Clinical trial NCT04543279
Conditions: Myelofibrosis Thrombocytopenia
Sponsor: Washington University School of Medicine
Start date: 2021-05-03; Completion date: 2022-07-30
Enrollment: 3 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Fostamatinib may improve thrombocytopenia in myelofibrosis patients with severe thrombocytopenia (platelet \<50,000/microL) and allow them to initiate treatment with a JAK2 inhibitor, ruxolitinib. Additionally, fostamatinib monotherapy may also improve myelofibrosis related symptoms and splenomegaly.

Detailed description:

Arms: arm 1: The starting dose of fostamatinib is 100 mg twice daily (BID). After the first cycle, if no major dose related safety issue is observed and the platelet count is less than 50K/microL, then the fostamatinib dose will be increased to 150 mg BID for the next 2 cycles; otherwise the dose may be continued at 100 mg BID. arm 2: After 3 cycles of fostamatinib monotherapy, all patients with a sustained platelet count ≥ 50K/microL, will continue on the current fostamatinib dose plus ruxolitinib at the recommended dose per standard prescribing guidelines for an additional 9 cycles.

Patients who do not reach platelet count of at least 50K/microL but who achieve clinical benefit per the treating provider may continue on single agent fostamatinib for up to 12 total treatment cycles. If these patients achieve a sustained platelet count of ≥ 50K/microL at any point prior to Cycle 10 Day 1, then they may be eligible to enroll in Part B of the study and continue treatment with fostamatinib and ruxolitinib for the remainder of the study.
Interventions: intervention 1: Fostamatinib intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: Fostamatinib will be supplied by Rigel Pharmaceuticals. intervention 2: Ruxolitinib is commercially available.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 03 Nov2020  
 
Page 1 of 56 
 
 
 
Fostamatinib as a single agent or in combination with ruxolitinib for treatment of patients 
with myelofibrosis with severe thrombocytopenia 
 
Washington University School of Medicine 
Department of Internal Medicine, Division of Hematology 
660 South Euclid Avenue, Campus Box 8125 
St. Louis, MO  63110 
 
Protocol #: 20-X304 
Version Date: 11/03/20 
 
Principal Investigator: 
Amy Zhou, M.D. 
Phone:  (314) 362-8814 
E-mail:  a.zhou@wustl.edu  
 
Sub-Investigators 
 
 
 
Modality 
Camille Abboud, M.D. 
 
 
Medical Oncology 
Morey Blinder, M.D.  
 
 
Hematology 
Elaine Majerus, M.D., Ph.D.  
 
Hematology 
Stephen T. Oh, M.D., Ph.D.  
 
Hematology 
Sana Saif Ur Rehman, M.D.  
 
Hematology 
Kristen Sanfilippo, M.D. 
 
 
Hematology 
Amber Afzal, MD 
 
 
 
Hematology 
Peter Westervelt, M.D., Ph.D. 
 
Medical Oncology 
Feng Gao, M.D., Ph.D. 
 
 
Biostatistics 
 
Study Drugs:  
 
Fostamatinib 
Ruxolitinib 
 
IND#: 
153355 
IND Sponsor: 
Amy Zhou, M.D. 
NCT#: 
NCT04543279 
Funded by: 
Rigel Pharmaceuticals, Inc. 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 


Protocol Version: 03 Nov2020  
 
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Fostamatinib in combination with ruxolitinib for treatment of patients with myelofibrosis 
with severe thrombocytopenia 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
day month year 
Amendment #1 Version 
 
 
 
 
 
 
day month year 
 
 
 


Protocol Version: 03 Nov2020  
 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
 United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must 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.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 


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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BMT 
Bone marrow transplant 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CR 
Complete response 
CRc 
Cytogenetic complete remission 
CRi 
Complete remission incomplete 
CRm 
Morphologic complete remission 
CRF 
Case report form 
CST 
Central standard time 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FWA 
Federal wide assurance 
GCP 
Good Clinical Practice 
HHS 
Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MDS 
Myelodysplastic syndrome 
MM 
Multiple myeloma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Cancer Center Network 


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NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PI 
Principal investigator 
PR 
Partial response 
PSA 
Prostate-specific antigen 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RFS 
Relapse free survival 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SCT 
Stem cell transplant 
SD 
Stable disease 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
UPN 
Unique patient number 
US 
Ultrasound 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell (count) 
 
 


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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................. 8 
Synopsis ...................................................................................................................................... 8 
STUDY SCHEMA........................................................................................................................ 11 
SCHEDULE OF ACTIVITIES ..................................................................................................... 12 
1.0 
INTRODUCTION ............................................................................................................. 13 
1.1 
Background .................................................................................................................... 13 
1.2 
JAK2 inhibitors in MF ................................................................................................... 13 
1.3 
Thrombocytopenia in MF and rationale for SYK inhibition .......................................... 14 
1.4 
Fostamatinib ................................................................................................................... 14 
1.5 
Study Rationale .............................................................................................................. 21 
2.0 
OBJECTIVES AND ENDPOINTS ................................................................................... 22 
2.1 
Part A Objectives and Endpoints ................................................................................... 22 
2.2 
Part B Objectives and Endpoints .................................................................................... 23 
3.0 
STUDY POPULATION .................................................................................................... 24 
3.1 
Inclusion Criteria ............................................................................................................ 24 
3.2 
Exclusion Criteria ........................................................................................................... 25 
3.3 
Inclusion of Women and Minorities ............................................................................... 26 
4.0 
REGISTRATION PROCEDURES ................................................................................... 26 
4.1 
Confirmation of Patient Eligibility ................................................................................. 26 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 26 
4.3 
Assignment of UPN ....................................................................................................... 26 
4.4 
Screen Failures ............................................................................................................... 26 
4.5 
Strategies for Recruitment and Retention ...................................................................... 27 
5.0 
TREATMENT PLAN ........................................................................................................ 27 
5.1 
Premedication Administration ........................................................................................ 27 
5.2 
Study Intervention Description ...................................................................................... 27 
5.3 
Study Intervention Administration ................................................................................. 27 
5.4 
Toxicity Monitoring (Stopping Rules) ........................................................................... 28 
5.5 
Adverse Events of Interest (AEIs) ................................................................................. 29 
5.6 
Definitions of Evaluability ............................................................................................. 29 
5.7 
Concomitant Therapy and Supportive Care Guidelines ................................................. 29 
5.8 
Prohibited Concurrent Therapy ...................................................................................... 29 
5.9 
Women of Childbearing Potential .................................................................................. 29 
5.10 Duration of Therapy ....................................................................................................... 30 
5.11 Duration of Follow-up .................................................................................................... 30 
5.12 Lost to Follow-Up .......................................................................................................... 31 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 31 
6.1 
Dose Modifications for Fostamatinib ............................................................................. 31 
6.2 
Dose Modifications for Ruxolitinib ............................................................................... 33 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 33 
7.1 
Sponsor-Investigator Reporting Requirements .............................................................. 34 
7.2 
Exceptions to Expedited Reporting ................................................................................ 36 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 37 
8.1 
Fostamatinib ................................................................................................................... 37 
8.2 
Ruxolitinib ...................................................................................................................... 38 


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9.0 
DATA SUBMISSION SCHEDULE ................................................................................. 39 
9.1 
Adverse Event Collection in the Case Report Forms ..................................................... 39 
10.0 MEASUREMENT OF EFFECT........................................................................................ 40 
10.1 IWG-MRT Response Criteria ........................................................................................ 40 
10.2 Hematologic Response ................................................................................................... 41 
10.3 Symptoms Response ...................................................................................................... 41 
10.4 Spleen Response ............................................................................................................. 41 
11.0 DATA AND SAFETY MONITORING ............................................................................ 42 
12.0 STATISTICAL CONSIDERATIONS............................................................................... 43 
12.1 Hypothesis ...................................................................................................................... 43 
12.2 Study Design .................................................................................................................. 43 
12.3 Analysis Plan .................................................................................................................. 44 
12.4 Sample Size and Study Power ........................................................................................ 44 
13.0 REFERENCES .................................................................................................................. 45 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 47 
APPENDIX B: PATIENT’S MEDICATION DIARY ................................................................. 48 
APPENDIX C: PATIENT’S MEDICATION DIARY ................................................................. 49 
APPENDIX D: Definitions for Adverse Event Reporting ........................................................... 50 
APPENDIX E: Reporting Timelines ............................................................................................ 53 
APPENDIX F: Symptom Assessment Form ................................................................................ 56 
 
 


Protocol Version: 03 Nov2020  
 
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PROTOCOL SUMMARY 
 
Synopsis 
 
Title: 
Fostamatinib as a single agent or in combination with ruxolitinib for 
treatment 
of 
patients 
with 
myelofibrosis 
with 
severe 
thrombocytopenia 
Study Description: 
Our hypothesis is that fostamatinib will be safe, tolerable, and 
effective 
in 
patients 
with 
myelofibrosis 
with 
severe 
thrombocytopenia (platelet < 50K/microL) as a single agent and in 
combination 
with 
ruxolitinib. 
Fostamatinib 
will 
improve 
thrombocytopenia in patients with myelofibrosis (MF) with severe 
thrombocytopenia (platelet < 50K/microL) and allow them to initiate 
treatment with ruxolitinib.  
 
This study will be executed in two parts (Part A and Part B).  For 
Part A, patients with MF with severe thrombocytopenia will initially 
receive 12 weeks of single agent fostamatinib (by mouth twice daily) 
until a sustained platelet count of ≥ 50K/microL is achieved (defined 
as two separate measurements at least two weeks apart).   
 
Patients who achieve a sustained platelet count of ≥ 50K/microL will 
be eligible to continue on to Part B where they will begin treatment 
with ruxolitinib (dosed as per standard of care) while continuing to 
take fostamatinib.  Patients who do not achieve a sustained platelet 
count of ≥ 50K/microL by the end of 12 weeks of treatment may 
continue on fostamatinib monotherapy if they are receiving benefit 
for up to an additional 36 weeks of treatment, and may be eligible to 
continue on to Part B of the study if they achieve a sustained platelet 
count of ≥ 50K/microL at any point before Cycle 10 Day 1.   
 
