A Phase II Study Using Fostamatinib to Treat Post-Hematopoietic Stem Cell Transplant Immune-Mediated Cytopenias
Phase: PHASE2
Conditions: Immune Mediated Anemia, Immune Mediated Thrombocytopenia, Chronic GVHD
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
A Phase II Study using Fostamatinib to treat Post-Hematopoietic Stem Cell 
Transplant Immune-mediated Cytopenias 
NCT number: 
 
NCT05502783 
Document Type:  
Protocol with Statistical Analysis Plan (SAP)  
Document Date: 
November 28, 2023 
 
 

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Abbreviated Title: Fostamatinib for post-transplant cytopenias 
NHLBI Clinical Trial 
NIH Protocol #: 000758 
Version Date: 11/28/2023 
 
Title: A Phase II Study using Fostamatinib to treat Post-Hematopoietic Stem Cell Transplant 
Immune-mediated Cytopenias  
 
NIH Principal Investigator:  
 
Jamie Hur, DO, NHLBI (E) 
NHLBI, NIH 
10 Center Drive, Room 4-5140 
Bethesda, MD 20892 
Phone: (301) 402-2399 
E-mail: jamie.hur@nih.gov 
 
Medically Responsible and Accountable Investigator: 
Richard Childs, M.D., HB, NHLBI (E)          
 
  
 
Investigational Agents: 
Drug Name: 
Fostamatinib 
IND Number: 
160573 
Sponsor: 
NHLBI OCD 
Manufacturer: 
Rigel Pharmaceuticals 
 
Responsible Data and Safety Monitoring Board (DSMB): NHLBI Blood DSMB 
 
 

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TABLE OF CONTENTS  
TABLE OF CONTENTS ................................................................................................................ 2 
STATEMENT OF COMPLIANCE ................................................................................................ 6 
1 
PROTOCOL SUMMARY ...................................................................................................... 7 
1.1 
Synopsis ............................................................................................................................................ 7 
1.2 
Schema ............................................................................................................................................ 10 
1.3 
Schedule of Activities (SOA) ......................................................................................................... 11 
2 
INTRODUCTION ................................................................................................................ 13 
2.1 
Study Rationale ............................................................................................................................... 13 
2.2 
Background ..................................................................................................................................... 13 
2.3 
Risk/Benefit Assessment................................................................................................................. 15 
2.3.1 
Known Potential Risks ............................................................................................ 15 
2.3.2 
Known Potential Benefits ....................................................................................... 16 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................... 17 
3 
STUDY DESIGN.................................................................................................................. 17 
3.1 
Overall Design ................................................................................................................................ 17 
3.2 
Scientific Rationale for Study Design ............................................................................................. 18 
3.3 
Justification for Dose ...................................................................................................................... 18 
4 
OBJECTIVES AND ENDPOINTS ...................................................................................... 18 
5 
STUDY POPULATION ....................................................................................................... 21 
5.1 
Inclusion Criteria ............................................................................................................................ 21 
5.2 
Exclusion Criteria ........................................................................................................................... 22 
5.3 
Inclusion of Vulnerable Participants ............................................................................................... 23 
5.4 
Lifestyle Considerations ................................................................................................................. 23 
5.5 
Screen Failures ................................................................................................................................ 24 
5.6 
Strategies for Recruitment and Retention ....................................................................................... 24 
5.6.1 
Costs ........................................................................................................................ 25 
5.6.2 
Compensation ......................................................................................................... 25 
6 
STUDY INTERVENTION ................................................................................................... 25 
6.1 
Study Interventions(s) Administration ............................................................................................ 25 
6.1.1 
Study Intervention Description ............................................................................... 25 
6.1.2 
Dosing and Administration ..................................................................................... 26 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 30 

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6.2.1 
Acquisition and Accountability .............................................................................. 30 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 30 
6.2.3 
Product Storage and Stability.................................................................................. 30 
6.2.4 
Preparation .............................................................................................................. 30 
6.2.5 
Return and Reconciliation....................................................................................... 31 
6.2.6 
IP Destruction ......................................................................................................... 31 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................................................ 31 
6.4 
Study Intervention Compliance ...................................................................................................... 31 
6.5 
Concomitant Therapy ...................................................................................................................... 31 
6.6 
Transfusions .................................................................................................................................... 31 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 31 
7.1 
Discontinuation of Study Intervention ............................................................................................ 31 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................................................ 32 
7.3 
Lost to Follow-up ............................................................................................................................ 32 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 33 
8.1 
Screening Procedures ...................................................................................................................... 33 
8.1.1 
Screening activities performed prior to obtaining informed consent ...................... 33 
8.1.2 
Screening activities performed after a consent for screening has been signed ....... 33 
8.2 
Efficacy Assessments ...................................................................................................................... 33 
8.2.1 
Clinical Evaluations ................................................................................................ 33 
8.2.2 
Biospecimen Evaluations ........................................................................................ 34 
8.2.3 
Correlative Studies for Research/Pharmacokinetic Studies .................................... 36 
8.2.4 
Samples for Genetic/Genomic Analysis ................................................................. 36 
8.3 
Safety and Other Assessments ........................................................................................................ 36 
8.4 
Adverse Events and Serious Adverse Events .................................................................................. 36 
8.4.1 
Definition of Adverse Event ................................................................................... 36 
8.4.2 
Definition of Serious Adverse Events (SAE) ......................................................... 36 
8.4.3 
Classification of an Adverse Event ......................................................................... 37 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 38 
8.4.5 
Adverse Event Recording ....................................................................................... 38 
8.4.6 
Serious Adverse Event Reporting ........................................................................... 38 
8.4.7 
Events of Special Interest........................................................................................ 39 

