
 
• 
Results in death; 
• 
Is life-threatening (i.e., 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); 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 

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• 
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 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 (e.g., 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 (i.e., planned prior to starting 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. 
• 
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
 
 
 
 
Unanticipated problems (UPs) involving risks to participants or others to include, in general, any 
incident, experience, or outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS 

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(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
 
 
For both AEs and SAEs, 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); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to the 
following scale: 
• 
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
• 
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required 
• 
Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible 
• 
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
• 
Grade 5 = Death - the event results in death 
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is based 
on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the event. 
 
 
 
 
For all collected AEs, the investigator will evaluate the participant and will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. Causality should be 
assessed and provided for every AE/SAE based on currently available information. Causality is to 
be reassessed and provided as additional information becomes available. 
The degree of certainty about causality will be graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 
SEVERITY OF EVENT 
8.2.2 
RELATIONSHIP TO STUDY AGENT 

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laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time after administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not required 
to fulfill this definition. 
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, 
other factors may have contributed to the event (e.g., the participant’s clinical condition, 
other concomitant events). Although an AE may rate only as “possibly related” soon after 
discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of 
the trial medication) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant 
treatments). 
• 
Unrelated – The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
 
 
The PI will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the 
risk information previously described for the study agent. 
 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event. 
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable (e.g., 
discontinuation, interruption of IP, as appropriate) and report if concomitant and/or additional 
treatments were given for the event. 
The Investigator will report the outcome of the event for both AEs and SAEs.  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). 
 
 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews with study participants presenting for medical care, or upon review by a study 
8.2.3 
EXPECTEDNESS/DURATION/ACTION TAKEN/OUTCOME 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 

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monitor. All AEs, including local and systemic reactions not meeting the criteria for SAEs, will be 
captured on the appropriate CRF. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of resolution/stabilization of event. 
All AEs occurring during the study must be documented appropriately, regardless of relationship. 
All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE. UPs will be recorded in the data 
collection system throughout the study. 
 
Changes in the severity of AEs will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as “intermittent” require 
documentation of onset and duration of each episode in the medical record. 
 
Adverse events for the purpose of this study will be reported from the time period beginning 
when patient has received first dose of study drug until 30 days after study drug discontinuation 
up to 3 years. Events will be followed for outcome information until resolution or stabilization is 
achieved. Any AE present at the time of final study closure will be considered ongoing.  
 
 
 
 
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 adverse clinical experiences, whether observed by the investigator or reported by the patient, 
must be recorded, with details about the duration and intensity of each episode, the action taken 
with respect to the test drug, and the event’s outcome, including lab abnormalities.  AEs will be 
recorded in the patient’s source documents.  
The investigator must evaluate each adverse experience for its relationship to the test drug and 
for its seriousness. 
The investigator must appraise all abnormal laboratory results for their clinical significance.  If any 
abnormal laboratory result is considered clinically significant, the investigator must provide details 
about the action taken with respect to the test drug and about the event’s outcome or lab 
abnormality. 
Adverse event documentation will be performed by entry into the Moffitt OnCore electronic 
database. Reporting of adverse events to the FDA for IND renewal will occur annually by a report 
obtained from the AEs collected in OnCore.   
 
All AEs will be documented on a paper log with columns for the replication of the fields in the 
OnCore AE data form. The treating physician/investigator will review the log for accuracy and 
assign CTCAE grade and the attribution of a study agent to the AE.  
.  
8.4 
REPORTING PROCEDURES 
8.4.1 
ADVERSE EVENT REPORTING 

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If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form must 
be completed.  For each SAE, the Investigator will provide information on severity, start and stop 
dates, relationship to IP, action taken regarding IP, and outcome. All SAEs made known to the 
investigator at any time after treatment that are suspected of being related to the IP must be 
record by the Investigator. All SAEs must be must be recorded in the patient’s source documents 
and reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event 
by facsimile, or other appropriate method, using the SAE Report Form, or approved equivalent 
form. 
 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to 
be chronic or the adherence to be stable. Other supporting documentation of the event may be 
requested by Bristol-Myers Squibb and should be provided as soon as possible.  
 
Investigator Reporting to the FDA 
Serious adverse events (SAEs) that are unlisted/unexpected, and at least possibly associated to the 
drug, and that have not previously been reported in the Investigators brochure, or reference safety 
information document should be reported promptly to the Food and Drug Administration (FDA) by 
telephone or by fax.  Moffitt as the study sponsor will be responsible for notifying FDA of any 
unexpected fatal or life threatening SAEs that meet the criteria for reporting to the FDA within 7 
calendar days after awareness of the event.  All other SAEs that meet the criteria for reporting to 
the FDA must be reported to the FDA within 15 calendar days after awareness of the event.  A clear 
description of the suspected reaction should be provided along with an assessment as to whether 
the event is drug or disease related.    
 
SAE Reporting From External Sites 
Information about all serious adverse events will be collected and recorded. To ensure patient safety, 
each SAE must be reported to the PI and to the sponsor expeditiously. Moffitt Cancer Center and all 
participating sites will report SAEs by completing an SAE report in OnCore, the electronic data 
capture system. The SAE Report from OnCore must be signed and reported by email 
(ESC_Partnerships@moffitt.org) to the External Site Coordination (ESC) office within 2 working days. 
If applicable, the site should also follow protocol guidelines for additional reporting to Financial 
Sponsors and government agencies. 
 
 
 
 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an 
UP report form. It is the site investigator’s responsibility to report UPs to their IRB and to Bristol-
Myers Squibb. The UP report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• A detailed description of the event, incident, experience, or outcome; 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING 
8.4.3 
UNANTICIPATED PROBLEM REPORTING 

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• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• UPs that are SAEs will be reported to the IRB and to the study sponsor within 24 hours of the 
investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the study sponsor within 2 business days of the 
investigator becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures) and the supporting agency head (or designee), within 7 days of 
the IRB’s receipt of the report of the problem from the investigator.  
 