Patients in Part B will continue treatment with fostamatinib and 
ruxolitinib for up to an additional 36 weeks (total duration of 
treatment with fostamatinib monotherapy and fostamatinib and 
ruxolitinib combination therapy will be 48 weeks).   
Objectives: 
Part A:  
Primary Objective: 
Evaluate the impact of fostamatinib on platelet counts in patients 
with myelofibrosis and severe thrombocytopenia (platelets < 
50K/microL) 
 
Secondary Objectives: 
1. Evaluate the safety and tolerability of single agent 
fostamatinib in patients with MF and thrombocytopenia 
2. Evaluate spleen response to fostamatinib  


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3. Evaluate anemia response to fostamatinib  
4. Evaluate the impact of fostamatinib on transfusion 
requirements 
5. Evaluate the impact of fostamatinib on MF symptoms 
6. Evaluate the ability of fostamatinib treatment to enable 
initiation with ruxolitinib  
7. Evaluate the impact of fostamatinib on marrow fibrosis 
 
Part B: 
Primary Objective: 
Evaluate the safety and tolerability of fostamatinib plus ruxolitinib 
in patients with MF and thrombocytopenia  
 
Secondary Objectives: 
1. Evaluate spleen response with the combination of fostamatinib 
and ruxolitinib  
2. Evaluate the impact of fostamatinib and ruxolitinib on 
symptoms  
3. Evaluate the ability of fostamatinib to enable sustained 
treatment with ruxolitinib  
4. Evaluate the impact of fostamatinib and ruxolitinib on marrow 
fibrosis  
Endpoints: 
Part A: 
Primary Endpoint: Platelet response as defined as an increase in 
platelet count ≥ 50K/microL with at least one more confirmatory 
platelet count separated by at least 2 weeks (in the absence of platelet 
transfusion) within the first 12 weeks of fostamatinib treatment  
 
Secondary Endpoints:  
1. Platelet response by week 12 and at end of fostamatinib 
monotherapy treatment 
2. Number of patients eligible to initiate therapy with 
ruxolitinib 
3. Adverse events (AEs), serious AEs (SAEs), and laboratory 
abnormalities on fostamatinib treatment 
4. Patients who permanently discontinued fostamatinib due to 
fostamatinib related AEs 
5. Patients who required treatment interruption of fostamatinib 
due to AEs 
6. Patients who were dose escalated who tolerated fostamatinib 
dose greater than 100 mg BID  
7. Patients who achieve 35% or greater reduction in spleen 
volume as determined by ultrasound at week 12 of 
fostamatinib treatment and end of fostamatinib monotherapy 
treatment 


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8. Mean reduction in spleen volume as determined by 
ultrasound at week 12 of fostamatinib treatment and end of 
fostamatinib monotherapy treatment 
9. Patients with 50% or greater improvement in Total Symptom 
Score at week 12 of treatment and end of fostamatinib 
monotherapy treatment  
10. Patients who achieve platelet transfusion independence 
11. Patients with anemia who achieve RBC transfusion 
independence 
12. Change in marrow fibrosis by WHO grading  
 
Part B: 
Primary Endpoint: Incidence, severity, and outcomes of AEs per NCI 
CTCAE v 5.0, SAEs, AEs of interest (AEIs) and laboratory 
abnormalities during fostamatinib and ruxolitinib treatment  
 
Secondary Endpoints: 
1. Patients with 35% or greater reduction in spleen volume as 
determined by ultrasound after 12 weeks of combination 
therapy and end of treatment  
2. Mean reduction in spleen volume as determined by 
ultrasound after 12 weeks of combination therapy and end of 
treatment  
3. Patients with a 50% or greater improvement in Total 
Symptom Score after 12 weeks of combination therapy and 
at end of treatment  
4. Duration of uninterrupted ruxolitinib treatment 
5. Change in marrow fibrosis by WHO grading 
Study Population: 
Twelve adult patients of any race or ethnicity with primary or 
secondary myelofibrosis with severe thrombocytopenia (platelet 
count < 50K/microL) with intermediate or high risk disease by IPSS. 
Phase: 
Pilot Phase II Study  
Description of Sites / 
Facilities Enrolling: 
This study will be active at Washington University School of 
Medicine. 
Description 
of 
Study 
Intervention: 
Both fostamatinib and ruxolitinib are oral drugs taken twice daily on 
a continuous basis. 
Study Duration: 
2 years  
Participant Duration: 
48 weeks  
 
 
 
 
 
 
 
 


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STUDY SCHEMA 
 
Part A: 
The starting dose of fostamatinib is 100 mg twice daily (BID).  After the first cycle, if no major 
dose related safety issue is observed and the platelet count is less than 50K/microL, then the 
fostamatinib dose will be increased to 150 mg BID for the next 2 cycles; otherwise the dose may 
be continued at 100 mg BID.   
 
Part B: 
After 3 cycles of fostamatinib monotherapy, all patients with a sustained platelet count ≥ 
50K/microL, will continue on the current fostamatinib dose plus ruxolitinib at the recommended 
dose per standard prescribing guidelines for an additional 9 cycles.   
 
Patients who do not reach platelet count of at least 50K/microL but who achieve clinical benefit 
per the treating provider may continue on single agent fostamatinib for up to 12 total treatment 
cycles.  If these patients achieve a sustained platelet count of ≥ 50K/microL at any point prior to 
Cycle 10 Day 1, then they may be eligible to enroll in Part B of the study and continue treatment 
with fostamatinib and ruxolitinib for the remainder of the study. 
 
 
 
 
 
 
 
 
Part A                                             
 
 
 
 
Part B               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose related 
safety issue? 
Cycle 2 – 3 
If no safety issue, 
increase fostamatinib 
dose to 150 mg BID 
Cycle 4– 12 
Fostamatinib 150 or 100 mg 
BID + Ruxolitinib 
Cycle 1 
Fostamatinib 
100 mg BID 
Platelet Count 
≥ 50,000?  
PLT < 50,000   
Continue on fostamatinib monotherapy if 
achieving clinical benefit.  Eligible to 
enroll in Part B if platelet count ≥ 50,000 
by Cycle 10 Day 1  
No 
Yes 


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SCHEDULE OF ACTIVITIES 
 
 
Screening1 
D1 of 
each 
cycle2 
D15 of 
each 
cycle  
EOT 
Part 
A 
C4D1 
After 3 
cycles 
Part B 
EOT 
Part 
B 
Follow-
up3 
Informed consent 
X 
 
 
 
 
 
 
 
H&P, ECOG PS, con 
meds 
X 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
CBC 
X 
X4 
X⁴ 
 
 
 
 
 
Select chemistry5 
X 
X 
X 
 
 
 
 
 
PT/INR, PTT 
X 
 
 
 
 
 
 
 
Lipid Panel6  
X 
X6 
 
 
 
 
 
 
Pregnancy test7 
X 
X 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
Abdominal 
ultrasound for spleen 
volume8 
X 
 
 
X 
X 
X 
X 
 
Bone marrow biopsy 
X9 
 
 
X8 
 
 
X8 
 
MPN symptom 
assessment form 
 
X 
 
 
 
 
 
 
Fostamatinib 
 
Oral drug taken on a twice daily basis 
 
 
Ruxolitinib 
 
As per SOC 
 
AE assessment 
 
Start of treatment through 30 days after last day of study treatment 
Progression and 
survival 
 
 
 
 
 
 
 
X 
1. Screening evaluations must be conducted within 3 weeks prior to the start of therapy. 
2. Each cycle is 28 days. +/- 3 day for Day 1 assessments 
3. Every 6 months for up to 2 years. 
4. Also on D8 and D22 (weekly) the first cycle of fostamatinib monotherapy and first cycle of fostamatinib + 
ruxolitinibib combination therapy (+/- 2 days)  
5. BUN, creatinine, total bilirubin, AST, ALT, albumin 
6. Total Cholesterol, LDL, HDL, non-HDL, Triglycerides, check every 2 cycles after starting ruxolitinib therapy 
7. Women of childbearing potential only; test may be a urine test, and if positive, confirm with a serum test. 
 
8. +/- 7 days 
9. May be done up to 30 months before signing consent 
 
 
 
 


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1.0 
INTRODUCTION 
 
1.1 
Background 
 
Myelofibrosis (MF) is a clonal stem cell disorder classified within the category of 
Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPN) that 
includes polycythemia vera (PV) and essential thrombocythemia (ET) [1].  The disease is 
characterized by ineffective erythropoiesis and extramedullary hematopoiesis leading to 
progressive bone marrow failure, severe anemia, constitutional symptoms (e.g., night 
sweats, fever, fatigue), marked hepatosplenomegaly, thrombosis, and cachexia.  MF can 
arise following a history of PV or ET or can present de novo as primary myelofibrosis 
(PMF). 
 
Among the Ph-negative MPNs, somatic mutations in Janus kinase 2 (JAK2) constitute the 
most frequent mutation in PV, ET, and PMF [2].  Approximately 50 – 60% of patients with 
PMF harbor the JAK2 V617F mutation.  Mutations in calreticulin (CALR) and 
myeloproliferative leukemia virus oncogene (MPL) have subsequently been identified in 
patients with ET and PMF who are negative for the JAK2 mutation [3- 7].  Patients with 
CALR mutation appear to have a more indolent clinical course than patients with the JAK2 
V617F mutation as manifested by lower risk of thrombosis and longer overall survival [3-
4].  Several additional molecular mutations have been identified in patients with MF that 
have also shown to have prognostic impact [8-9].  Mutations in ASXL1, SRSF2, and 
IDH1/IDH2, for example, are associated with increased risk for leukemic transformation 
and decreased overall survival.   
 
MF generally affects an older population, with the age at diagnosis around 65 years of age 
[10].  Median survival can range from months to years depending on the presence or 
absence of adverse clinical and molecular prognostic factors [11-13], but ultimately 
survival is significantly reduced in patients with MF compared to the general population 
and patients with PV and ET [14].  MF can evolve into acute leukemia in about 10 – 20% 
of patients [15-17] and while current therapies such as JAK2 inhibitors can improve 
symptoms and have a modest survival benefit [18-21], the only curative treatment remains 
allogeneic stem cell transplantation.   
 
1.2 
JAK2 inhibitors in MF 
 
The JAK-STAT pathway is an important downstream signaling pathway of multiple 
cytokine and growth receptors.  The discovery of the JAK2V617F mutation in 2005 as the 
most common molecular abnormality in Ph negative MPNs has led to the development of 
several Janus kinase 2 (JAK2) inhibitors in the treatment of patients with primary 
myelofibrosis [22].  Ruxolitinib (Jakafi; Incyte, Wilmington, Delaware, USA), a 
JAK1/JAK2 inhibitor, was the first JAK2 inhibitor approved by the FDA for treatment of 
patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and 
post-ET MF.   
 
The FDA approval of ruxolitinib for treatment of patients with MF was based on two phase 


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III prospective randomized clinical trials (COMFORT-I and COMFORT-II).  In these two 
studies, ruxolitinib demonstrated superiority over placebo and best available therapy 
(BAT) in reducing spleen size and improving constitutional symptoms in patients with 
intermediate and high risk primary myelofibrosis [23, 24].  Long term follow up at 3 years 
of both the COMFORT-I and COMFORT-II trials have also demonstrated a modest 
survival benefit compared to placebo and BAT, respectively [21, 25, 26]. 
 
Targeted inhibitors of JAK2 alleviate clinical symptoms and have demonstrated a modest 
survival benefit, but they have not been found to improve cytopenias in patients with MF 
[22].  Their use may also be limited in patients with thrombocytopenia due to their 
myelosuppresive effects and are generally not recommended for patients with severe 
thrombocytopenia [27, 28].  Therefore, therapies that can improve platelet counts in MF 
patients with severe thrombocytopenia are needed.    
 
1.3 
Thrombocytopenia in MF and rationale for SYK inhibition  
 
Thrombocytopenia is a hematologic complication of MF resulting from ineffective 
erythropoiesis as well as hypersplenism in the setting of splenomegaly.  There are currently 
few effective therapies for the treatment of thrombocytopenia in MF.  Treatment with 
ruxolitinib can further lower the platelet count, leading to dose attenuations that may limit 
the efficacy or prohibit continuation of the medication.  Ruxolitinib (as well as Fedratinib) 
are also not recommended for patients with platelets < 50,000/microL, thereby limiting the 
treatment options for patients with MF with severe thrombocytopenia.   
 
Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor recently approved for the 
treatment of chronic idiopathic thrombocytopenic purpura (ITP), and may be a potential 
therapeutic option for patients with MF with severe thrombocytopenia.  As hypersplenism 
from splenomegaly can be a contributing factor to thrombocytopenia in MF, an agent that 
blocks spleen tyrosine kinase signaling may improve the platelet count in these patients.  
Additionally, increasing the platelet count >= 50,000/microL would allow patients with 
severe thrombocytopenia to be treated with ruxolitinib.  Another feature of fostamatinib is 
that there was no reported increased risk of thrombosis in the phase 3 studies [29], which 
makes it an attractive agent for patients with MF where thrombosis is a concern.   
 
1.4 
Fostamatinib 
Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor that has been developed by 
Rigel for the treatment of adult patients with persistent or chronic ITP who have had an 
insufficient response to a previous treatment. Fostamatinib was granted orphan-drug 
designation for ITP on 25 August 2015. Three Phase 3 studies in ITP provided the basis 
for the safety and efficacy evaluation of fostamatinib in the treatment of thrombocytopenia 
in ITP subsequently leading to its FDA approval for the treatment of patients with ITP.   
Rigel has also conducted exploratory clinical studies with fostamatinib in patients with B-
cell and T-cell lymphomas, and in patients with advanced cancer through a collaboration 
with the National Cancer Institute (NCI).  Syk has been implicated in the pathogenesis of 
multiple hematologic malignancies including non-Hodgkin’s lymphomas (as a component 
of the B-cell receptor pathway), acute myelogenous leukemia (AML), myelodysplastic 


Protocol Version: 03 Nov2020  
 
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syndrome (MDS), and myelofibrosis (MF).  In FMS-like tyrosine kinase-3-internal tandem 
duplication (FLT3-ITD) positive AML, Syk cooperates with FLT3ITD in promoting the 
survival and proliferation of AML blasts.  Syk has also been implicated as a mediator of 
venetoclax resistance in chronic lymphocytic leukemia (CLL) and diffuse large B-cell 
lymphoma cell lines, suggesting inhibition of Syk may be important in mitigating 
venetoclax resistance during treatment of AML and that Syk inhibition may be beneficial 
in combination with venetoclax treatment.  One of the key mechanisms behind the 
excessive hematopoietic stem cell death that occurs in MDS is inflammasome activation, 
which occurs in a Syk-dependent manner.  Similar mechanisms have been proposed for 
MF, and a role for Syk in this disease is supported by the finding that a translocation–Ets–
leukemia or ETV6 (TEL) Syk fusion described in MDS patients in mice induces MF-like 
disease [30].  Many of the symptoms in these mice can be ameliorated by treatment with 
fostamatinib [31].  These data suggest that Syk is important to the development and 
progression of these various hematologic malignancies, and that inhibition of Syk, either 
as a single agent, or in combination with other therapeutic approaches, may be an important 
new approach to the treatment of these malignancies. 
 
1.4.1 Nonclinical Studies with Fostamatinib  
 
Fostamatinib is the first oral spleen tyrosine kinase (SYK) inhibitor. R406 and its 
orally administered prodrug (fostamatinib) were effective in rodent models of 
immune complex activation, arthritis, antibody-mediated glomerulonephritis, 
immune autoantibody-mediated thrombocytopenia, and non-Hodgkin’s lymphoma. 
In safety pharmacology studies (respiratory, central nervous system [CNS], and 
cardiovascular including human ether-a-go-go related gene [hERG]), R406 was 
well tolerated. There was a slight reduction in heart rate at 50 mg/kg and a trend for 
increased blood pressure (BP) in the monkey cardiovascular study, and there were 
mild behavioral abnormalities (e.g., hypoactivity) at 50 mg/kg R406 in the rat CNS 
study. 
 
Nonclinical PK studies demonstrated that fostamatinib was converted to R406 
pre-systemically, most likely by phosphatases in the intestinal mucosa, such that 
little or no R788 could be detected in the plasma. Approximately 40% to 60% of 
the fostamatinib dose is estimated to be available as R406 in the systemic 
circulation. In all species tested, R406 exhibits low to moderate clearance, and the 
elimination half-life of R406 ranges from approximately 0.6 to 3.4 hours. R406 is 
extensively metabolized by oxidation and conjugation reactions in rats and 
monkeys. R406 is highly protein bound in plasma (> 97%) and preferentially 
distributed into blood cells. This distribution is reversible. 
 
Toxicology studies in rats and monkeys (doses ≤ 100 mg/kg/day fostamatinib) for 
4 to 26 and 4 to 39 weeks, respectively, identified lymphohematopoietic and liver 
function test abnormalities (mild and fully reversible), and reproductive and/or 
developmental liabilities in rats and rabbits. Consistent with bone growth plate 
effects in rats in the general toxicity studies, similar findings were observed in the 
rat and mouse carcinogenicity studies and in a 1 month juvenile study in rabbits 


Protocol Version: 03 Nov2020  
 
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(doses of 12.5 to 50 mg/kg/day). A related finding of odontodysplasia was also 
observed in the rat 2-year carcinogenicity study. There were no adverse effects on 
any male reproductive parameters in the rat at doses up to 40 mg/kg/day. There was 
no evidence for mutagenic or clastogenic effects in genotoxicity studies, or any 
carcinogenic potential in mouse and rat carcinogenicity studies. Fostamatinib 
promoted no remarkable adverse effects on host response in immunological host 
resistance models in mice (Streptococcus, Listeria, and Influenza). 
 
1.4.2 Clinical Studies with Fostamatinib  
 
Clinical studies with fostamatinib have included the following: 
Table 1: Summary of Subjects/Patients Treated with Fostamatinib (Rigel 
Fostamatinib Investigator’s Brochure v17.  Date of Edition: October 2, 2019) 
 
Population 
Number of Studies 
Number of Subjects  
Exposed to Fostamatinib as of  
18 April 2019 
Completed Studies 
50 
4585 
 
Healthy Subjects 
26 
724a 
 
Other Clinical Pharmacology Studies 
4 
101
b 
 
ITP 
3 
119  
(Phase 3 studies: N=102 
Phase 2 study: N=17)c 
 
Rheumatoid Arthritis 
13 
3,437
d 
 
Oncology 
4 
204  
(Sponsor studies: N =167 
NCI study: N=37)e 
Ongoing Studies  
3 
193 
 
ITP (Study C-935788-049) 
1 
123
f 
Ongoing Studies (Other Indications) 
2 
77 
 
IgAN (Study C-935788-050) 
1 
51  
 
AIHA (Study C-935788-053) 
1 
26g 
Total number of subjects exposed to fostamatinib 
4706 
 
Abbreviations: AIHA = autoimmune hemolytic anemia; IgAN = immunoglobulin A nephropathy; ITP = immune 
thrombocytopenia; NCI = National Cancer Institute 
a. 
Includes 26 Studies:  N = 439 (single dose); N= 183 (multiple dose), N = 183 (drug-drug interaction) 
b. Includes clinical pharmacology studies in subjects with renal impairment (N=16), and with hepatic impairment 
(N = 24), a drug-drug interaction study with methotrexate in RA subjects (N = 16), and a Phase 1 study with 
R406 the active metabolite of fostamatinib (N =45). 
c. 
Includes one Phase 2 study (N = 17 unique subjects) and 2 Phase 3 Studies (N=102) 
d. Includes 9 placebo-controlled studies (N = 2414) and 4 extension studies in rheumatoid arthritis. 
e. 
Includes 3 studies conducted by the sponsor in lymphoma subjects (N=167) and one NCI-sponsored study in 
subjects with solid tumors (N=37). 
f. 
Includes extension study where 79 subjects received prior fostamatinib and 44 subjects received prior placebo 
in the placebo-controlled ITP studies.   
g. Includes subjects who have completed Stage 1 and Stage 2 of the ongoing study 
 


Protocol Version: 03 Nov2020  
 
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1.4.3 Pharmacokinetics and Drug Metabolism in Humans  
 
1.4.3.1 Absorption 
 
Oral doses of fostamatinib are converted rapidly and extensively in the gut 
to the major active metabolite, R406, with a median time to reach maximum 
concentration following drug administration (Tmax) of approximately 1.5 
hours. Negligible levels of fostamatinib were found in plasma. 
 
Following oral dosing at 150 mg, plasma concentrations of R406 increase 
rapidly, reaching maximum levels within 1.5 hours. Mean maximum 
plasma (peak) drug concentration (Cmax) and area under the plasma 
concentration-time curve from 0 to infinity (AUC0-∞) estimates are 
550 ng/mL and 7080 ng•h/mL, respectively. R406 exposure is 
approximately dose proportional up to 200 mg twice daily (bid). After 
administration of fostamatinib, the absolute oral bioavailability of R406 was 
55%. R406 accumulates approximately 2- to 3-fold upon bid dosing at 
100 to 200 mg. 
 
1.4.3.2 Effect of Food 
 
Administration of fostamatinib with a high-calorie, high-fat meal (deriving 
approximately 150, 250, and 500-600 calories from protein, carbohydrate, 
and fat, respectively) increased R406 area under the plasma concentration-
time curve (AUC) by 23% and Cmax by 15%, indicating that fostamatinib 
can be given with or without food. 
 
1.4.3.3 Distribution 
 
The major active metabolite (R406) is 98.3% protein bound in human 
plasma. The red blood cell to plasma concentration ratio is approximately 
2.6:1. The volume of distribution at steady state of R406 is 256 L. 
 
1.4.3.4 Metabolism 
 
Fostamatinib is metabolized in the gut by alkaline phosphatase to the major 
active metabolite (R406), which is absorbed into the systemic circulation. 
R406 is extensively metabolized, primarily through pathways of 
cytochrome P450 (CYP450)-mediated oxidation (by CYP3A4) and 
glucuronidation (by UGT1A9). R406 is the predominant moiety in the 
systemic circulation, and there was minimal exposure to any R406 
metabolites. 
 
1.4.3.5 Excretion 
 
Following an oral dose of fostamatinib, the majority (~80%) of the 


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metabolite is excreted in feces with ~20% excreted in the urine. The major 
component excreted in urine was R406 N-glucuronide. The major 
components excreted in feces were R406, O-desmethyl R406 and a 
metabolite produced by gut bacteria from the O-desmethyl metabolite of 
R406. The terminal half-life of R406 was approximately 15 hours. 
 
1.4.3.6 Specific Populations 
 
Population pharmacokinetics analyses indicate fostamatinib is not altered 
based on age, sex, race/ethnicity. The pharmacokinetics of fostamatinib is 
not altered in subjects with renal impairment (creatinine clearance [CLcr] = 
30 to < 50 mL/min, estimated by Cockcroft Gault equation and end stage 
renal disease requiring dialysis), or hepatic impairment (Child-Pugh Class 
A, B and C). 
 
1.4.4 Efficacy in Humans 
 
1.4.4.1 ITP Studies 
 
Efficacy results from 2 Phase 3 studies and the long-term extension study 
demonstrate a rate of stable platelet response of 17.6%–22.7% in patients 
treated with fostamatinib. The initial signal of a fostamatinib-associated 
increase in platelets was evident within 2 to 12 weeks of drug exposure. The 
platelet response was generally robust and durable and prompted most 
responders to continue on fostamatinib in the extension study. In addition, 
treatment with fostamatinib resulted in a substantial reduction (~50%) in the 
incidence of important bleeding-related events compared to placebo. 
Although the numbers are small, it should be noted that only a single patient 
(1%) had a severe bleeding-related event in the fostamatinib group, as 
opposed to 3 (6.1%) in the placebo group. 
 