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8.4.8 
Reporting of Pregnancy .......................................................................................... 39 
8.5 
Unanticipated Problems .................................................................................................................. 39 
8.5.1 
Definition of Unanticipated Problems (UP) ........................................................... 39 
8.5.2 
Unanticipated Problem Reporting........................................................................... 40 
8.5.3 
NIH IRB Reporting of IND Safety Reports ............................................................ 40 
9 
STATISTICAL CONSIDERATIONS.................................................................................. 40 
9.1 
Statistical Hypothesis and Sample Size Determination .................................................................. 40 
9.2 
Populations for Analyses ................................................................................................................ 41 
9.2.1 
Evaluable for response ............................................................................................ 41 
9.3 
Statistical Analyses ......................................................................................................................... 41 
9.3.1 
General Approach ................................................................................................... 41 
9.3.2 
Analysis of the Primary Endpoints ......................................................................... 41 
9.3.3 
Analysis of the Secondary and Exploratory Endpoint(s) ........................................ 41 
9.3.4 
Interim Analyses and stopping rules ....................................................................... 41 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 43 
10.1 
Informed Consent Process .............................................................................................................. 43 
10.1.1 Consent/Assent Procedures and Documentation .................................................... 43 
10.1.2 Consent for minors when they reach the age of majority ....................................... 44 
10.1.3 Participation of Subjects who are/become Impaired in Decision Making .............. 44 
10.2 
.Study Discontinuation and Closure ................................................................................................ 44 
10.3 
Confidentiality and Privacy ............................................................................................................ 45 
10.4 
Future use of Stored Specimens and Data ...................................................................................... 46 
10.5 
Safety Oversight .............................................................................................................................. 46 
10.6 
Clinical Monitoring ......................................................................................................................... 46 
10.7 
Quality Assurance and Quality Control .......................................................................................... 47 
10.8 
Data Handling and Record Keeping ............................................................................................... 47 
10.8.1 Data Collection and Management Responsibilities ................................................ 47 
10.8.2 Study Records Retention......................................................................................... 47 
10.9 
Protocol Deviations ......................................................................................................................... 47 
10.9.1 NIH Definition of Protocol Deviation .................................................................... 48 
10.10 Publication and Data Sharing Policy .............................................................................................. 48 
10.10.1 Human Data Sharing Plan ....................................................................................... 48 
10.10.2 Genomic Data Sharing Plan .................................................................................... 48 

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10.11 Collaborative Agreements............................................................................................................... 48 
10.11.1 Agreement Type...................................................................................................... 48 
10.12 Conflict of Interest Policy ............................................................................................................... 48 
11 ABBREVIATIONS .............................................................................................................. 48 
12 REFERENCES ..................................................................................................................... 50 
Appendix A.  Inhibitors and Inducers of CYP3A ......................................................................... 52 
Appendix B.  Immune Thrombocytopenic Purpura Bleeding Score [1] ...................................... 54 
 
 
 

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STATEMENT OF COMPLIANCE 
Each engaged institution must have a current Federal-Wide Assurance (FWA) issued by the Office for 
Human Research Protections (OHRP) and must provide this protocol and the associated informed consent 
documents and recruitment materials for review and approval by an appropriate Institutional Review 
Board (IRB) or Ethics Committee (EC) registered with OHRP. Any amendments to the protocol or 
consent materials must also be approved before implementation.  
 
The trial will be carried out in accordance with International Conference on Harmonization 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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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
A Phase II Study of Fostamatinib to Treat Post-transplant Immune-
mediated Cytopenias  
Study Description: 
This open label phase II trial is designed to evaluate the efficacy of 
fostamatinib in the treatment of post-transplant cytopenias as assessed by 
hematologic improvement in anemia and/or thrombocytopenia following a 
12-week treatment course. Patients who respond to the 12-week treatment 
course on this single arm study are eligible and have the option to enroll on 
the extended access trial. 
Objectives: 
The primary objective is to assess efficacy of fostamatinib for stable 
hematologic recovery during post-hematopoietic stem cell transplant 
immune mediated anemia and/or thrombocytopenia. 
The secondary objective is to assess efficacy of fostamatinib for 
clinically-relevant outcomes in post-hematopoietic stem cell transplant 
patients. 
 
The exploratory objective is to evaluate changes in serologic markers that 
may be associated with cytopenias while on treatment to identify key 
elements for fostamatinib response.  
Endpoints: 
Primary endpoints: 
 
The proportion of subjects with hematologic recovery that is stable, defined 
as improvement documented in 2 consecutive available readings at least 2 
weeks apart, without recent blood product transfusion support in the past 7 
days.  
 
Hematologic recovery is defined as: 
• 
Hemoglobin ≥10 g/dL (or at least ≥2 g/dL above baseline) in 
subjects enrolled with posttransplant anemia. In subjects with 
symptomatic anemia, a hemoglobin increase of at least ≥2 g/dL 
above baseline is required 
 
OR 
• 
Platelets ≥ 50 x 109/L (or at least ≥20 x 109/L above baseline) in 
subjects enrolled with posttransplant thrombocytopenia  
 
OR  
• 
Both of the above criteria in subjects with posttransplant Evans 
syndrome 
 
Secondary endpoints: 
1. 
Proportion of subjects who achieve objective hematologic recovery 
within the 12-week treatment course defined as: 
 

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• 
Hemoglobin ≥9 g/dL (or at least ≥1 g/dL above baseline) in 
subjects enrolled with anemia or at least ≥1 g/dL above baseline in 
subjects with symptomatic anemia 
 
OR 
• 
Platelets ≥ 30 x 109/L (or at least ≥10 x 109/L above baseline) in 
subjects enrolled with thrombocytopenia  
 