 
 
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 of patients and 
rapid communication by the investigator to the study PI. AESIs will additionally be reported back 
to Celgene/BMS. An AESI may be serious or non-serious. The rapid reporting of AESIs allows 
ongoing surveillance of these events in order to characterize and understand them in association 
with the use of this investigational product 
 
The following are considered to be Adverse Events of Special Interest (AESIs): 
• Wernicke encephalopathy (WE) or suspected cases of WE associated with thiamine 
levels below normal range. 
• Thiamine levels below normal range with or without signs or symptoms of WE 
• Cardiac failure or cardiomegaly 
 
 
 
 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 4 months, are 
considered immediately reportable events.  IP is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene/BMS Drug Safety 
immediately by 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 
(not necessarily one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy and must notify 
Celgene/BMS 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 (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any 
8.4.4 
EVENTS OF SPECIAL INTEREST 
8.4.5 
REPORTING OF PREGNANCY 

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of the serious criteria, it must be reported as an SAE to Celgene/BMS Drug Safety immediately by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene/BMS Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form.   
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant while the 
male subject is on study treatment or within 4 months of the male subject’s last study treatment, 
the male subject taking IP should notify the Investigator, and the pregnant female partner should 
be advised to call their healthcare provider immediately. 
 
 
 
 
Safety assessments will consist of monitoring and recording all adverse events and serious adverse 
events, the regular monitoring of hematology and blood chemistry parameters and regular physical 
examinations. Adverse events will be evaluated continuously throughout the study. Safety and 
tolerability will be assessed according to the NIH/NCI Common Terminology Criteria for Adverse Events 
version (CTCAE v5.0) that is available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
The Protocol Monitoring Committee (PMC) at Moffitt monitors its assigned ongoing research protocols 
for: adverse event reporting, data and safety monitoring, and internal audit findings. The PMC, upon 
review of any agenda item, may approve the study for continuation, require revisions, suspend or close 
a protocol.  The PMC meets monthly and reviews accrual, patterns and frequencies of all adverse 
events, protocol violations and when applicable, internal audit results. 
 
Investigators of studies which are designated to be reviewed by the PMC for data and safety monitoring,  
shall provide a statistical report of the study’s progress and summary of adverse events and deviations 
based on the phase of the study and the associated risk of the study or more often if applicable. The PI 
will be notified for recommendations or notifications after the PMC review in regards of continuation or 
stopping the clinical trial. 
 
  
 
 
 
Serious Adverse Events: Serious Adverse Events (SAEs) from this protocol will be reported concurrently 
to the IRB (per IRB guidelines) and Bristol-Myers Squibb within 24 hours of staff awareness of the 
event. The Protocol Monitoring Committee (PMC) will review these SAEs in accordance with their 
policy. The data and safety plan will define dose limiting toxicities and criteria for stopping the trial 
according to rules set forth by this protocol. This trial will be continuously monitored by the PI and the 
research team. A final safety and monitoring report will be submitted to the PMC. This protocol will be 
subject to periodic internal audits based on risk or as recommended by the PMC. 
8.5 
STUDY HALTING RULES 
8.6 
SAFETY OVERSIGHT 

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Data will be captured in OnCore, Moffitt’s electronic Clinical Trials Database. For each participant 
enrolled, the electronic CRF must be completed by the assigned data manager or other authorized 
study staff. Any paper forms should be typed or filled out indelible ink and must be legible. Errors 
should be crossed out but not obliterated, the correction inserted, and the change initialed and dated 
by the investigator or his/her authorized delegate. This also applies to records for those patients who 
fail to complete the study. If a patient stops dosing or terminates from the study, the dates and 
reasons must be noted on the CRF. If a patient terminates from the study because of a DLT, thorough 
efforts should be made to clearly document the outcome.  
 
Regulatory documents and case report forms will be monitored internally according to Moffitt Cancer 
Center Monitoring Policies. Monitoring will be performed regularly by the MCC Clinical Monitoring 
Core for accuracy, completeness, and source verification of data entry, validation of appropriate 
informed consent process, reporting of SAEs, adherence to the protocol, Good Clinical Practice (GCP) 
guidelines, and applicable regulatory requirements. 
 
 
External Site Monitoring 
 
Compliance to the Protocol and Adherence to Moffitt External Site Coordination Handbook 
Moffitt is responsible for monitoring each sites compliance to adherence to applicable Moffitt External 
Site Coordination Handbook. In coordination with the Monitoring office, the ESC Office assists to monitor 
compliance to the protocol.  
 
 
External Site Access to Clinical Trial Database 
To obtain access to OnCore, the External Site Coordinator will supply forms required to be completed by 
the site staff. Once the completed forms are received, the site coordinator will receive VPN access, 
logon/password, and information on how to access OnCore. The ESC office will provide OnCore training 
to the site once initial access is granted and on an ongoing basis, as needed.  
 
Registration Procedures for External Sites 
All external enrolled subjects must be registered with the External Site Coordination (ESC) office to be 
able to participate in a trial. The participating site must email the completed c u r r e n t  eligibility 
checklist, registration form, all supporting documents, and signed, unredacted informed consent to 
the Coordinating Center. Unsigned or incomplete forms will be returned to the site. Once 
documents are received, the ESC Coordinator will review them to confirm eligibility and complete the 
registration process. If eligibility cannot be confirmed, the research coordinator will query the site 
for clarification or additional documents as needed. Subjects failing to meet all study eligibility 
requirements will not be registered and will be unable to participate in the trial. 
 
Upon completion of registration, the ESC Coordinator will provide the participating site with the study 
sequence number and, when applicable, randomization information. Within 48 hours after registration, it 
is the site’s responsibility to enter the on-study patient information into the OnCore database and order 
investigational agent(s), if indicated per protocol.  
 
9 
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It is the responsibility of the participating Investigator or designee to inform the subject of the 
research treatment plan and to conduct the study in compliance with the protocol as agreed upon 
with Moffitt Cancer Center and approved by the site’s IRB. 
To register a patient send the completed signed eligibility checklist along with the patient registration 
form and supporting documentation to the ESC via email at ESC_Partnerships@Moffitt.org, Monday 
through Friday between 8:00AM and 5:00PM (EST). If a short turnaround time is required between 
registration and first treatment, please consider discussing this with you ESC Coordinator and, if possible, 
submit a partial submission.  
 