1.4.4.2 RA Studies 
 
In the Phase 2 and Phase 3 randomized, placebo-controlled trials evaluating 
fostamatinib in RA patients with active disease despite treatment with oral 
disease modifying anti-rheumatic drugs (DMARDs), a statistically 
significant improvement in signs and symptoms was established for 
fostamatinib doses of 150 mg once daily (qd) or greater (100 mg bid, 100 
mg bid followed by 150 mg qd, 150 mg qd, and 150 mg bid). However, in 
both Phase 3 trials assessing prevention of progression of structural joint 
damage (oral SYK inhibition in RA [OSKIRA-1 and OSKIRA-3]), no 
statistically significant difference in modified total Sharp score (mTSS) 
compared to placebo was observed. The RA indication is no longer being 
pursued by Rigel but is briefly mentioned in this IB for completeness. 
 


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1.4.4.3 Other Indications 
 
In the Phase 2 study in IgAN, a reduction in the primary endpoint of spot 
urine protein/creatinine ratio (sPCR) was observed for all 3 treatment 
groups (fostamatinib 150 mg bid, fostamatinib 100 mg bid, placebo) at 24 
weeks. The differences between the fostamatinib groups (combined or by 
individual dose groups) were not statistically significant; thus, the primary 
endpoint was not achieved. In the Phase 2 study in AIHA, 8 of 17 patients 
(47%) treated with fostamatinib 150 mg bid who were evaluable for efficacy 
achieved the efficacy endpoint of hemoglobin response in Stage 1 of the 
study. Hence, the criteria were met for continuing treatment in Stage 2. 
Hemoglobin response was defined as hemoglobin > 10 g/dL and ≥ 2 g/dL 
higher than baseline. 
 
1.4.5 Safety in Humans  
 
1.4.5.1 ITP Studies 
 
The safety profile of fostamatinib in patients with ITP comes primarily from 
the analyses of the 3 Phase 3 studies. Table 1 presents the incidence of 
common adverse drug reactions from the 2 ITP placebo-controlled Phase 3 
studies. In these studies, serious adverse drug reactions were febrile 
neutropenia, diarrhea, pneumonia, and hypertensive crisis, which each 
occurred in 1% of patients receiving fostamatinib. In addition, severe 
adverse reactions observed in patients receiving fostamatinib included 
dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest 
pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, 
syncope and hypoxia (all 1%). Serious adverse events (SAEs) were reported 
in 13 patients (12.7%) receiving fostamatinib and 10 patients (20.8%) 
receiving placebo. The SAEs were deemed related to study drug by the 
investigator in 4 patients (3.9%) receiving fostamatinib (febrile neutropenia, 
diarrhea, pneumonia, hypertensive crisis) and 1 patient (2.1%) receiving 
placebo (menorrhagia). All adverse reactions were reversible and 
manageable with appropriate monitoring, dose modifications or 
interruptions, and standard therapeutic approaches. 
 
Table 1: 
Incidence of Common (≥ 5%) Adverse Reactions from Double-Blind 
Clinical Studies (C788-047 and C788-048) 
Adverse Reaction 
Fostamatinib 
(N=102) 
Placebo 
(N=48) 
Mild 
% 
Moderate 
% 
Severe 
% 
TOTAL 
% 
Mild 
% 
Moderate 
% 
Severe 
% 
TOTAL 
% 
Diarrhea
a 
21 
10 
1 
31 
13 
2 
0 
15 
Hypertension
b 
17 
9 
2 
28 
10 
0 
2 
13 
Nausea 
16 
3 
0 
19 
8 
0 
0 
8 
Dizziness 
8 
2 
1 
11 
6 
2 
0 
8 


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ALT increased 
5 
6 
0 
11 
0 
0 
0 
0 
AST increased 
5 
4 
0 
9 
0 
0 
0 
0 
Respiratory infection
c 7 
4 
0 
11 
6 
0 
0 
6 
Rash
d 
8 
1 
0 
9 
2 
0 
0 
2 
Abdominal paine 
5 
1 
0 
6 
2 
0 
0 
2 
Fatigue 
4 
2 
0 
6 
0 
2 
0 
2 
Chest pain 
2 
3 
1 
6 
2 
0 
0 
2 
Neutropeniaf 
3 
2 
1 
6 
0 
0 
0 
0 
ALT = alanine aminotransferase; AST = aspartate aminotransferase 
Note: Common adverse reactions were defined as all adverse reactions occurring at a rate of ≥ 5% of patients in the 
fostamatinib group and greater than placebo rate. 
a. 
Includes diarrhea and frequent bowel movement. 
b. Includes hypertension, blood pressure (BP) increased, BP diastolic abnormal, and BP diastolic increased. 
c. 
Includes upper respiratory tract infection, respiratory tract infection, lower respiratory tract infection, and viral 
upper respiratory tract infection. 
d. Includes rash, rash erythematous, and rash macular. 
e. 
Includes abdominal pain and abdominal pain upper. 
f. 
Includes neutropenia and neutrophil count decreased. 
 
1.4.5.2 RA Studies 
 
Overall, fostamatinib was well tolerated at doses up to 300 mg per day given 
for extended periods of time to patients with RA. The most commonly 
occurring adverse reactions —diarrhea, hypertension, neutropenia, and liver 
function test elevations were the same as those observed in the ITP 
program—were generally mild to moderate, predictable, easily managed, 
and reversible, allowing patients to receive long-term fostamatinib for 
multiple years. In general, these adverse events (AEs) did not worsen over 
time or resolved during continued treatment. 
1.4.5.3 AIHA Study  
The safety profile of fostamatinib in the Phase 2 AIHA study was consistent 
with the overall safety profile of fostamatinib.  The most commonly 
reported AEs were diarrhea, fatigue, hypertension; dizziness, insomnia and 
nausea.  The most commonly reported treatment-related AEs were diarrhea, 
hypertension, fatigue and neutrophil count decreased.  The majority of AEs 
were mild or moderate and SAEs were reported in 7 patients, none which 
were considered treatment-related.  Two fatal AEs were reported; however, 
they were attributed to underlying conditions. 
 
1.4.5.4 Other Indications 
 
Safety data in lymphoma patients showed that fostamatinib was well 
tolerated at all doses administered to patients with various lymphoma 
histologies that had received multiple prior therapies for their malignancy. 
Fostamatinib was administered at doses higher than those intended for the 


Protocol Version: 03 Nov2020  
 
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market indication of ITP. The most common AEs, i.e., fatigue, diarrhea, 
nausea, pyrexia, and cytopenias were generally mild to moderate in 
severity, manageable and reversible, allowing most patients to receive their 
full dose of fostamatinib for the intended duration. In patients with solid 
tumors, cytopenias, hypertension and fatigue were commonly reported. 
Treatment-related elevations in aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), and bilirubin were also noted. Differences 
between patients with solid tumors and those with lymphomas were felt to 
be due to underlying disease in the different patient populations. 
Fostamatinib was not well tolerated in patients with colorectal cancer—
particularly those with liver involvement—but was well tolerated in the 
other tumor types.  The AEs reported in IgAN and AIHA studies are 
consistent with the safety profile established to date for fostamatinib. 
 
1.4.5.5 Safety Conclusions 
 
Nearly 4700 subjects/patients have received fostamatinib as part of clinical 
studies in a variety of indications, including 163 patients with ITP, more 
than 3400 RA patients at doses of 100 to 300 mg/day, and more than 160 
oncology patients at doses of 200 to 500 mg/day. The safety profile of 
fostamatinib in these studies shows a consistent pattern of adverse reactions 
across indications with diarrhea, hypertension, nausea, and increased 
transaminases being the most frequent adverse reactions reported from 
these populations.  
 
1.5 
Study Rationale 
 
Thrombocytopenia is a common hematologic complication of MF and can limit a patient’s 
ability to be treated with a JAK2 inhibitor if their thrombocytopenia is severe 
(<50,000/microL). Approximately 16 to 26% of MF patients will have a platelet count of 
< 100,000/microL and 11 to 16% will have a platelet count of < 50,000/microL at 
diagnosis.  And given the progressive nature of the disease, an additional 20% of patients 
will develop thrombocytopenia at some point during their disease course [32].  
Additionally, severe thrombocytopenia may lead to serious complications such as bleeding.   
 
There are currently few effective therapies for the treatment of thrombocytopenia in 
patients with MF and this is an area of unmet need.  Fostamatinib may be effective in 
improving platelet counts in MF through its inhibition of spleen tyrosine kinase signaling, 
as hypersplenism can be a contributing factor to thrombocytopenia in these patients.  
Furthermore, preclinical studies suggest a possible therapeutic benefit of fostamatinib in a 
MF mouse model, further supporting its evaluation in the treatment of MF patients.  
Fostamatinib at dosages of 100 mg BID and 150 mg BID have been shown to be effective 
and well tolerated for the treatment of thrombocytopenia in patients with ITP, and these 
dosages will be used in this study.  
 
In summary, fostamatinib may improve thrombocytopenia in MF patients with severe 


Protocol Version: 03 Nov2020  
 
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thrombocytopenia (platelet <50,000/microL) and allow them to initiate treatment with a 
JAK2 inhibitor, ruxolitinib.  Additionally, fostmatinib monotherapy may also improve MF 
related symptoms and splenomegaly.         
 
 
2.0 
OBJECTIVES AND ENDPOINTS 
 
2.1 
Part A Objectives and Endpoints 
 
Objectives 
Endpoints 
Justification for 
Endpoints 
Primary 
To evaluate the impact of 
fostamatinib on platelet counts in 
patients with myelofibrosis and 
severe thrombocytopenia  
Platelet response as detailed 
in Section 11.2.2, platelet 
response by week 12 and 
end of fostamatinib 
monotherapy treatment, and 
number of patients eligible 
to initiate treatment with a 
JAK2 inhibitor (ruxolitinib) 
The efficacy of fostmatinib 
on thrombocytopenia in 
MF patients is unknown  
Secondary 
To evaluate the safety and 
tolerability of single agent 
fostamatinib in patients with MF 
and thrombocytopenia 
 
Incidence, severity, 
frequency, and outcomes of 
AEs and SAEs as defined 
by CTCAE v5.0 criteria, 
AEIs, laboratory 
abnormalities, and number 
of patients who permanently 
discontinue fostamatinib 
due to fostamatinib-related 
AEs, number of patients 
who require treatment 
interruptions due to 
fostamatinib-related AEs 
The safety and tolerability 
of fostamatinib in MF 
patients is unknown. 
To evaluate spleen response in 
patients with MF receiving 
fostamatinib  
Spleen response as detailed 
in Section 11.4 at week 12 
and end of fostamatinib 
monotherapy treatment, 
mean reduction in spleen 
volume as determined by 
ultrasound at week 12 and 
end of fostamatinib 
monotherapy treatment 
The efficacy of 
fostamatinib on reducing 
spleen size in MF patients 
is unknown  
 
To evaluate anemia response in 
patients with MF receiving 
fostamatinib  
Anemia response as detailed 
in Section 11.2.1 
The impact of fostamatinib 
on anemia in MF patients 
is unknown  


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To evaluate the impact of 
fostamatinib on constitutional 
symptoms in patients with MF 
Constitutional symptoms as 
detailed in Section 11.3 at 
week 12 and end of 
fostamatinib monotherapy 
treatment 
The efficacy of 
fostamatinib on improving 
symptoms in MF patients is 
unknown  
To evaluate the impact of 
fostamatinib on transfusion 
requirements 
Number of patients who 
achieve platelet and RBC 
transfusion independence 
who were previously 
requiring transfusions  
The impact of fostamatinib 
on transfusion burden in 
MF patients is unknown   
 