OR 
• 
Either of the above criteria in subjects with Evans syndrome 
 
2. Average weekly requirement of transfused blood component or growth 
factor requirement (total units of PRBC or Platelets/week, total dose of 
growth factor/week) by week 12, compared to the week prior to the 
start of the study drug.  
3. Change in corticosteroid dose over time, measured by median daily 
weight-based prednisone-equivalent corticosteroid dose in a week, from 
week 1 to week 12  
4. Change in other immunosuppressant dose over time, measured by 
median daily dose of the immunosuppressant in a week, from week 1 to 
week 12 
5. Number of patients who achieved ≥50% steroid dose reduction by week 
12 compared to week 1 
6. Incidence and severity of cGVHD according to 2014 NIH Consensus 
Criteria, at baseline before the initiation of treatment, and at week 12 
 
Exploratory endpoints: 
1. Absolute percentage change in B cell chimerism pre-treatment, vs 
weeks 4 and 12. 
2. cPRA change in the preformed HLA antibodies before and after 
treatment in subjects with thrombocytopenia or Evans syndrome  
3. Percent MFI change of preformed HLA antibodies before and after 
treatment. This applies for antibodies with an MFI >1,000.  
4. Anti-RBC alloantibody titer change in patients with hemolytic anemia 
before and after treatment  
5. Assessment of serial cytokines pre-treatment and weeks 4 and 12. 
Cytokines include CRP, IL-1, IL-2, IL-6, IFN𝛾, TNFα, EPO and TPO  
6. Immunoglobulin level changes pre-treatment, and weeks 4 and 12. 
7. Absolute reticulocyte count, lactate dehydrogenase, haptoglobin 
changes pre-treatment, and at each biweekly study visit, in patients 
with anemia or Evans syndrome  
8. Change in the weekly rate and severity of bleeding according to the 
total score of the ITP-Bleeding Scale (IBLS), from week -1 (one week 
before the start of the study drug) to week 12, in subjects with 
thrombocytopenia or Evans syndrome 
Study Population: 
This trial is intended to include adult patients with post hematopoietic stem 
cell transplant immune-mediated anemia, thrombocytopenia, or both (Evans 
syndrome) evaluated on or after day 60 post transplantation.  
Phase: 
Phase II  

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Description of 
Sites/Facilities  
Enrolling Participants: 
 
This will be a multi-center study. Enrollment will take place at the NIH 
Clinical Center  and at up to three additional participating sites. 
We will enroll a total of 20 patients. The study will be conducted 
exclusively in the United States. 
Data Coordinating Center (DCC): National Heart, Lung and Blood Institute 
(NHLBI) 
 
Description of Study 
Intervention: 
The study intervention is fostamatinib, an inhibitor of spleen tyrosine kinase 
that will be prescribed orally at a dose of 100 mg twice daily for 4 weeks 
followed by a hematological response assessment. On the week 4 evaluation 
visit, a) if cytopenias improve (hemoglobin ≥10 g/dL, platelets ≥ 50 x 
109/L), patients will continue the same dose for a total of 12 weeks, b) if 
refractory cytopenias persist (hemoglobin < 10 g/dL, platelets < 50 x 109/L), 
fostamatinib dose will be increased to 150 mg BID. The duration of the 
study is 12 weeks with the option to enrol patients who respond on an 
extended access trial 
  
Study Duration: 
This study will enroll over 48 months followed by an additional 4months 
for data analysis 
 
Participant Duration: 
An individual subject will complete the study in 15 weeks, from screening 
at week -1 or 0 to follow-up on week 14 ± 3 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.2 
SCHEMA 
 
 
 
 
All subjects will receive fostamatinib 100 mg BID for 4 weeks. On the 4-week evaluation,  
a) if the cytopenia/s improves (hemoglobin ≥10 g/dL and/or platelets ≥ 50 x 109/L), patients will 
continue the same dose for a total of 12 weeks; b) if refractory cytopenias persist (hemoglobin < 
10 g/dL, platelets < 50 x 109/L), pts will increase dose to 150 mg BID. 
 
* Subjects with persistent (≥2 readings, 2 weeks apart) loss of hematologic response after week 5 can 
increase dose to 150mg BID until end of the study on week 12.     
*Temporary drug interruption: Patient to receive total of 12 weeks of fostamatinib despite drug 
interruptions. If patient have drug interruptions, patient will be maintained in protocol until finishing the 
total 12 weeks of the treatment.  
 
 
 
 
* 

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1.3 
 SCHEDULE OF ACTIVITIES (SOA) 
 
Study Weekk  
-1 
0 
2d 
4d 
6d 
8d 
10d 
12d 
14e,f 
(end of study safety visit)  
Informed Consent 
Xb 
Xb 
 
 
 
 
 
 
 
Inclusion/exclusion 
Xb 
Xb 
 
 
 
 
 
 
 
Pregnancy Test 
Xb 
Xb 
 
X 
 
X 
 
X 
 
HIV, HBV, HCV testing 
Xb,j 
Xb,j 
 
 
 
 
 
 
 
Medical History 
Xb 
Xb 
 
 
 
 
 
 
 
Medical assessment a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
Xb 
Xb 
 
 
 
 
 
 
 
Follow up and labs c,d: 
CBC, BMP, LFTs, LDH, 
absolute reticulocyte count, 
haptoglobin, stool occult 
blood, urinalysis 
Xb 
Xb 
X 
X 
X 
X 
X 
X 
X 
Study drug (fostamatinib) 
administration g 
 
X 
X 
X 
X 
X 
X 
 
 
B-cell chimerism and 
Cytokines h 
 
Xb 
 
X 
 
X 
 
X 
 
IBLS [1]i 
Xb 
Xb 
X 
X 
X 
X 
X 
X 
 
cPRA, MFI, immunoglobulin 
level, RBC antibody 
 
X 
 
X 
 
X 
 
X 
 
 
a) Vital signs, transfusion support evaluation, concomitant medication review and steroids taper assessment  
b) Can be done within 7 days before or at time of enrollment   
c) Follow up visits will be completed as outpatient in-person visits at the NIH Clinical Center, or via telehealth/telephone if patients are 
unable to travel for any reason (except for weeks 4 and 12 where patients are required to return to the NIH Clinical Center). Labs can be 
completed locally, and results will be provided to the research team.  
d) Can be performed +/- 4 days from scheduled visit. 
e) Outpatient visit can be +/- 3 days from scheduled visit.  
f) Patients who rolled over to 000760-H will not need to return for week 14 visit, they will transition all study follow up to 000760-H. The 
patients who do not roll over will complete their week 14 safety visit on 000758-H. 