Required Documentation for External Sites 
Before the study can be initiated at any site, the site will be required to provide regulatory documentation 
to the External Site Coordination (ESC) office at Moffitt Cancer Center. Sites must provide a copy of 
their informed consent to the ESC office for review and approval prior to submission of any documents 
to the site’s IRB. Any changes requested by the site’s IRB must be provided to the ESC staff for review and 
approval prior to resubmission to the IRB. 
 
The ESC office must receive the following trial specific documents either by hardcopy  or email before a 
site can be activated for any trial. All corresponding updates to these documents are required to be 
submitted to the ESC office throughout the trial: 
 
• 
IRB Approval Letter that includes the protocol version and date 
• 
FDA Form 1572Protocol Signature Page 
• 
Investigator Brochure (or Package Insert) Signature Page(s) 
• 
IRB Approved Consent Form 
• 
Site Delegation of Authority Log 
• 
Signed Financial Interest Disclosure Forms ( For all individuals listed on the 1572) 
• 
Investigator/Personnel documents (CVs, licenses, GCP and HSP training certificates, etc.) 
as needed 
• 
Laboratory Documents (certifications, normal ranges, etc.) as needed  
• 
Signed Clinical Trial Agreement 
• 
Protocol specific documentation as needed 
 
A study initiation teleconference will be held prior to the start of any study related activity at the site. 
Attendance is required for:  
• 
The site PI and appropriate research staff 
• 
Moffitt PI and ESC Coordinator 
 
The requirements of the protocol and all associated procedures and processes will be reviewed and 
agreed upon prior to the activation of the study. The ESC utilizes the EDC system, OnCore. OnCore training 
will be scheduled, if indicated, with the appropriate staff from the site. External sites are required to send 
updated documentation to the ESC Office at ESC_Partnerships@Moffitt.org within 10 business days of 
updating.   
 
External Site Monitoring and Reporting  
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant safety. 
Monitoring practices may include but are not limited to source data verification, and review and analysis 
of eligibility requirements, informed consent procedures, adverse events and all associated 
documentation, review of study drug administration/treatment, regulatory files, protocol departures 

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reporting, pharmacy records, response assessments, and data management. All monitoring efforts will 
occur based on the protocol specific monitoring plan. 
 
Following each monitoring visit, a monitoring follow-up report will be provided to the Participating Site 
(i.e. Site PI and Coordinator). The monitoring report will summarize any issued queries or data clarification 
requests, identify any reportable events or required follow-up on prior events and will specify details of 
any non-compliance. Participating Sites are requested to respond to all queries and data clarifications 
requests within 20 business days. The Moffitt Cancer Center Protocol Monitoring Committee will review 
all monitoring reports and issue resolution. This Committee reserves the right to close accrual for non-
compliance to monitoring.  
 
 
 
 
 
 
 
The following study is a phase 2 trial. Analysis of response rate and safety are planned. Exploratory analyses 
of progression free survival, overall survival, and duration of response are planned.  
 
 
• 
Primary Efficacy Endpoint(s): 
• 
Overall response rate will serve as the primary endpoint 
• 
Secondary Efficacy Endpoint(s): 
• 
Proportion of patients achieving spleen response at week 12 in patients with 
baseline splenomegaly.  
• 
Proportion of patients achieving spleen response at week 24 in patients with 
baseline splenomegaly.  
• 
Proportion of patients who have a 50% reduction in MPN-SAF TSS from baseline to 
week 12 in patients with baseline TSS ≥ 10 
• 
Proportion of patients who have a 50% reduction in MPN-SAF TSS from baseline to 
week 24 in patients with baseline TSS ≥ 10 
• 
Change in TSS from baseline to week 12 in patients with baseline TSS ≥ 10 
• 
Change in TSS from baseline to week 24 in patients with baseline TSS ≥ 10 
• 
Change in TSS from baseline to time of best response in patients with baseline TSS ≥ 
10 
• 
Patient’s global impression of change (PGIC) at week 12 
• 
PGIC at week 24 
 
 
• 
All patients receiving at least one dose of fedratinib will be evaluable for safety and efficacy. 
Patients who do not complete at least 28 days of therapy will be considered non-responders.  
 
 
 
This will be a phase 2 trial to assess the efficacy of fedratinib in MDS/MPN and CNL. Patients with a 
10 STATISTICAL CONSIDERATIONS 
10.1 
STATISTICAL AND ANALYTICAL PLANS 
10.2 
STATISTICAL HYPOTHESES 
10.3 
ANALYSIS DATASETS 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
10.4.1 
GENERAL APPROACH 

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diagnosis of MDS/MPN-U, aCML, MDS-MPN-RS-T, or CNL will be enrolled using modified Simon’s 
minimax 2-stage approach.31 The primary endpoint of the study is the proportion of patients 
achieving an objective clinical response at week 24 which is determined based upon the Modified 
MDS/MPN IWG Proposed Response Criteria. 
 
An interim analysis will be performed after 9 patients have completed their week 24 disease 
assessment or have discontinued study treatment prior to week 24 to assess for futility. If there are ≥ 3 
responses among these 9 patients, an additional 16 patients will be enrolled for a total of 25. This will 
be sufficient to test our hypothesis that fedratinib will increase the ORR from a historical standard of 
30% to 55% using a power of 80% and a one-sided type 1 error rate of 0.05. The null hypothesis will be 
rejected if 12 or more responses are observed.  
  
 
 
The primary endpoint is overall response rate. This is defined as the proportion of patients achieving a 
clinical response from baseline to week 24. Clinical response is defined as those achieving complete 
response, partial response or clinical benefit per Modified MDS/MPN IWG Proposed Response Criteria. 
Formal response assessments will be performed after cycle 3, cycle 6 and every 6 cycles thereafter. If a 
patient does not complete 3 cycles (does not undergo formal response assessment), the patient will be 
considered a non-responder. A patient who completes at least 3, but not 6 cycles, will have week 24 
response assessment carried forward from week 12.  
 