To evaluate the impact of 
fostamatinib on marrow fibrosis  
Change in marrow fibrosis 
per WHO grading on bone 
marrow biopsy performed at 
the end of fostamatinib 
monotherapy  
The impact of fostamatinib 
on marrow fibrosis is 
unknown  
 
2.2 
Part B Objectives and Endpoints 
 
Objectives 
Endpoints 
Justification for 
Endpoints 
Primary 
To evaluate the safety and 
tolerability of the combination of 
fostamatinib and ruxolitinib in 
MF patients   
Incidence, severity, 
frequency, and outcomes of 
AEs and SAEs as defined 
by CTCAE v5.0 criteria and 
AEs of interest (AEIs) as 
defined in section 5.5 
The safety of this 
combination therapy in MF 
patients is not known. 
Secondary 
To evaluate the spleen response 
in patients with MF receiving 
fostamatinib in combination with 
ruxolitinib 
Spleen response as detailed 
in Section 11.4 after 12 
weeks of combination 
therapy, mean reduction in 
spleen volume as 
determined by ultrasound 
after 12 weeks of 
combination therapy and at 
the end of treatment 
The efficacy of 
fostamatinib in 
combination with a JAK 
inhibitor on reducing 
spleen size in patients with 
MF is unknown  
 
To evaluate the impact of 
fostamatinib in combination with 
ruxolitinib on constitutional 
symptoms in patients with MF 
Constitutional symptoms as 
detailed in Section 11.3 
after 12 weeks of 
combination therapy and at 
the end of treatment  
The efficacy of 
fostamatinib in 
combination with a JAK 
inhibitor on symptoms in 
MF is unknown  
Evaluate the ability of 
fostamatinib to enable sustained 
treatment with ruxolitinib  
 
Duration of uninterrupted 
JAK inhibitor (ruxolitinib) 
therapy 
The ability of fostamatinib 
to maintain an adequate 
platelet count for patients 


Protocol Version: 03 Nov2020  
 
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to remain on JAK inhibitor 
therapy is unknown  
To evaluate the impact of 
fostamatinib and ruxolitinib on 
marrow fibrosis  
Change in marrow fibrosis 
per WHO grading on bone 
marrow biopsy performed at 
the end of fostamatinib and 
ruxolitinib therapy 
The impact of fostamatinib 
and ruxolitinib 
combination therapy on 
marrow fibrosis is 
unknown 
 
 
3.0 
STUDY POPULATION 
 
3.1 
Inclusion Criteria 
 
1. Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera/essential 
thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or 
intermediate 1 risk by IPSS.   
 
2. Severe thrombocytopenia defined as platelet count < 50,000/microL (confirmed on at 
least two measurements over an 8-week period prior to date of consent). 
 
3. At least 18 years of age. 
 
4. ECOG performance status ≤ 2 (see Appendix A) 
 
5. Able to swallow pills  
 
6. Adequate bone marrow and organ function as defined below: 
a. ANC ≥ 1000/microL 
b. Peripheral blood blasts ≤ 10% 
c. Albumin > 2.7 g/dL 
d. Total bilirubin ≤ 1.5 x IULN; patients with Gilbert’s syndrome may enroll if direct 
bilirubin ≤ 1.5 x IULN 
e. AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN 
f. Creatinine clearance > 30 mL/min by Cockcroft-Gault 
 
7. Female subjects must be either post-menopausal for at least 1 year or surgically sterile; 
or, if of childbearing potential, must not be pregnant or lactating and must agree to use 
a highly effective method of birth control throughout the duration of the trial and for 
30 days following the last dose. Acceptable methods of birth control are defined as: 
hormonal contraception (pill, injection or implant) used consistently for at least 30 days 
prior to screening, an intrauterine device (IUD), or intrauterine hormone-releasing 
system (IUS), or true abstinence (i.e. abstinence is in line with the preferred and usual 
lifestyle of the subject.).  Male subjects do not need to use contraception for 
fostamatinib because human studies showed minimal R406 in sperm. 
 
8. Ability to understand and willingness to sign an IRB approved written informed 


Protocol Version: 03 Nov2020  
 
Page 25 of 56 
 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. History of allogeneic stem cell transplant.  
 
2. Any solid tumor or hematologic malignancy (other than myelofibrosis) requiring active 
treatment at the time of study entry  
 
3. Currently receiving any other investigational agents. 
 
4. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to fostamatinib, ruxolitinib, or other agents used in the study. 
 
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmia. 
 
6. Subject has uncontrolled or poorly controlled hypertension, defined as systolic blood 
pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg, whether or not the subject 
is receiving anti-hypertensive treatment.  
 
7. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry and prior to the first dose of fostamatinib. 
 
8. Known positive status for human immunodeficiency virus (HIV) 
 
9. Chronic, active, or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier. 
 
10. Treatment with strong CYP3A inhibitors or inducers within 14 days before the first 
dose of study drug.  Strong CYP3A inhibitors and CYP3A inducers are not permitted 
during the study. 
 
11. Ongoing gastrointestinal medical condition such as Crohn’s disease, inflammatory 
bowel disease, or chronic diarrhea that is not well controlled and could interfere with 
absorption of oral medication or be exacerbated by study medication  
 
12. Known hepatic cirrhosis or severe pre-existing hepatic impairment.  
 
13. Uncontrolled coagulopathy or bleeding disorder.  
 
14. Female patients who intend to donate eggs and male patients who intend to donate 
sperm during the course of this study or for 4 months after receiving the last dose of 
study treatment.  
 


Protocol Version: 03 Nov2020  
 
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3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (if applicable).   
 


Protocol Version: 03 Nov2020  
 
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4.5 
Strategies for Recruitment and Retention 
 
The study will enroll 12 patients who are over 18 years of age of all genders, races, and 
ethnicities.  The anticipated accrual rate will be approximately 1 patient per month.  This 
pilot study will be a single center study and participants will be screened in the outpatient 
clinics of the PI and sub-investigators.  Potential participants will be identified by the PI or 
sub-investigators and approached by the study coordinator(s) for the study.  Financial 
compensation in the form of parking vouchers or reimbursement for travel expenses (ie 
gas, mileage, etc.) may be provided depending on the distance the participant may live 
from the study site.   
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Premedication Administration 
 
No pre-medications are required for either fostamatinib or ruxolitinib.   
 
5.2 
Study Intervention Description 
 
Fostamatinib is a kinase inhibitor indicated for the treatment of thrombocytopenia in adult 
patients with chronic immune thrombocytopenia.  It is considered investigational in this 
study. 
 
Ruxolitinib is a kinase inhibitor indicated for the treatment of intermediate or high risk 
myelofibroisis, polycythemia vera, and steroid-refractory acute GVHD.  Because it is being 
given in combination with fostamatinib, it is considered investigational in this study. 
 
5.3 
Study Intervention Administration 
 
In Part A of the study, patients will initially receive fostamatinib single agent at a starting 
dose of 100 mg PO twice daily (BID) for three cycles (12 weeks).  Each cycle is 28 days 
(4 weeks).   
 
Patients who tolerate single agent fostamatinib and achieve a sustained platelet count of  ≥ 
50,000/microL on at least two separate measurements taken at least two weeks apart at any 
point before Cycle 10 Day 1 will be eligible to proceed to Part B of the study and initiate 
treatment with ruxolitinib (starting dose will be determined by platelet count as per package 
insert).   
 
For patients who do not achieve a sustained platelet count of ≥ 50,000/microL following 
the first cycle (4 weeks) of fostamatinib 100 mg BID and no AEIs (see Section 5.5) are 
reported, then the dose of fostamatinib may be increased to 150 mg BID and continued for 
subsequent cycles.  If a platelet count of ≥ 50,000/microL is not achieved after three cycles 
of fostamatinib, but the patient is achieving clinical benefit, then the patient may continue 
on fostamatinib monotherapy for up to a total of 12 cycles of treatment and may continue 


Protocol Version: 03 Nov2020  
 
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on to Part B of the study if they achieve a sustained platelet count of ≥ 50,000/microL by 
Cycle 10 Day 1.  If the patient is not achieving clinical benefit or has evidence of disease 
progression, then the patient will be taken off study.   
 
For Part B of the study, patients will continue on treatment with fostamatinib for up to an 
additional nine cycles (36 weeks) to complete a total treatment duration of 48 weeks. 
Ruxolitinib will be initiated in combination with fostamatinib at the start of Part unless the 
patient is experiencing progressive MF symptoms and is eligible to initiate ruxolitinib, in 
which case ruxolitinib may be initiated sooner at the discretion of the PI.  If the platelet 
count decreases to < 50,000/microL following initiation of ruxolitinib, then the dose of 
fostamatinib may be increased to 150 mg BID if the patient is on the 100 mg BID dose.   
 
5.3.1 Dosing of Fostamatinib 
 
Fostamatinib is an oral drug which will be given at a starting dose of 100 mg BID 
each day of a 28-day cycle.  The dose of fostamatinib can be increased to 150 mg 
BID after Cycle 1 if the platelet count remains < 50,000/microL.  Fostamatinib 
should be taken at approximately the same times each day, with or without food.  
In case of a missed dose, patients should be instructed to resume dosing at the next 
scheduled dose.  Patients will be instructed to bring all unused drug and their 
medication diary (Appendix B) to each study visit for assessment of compliance. 
 
5.3.2 Dosing of Ruxolitinib 
 
Ruxolitinib is an oral drug which will be taken twice daily each day of a 28-day 
cycle.  The starting dose of ruxolitinib given will depend on the patient’s baseline 
platelet count.  If platelets are > 200,000/microL, patients should take 20 mg BID.  
If platelets are between 100,000/microL and 200,000/microL, patients should take 
15 mg BID.  If platelets are between 50,000/microL and 100,000/microL, patients 
should take 5 mg BID.  Ruxolitinib should be taken at approximately the same 
times each day, with or without food.  In case of a missed dose, patients should be 
instructed to resume dosing at the next scheduled dose.  Patients will be instructed 
to bring their medication diary (Appendix C) to each study visit for assessment of 
compliance. 
 
5.4 
Toxicity Monitoring (Stopping Rules)  
 
A Bayesian sequential monitoring rule will be used to protect patients from excessive 
toxicities (see Section12.2 for technique details), and the table below shows the boundaries 
of early stopping rule. That is, an early stopping of the study due to excessive toxicities 
will be recommended if we observe 3 patients who experienced AEs of interest (as defined 
in Section 5.5) out of the first 5 patients or 4 patients who experience AEs of interest out 
of first 9 patients. 
 


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# Patients 
treated  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 
Stop if the # 
AEIs  ≥ 
N/A N/A N/A N/A 3 
3 
3 
3 
4 
4 
4 
4 
 
5.5 
Adverse Events of Interest (AEIs) 
 
Adverse events of interest (AEIs) are defined as clinically relevant grade 3 or 4 adverse 
events considered possibly, probably, or definitely related to either fostamatinib or 
ruxolitinib as defined by CTCAE v5.0 criteria and are not related to the underlying disease. 
 
5.6 
Definitions of Evaluability 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. 
 
All patients are evaluable for disease response unless they discontinue treatment prior to 
completion of Cycle 1 and have not had any disease assessment. 
 