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g) Study drug will be mailed from Rigel or the clinical center pharmacy and be distributed to the research subjects from the pharmacy 
directly to the research subjects. The pill count will be reviewed every 2 weeks at the medical assessment visit.   
h) Including CRP, IL-1, IL-2, IL-6, IFN𝛾, TNFα, EPO and TPO 
i) See Appendix B 
j) Within 6 months  
k) Temporary drug interruption. Patient to receive total of 12 weeks of fostamatinib despite drug interruptions. If patient have drug 
interruptions, patient will be maintained in protocol until finishing the total 12 weeks of the treatment. Treatment may be delayed for a 
maximum of 14 days after holding the treatment for toxicities that develop and do not resolve as defined at 6.1.2.3 (neutropenia, LFT 
elevation, and diarrhea). The timing of subsequent lab and the study week are then adjusted to the study week that was stopped. 
 
 

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2 
INTRODUCTION 
 
2.1 
STUDY RATIONALE 
Post-allogeneic hematopoietic stem cell transplant (HSCT) associated cytopenias often result from 
immunologic causes, where adequate bone marrow precursor cells are still maintained but RBCs and/or 
platelets are decreased either by peripheral destruction through antibody mediated processes or 
suppressed bone marrow production as a consequence of graft versus host disease (GVHD) [2]. 
Autoimmune cytopenia is a well-recognized manifestation of chronic GVHD (cGVHD) that usually 
occurs in the presence of other clinical signs of cGVHD [3, 4]. Several treatment options used in 
treatment of posttransplant cytopenias have been extrapolated from therapies used to manage idiopathic 
thrombocytopenic purpura (ITP) and from autoimmune hemolytic anemia (AIHA) guidelines. 
Additionally, Thrombopoietin (TPO) mimetics have recently been shown to induce modest hematological 
responses in patients developing posttransplant cytopenias [5, 6]. A phase II trial evaluated a total of 60 
patients, 42 received at least one dose of eltrombopag (EPAG) while 18 received placebo [7]; 36% in the 
EPAG arm achieved platelets ≥ 30 x 109/L at the end of 8 weeks vs 28% in the placebo arm. Further, 21% 
of patients in EPAG arm achieved platelets ≥ 50 x 109/L. TPO mimetics function as growth factor rather 
than immune modulators.  
Fostamatinib, a spleen tyrosine kinase (Syk) inhibitor with the active metabolite R406, has been shown to 
reduce antibody-mediated platelet destruction [8]. It was FDA approved in April 2018 for patients with 
chronic ITP who have had an insufficient response to a previous treatment. Moreover, it is currently being 
studied in a phase III clinical trial for subjects with warm autoimmune hemolytic anemia (NCT03764618) 
and in an early phase chronic GVHD trial (NCT02611063). This phase II trial is designed to evaluate the 
efficacy of fostamatinib in the treatment of posttransplant cytopenias as assessed by hematologic 
improvement in anemia and/or thrombocytopenia following a 12-week treatment course.  
2.2 
BACKGROUND  
Posttransplant cytopenias occur in >20% of allogeneic HSCT patients and can lead to severe anemia, 
virulent infections and life-threatening bleeding [9, 10]. Patients with heavy transfusion requirements 
prior to HSCT often develop HLA-alloimmunization, with antibody-mediated anemia developing after 
transplantation as a consequence of donor-recipient RBC antigen mismatch. Post-transplant cytopenias 
due to underlying antibody-mediated immunologic causes are typically treated by conventional therapies 
including steroids, intravenous immunoglobulin (IVIG) or targeted B-cell therapy (e.g. Rituximab). 
Posttransplant cytopenias can also result from underlying cGVHD which is primarily mediated by the 
interaction of cytokines and lymphocyte populations leading to suppression of hematopoietic progenitor 
cells. [11-13]. Alternatively, autoimmune cytopenia can occur as a consequence of immune dysregulation 
in the setting of incomplete immune recovery post-HSCT [14]. Godder et al. reported a retrospective 
analysis of 5 out of 40 patients developing autoimmune hemolytic anemia (AIHA) as a manifestation of 
cGVHD [15]. Although several mechanisms were suggested, the exact underlying pathophysiology 
leading to cytopenias in these patients is unclear. Investigators have hypothesized that GVHD prophylaxis 
selectively targeting T cells while not effecting B-cells could augment B cell function causing 
autoimmune cytopenia [16-18] .  
The Syk pathway (shown below in Figure 1) has an important quantitative and qualitative effects on both 
B and T-cells which play a critical role in the pathogenesis of GVHD. It is critical in B-cell signaling, 
cytokine release, antibody mediated immune responses and T-cell mediated GHVD complications. After 
B-cell receptor ligation by an antigen, activation by phosphorylation of SH2 domain of Syk can lead to 
further downstream autophosphorylation mediated by two secondary messengers inositol triphosphate 

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(IP3) and diacyl glycerol (DAG) [19]. IP3 and DAG effects are mediated through mitogen activated 
protein kinase (MAPK) pathways leading to production of proinflammatory cytokines that enhance T-cell 
proliferation and differentiation (Figure 1). Preclinical reports in xenograft models using PBMCs from 
patients with active cGVHD have shown that Syk inhibition augments B-cells apoptosis [20]. The 
combined effects of Syk inhibition leading to quantitative B-cell depletion, reduced functional B-cell 
signaling and reduced proinflammatory cytokine production could all potentially play a therapeutic role in 
the treatment of cGVHD-related cytopenias.  
 