Patients lacking evidence of response, whether this is due to failure to meet response criteria or 
unavailable information to determine response, will be considered non-responders.  
 
The p-value and confidence interval will be computed by using conditional distribution in order to 
reflect the nature of two-stage design.32 
 
 
 
• 
Proportion of patients achieving spleen response at week 12 in patients with 
baseline splenomegaly.  
• 
This will be measured by comparing spleen measurement at day 84 
assessment with baseline spleen measurement. Spleen response is 
defined as 50% reduction in palpable splenomegaly of a spleen that is at 
least 10 cm at baseline, a spleen that is palpable at more than 5 cm at 
baseline becoming non-palpable, or, in cases where volumetric evaluation 
is feasible, a ≥ 35% reduction in spleen volume in patients with a baseline 
spleen volume > 450 cc. Spleen responses by palpation will need to 
correlate with a 50% reduction in longest diameter of the spleen by 
imaging.  
• 
Only patients with a palpable spleen or spleen volume > 450 cc will be 
eligible for spleen response 
• 
Patients with baseline splenomegaly who do not have spleen size 
assessment performed at day 84 assessment or who have discontinued 
study drug prior to day 84 assessment will be considered not to have had a 
spleen response.  
• 
Proportion of patients achieving spleen response at week 24 in patients with 
palpable spleen at baseline.  
10.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
10.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 

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• 
This will be measured by comparing spleen measurement at day 168 
assessment visit with baseline spleen measurement. Spleen response is 
defined as 50% reduction in palpable splenomegaly of a spleen that is at 
least 10 cm at baseline, a spleen that is palpable at more than 5 cm at 
baseline becoming non-palpable, or, in cases where volumetric evaluation 
is feasible, a ≥ 35% reduction in spleen volume in patients with a baseline 
spleen volume > 450 cc. Spleen responses by palpation will need to 
correlate with a 50% reduction in longest diameter of the spleen by 
imaging.  
• 
Only patients with a palpable spleen or spleen volume > 450 cc will be 
eligible for spleen response 
• 
Patients with baseline splenomegaly who do not have spleen size 
assessment performed at day 168 assessment or who have discontinued 
study drug prior to day 168 assessment will be considered not to have had 
a spleen response.  
• 
Proportion of patients who have a 50% reduction in MPN-SAF TSS from baseline to 
week 12 in patients with baseline TSS ≥ 10 
• 
Reduction in MPN-SAF TSS score will be measured by comparing TSS score 
at day 84 assessment to TSS score on cycle 1 day 1.  
• 
Only patients with baseline TSS ≥ 10 will be eligible for symptom response. 
• 
Patients who do not have a TSS score performed at day 84 assessment or 
who have discontinued study drug prior to day 84 assessment will be 
considered to not have 50% reduction in TSS.  
• 
Proportion of patients who have a 50% reduction in MPN-SAF TSS from baseline to 
week 24 in patients with baseline TSS ≥ 10 
• 
Reduction in MPN-SAF TSS score will be measured by comparing TSS score 
at day 168 assessment to TSS score on cycle 1 day 1.  
• 
Only patients with baseline TSS ≥ 10 will be eligible for symptom response. 
• 
Patients who do not have a TSS score performed at day 168 assessment or 
who have discontinued study drug prior to day 168 assessment will be 
considered to not have 50% reduction in TSS.  
• 
Change in TSS from baseline to week 12 in patients with baseline TSS ≥ 10 
• 
These will be reported as a nominal value calculated by subtracting the 
TSS on cycle 1 day 1 from the TSS at day 84 assessment. Improvements in 
TSS will be represented with values less than zero, while progression of 
symptoms will be represented with values greater than zero.  
• 
All enrolled patients’ baseline TSS ≥ 10 and documented day 84 TSS will be 
included in this analysis.  
• 
Patients who do not have a TSS score performed at day 84 assessment or 
who have discontinued study drug prior to day 84 assessment will not be 
included in this analysis.  
• 
Change in TSS from baseline to week 24 in patients with baseline TSS ≥ 10 
• 
These will be reported as a nominal value calculated by subtracting the 
TSS on cycle 1 day 1 from the TSS at day 168 assessment. Improvements in 
TSS will be represented with values less than zero, while progression of 
symptoms will be represented with values greater than zero.  
• 
All enrolled patients’ baseline TSS ≥ 10 and documented day 168 TSS will 
be included in this analysis.  
• 
Patients who do not have a TSS score performed at day 168 assessment or 
who have discontinued study drug prior to day 168 assessment will not be 

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included in this analysis.  
• 
Change in TSS from baseline to time of best response in patients with baseline TSS ≥ 
10 
• 
These will be reported as a percent change from the baseline value by 
subtracting the TSS on cycle 1 day 1 from the lowest TSS score 
documented for the patient between cycle 2 day 1 and cycle 7 day 1 and 
dividing the difference by the baseline TSS score. Improvements in TSS will 
be represented with values less than zero, while progression of symptoms 
will be represented with values greater than zero.  
• 
All enrolled patients’ baseline TSS ≥ 10 and at least one other documented 
TSS score after cycle 1 will be included in this analysis. 
• 
Patients who do not have a TSS score documented at or beyond cycle 2 
day 1 will not be included in this analysis. 
• 
Patient’s global impression of change (PGIC) at week 12 
• 
This will be measured using the validated questionnaire wherein patients 
are asked about the change in their myelofibrosis symptoms since starting 
on the study. Patients can choose from one of seven potential answers: 
Very much improved, Much improved, Minimally improved, No change, 
Minimally worse, Much worse, Very much worse.  
• 
This will be reportedly qualitatively wherein the number of patients 
choosing particular answers will be tabulated and frequencies will be 
reported.  
• 
PGIC at week 24 
• 
This will be measured using the validated questionnaire wherein patients 
are asked about the change in their myelofibrosis symptoms since starting 
on the study. Patients can choose from one of seven potential answers: 
Very much improved, Much improved, Minimally improved, No change, 
Minimally worse, Much worse, Very much worse.  
• 
This will be reportedly qualitatively wherein the number of patients 
choosing particular answers will be tabulated and frequencies will be 
reported.  
 