5.7 
Concomitant Therapy and Supportive Care Guidelines 
 
General supportive care measures, including blood and platelet transfusions, antiemetics, 
administration of granulocyte colony-stimulating growth factors, corticosteroids, and use 
of antibiotics and antivirals are permitted at the discretion of the treating physician. 
 
It is recommended that nausea, vomiting, diarrhea, or blood pressure elevation be 
medically managed according to the investigator’s discretion.   
 
5.8 
Prohibited Concurrent Therapy 
 
Patients should not receive treatment with any potent CYP3A4 inhibitors for one week 
prior to the start of and for the duration of study treatment.  
 
Other chemotherapeutic or investigational agents are not permitted while the patient is 
receiving active treatment on protocol.   
 
The use of thrombopoietin (TPO) stimulating agents are not permitted while the patient is 
receiving active treatment on protocol. 
 
Patients cannot receive radiotherapy within 14 days prior to study enrollment or while on 
study. 
 
5.9 
Women of Childbearing Potential 
 
Female subjects must be either post-menopausal for at least 1 year or surgically sterile; or, 


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if of childbearing potential, must not be pregnant or lactating and must agree to use a highly 
effective method of birth control throughout the duration of the trial and for 30 days 
following the last dose. Acceptable methods of birth control are defined as: hormonal 
contraception (pill, injection or implant) used consistently for at least 30 days prior to 
screening, an intrauterine device (IUD), or intrauterine hormone-releasing system (IUS), 
or true abstinence (i.e. abstinence is in line with the preferred and usual lifestyle of the 
subject.).  Male subjects do not need to use contraception for fostamatinib because human 
studies showed minimal R406 in sperm. 
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
5.10 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for up to 
48 weeks or until one of the following criteria applies: 
 
 Documented and confirmed progression of underlying myelofibrosis 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 Dose interruptions due to fostamatinib-related AE lasting > 4 weeks (dose 
interruptions due to other reasons would not warrant permanent discontinuation) 
 General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious noncompliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will still be followed as 
indicated in the study calendar. 
 
5.11 
Duration of Follow-up 
 
Following the end of treatment, patients will be followed every 6 months for up to 2 years 
or until the patient is lost to follow up or death, whichever occurs first.  Patients removed 
from study for unacceptable adverse events will be followed until resolution or stabilization 


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of the adverse event.  Decisions regarding future therapy for both responding and refractory 
patients will be made at the discretion of the treating physician.  
 
5.12 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled 
visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 14 days and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Besides the modifications described below, other dose holds and modifications will be made at the 
discretion of the PI. 
 
6.1 
Dose Modifications for Fostamatinib   
 
For each individual patient, if no AEIs are observed following Cycle 1 of fostamatinib at 
the starting dose of 100 mg BID, but their platelet count remains < 50,000/microL, then 
the dose of fostamatinib may be increased to 150 mg BID for all subsequent cycles in the 
absence of toxicity.  Additionally, for each patient whose platelet count improves to 
≥50,000/microL on 100 mg BID of fostamatinib, but then decreases to <50,000/microL 
after starting ruxolitinib (for at least two platelet measurements at least 2 weeks apart), the 
dose of fostamatinib may be increased to 150 mg BID for all subsequent cycles. 
Dose reductions for fostamatinib will be performed as per the US package insert.   
 
For dose interruptions due to a fostamatinib related AE lasting > 4 weeks, treatment will 
be permanently discontinued, and the patient will be taken off study.   
 
Recommended Dose Modifications and Management for Specific Adverse Reactions 
 


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Adverse Reaction 
Recommended Action 
Hypertension 
Stage 1:  systolic between 
130-139 or diastolic between 
80-89 mmHg 
• Initiate or increase dosage of antihypertensive 
medication for patients with increased 
cardiovascular risk, and adjust as needed until BP 
is controlled. 
• If the BP target is not met after 8 weeks, reduce 
fostamatinib to next lower daily dose. 
Stage 2:  systolic at 
least 140 or diastolic at 
least 90 mmHg 
• Initiate or increase dosage of antihypertensive 
medication, and adjust as needed until BP is 
controlled. 
• If BP remains 140/90 mmHg or higher for more 
than 8 weeks, reduce fostamatinib to next lower 
daily dose. 
• If BP remains 160/100 mmHg or higher for more 
than 4 weeks despite aggressive antihypertensive 
therapy, interrupt or discontinue fostamatinib. 
Hypertensive crisis:  systolic 
over 180 and/or diastolic 
over 120 mmHg 
•   Interrupt or discontinue fostamatinib. 
• Initiate or increase dosage of antihypertensive 
medication, and adjust as needed until BP is 
controlled.  If BP returns to less than the target 
BP, resume fostamatinib at same daily dose. 
• If repeat BP is 160/100 mmHg or higher for 
more than 4 weeks despite aggressive 
antihypertensive treatment, discontinue 
fostamatinib. 
Hepatotoxicity 
AST/ALT is 3 x ULN or 
higher and less than 5 x 
ULN 
If patient is symptomatic (e.g., nausea, vomiting, 
abdominal pain): 
 Interrupt fostamatinib. 
 Recheck LFTs every 72 hours until ALT/AST 
values are no longer elevated (below 1.5 x ULN) 
and total BL remains less than 2 x ULN. 
 Resume fostamatinib at next lower daily dose. 
If patient is asymptomatic: 
•    Recheck LFTs every 72 hours until ALT/AST are 
below 1.5 x ULN) and total BL remains less than 2 x 
ULN. 
• Consider interruption or dose reduction of 
fostamatinib if ALT/AST and TBL remain in this 
category (AST/ALT is 3 to 5 x ULN; and total BL 
remains less than 2 x ULN) 
• If interrupted, resume fostamatinib at next lower 
daily dose) when ALT/AST are no longer elevated 
(below 1.5 x ULN) and total BL remains less than 
2 x ULN. 


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AST/ALT is 5 x ULN or 
higher and total BL is less 
than 2 x ULN 
•    Interrupt fostamatinib. 
•    Recheck LFTs every 72 hours: 
• 
If AST and ALT decrease, recheck until ALT and 
AST are no longer elevated (below 1.5 x ULN) and 
total BL remains less than 2 x ULN; resume 
fostamatinib at next lower daily dose. 
• 
If AST/ALT persist at 5 x ULN or higher for 2 
weeks or more, discontinue fostamatinib. 
AST/ALT is 3 x ULN or 
higher and total BL is 
greater than 2 x ULN 
•    Discontinue fostamatinib. 
Elevated unconjugated 
(indirect) BL in absence of 
other LFT abnormalities 
• 
Continue fostamatinib with frequent monitoring 
since isolated increase in unconjugated (indirect) BL 
may be due to UGT1A1 inhibition 
Diarrhea 
Diarrhea 
• Manage diarrhea using supportive measures (e.g., 
dietary changes, hydration and/or antidiarrheal 
medication) early after the onset until symptom(s) 
have resolved. 
• If symptom(s) become severe (Grade 3 or 
above), temporarily interrupt fostamatinib. 
• 
If diarrhea improves to mild (Grade 1), resume 
fostamatinib at the next lower daily dose. 
Neutropenia 
Neutropenia 
• If absolute neutrophil count decreases (ANC less 
than 1.0 x 109/L) and remains low after 72 hours, 
temporarily interrupt fostamatinib until resolved 
(ANC greater than 1.5 x 109/L). 
•   Resume fostamatinib at the next lower daily dose.  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BL = bilirubin; 
ULN = upper limit of normal; LFT = liver function tests (AST, ALT, total BL with fractionation if elevated, 
alkaline phosphatase); AST/ALT = AST or ALT 
 
6.2 
Dose Modifications for Ruxolitinib 
 
Ruxolitinib dose modifications will be performed as per standard of care.  Refer to the 
package insert for guidance. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. Please refer to Appendix D for definitions and Appendix E for a grid of reporting 
timelines. 
 
Adverse events will be tracked from start of treatment through 30 days after last day of study 
treatment.  All adverse events must be recorded on the toxicity tracking case report form (CRF) 


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with the exception of: 
 Baseline adverse events, which shall be recorded on the medical history CRF 
 
Refer to the data submission schedule in Section 9 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.   
 
7.1 
Sponsor-Investigator Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Sponsor-Investigator (or designee) is required to notify the QASMC of any 
unanticipated problems involving risks to participants or others occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by 
HRPO.  (Unanticipated problems reported to HRPO and withdrawn during the 
review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
7.1.3 Reporting to Rigel Pharmaceuticals 
 
7.1.3.1 Expedited Reporting Requirements for Serious Adverse Events 
An investigator should report all SAEs as soon as possible after his/her 
awareness of the event via a MedWatch form to Rigel’s authorized safety 
representative.   
 
The MedWatch form should be sent to the following email or fax: 
Email: clinsafety@rigel.com 
Fax: +1.650.745.0971 
 
The site may contact Rigel Drug Safety at the above fax/e-mail with 
questions regarding reporting of SAEs. 
 


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7.1.3.2 Pregnancy 
 
Although pregnancy itself is not regarded as an AE, the initial notification 
and outcome of any pregnancy that occurs during the study must be 
documented. The pregnancy in a female study participant and the pregnancy 
outcome must be reported to Rigel Drug Safety within 24 hours of 
awareness. Partners that become pregnant by a male subject do not need to 
report pregnancy.  
 
Prior to screening, females of childbearing potential must agree in the ICF 
to take appropriate measures to avoid pregnancy at all times during the 
study, commencing from the time of consent to 30 days after the last dose 
of study drug, and, if pregnancy occurs, they must agree to report the 
pregnancy and cooperate with the investigator as set forth below. 
 
Should a pregnancy occur, the female study participant must immediately 
inform the investigator and must immediately discontinue study drug. The 
investigator should counsel the study participant on any risks of continuing 
the pregnancy and any possible effects on the fetus in view of the subject’s 
participation in the study. The study participant must agree to follow-up by 
the investigator regarding the outcome of any pregnancy that occurs during 
the study.  Outcome is defined as elective termination of the pregnancy, 
miscarriage, or delivery of the fetus. Any congenital anomaly/birth defect 
noted in the infant must be reported as an SAE. 
 
7.1.4 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Sponsor-Investigator to the FDA as follows: 
 
 Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix D for definitions) no later than 7 calendar days after 
initial receipt of the information.   
 Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix D) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix D) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 


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o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
 Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
 Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
 Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 8.1 include: 
 planned hospitalizations 
 hospitalizations < 24 hours 
 respite care 
 events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 


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8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Fostamatinib 
 
8.1.1 Fostamatinib Description 
 
Fostamatinib is a tyrosine kinase inhibitor. Fostamatinib is formulated with the 
disodium hexahydrate salt of fostamatinib, a phosphate prodrug that converts to its 
pharmacologically active metabolite, R406, in vivo. 
 
The chemical name for fostamatinib disodium hexahydrate is disodium (6-[[5-
fluoro-2-(3,4,5trimethoxyanilino) 
pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-
pyrido[3,2-b][1,4]oxazin-4-yl)methylphosphate 
hexahydrate. 
The 
molecular 
formula is C23H24FN6Na2O9P·6H2O, and the molecular weight is 732.52. 
 