 
Figure 1. Syk Pathway effects on B and T-cells in cGVHD (adapted from SL Tan, et al. Pharmacol Ther 2013) 
Syk inhibitors could potentially be used to treat antibody-mediated cytopenias occurring post-transplant 
by blocking the Fc receptor on B-cell and other hematopoietic cells including monocytes, macrophage 
and mast cells [21], figure 2.  
 
Figure 2. Current ITP therapies and their mechanisms of action (adapted from O Miltiadous, et al. Blood 2020) 

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The primary driver of Syk pathway signaling is through the FcgRIIA which is driven by antigen-antibody 
complex immune response. Patients with immune mediated cytopenias have rapid clearance of IgG-coated 
circulating blood cells through reticuloendothelial system macrophages carrying the FcgR [22]. Syk 
inhibition using fostamatinib has a central role in blocking this pathway counteracting the underlying 
pathophysiology for antibody mediate cytopenias, figure  3. 
 
  
 
Figure 3. Role of Syk pathway in immune mediated cytopenias (adapted from A McBride, et al. AJMC  2019) 
Therefore, in contrast to TPO mimetics which enhance hematopoietic precursor growth,  one mechanism 
by which fostamatinib induced Syk inhibition could potentially improve post-transplant cytopenias would 
be by inhibiting antibody mediated cellular destruction and/or cytokine related suppression of 
hematopoietic progenitors (see above).  
Based on the above potential mechanism of action, we hypothesize that fostamatinib administration given 
to patients with immune-mediated anemia and/or thrombocytopenia following HSCT will improve 
cytopenias, decrease transfusion hematopoietic growth factor support and the need for 
immunosuppressive therapies.   
Eligible subjects for enrollment include those with antibody immune-mediated cytopenias including a) 
anemia occurring as a consequence of an auto or alloantibody due to an ABO or non-ABO RBC antigen 
mismatch, b) thrombocytopenia due to HLA/HPA auto or alloantibodies, and c) clinically diagnosed 
(with or without serologic confirmation) idiopathic thrombocytopenic purpura and autoimmune hemolytic 
anemia. Further, patients with GVHD related anemia and/or thrombocytopenia will also be eligible for 
treatment. We will exclude subjects with graft rejection as well as non-immune mediated causes of 
cytopenias including but not exclusive to acute bleeding with consumptive coagulopathy, fever, active 
infections, medication induced cytopenias, thrombotic microangiopathies (disseminated intravascular 
coagulation), splenomegaly or hemophagocytic lympho-histiocytosis (HLH). See inclusion and exclusion 
criteria for more details.    
2.3 
RISK/BENEFIT ASSESSMENT 
2.3.1 
Known Potential Risks 
Fostamatinib 

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Fostamatinib is currently FDA approved for the treatment of refractory chronic ITP. To date, over 4,000 
patients have received fostamatinib as part of randomized controlled and open label trials across a variety 
of disease states including rheumatoid arthritis, ITP, autoimmune hemolytic anemia, and oncologic 
diseases. It has a consistent safety profile and the most common adverse reactions (≥5% and more than 
placebo) are diarrhea, hypertension, nausea, respiratory infection, dizziness, ALT/AST increased, rash, 
abdominal pain, fatigue, chest pain and neutropenia. Warnings and precautions included in the US 
product label include hypertension, elevated liver function tests, diarrhea, neutropenia, and embryo-fetal 
toxicity. 
Hypertension 
Hypertensive crisis occurred in 1% of patients and patients with pre-
existing hypertension may be more susceptible 
Hepatotoxicity 
AST/ALT levels more than 3x the upper limited of normal occurs in 9% of 
patients  
Diarrhea 
Occurred in 31% of patients treated but with only 1% of patients 
developing  severe diarrhea  
Neutropenia 
Occurred in 6% of patients with febrile neutropenia occurring in 1% 
Embyro-fetal toxicity 
Based on findings from animal studies and mechanism of action 
fostamatinib can cause fetal harm.  
Concomitant use of strong CYP3A4 inhibitors with fostamatinib will increase exposure to R406 that may 
result in increased risk of adverse reactions while concomitant use of strong CYP3A4 inducers reduces 
exposure to R406. Fostamatinib may increase the concentration  of some CYP3A4 substrate drugs, some 
BCRP substrate drugs (ex. rosuvastatin), and some P-glycoprotein substrate drugs (e.g. Digoxin). 
Especially in transplant subjects, there is the concern for drug-drug interactions with strong CYP3A4 
inhibitors, particularly  frequently used anti-fungal medications including voriconazole, posaconazole, 
ketoconazole and itraconazole. If a subject is on a strong CYP3A4 inhibitor and is unable to be switched 
to a moderate or low CYP3A4 inhibitor, the starting dose of fostamatinib for the 1st 4 weeks would be 150 
mg daily which can be escalated to 100 mg BID if refractory cytopenias persist AND the patient appears 
able to tolerate the higher dose of treatment as determined on the  4-week assessment visit. 
It is not expected that there will be additive or synergistic adverse events with the addition of fostamatinib 
to routinely used transplant medications except for TPO mimetics, which can cause an increase in 
AST/ALT.In addition to the fostamatinib’s adverse reactions listed above, the major potential risks of this 
study relate to complications that stem from a participant’s underlying cytopenia(s) including anemia or 
bleeding.  
Based on findings from animal studies and the mechanism of action, fostamatinib can cause fetal harm 
when administered to a pregnant woman. There are no available data in pregnant women to inform the 
drug-associated risk. 
Blood Draws 
No major risks are involved with blood draws. Minor complications including bleeding, pain, and 
hematoma formation at the site of blood draws, vasovagal reactions or infections may rarely occur. 
 