The analysis of binary endpoint including spleen response will be analyzed by the exact binomial 
distribution. The change of baseline to week 12 or 24 of the continuous variables including patient-
reported outcomes (PROs) will be examined by paired-t test or Wilcoxon signed-rank test, as 
appropriate. 
 
 
 
Using summary statistics, safety data will be coded using CTCAE 5.0 criteria, with each AE being 
counted only once for a given participant. The severity, frequency, duration, outcome and relationship 
of AEs to the study agent, as defined by the treating investigator, will be presented by System Organ 
Class (SOC) and preferred term groupings. Adverse events leading to premature discontinuation from 
the study drug, adverse events of special interest, and serious treatment-emergent AEs will be 
presented in a table.  
 
The proportion of patients experiencing grade ≥ 3 AEs will be calculated and presented separately in a 
table. Hematologic grade ≥ 3 AEs will be included if not present at baseline.    
 
10.4.4 
SAFETY ANALYSES 

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Hematologic values (hemoglobin, WBC, platelet count) will be calculated at the beginning of each cycle 
with median values being presented as a function of time while receiving treatment with study drug.  
 
 
 
 
 
 
The investigator or his/her designated and qualified representatives will administer/dispense study 
drug only to patients enrolled in the study in accordance with the protocol. The study drug must not 
be used for reasons other than that described in the protocol. To document compliance with the 
treatment regimen, patients will be instructed to return all fedratinib bottles (empty, partially filled or 
full), to the study site personnel prior to each visit and at the treatment completion visit. The site staff 
will document the bottles returned and the number of capsules per bottle on the appropriate form. 
Compliance below 80% require counseling of the patient by study site personnel.  
 
Reason for treatment discontinuation will be documented in the treatment completion visit. This will 
be reported descriptively.  
 
 
 
Planned baseline demographic and clinical information will include age, gender, specific disease-
associated mutations, cytogenetics, prior therapies, spleen size, hematologic laboratory parameters 
(hemoglobin, WBC, immature myeloid cell percentage, platelet, peripheral blast percentage), LDH, 
bone marrow/aspirate parameters (blast percentage, fibrosis grade, ring sideroblast percentage, 
cellularity). 
 
Demographics will be presented using summary statistics.  
 
 
 
The interim efficacy review will take place after 9 patients are evaluable for efficacy (i.e., completed 
week 24 disease assessment or discontinued study treatment prior to week 24). Enrollment will be 
halted if there are ≤ 2 responses among the first 9 patients. Enrollment will not be stopped while 
waiting for the first 9 patients to become evaluable for efficacy. If ≥ 3 responses are seen in the first 9 
patients, an additional 16 patients will be enrolled for a total enrollment of 25 patients.  
 
Overall response data will be presented in aggregate.  
 
Individual patient TSS, PGIC will be measured at week 12 and week 24 assessment and presented as a 
function of time.  
 
 
 
 
• 
Overall Survival: OS will be measured for each patient on the study. OS will be defined as time from 
first treatment to death due to any cause or censored at last follow-up. OS will be measured by 
Kaplan-Meier method. Median OS, as well as OS rate at 1-year and 2-year will be reported 
10.4.5 
ADHERENCE AND RETENTION ANALYSES 
10.4.6 
BASELINE DESCRIPTIVE STATISTICS 
10.4.7 
PLANNED INTERIM ANALYSES 
10.4.11 EXPLORATORY ANALYSES 

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10.6.1 
ENROLLMENT 
descriptively. The confidence interval will be computed by log-log transformation. 
• 
Progression free survival: Progression will be measured for each patent as defined by Modified 
MDS/MPN IWG Proposed Criteria for Disease Progression in adult MDS/MPNs (Appendix H). PFS will 
be defined as time from first treatment to progression or censored at last follow-up. PFS will be 
measured by Kaplan-Meier method. Median PFS, as well as PFS  at 1-year and 2-year will be 
reported descriptively. The confidence interval will be computed by log-log transformation. 
• 
Duration of response: Response duration will be measured for each responding patient. Response 
and progression will be defined by Modified MDS/MPN IWG Proposed Criteria.1 Duration of 
response is defined as the amount of time from the date of initial response to the date of disease 
progression or death.   
• 
Correlation between mutations detected from NGS at baseline and response will be assessed using 
contingency tables and Mantel-Haenszel test to calculate relative risk and p-values.  
• 
Correlation between the number of mutations detected from NGS at baseline and response will be 
assessed using cut-points of 2 and 3 mutations with relative risk and p-values calculated using 
contingency tables and Mantel-Haenszel test.  
• 
For correlative study, the primary endpoint is the response. The difference between vehicle and 
fedratinib will be examined by Mantel-Haenszel test. The difference in survival between arms will be 
evaluated by the log-rank test. In addition, the agreement between PDX mouse response and 
patients’ response will be measured by Kappa index. 
 
 
 
 
MDS/MPNs and CNL are rare diseases with few FDA approved treatment options. Cases are often 
referred to academic, tertiary care centers for evaluation. As stated in section 10.4.1 25 patients will be 
enrolled to test our hypothesis that fedratinib will increase the ORR from a historical standard of 30% 
to 55% with 80% power and a one-sided type 1 error rate of 0.05.  
 
An interim efficacy analysis will be conducted after 9 patients have completed week 24 disease 
assessment or discontinued study treatment prior to week 24. If ≥ 3 responses are observed among 
these 9 patients, this will support continued investigation and an additional 16 patients will be 
enrolled for a total of 25.  
 