8.1.2 Clinical Pharmacology 
 
Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen 
tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal 
transduction of Fc-activating receptors and B-cell receptor. The fostamatinib 
metabolite R406 reduces antibody-mediated destruction of platelets. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
Fostamatinib is a prodrug that is converted in the gut to the major active metabolite, 
R406. Mean (± standard deviation [SD]) exposure estimates of R406 are 550 (± 
270) ng/mL for Cmax and 7080 (± 2670) ng•h/mL for AUC. R406 exposure is 
approximately dose proportional up to 200 mg twice daily (1.3 times the 150 mg 
dosage). R406 accumulates approximately 2-to 3-fold upon twice daily dosing at 
100–160 mg (0.67 to 1.06 times the 150 mg dosage). R406 is extensively 
metabolized, primarily through pathways of CYP450-mediated oxidation (by 
CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). 
R406 is the predominant moiety in the systemic circulation, and there was minimal 
exposure to any R406 metabolites. Refer to the prescribing information of 
TAVALISSETM (fostamatinib) for details on drug-drug interaction potential. 
 
8.1.4 Supplier 
 
Fostamatinib will be supplied by Rigel Pharmaceuticals. 
 
8.1.5 Dosage Form and Preparation 
 
Fostamatinib is available as a 100 mg or 150 mg tablet. 
 


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8.1.6 Storage and Stability 
 
Store at room temperature, 20oC to 25oC (68oF to 77oF); excursions permitted 
between 15oC to 30oC (59oF to 86oF). Do not remove desiccants. 
 
8.1.7 Administration 
 
Please refer to Section 6.3. 
 
8.2 
Ruxolitinib 
 
8.2.1 Ruxolitinib Description 
 
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-
pyrrolo[2,3d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile 
phosphate and a molecular weight of 404.36. 
 
8.2.2 Clinical Pharmacology 
 
Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and 
JAK2 which mediate the signaling of a number of cytokines and growth factors that 
are important for hematopoiesis and immune function. JAK signaling involves 
recruitment of STATs (signal transducers and activators of transcription) to 
cytokine receptors, activation and subsequent localization of STATs to the nucleus 
leading to modulation of gene expression. 
 
MF and PV are myeloproliferative neoplasms (MPN) known to be associated with 
dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617F-positive 
MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially 
decreased JAK2V617F mutant cells in the spleen and decreased circulating 
inflammatory cytokines (e.g., TNF-α, IL-6). 
 
JAK-STAT signaling pathways play a role in regulating the development, 
proliferation, and activation of several immune cell types important for GVHD 
pathogenesis. In a mouse model of acute GVHD, oral administration of ruxolitinib 
was associated with decreased expression of inflammatory cytokines in colon 
homogenates and reduced immune-cell infiltration in the colon. 
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
Mean ruxolitinib maximal plasma concentration (Cmax) and AUC increased 
proportionally over a single dose range of 5 mg to 200 mg. Mean ruxolitinib Cmax 
ranged from 205 nM to 7100 nM and AUC ranged from 862 nM*hr to 30700 nM*hr 
over a single dose range of 5 mg to 200 mg. 
 
Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. Refer to 


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the prescribing information of JAKAFITM (ruxolitinib) for details on drug-drug 
interaction potential. 
 
8.2.4 Supplier 
 
Ruxolitinib is commercially available. 
 
8.2.5 Dosage Form and Preparation 
 
Ruxolitinib is available at 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg tablets. 
 
8.2.6 Storage and Stability 
 
Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted 
between 15°C and 30°C (59°F and 86°F) 
 
8.2.7 Administration 
 
Refer to Section 6.3. 
 
 
9.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
CBC Form 
Baseline, C1D1, C1D8, C1D15, C1D22, Weekly the first 
cycle of combination therapy and Day 1 & Day 15 of all 
other cycles  
Treatment Form 
Every cycle 
Toxicity Form 
Transfusion Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 6 months for 2 years 
Progression Form 
Time of progression 
Death Form 
Time of death 
Spleen Response Form 
Baseline, end of Part A treatment, Cycle 4 Day 1, after 3 
cycles in Part B, end of Part B treatment 
MPN TSS Form 
Day 1 of each cycle 
MedWatch Form 
See Section 8.0 for reporting requirements 
 
9.1 
Adverse Event Collection in the Case Report Forms 


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All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 8.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
10.0 
MEASUREMENT OF EFFECT 
 
10.1 
IWG-MRT Response Criteria  
 
Objective response is defined as CR (complete remission/response) + PR (partial 
remission/response) + CI (clinical improvement). Responses are defined by the 
International Working Group-Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) consensus [59]: 
 
Complete Response (CR):  
o Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤ grade 1 MF 
AND  
o Peripheral blood: Hemoglobin ≥ 10 g/dL; neutrophil count ≥ 1 x 109/L; platelet count 
≥ 100 x 109/L and < UNL; <2% immature myeloid cells 
AND 
o Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence 
of extramedullary hematopoiesis (EMH) 
 
Partial Response (PR):  
o Peripheral blood: Hemoglobin ≥ 10 g/dL; neutrophil count ≥ 1 x 109/L; platelet count 
≥ 100 x 109/L and < UNL; <2% immature myeloid cells 
AND 
o Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence 
of extramedullary hematopoiesis (EMH)  
OR 
o Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF  
AND 
o Peripheral blood: Hemoglobin ≥ 8.5but < 10 g/dL and <UNL; neutrophil count ≥ 1 x 
109/L and <UNL; platelet count ≥ 50 x 109/L, but < 100 x 109/L and <UNL; <2% 
immature myeloid cells 
AND 
o Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence 
of EMH 
 
Clinical Improvement (CI):  


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o The achievement of anemia (10.2.1), spleen (10.4) or symptoms response (10.3) 
without progressive disease or increase in severity of anemia, thrombocytopenia, or 
neutropenia 
 
Stable Disease (SD):  
o Not meeting the definition of CR, PR, CI or PD 
 
Progressive Disease (PD):  
o Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM  
OR 
o A ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-
10 cm 
OR 
o A ≥ 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 
cm 
OR 
o Leukemic transformation confirmed by a bone marrow blast count of > 20% 
OR 
o A peripheral blood blast content of > 20% with an absolute blast count of > 1 x 109/L 
for at least 2 weeks 
 
10.2 
Hematologic Response 
 
10.2.1 Anemia Response  
 
Anemia response is only applicable for patients with a baseline hemoglobin level 
less than 10 g/dL for 8 weeks or more, and requires: 
o  ≥ 2 g/dL increase in hemoglobin level 
OR 
o becoming transfusion-independent (no RBC transfusions in past 1 month) 
 
10.2.2 Platelet Response 
 
Platelet response is only applicable for patients with a baseline platelet count of less 
than 50 x 109/L for 8 weeks or more, and requires: 
o An absolute platelet count of at least 50 x 109/L on two separate measurements 
at least 2 weeks apart  
 
10.3 
Symptoms Response  
 
A ≥ 50% reduction in the myeloproliferative neoplasm symptom assessment total symptom 
score (see Appendix F) 
 
10.4 
Spleen Response 
 


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o 
A baseline splenomegaly that is palpable at 5-10 cm below the left costal margin 
becomes not palpable  
OR 
o 
A baseline splenomegaly that is palpable > 10 cm below the left costal margin 
decreases by ≥50%  
OR 
o 
A baseline splenomegaly that is palpable < 5 cm below the left costal margin is not 
eligible for spleen response  
OR 
o 
Ultrasound shows ≥35% spleen volume reduction (calculated) 
 
 
11.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual 
 Protocol activation date 
 Average rate of accrual observed in year 1, year 2, and subsequent years 
 Expected accrual end date 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
 Summary of toxicities 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 


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12.0 
STATISTICAL CONSIDERATIONS 
 
12.1 
Hypothesis 
 
Our primary hypothesis is that fostamatinib alone and in combination with ruxolitinib will 
provide a safe and tolerable treatment in patients with myelofibrosis with severe 
thrombocytopenia (platelet < 50K/microL). Treatment with fostamatinib will improve 
thrombocytopenia in patients with myelofibrosis with severe thrombocytopenia (platelet < 
50K/microL) and allow them to initiate treatment with ruxolitinib. 
 
12.2 
Study Design 
 
This is a hypothesis generating limited pilot phase II study evaluating the efficacy and 
safety of the use of fostamatinib as a single agent and when given in combination with 
ruxolitinib in patients with intermediate to high risk myelofibrosis. Previous studies with 
fostamatinib and ruxolitinib monotherapy indicate that toxicity will be low grade and 
reversible with standard treatment.  
 
This study consists of two parts.  For Part A, patients with MF and severe 
thrombocytopenia will initially receive 12 weeks of single agent fostamatinib and the 
primary endpoint will be platelet response (defined as platelet count of ≥ 50K/microL as 
two separate measurements at least two weeks apart) at the end of the 12 week treatment 
period.  Patients who achieve a sustained platelet response will then be eligible to proceed 
to Part B of the study and begin treatment with ruxolitinib while continuing to take 
fostamatinib.  For Part B, patients will continue treatment with fostamatinib and ruxolitinib 
for up to an additional 36 weeks and the primary endpoint will be safety as assessed by 
NCI CTCAE v 5.0.  Patients who do not have a sustained platelet response after 12 weeks 
of treatment but are clinically benefiting from fostamatinib may remain on Part A of the 
study and be eligible to enroll in Part B if they achieve a sustained platelet response prior 
to Day 1 Cycle 10 of treatment.  
 
A maximum of 12 patients will be enrolled. A Bayesian sequential monitoring rule will be 
implemented for safety.  
 
Safety monitoring (Part B):  The stopping rule is defined as Pr(θ > θT |data) >0.8, where 
θ denotes the proportion of AEs of interest as defined in Section 5.5 and θT denotes the rate 
of AEs of interest under the null hypotheses (i.e., 20% AEs of interest). That is, an early 
termination of the study due to excessive toxicities will be recommended whenever, given 
the accumulated observed data, there is high chance (i.e., >80% probability) for the “true” 
AEs of interest rate >20%. The stopping boundaries were obtained using Multc99 version 
2.1, a free-download software from M.D. Anderson Cancer Center. Specifically, we 
assume that the parameter θ follows a prior distribution of beta (0.2, 0.8), i.e., θ with mean 
= 0.2 but with relatively large variability (non-informative prior). Early stopping will be 
recommended if we observe 3 patients who experience AEs of interest out of first 5 patients 


Protocol Version: 03 Nov2020  
 
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or 4 patients who experience AEs of interest out of first 9 patients. A simulation study was 
also performed to assess the operating characteristics for the above stopping rule (all 
scenarios are based on 10,000 simulated trials). If the “true” AEs of interest rate is 10%, 
there will be only 4% chance to stop. In contrast, we will have 76% chance to stop if the 
“true” rate is 40%. 
 
# Patients 
treated  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 
Stop if the # 
AEIs ≥ 
N/A N/A N/A N/A 3 
3 
3 
3 
4 
4 
4 
4 
 
12.3 
Analysis Plan 
 
All data analyses will be descriptive in nature. Demographic and clinical characteristics of 
the sample, as well as response to treatment, and loss to follow up will be summarized 
using descriptive statistics. Rate of AEs, overall response rate, hematologic response rate, 
symptom response rate, and spleen response rate will be documented with exact 95% 
confidence intervals.  
 