2.3.2 
Known Potential Benefits 
Fostamatinib may or may not improve the clinical outcome of individuals with posttransplant 
cytopenia(s) which will be further investigated in this trial. This will be a proof of concept trial and have 
future clinical and research implications if proven to be successful. Subjects will potentially have 
significant improvement in their quality of life, potentially decreasing requirements for transfusion 
support, hematopoietic growth factors and the need for immunosuppressive therapies.  

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2.3.3 
Assessment of Potential Risks and Benefits 
Fostamatinib has a consistent safety profile and adverse events related to the drug are clearly documented 
and understood.  
The underlying pathophysiology of immune mediated posttransplant cytopenias can be divided into 
antibody-mediated or cGVHD associated mechanisms. There are no specific guidelines for post-
transplant cytopenias and all the current treatment algorithms are extrapolated from autoimmune 
hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) treatment. Conventional 
therapies including steroids, IVIG or targeted B-cell therapy (e.g. rituximab) are currently used as 
treatment but many patients have refractory cytopenias despite these treatments. The Fostamatinib in 
Thrombocytopenia (FIT) trials that led to the FDA approval of fostamatinib in chronic ITP showed 
around 15% higher durable response in comparison with the placebo arm. Additionally, the FIT trials 
showed around 30% higher overall response rates in comparison with placebo.  
For post-transplant cytopenias, fostamatinib has potential advantages over other conventional therapies 
targeting B-cells as the Syk pathway is upstream of BTK, which is a validated target for GVHD 
treatment. Further, since fostamatinib inhibits FcGRII signaling, we hypothesize this agent will be of 
therapeutic benefit in HSCT patients who have antibody mediated destruction of platelets and RBCs. We 
therefore hypothesize that fostamatinib administration given to patients with immune mediated 
anemia/and or thrombocytopenia posttransplant will improve cytopenias, potentially decreasing 
requirements for transfusion support, hematopoietic growth factors and the need for immunosuppressive 
therapies.   
3 
STUDY DESIGN 
 
3.1 
OVERALL DESIGN 
Our plan is to study fostamatinib for the treatment of immune-mediated posttransplant cytopenias 
(anemia, thrombocytopenia or both)  
• 
This will be a multicenter,  open label, phase II study, with no control arm with the 
primary objective to test the efficacy of fostamatinib in the treatment of posttransplant 
cytopenias.   
• 
All study participants will receive fostamatinib 100 mg BID for 4 weeks. On the 4-week 
evaluation, a) if the cytopenia improves (hemoglobin ≥10 g/dL, platelets ≥ 50 x 109/L), 
patients will continue the same dose for a total of 12 weeks b) if  refractory cytopenias 
persist (hemoglobin < 10 g/dL, platelets < 50 x 109/L), subjects will increase dose to 
150mg BID. Subjects with persistent (≥2 readings, 2 weeks apart) loss of hematologic 
response after week 5 can increase the study drug dose to 150mg BID until they are at the 
end of the study on week 12.     
• 
This trial will be done primarily in an outpatient setting. Follow up visits will be 
completed as outpatient in-person visits at the participating site or via telehealth or 
telephone if patients are unable to travel for any reason, with labs drawn by local 
providers in this circumstance.  
• 
The 4-week assessment is the first milestone where dose can be adjusted if necessary. At 
the end of the trial, participants with objective hematologic recovery will be given the 
option to enroll onto an extended access trial, including: 
▪ 
Post-transplant anemia who achieved a hemoglobin ≥9 g/dL (or 1 g/dL above 
baseline) without transfusion support, at least once in the 12-week phase II study 
period 

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▪ 
Post-transplant thrombocytopenia who achieved a platelet count ≥ 30 x 109/L (or 
10 x 109/L above baseline), without transfusion support, at least once in the 12-
week phase II study period 
▪ 
Either of the above in subjects with Evans syndrome 
• 
The plan is to treat and include a total of 20 patients in the analysis in this single arm 
trial. 
 
3.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Post-allogeneic hematopoietic stem cell transplant (HCT) cytopenias often result from immunologic 
causes, where adequate bone marrow precursor cells exists but RBCs and/or platelets are peripherally 
destroyed by antibody mediated processes or their production is suppressed as a consequence of graft 
versus host disease (GVHD) [2]. Autoimmune cytopenia is a well-recognized manifestation of chronic 
GVHD (cGVHD) that usually occurs in the presence of other clinical signs of cGVHD [3, 4]. Several 
treatment options used to treat posttransplant cytopenias have been extrapolated from therapies used to 
manage idiopathic thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) 
guidelines.  
Fostamatinib, a spleen tyrosine kinase (Syk) inhibitor with the active metabolite R406, has been shown to 
reduce antibody-mediated platelet destruction [8]. It was FDA approved in April 2018 for patients with 
chronic ITP who had an insufficient response to a previous treatment. Additionally, it is currently being 
studied in a phase III clinical trial for subjects with warm autoimmune hemolytic anemia (NCT03764618) 
and in an early phase chronic GVHD trial (NCT02611063). This phase II trial is designed to evaluate the 
efficacy of the novel Syk inhibitor (fostamatinib) in the treatment of posttransplant cytopenias as assessed 
by hematologic improvement in anemia and/or thrombocytopenia following a 12-week treatment course.  
3.3 
JUSTIFICATION FOR DOSE 
The dose was based on prior FDA approval of fostamatinib use in chronic ITP and the ongoing phase III 
trial for wAIHA. The starting dose is 100 mg BID which can be increased to 150 mg BID if still 
refractory on the 4-week evaluation. Taper and dose modification are described in details in Section 
5.1.2.3.  
 
4 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
Efficacy of fostamatinib for stable 
hematologic recovery during post-
hematopoietic stem cell transplant 
immune mediated anemia and/or 
thrombocytopenia. 
 