The lead site for this study, Moffitt Cancer Center, is a high-volume center for myeloid malignancies, 
with approximately 150 new cases of MDS/MPN or CNL seen annually. Based on the current 
inclusion/exclusion criteria, we estimate 25 cases of MDS/MPN-U, CNL, aCML, or MDS/MPN-RS-T 
would meet eligibility criteria for study enrollment on an annual basis. Historical enrollment patterns 
support a 30% rate of enrolling eligible patients, a screen failure rate of < 10% and a dropout rate of < 
10%. Accordingly, we anticipate annual accrual of 8 patients. In order to expedite full accrual, three 
additional high-volume centers with expertise in myeloid malignancies will participate. 
Conservatively, each additional site will be expected to enroll 3-4 patients annually. Allowing for 4 
months of lag time for additional sites to open the study, we expect full enrollment at 18 months 
from when the study is opened at the lead site.   
 
 
 
As this study is a single-arm study  randomization is not considered. 
 
10.5 
SAMPLE SIZE 
10.6 
MEASURES TO MINIMIZE BIAS 

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Patients with morphologically confirmed diagnosis of aCML, MDS/MPN-U, MDS/MPN-RS-T, or CNL will be 
enrolled from the Malignant Hematology clinic at the Moffitt Cancer Center and other participating sites.  
Patients will not be blinded to therapy.  Patients who fail to meet the eligibility requirements (i.e screen 
fail) may be replaced.  
 
 
 
The PI and other appropriate study staff are responsible for maintaining appropriate medical and 
research records for this trial, in compliance with ICH E6 and regulatory and institutional requirements 
for the protection of confidentiality of participants. Representatives of Bristol-Myers Squibb and federal 
regulatory agencies may examine records for the purpose of quality assurance reviews, evaluation of 
the study safety, progress of the trial, and data validity.  
 
Source documentation in both electronic and paper form shall be retained for at least two years after 
the final closure of the trial. These include hospital records, clinical research subject charts (with paper 
AE logs), research laboratory notes, electronic CRFs, and pharmacy dispensing records.  
 
 
 
Quality control procedures will be implemented beginning with the OnCore data entry system and data 
QC checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the staff for clarification/resolution. 
 
Following written SOPs, the Moffitt internal monitors will verify that the clinical trial is conducted and 
data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., good laboratory practices (GLP), good manufacturing 
practices (GMP)). 
 
The investigational site will provide direct access to source data/documents, and reports for the 
purpose of monitoring and auditing, and inspection by local and regulatory authorities. 
 
All staff will be trained by the PI through a site initiation presentation, power point training for training 
on the initial protocol for those staff unable to attend the initiation presentation, and ongoing self-study 
as protocol amendments are approved. Training will be documented on a signature log that will be filed 
in the electronic regulatory binder.  
 
 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
 
 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
13 ETHICS/PROTECTION OF HUMAN PATIENTS 
13.1 
ETHICAL STANDARD 
13.2 
INSTITUTIONAL REVIEW BOARD 

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be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented 
participants need to be re-consented. 
 
 
. 
 
13.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS  
 
Consent forms describing in detail the study agent, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be required prior to starting 
intervention/administering study product. 
 
 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The investigator will 
explain the research study to the participant and answer any questions that may arise. All participants 
will receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, 
and potential risks of the study and of their rights as research participants.  Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. 
 
The participants should have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to participate 
in this study. 
 
 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
 
The Moffitt study monitor, other authorized representatives of Moffitt, representatives of the IRB or 
pharmaceutical companies supplying study products may inspect all documents and records required to 
be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
13.3 
INFORMED CONSENT PROCESS 
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY 

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The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Moffitt. This will not include the participants’ contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and 
by Moffitt research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the Moffitt. 
 
 
 
• 
Intended Use: Samples and data collected under this protocol may be used to study 
myelodysplastic and myeloproliferative neoplasms.  
• 
Storage: Samples and data will be stored using codes assigned by the investigators and only 
known to investigators and authorized study personnel. Data will be kept in password-
protected computers  
• 
Patients are free at any time in the future to decide not to provide specimens or to withdraw 
his/her specimens from further scientific research. Such a decision will have no impact on 
his/her treatment or other aspects of participation in this study.  
above. 
 
 
 
With the participant’s approval and as approved by local IRBs, de-identified biological samples will be 
stored in Dr. Eric Padron’s lab at Moffitt Cancer Center. These samples could be used for research into 
the causes of myeloid malignancies, their complications and other conditions for which individuals with 
myeloid malignancies are at increased risk, and to improve treatment. The lab of Dr. Eric Padron will 
also be provided with a code-link that will allow linking the biological specimens with the phenotypic 
data from each participant, maintaining the masking of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage will not be possible after the study is completed. 
 
When the study is completed, access to study data and/or samples will be provided through the lab of 
Dr. Eric Padron.  
 
 
 
 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
13.4.1 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA 
13.5 
FUTURE USE OF STORED SPECIMENS 
14 DATA HANDLING AND RECORD KEEPING 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 

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All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data. Black ink is required to ensure clarity of reproduced copies. When making changes or 
corrections, cross out the original entry with a single line, and initial and date the change.  All paper 
source documents will be scanned into the electronic medical record of each subject for storage. DO 
NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from 
source documents should be consistent with the source documents or the discrepancies should be 
explained and captured in a progress note and maintained in the participant’s official electronic study 
record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into OnCore, a 21 CFR Part 11-compliant data capture system provided 
by Moffitt. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical 
data will be entered directly from the source documents. 
 
 
Study documents should be retained for a minimum of 10 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or until at least 10 years have 
elapsed since the formal discontinuation of clinical development of the drug combination studied in 
this protocol. No records will be destroyed without the written consent of the sponsor, if applicable. 
It is the responsibility of the sponsor to inform the investigator when there is no longer a need for 
these documents to be retained. Permission must be acquired from the State of Florida for document 
destruction after the 10-year minimum record-retention period described above has elapsed. 
 
 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. 
The noncompliance may be either on the part of the participant, the investigator, or the study site 
staff. As a result of deviations, corrective actions are to be developed by the site and implemented 
promptly. 
 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations as 
defined by the Moffitt Clinical Trials Office standard. All deviations must be addressed in study 
source documents. Protocol deviations must be sent to the local IRB per their guidelines. The site 
PI/study staff is responsible for knowing and adhering to their IRB requirements.  
 