12.4 
Sample Size and Study Power 
 
A total of 12 patients will be enrolled.  As a pilot phase II study for hypothesis generating, 
formal power calculations to determine sample size were not performed. Based on 
simulation studies regarding the sample size for translational studies, however, Piantadosi 
recommends that a sample size of 10 to 20 patients be adequate to provide preliminary 
information [33]. For efficacy, for example, the probability of observing at most 1 platelet 
response out of 12 patients is 27% given that the true rate is 20%.    However, the 
probability of observing at least 2 platelet responses is 98% given that the true is 40%.  For 
safety, if the “true” AEs of interest rate is 20% or higher, there will be more than 93% 
chance to observe at least 1 patient with AE of interest out of 12 patients. Conversely, there 
is less than 2% chance to observe 3 or more patients with AE of interests if the “true” rate 
is 5% or less. 
 
 
 


Protocol Version: 03 Nov2020  
 
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13.0 
REFERENCES 
 
1.  
Arber, D.A., et al., The 2016 revision to the World Health Organization classification of 
myeloid neoplasms and acute leukemia. Blood, 2016. 127(20): p. 2391-405. 
2.  
Tefferi, A. and W. Vainchenker, Myeloproliferative neoplasms: molecular 
pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol, 
2011. 29(5): p. 573-82. 
3.  
Nangalia, J., et al., Somatic CALR mutations in myeloproliferative neoplasms with 
nonmutated JAK2. N Engl J Med, 2013. 369(25): p. 2391-405. 
4.  
Klampfl, T., et al., Somatic mutations of calreticulin in myeloproliferative neoplasms. N 
Engl J Med, 2013. 369(25): p. 2379-90. 
5.  
Pardanani, A., et al., Primary myelofibrosis with or without mutant MPL: comparison of 
survival and clinical features involving 603 patients. Leukemia, 2011. 25(12): p. 1834-9. 
6.  
Pardanani, A.D., et al., MPL515 mutations in myeloproliferative and other myeloid 
disorders: a study of 1182 patients. Blood, 2006. 108(10): p. 3472-6. 
7.  
Boyd, E.M., et al., Clinical utility of routine MPL exon 10 analysis in the diagnosis of 
essential thrombocythaemia and primary myelofibrosis. Br J Haematol, 2010. 149(2): p. 
250-7. 
8.  
Vannucchi, A.M., et al., Mutations and prognosis in primary myelofibrosis. Leukemia, 
2013. 27(9): p. 1861-9. 
9.  
Lasho, T.L., et al., SRSF2 mutations in primary myelofibrosis: significant clustering with 
IDH mutations and independent association with inferior overall and leukemia-free 
survival. Blood, 2012. 120(20): p. 4168-71. 
10.  
Tefferi, A., Primary myelofibrosis: 2019 update on diagnosis, risk-stratification, and 
management. Am J Hematol, 2018 Dec. 93(12): p. 1551-1560. 
11.  
Gangat, N., et al., DIPSS plus: a refined Dynamic International Prognostic Scoring 
System for primary myelofibrosis that incorporates prognostic information from 
karyotype, platelet count, and transfusion status. J Clin Oncol, 2011. 29(4): p. 392-7. 
12.  
Passamonti, F., et al., A dynamic prognostic model to predict survival in primary 
myelofibrosis: a study by the IWG-MRT (International Working Group for 
Myeloproliferative Neoplasms Research and Treatment). Blood, 2010. 115(9): p. 1703-8. 
13.  
Cervantes, F., et al., New prognostic scoring system for primary myelofibrosis based on a 
study of the International Working Group for Myelofibrosis Research and Treatment. 
Blood, 2009. 113(13): p. 2895-901. 
14.  
Hultcrantz, M., et al., Risk and Cause of Death in Patients Diagnosed With 
Myeloproliferative Neoplasms in Sweden Between 1973 and 2005: A Population-Based 
Study. J Clin Oncol, 2015. 33(20): p. 2288-95. 
15.  
Tefferi, A., et al., Long-term survival and blast transformation in molecularly annotated 
essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood, 2014. 124(16): 
p. 2507-13; quiz 2615. 
16.  
Mesa, R.A., et al., Leukemic transformation in myelofibrosis with myeloid metaplasia: a 
single-institution experience with 91 cases. Blood, 2005. 105(3): p. 973-7. 
17.  
Huang, J., et al., Risk factors for leukemic transformation in patients with primary 
myelofibrosis. Cancer, 2008. 112(12): p. 2726-32. 


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18.  
Verstovsek, S., et al., A double-blind, placebo-controlled trial of ruxolitinib for 
myelofibrosis. N Engl J Med, 2012. 366(9): p. 799-807. 
19.  
Harrison, C., et al., JAK inhibition with ruxolitinib versus best available therapy for 
myelofibrosis. N Engl J Med, 2012. 366(9): p. 787-98. 
20.  
Harrison, C.N., et al., Long-term findings from COMFORT-II, a phase 3 study of 
ruxolitinib vs best available therapy for myelofibrosis. Leukemia, 2016. 30(8): p. 1701-7. 
21.  
Verstovsek, S., et al., Efficacy, safety, and survival with ruxolitinib in patients with 
myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica, 
2015. 100(4): p. 479-88. 
22.  
Santos FPS, V.S., What is next beyond janus kinase 2 inhibitors for primary 
myelofibrosis? Curr Opin Hematol, 2013. 20. 
23.  
Verstovsek S, K.H., Mesa RA, et al, Safety and efficacy of INCB018424, a JAK1 and 
JAK2 inhibitor, in myelofibrosis. N Engl J Med, 2010. 363: p. 1117-1127. 
24.  
Harrison C, K.J., Al-Ali HK, et al., JAK inhibition with ruxolitinib versus best available 
therapy for myelofibrosis. N Engl J Med, 2012. 366: p. 787-798. 
25.  
Vannucchi, A.M., et al., A pooled analysis of overall survival in COMFORT-I and 
COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of 
myelofibrosis. Haematologica, 2015. 100(9): p. 1139-45. 
26.  
Cervantes, F., et al., Three-year efficacy, safety, and survival findings from COMFORT-
II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. 
Blood, 2013. 122(25): p. 4047-53. 
27. 
Ruxolitinib Prescribing Information: https://www.jakafi.com/pdf/prescribing-
information.pdf 
28. 
Fedratatinib Prescribing Information: https://media.celgene.com/content/uploads/inrebic-
pi.pdf  
29. 
Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult 
persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, 
placebo-controlled trials.  Am J Hematol. 2018;93:921-930. 
30. 
Kuno Y, Abe A, Emi N, et al. Constitutive kinase activation of the TEL-Syk fusion gene 
in myelodysplastic syndrome with t(9;12)(q22;p12).  Blood 2001 Feb 15;97(4):1050-5. 
31.  
Graham MT, et al. Expression of the TEL-Syk fusion protien in hematopoietic stem cells 
leads to rapidly fatal myelofibrosis in mice. PLoS One. 2013 Oct 8;8(10):e77542.  
32. 
Al-Ali HK, Vannucchi AM. Managing patients with myelofibrosis and low platelet 
counts. Ann Hematol 2017. 96:537-548. 
33.  
Piantadosi S: Translational clinical trials: an entropy-based approach to sample size. 
Clinical trials 2005, 2(2):182 
 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 


Protocol Version: 03 Nov2020  
 
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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


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APPENDIX B: PATIENT’S MEDICATION DIARY 
 
Today’s Date:    
 
 
Agent:  fostamatinib 
Cycle:    
   Study ID#:   
 
 
1. Complete one form for each month.  Take _____mg ( ___capsules) of fostamatinib twice daily with or without food 
at approximately the same time each day.  
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forgot to take your dose, do not make up that dose, but restart taking it with your next scheduled dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill count 
can be done. 
Day 
Date 
What time was dose taken? 
# of tablets taken 
Comments 
AM 
PM 
AM 
PM 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
 
 
 
30 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 


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APPENDIX C: PATIENT’S MEDICATION DIARY 
 
Today’s Date:    
 
 
Agent:  ruxolitinib 
Cycle:    
   Study ID#:   
 
 
1. Complete one form for each month.  Take _____mg ( ___capsules) of ruxolitinib twice daily with or without food at 
approximately the same time each day. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forgot to take your dose, do not make up that dose, but restart taking it with your next scheduled dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment. 
Day 
Date 
What time was dose taken? 
# of tablets taken 
Comments 
AM 
PM 
AM 
PM 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
 
 
 
30 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
 


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APPENDIX D: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 


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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the 
grade of an AE. “Serious” is a regulatory definition. 
 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at 
any dose: 
 Results in death; 
 Is life-threatening. (With regards to determining if an AE is serious, “life-threatening” 
is defined as an AE in which the subject was at risk of death at the time of the event. It 
does not refer to an event which hypothetically might have caused death if it were more 
severe. If either the investigator or the Sponsor believes that an AE meets the definition 
of life threatening, it will be considered life-threatening); 
 Requires in-patient hospitalization or prolongation of an existing hospitalization; 
 Results in persistent or significant disability/incapacity (e.g., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions); or 
 Is a congenital anomaly/birth defect; 
 Is considered an important medical event (or medically significant) that may not result 
in any of the above outcomes but based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed    
Medical and scientific judgment should be exercised in deciding whether other situations, such 
as important medical events, should also be considered serious. Some examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias, or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. Given that the investigator’s perspective may be informed by 
having actually observed the event and Rigel is likely to have broader knowledge of the study 
drug and its effects to inform its evaluation of the significance of the event, if either Rigel or 
the investigator believes that the event is serious, the event will be considered an important 
medical event. 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 


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including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
 


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APPENDIX E: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Rigel 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Report no later than 15 calendar 
days after it is determined that 
the information qualifies for 
reporting 
 
Serious adverse events 
 
 
 
Report as soon as possible after 
awareness to Rigel. 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
Report no later than 7 calendar 
days after initial receipt of the 
information 
 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 
1 working day. 
Report via email after IRB 
acknowledgment 
 
 
Major deviation 
Report within 10 working days.  If the 
event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 
1 working day. 
 
 
 
Pregnancy 
 
 
 
Notify Rigel within 24 hours of 
awareness. 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working days.   
 
 
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
 
 
Report no later than 15 calendar 
days after it is determined that 
the information qualifies for 
reporting 
 


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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Rigel 
that list in the protocol 
or IB 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 
10 working days.  If the event results in 
the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working 
day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Breach of 
confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the participant poses a 
safety issue, report within 10 working 
days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient 
will be withdrawn, report at continuing 
review. 
 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Rigel 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
 
 
 


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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Rigel 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
 
 
 


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APPENDIX F: Symptom Assessment Form 
 
Fostamatinib + Ruxolitinib  
 
Today’s Date: ______________                   Visit: _________________ 
 
Patient ID: _______________________________  
 
 
Myeloproliferative Neoplasm – Symptom Assessment Form  
Total Symptom Score (MPN-SAF-TSS) 
 
Rate your WORST level of fatigue 
during the past 24 hours 
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
 
 
Circle the number that describes in the PAST WEEK, how much difficulty you 
have had with each of the following symptoms  
1. Filling up quickly when you eat 
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
2. Abdominal discomfort 
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
3. Inactivity  
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
4. Problems with concentration 
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
5. Night sweats 
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
6. Itching  
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
7. Bone pain (not joint pain or 
arthritis) 
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
8. Fever (greater than 100º F) 
 (absent) 0  1  2  3  4  5  6  7  8  9  10 (daily) 
9. Unintentional weight loss in the 
last 6 months 
(absent) 0  1  2  3  4  5  6  7  8  9  10 (worst imaginable) 
 
 
Office use only below 
Add up Total Symptom Score from 
questions 1-9 above 
        TSS = 
Site Signature