 
• 
The proportion of subjects with 
hematologic recovery that is stable, 
defined as improvement 
documented in 2 consecutive 
available readings at least 2 weeks 
apart, without recent blood product 
transfusion support in the past 7 
days.  
 
Hematologic recovery is defined as: 
• 
Hemoglobin ≥10 g/dL (or at 
least ≥2 g/dL above 
The endpoints are all 
clinically relevant to 
answer the trial 
hypothesis and 
indicative of clinical 
recovery. The 
endpoints were chosen 
to be similar to the 
previous FIT trials that 
led to FDA approval of 
fostamatinib in chronic 
ITP.  

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baseline&) in subjects with 
posttransplant anemia. In 
subjects with symptomatic 
anemia*, a hemoglobin 
increase of at least ≥2 g/dL 
above baseline is required 
 
OR 
• 
Platelets ≥ 50 x 109/L (or at 
least ≥20 x 109/L above 
baseline) in subjects with 
posttransplant 
thrombocytopenia  
 
OR  
• 
Both of the above criteria in 
subjects with posttransplant 
Evans syndrome 
 
 
Secondary 
Efficacy of fostamatinib for 
clinically-relevant outcomes in 
post-hematopoietic stem cell 
transplant patients 
1. Proportion of subjects who 
achieve objective hematologic 
recovery within the 12-week 
treatment course defined as: 
 
• 
Hemoglobin ≥9 g/dL (or at 
least ≥1 g/dL above baseline) 
in subjects enrolled with 
anemia or at least ≥1 g/dL 
above baseline in subjects 
with symptomatic anemia 
 
OR 
• 
Platelets ≥ 30 x 109/L (or at 
least ≥10 x 109/L above 
baseline) in subjects enrolled 
with thrombocytopenia  
 
OR 
• 
Either of the above criteria in 
subjects with Evans 
syndrome 
 
2. Average weekly requirement of 
transfused blood component or 
growth factor requirement (total 
units of PRBC or Platelets/week, 
total dose of growth factor/week) 
The secondary 
endpoints are all 
relevant to safety of 
fostamatinib for post-
hematopoietic stem cell 
transplant setting 

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by week 12, compared to the 
week prior to the start of the study 
drug.  
3. Change in corticosteroid dose 
over time, measured by median 
daily weight-based prednisone-
equivalent corticosteroid dose in a 
week, from week 1 to week 12  
4. Change in other 
immunosuppressant dose over 
time, measured by median daily 
dose of the immunosuppressant in 
a week, from week 1 to week 12 
5. Number of patients who achieved 
≥50% steroid dose reduction by 
week 12 compared to week 1 
6. Incidence and severity of cGVHD 
according to 2014 NIH Consensus 
Criteria, at baseline before the 
initiation of treatment, and at 
week 12 
 
Tertiary/Exploratory 
The exploratory objective is to 
evaluate changes in serologic 
marker while on treatment to 
identify key biological pathways 
impacted by fostamatinib that may 
lead to a response to therapy  
 
1. Absolute percentage change in B 
cell chimerism pre-treatment, vs 
weeks 4 and 12. 
2. cPRA change in the preformed 
HLA antibodies before and after 
treatment in subjects with 
thrombocytopenia or Evans 
syndrome  
3. Percent MFI change of 
preformed HLA antibodies 
before and after treatment. This 
applies for antibodies with an 
MFI >1,000.  
4. Anti-RBC alloantibody titer 
change in patients with 
hemolytic anemia before and 
after treatment  
5. Assessment of serial cytokines 
pre-treatment and weeks 4 and 
12. Cytokines include CRP, IL-1, 
IL-2, IL-6, IFN𝛾, TNFα, EPO 
and TPO  
6. Immunoglobulin level changes 
pre-treatment, and weeks 4 and 
12. 
These exploratory 
endpoints are relevant 
to the ex vivo and in 
vitro analysis that will 
help predict response 
and define mechanisms 
of action of 
fostamatinib for 
resolving cytopenias 
 

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7. Absolute reticulocyte count, 
lactate dehydrogenase, 
haptoglobin changes pre-
treatment, and at each biweekly 
study visit, in patients with 
anemia or Evans syndrome  
8. Change in the weekly rate and 
severity of bleeding according to 
the total score of the IBLS, from 
week -1 (one week before the 
start of the study drug) to week 
12, in subjects with 
thrombocytopenia or Evans 
syndrome# 
&: Baseline is defined as the mean of the last two hemoglobin or platelet measured at least 24 hours apart, 
at least 72 hours from the last transfusion, within 14 days of the start of the study drug 
*: Symptomatic anemia is defined as anemia with fatigue, weakness, shortness of breath, palpitations/fast 
heartbeat, lightheadedness, and/or chest pain, and these symptoms are attributed to anemia 
#: the IBLS [1] is a bleeding score system that assess 11 different sites of bleeding by site-specific scales 
 
5 
STUDY POPULATION 
Subject inclusion and exclusion criteria will be reviewed as appropriate by a member of the site’s study 
team. If there is any uncertainty, the PI will make the final decision as to whether a potential subject is 
eligible for study enrollment. 
5.1 
INCLUSION CRITERIA 
▪ 
Ages 18-75 years inclusive  
▪ 
Ability to comprehend the investigational nature of the study and provide informed consent 
▪ 
Female patients of reproductive potential agree to avoid pregnancy through abstinence or the use 
two forms of highly effective birth control during and for 1 month after the last study treatment 
and agree not to donate eggs during this time  
▪ 
male patients of reproductive potential agree to avoid pregnancy of a partner through abstinence 
or the use two forms of highly effective birth control during and for 1 month after the last study 
treatment and agree not to donate sperm during this time. 
▪ 
Diagnosis of an immune mediated cytopenia (anemia and/or thrombocytopenia)‡ in a patient that 
either: 
o 
Failed or relapsed after at least one line of therapy including steroids, IVIG, TPO 
mimetics, rituximab, azathioprine, cyclophosphamide, cyclosporine, tacrolimus, danazol, 
vincristine, ESA or splenectomy 
o 
Or remains transfusion dependent (≥1 transfusion(s)/2 weeks) 
o 
Or is steroid dependent* 
▪ 
Subjects are ≥60 days post-allogeneic transplant with: 
▪ 
Thrombocytopenia, defined as average platelets count <30 x 109/L for 3 consecutive 
available readings at least 2 weeks apart, after other cell lines have engrafted, with no 
counts >40 x 109/L unless from rescue transfusions. Subjects failed at least one line of 
therapy outlined above with a clinical diagnosis of immune mediated thrombocytopenia.   