 
14.2 
STUDY RECORDS RETENTION 
14.3 
PROTOCOL DEVIATIONS 
14.4 
PUBLICATION AND DATA SHARING POLICY 

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The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health 
outcome. Medical interventions include drugs, surgical procedures, devices, behavioral treatments, 
process-of-care changes, and the like. Health outcomes include any biomedical or health-related 
measures obtained in patients or participants, including pharmacokinetic measures and adverse events. 
The ICMJE policy, and the Section 801 of the Food and Drug Administration Amendments Act of 2007, 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine.  
 
The PI will provide to the Protocol Information Specialist at Moffitt Cancer Center, details as requested 
for registering and reporting results for this clinical trial on ClinicalTrials.gov. At the conclusion of the 
trial, the PI will make study results available to the research community and the public-at-large.  
 
Authorship in publications will be determined by the PI depending on participation, enrollment, and 
significant contribution during the trial process and manuscript elaboration. 
 
 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial.  The study leadership and the Moffitt Cancer 
Center have established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest. 
 
 
 
1. 
Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform response 
criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 
2015;125(12):1857-1865. 
2. 
Zhang H, Wilmot B, Bottomly D, et al. Genomic landscape of Neutrophilic Leukemias of Ambiguous 
Diagnosis. Blood. 2019. 
3. 
Aribi A, Borthakur G, Ravandi F, et al. Activity of decitabine, a hypomethylating agent, in chronic 
myelomonocytic leukemia. Cancer. 2007;109(4):713-717. 
4. 
Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose 
decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 
2007;109(1):52-57. 
5. 
Braun T, Itzykson R, Renneville A, et al. Molecular predictors of response to decitabine in advanced 
chronic myelomonocytic leukemia: a phase 2 trial. Blood. 2011;118(14):3824-3831. 
6. 
Jabbour E, Short NJ, Montalban-Bravo G, et al. Randomized phase 2 study of low-dose decitabine vs 
low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood. 2017;130(13):1514-1522. 
7. 
Koldehoff M, Beelen DW, Trenschel R, et al. Outcome of hematopoietic stem cell transplantation in 
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16 LITERATURE REFERENCES 

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patients with atypical chronic myeloid leukemia. Bone Marrow Transplant. 2004;34(12):1047-1050. 
8. 
Choudhary D, Sharma SK, Gupta N, Handoo A. Stem cell transplant for juvenile myelomonocytic 
leukemia and chronic myelomonocytic leukemia. Indian J Hematol Blood Transfus. 2014;30(Suppl 
1):40-42. 
9. 
Pizzi M, Gergis U, Chaviano F, Orazi A. The effects of hematopoietic stem cell transplant on splenic 
extramedullary hematopoiesis in patients with myeloproliferative neoplasm-associated 
myelofibrosis. Hematol Oncol Stem Cell Ther. 2016;9(3):96-104. 
10. 
Hamilton BK, Visconte V, Jia X, et al. Impact of allogeneic hematopoietic cell transplant in patients 
with myeloid neoplasms carrying spliceosomal mutations. Am J Hematol. 2016;91(4):406-409. 
11. 
Sharma P, Shinde SS, Damlaj M, et al. Allogeneic hematopoietic stem cell transplant in adult patients 
with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. Leuk 
Lymphoma. 2017;58(4):872-881. 
12. 
Onida F, de Wreede LC, van Biezen A, et al. Allogeneic stem cell transplantation in patients with 
atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working 
Party of the European Society for Blood and Marrow Transplantation. Br J Haematol. 
2017;177(5):759-765. 
13. 
Hunter AM, Zhang L, Padron E. Current Management and Recent Advances in the Treatment of 
Chronic Myelomonocytic Leukemia. Curr Treat Options Oncol. 2018;19(12):67. 
14. 
Kuykendall AT, Padron E. Treatment of MDS/MPN and the MDS/MPN IWG International Trial: ABNL 
MARRO. Curr Hematol Malig Rep. 2019. 
15. 
Ihle JN, Gilliland DG. Jak2: normal function and role in hematopoietic disorders. Curr Opin Genet Dev. 
2007;17(1):8-14. 
16. 
Pardanani A, Harrison C, Cortes JE, et al. Safety and Efficacy of Fedratinib in Patients With Primary or 
Secondary Myelofibrosis: A Randomized Clinical Trial. JAMA Oncol. 2015;1(5):643-651. 
17. 
Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with 
myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-
randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317-e324. 
18. 
Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for 
myelofibrosis. N Engl J Med. 2012;366(9):787-798. 
19. 
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for 
myelofibrosis. N Engl J Med. 2012;366(9):799-807. 
20. 
Padron E, Painter JS, Kunigal S, et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with 
therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121(25):5068-5077. 
21. 
Padron E, DeZern A, Niyongere S, et al. Promising Results of a Phase 1/2 Clinical Trial of Ruxolitinib in 
Patients with Chronic Myelomonocytic Leukemia. Blood. 2017;130 (Suppl 1):162. 
22. 
Dao KH, Collins RH, Cortes J, et al. Phase 2 Study of Ruxolitinib in Patients with Chronic Neutrophilic 
Leukemia or Atypical Chronic Myeloid Leukemia. Blood. 2018;132 (Suppl 1):350. 
23. 
Assi R, Kantarjian HM, Garcia-Manero G, et al. A phase II trial of ruxolitinib in combination with 
azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. Am J Hematol. 
2018;93(2):277-285. 
24. 
DiNardo CD, Daver N, Jain N, et al. Myelodysplastic/myeloproliferative neoplasms, unclassifiable 
(MDS/MPN, U): natural history and clinical outcome by treatment strategy. Leukemia. 
2014;28(4):958-961. 
25. 
Giri S, Pathak R, Martin MG, Bhatt VR. Characteristics and survival of BCR/ABL negative chronic 
myeloid leukemia: a retrospective analysis of the Surveillance, Epidemiology and End Results 
database. Ther Adv Hematol. 2015;6(6):308-312. 
26. 
Patnaik MM, Pophali PA, Lasho TL, et al. Clinical correlates, prognostic impact and survival outcomes 
in chronic myelomonocytic leukemia patients with the JAK2V617F mutation. Haematologica. 2019. 
27. 
Padron E, Dezern A, Andrade-Campos M, et al. A Multi-Institution Phase I Trial of Ruxolitinib in 

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Patients with Chronic Myelomonocytic Leukemia (CMML). Clin Cancer Res. 2016;22(15):3746-3754. 
28. 
Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after 
ruxolitinib discontinuation. Blood. 2017. 
29. 
Kuykendall AT, Shah S, Talati C, et al. Between a rux and a hard place: evaluating salvage treatment 
and outcomes in myelofibrosis after ruxolitinib discontinuation. Ann Hematol. 2017. 
30. 
Jamieson C, Hasserjian R, Gotlib J, et al. Effect of treatment with a JAK2-selective inhibitor, fedratinib, 
on bone marrow fibrosis in patients with myelofibrosis. J Transl Med. 2015;13:294. 
31. 
Kim J, Schell MJ. Modified Simon's minimax and optimal two-stage designs for single-arm phase II 
cancer clinical trials. Oncotarget. 2019;10(42):4255-4261. 
32. 
Atkinson EN, Brown BW. Confidence limits for probability of response in multistage phase II clinical 
trials. Biometrics. 1985;41(3):741-744. 
33. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
34. 
Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment 
form total symptom score: prospective international assessment of an abbreviated symptom burden 
scoring system among patients with MPNs. J Clin Oncol. 2012;30(33):4098-4103. 
35. 
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization 
classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A.  
Patient Global Impression of Change (PGIC) 
 
Instructions: Circle the answer that is most appropriate. 
 
Since the start of the treatment you’ve received in this study, your 
myelofibrosis symptoms are: 
 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 
 
 
 
 
 
 
 
 
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APPENDIX B.  
ECOG Performance Status33 
 
Grade  
ECOG  
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, e.g., light house work, office work  
2  
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours  
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair  
5  
Dead  
 
APPENDIX C.  
Myeloproliferative Neoplasm Symptoms Assessment Form Total 
Symptom Score (MPN-SAF TSS)34 
Symptom 
1 to 10 (0 if absent) ranking 
1 is most favorable and 10 least favorable 
Please rate your fatigue (weariness, 
tiredness) by circling the one 
number that best describes your 
WORST level of fatigue during 
past 24 hours* 
(No Fatigue) 0 1 2 3 4 5 6 7 8 9 10 (Worst 
Imaginable) 
Circle the one number that describes how, during the past week how much difficulty you have had with each of the 
following symptoms 
Filling up quickly when you eat (Early satiety)    
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
 
 
Abdominal discomfort 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Inactivity 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Problems with concentration - Compared to prior to my 
MPD 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Night sweats 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Itching (pruritus) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Bone pain (diffuse not joint pain or arthritis) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Fever (>100 F)  
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Daily) 
Unintentional weight loss last 6 months 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 

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* Question used with permission from the MD Anderson Cancer Center Brief Fatigue Inventory 
 
APPENDIX D.  
Moderate/strong inhibitors/inducers of CYP3A4 
Strong inhibitors 
Moderate inhibitors 
CYP3A4 
boceprevir, cobicistat(h), danoprevir and ritonavir(j), 
elvitegravir and ritonavir(j), grapefruit juice(k), 
indinavir and ritonavir(j), itraconazole(h), 
ketoconazole, lopinavir and ritonavir(h,j), 
paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir)(j), posaconazole, ritonavir(h,j), 
saquinavir and ritonavir(h,j), telaprevir(h), tipranavir 
and ritonavir(h,j), telithromycin, troleandomycin, 
voriconazole 
aprepitant, ciprofloxacin, conivaptan(l), 
crizotinib, cyclosporine, diltiazem(m), 
dronedarone(h), erythromycin, fluconazole(f), 
fluvoxamine(a), imatinib, tofisopam, verapamil(h) 
 
Strong inducers 
Moderate inducers 
CYP3A 
apalutamide, carbamazepine(e), enzalutamide(g), 
mitotane, phenytoin(b), rifampin(a), St. John’s wort(h) 
bosentan, efavirenz(f), etravirine, phenobarbital, 
primidone 
 
APPENDIX E.  
Diagnostic Criteria35 
Chronic Neutrophilic Leukemia (CNL) 

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Atypical Chronic Myeloid Leukemia (aCML) 

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Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and 
Thrombocytosis (MDS/MPN-RS-T)
 

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APPENDIX F.  
MDS/MPN Response Criteria1 
 
 
 

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APPENDIX G.  Correlative Worksheet 
 
 Site name: ___________________     
Patient's Initials:_________    Pt. Study ID #:__________  
 
Blood or Bone Marrow (circle) Collections – all times must be recorded in military time  
Cycle/Day 
Date of Collection 
(mm-dd-yyyy) 
Collection Time 
 
 
 
 
 
 
Comments 
 
 
Please photocopy this for your records and maintain with a copy of the shipping waybill.   
Return the original to Moffitt with the specimens.  This source document stands as a custodial 
record.    
 
Ship all the above samples to: 
Maria Balasis 
12902 Magnolia Drive 
Stabile Research Building (SRB) Room #23234 
Tampa, FL 33612 
813-745-6458 
Please email (maria.balasis@moffitt.org, eric.padron@moffitt.org, Andrew.Kuykendall@moffitt.org)  
on the day of shipment with courier tracking information.       
 
Ship Monday through Thursday ONLY! 
 
______________________________Do not write below this line_____________________________ 
 
Condition received:  ________________________________________________   Initials: ________ 
 
Comments: _______________________________________________________   Initials: ________ 
 

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APPENDIX H1 Proposed Progression Criteria for MDS/MPN