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▪ 
Anemia, transfusion dependent, or defined as hemoglobin ≤9 g/dL for 3 consecutive 
available readings at least 2 weeks apart, after other cell lines have engrafted OR if 
hemoglobin 9-10 g/dL, subject must have symptomatic anemia or ongoing treatment for 
immune hemolytic anemia that have failed at least one line of therapy outlined above. 
Symptomatic anemia is defined as anemia with fatigue, weakness, shortness of breath, 
palpitations/fast heartbeat, lightheadedness, and/or chest pain, and these symptoms are 
attributed to anemia. Laboratory evaluation are recommended but not required for the 
diagnosis, such as a positive DAT, low haptoglobin <lower limit of normal (LLN), 
indirect bilirubin > upper limit of normal (ULN), or lactate dehydrogenase (LDH) >ULN.  
▪ 
Subjects must test negative for HIV, HBV, and HCV by standard serologic tests within the 
previous six months 
▪ 
Subjects on other standard of care therapeutic regimens for GVHD or cytopenias should be on a 
stable dose of medication (no change >=25%) for at least 15 days prior to enrollment.   
▪ 
Patients with a history of hypertension should be maintained on a stable antihypertensive regimen 
and with controlled blood pressure (Systolic blood pressure < 140 mmHg and diastolic blood 
pressure <90 mmHg) for at least one week prior to enrollment. 
▪ 
Peripheral blood or bone marrow T-cell chimerism >=50% donor cells 
▪ 
‡ Immune mediated anemia in subjects with auto or alloantibodies identified due to ABO or 
non-ABO mismatch transplant, or thrombocytopenia due to identified HLA/HPA antibody. 
Other causes of immune mediated cytopenias include clinically diagnosed (with or without 
serologic confirmation) idiopathic thrombocytopenic purpura or autoimmune hemolytic 
anemia. Subjects with cytopenias attributable to GVHD will be included. Subjects with 
idiopathic immune mediated cytopenias can also be included. Subjects with evidence for 
graft rejection per the investigator's opinion ARE NOT eligible for treatment.  
* Steroid dependence is defined as inability to tolerate a corticosteroid taper after demonstrating a 
response to an initial corticosteroid dose (typically 1-2 mg/kg/day). Patients will meet our definition of 
steroid dependence if their cytopenias relapse or progress before achieving a 50% decrease in the initial 
corticosteroid dose and/or are unable to have their steroid dose tapered to a dose of less than 20 mg/day of 
prednisone.  
5.2 
EXCLUSION CRITERIA 
▪ 
Severe psychiatric illness or mental deficiency sufficient to make making informed consent 
impossible  
▪ 
Positive pregnancy test for women of childbearing age within 1 week or being actively lactating  
▪ 
Immune mediated cytopenia responsive to the standard of care treatment  
▪ 
Immune mediated cytopenia due to other autoimmune causes, such as systemic lupus 
erythrocytosis, chronic lymphocytic leukemia 
▪ 
Patients who have previously received or currently take fostamatinib post-allogeneic transplant 
▪ 
Non-immune mediated cytopenias. Etiologies including, but not limited to, cytopenias due to 
HIV infection, lymphoproliferative disorders, myelodysplasia/acute leukemia, drug-induced 
thrombocytopenia, thrombotic microangiopathies, acute bleeding, consumptive coagulopathy, 
fever, infections leading to cytopenia, medications induced cytopenias, thrombotic 
microangiopathies (disseminated intravascular coagulation), splenomegaly or hemophagocytic 
lymphohistiophagocytosis, relapse of primary disease. 
▪ 
Patients with neutropenia, defined as absolute neutrophil count <=1.0 x 109/L, will be excluded  
▪ 
Uncontrolled hypertension (systolic blood pressure >=140mmHg or diastolic blood pressure 
>=90mmHg) 

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▪ 
ALT or AST >=3 times the upper limit of normal, or direct bilirubin >=2 times the upper limit of 
normal 
▪ 
Patients who have a history of medical disorders, that in the investigator's opinion, could affect 
the conduct of the study or the absorption, metabolism or excretion of the study drug are 
excluded.  
▪ 
Patients with lymphoma/chronic lymphocytic leukemia, hepatitis, or HIV associated with 
ITP/wAIHA 
▪ 
Patients with evidence of graft rejection (based on clinical suspicion supported by BM biopsy 
data and/or chimerism studies and/or MLR)  
▪ 
Subjects recently treated (within 30 days) with cytokine-targeting biologics (anti-TNF, IL6) or B-
cell or plasma-cell depleting antibody. 
▪ 
Other cancers except that for which the transplant was done < 2 years before study entry, except 
non-melanoma skin cancer or carcinoma in situ of the uterine cervix or breast 
 
5.3 
INCLUSION OF VULNERABLE PARTICIPANTS 
Adults unable to give consent are excluded from enrolling in the protocol. However, there is a possibility, 
though unlikely, that subjects could become decisionally impaired during the course of the study. Since 
there is a prospect of direct benefit from research participation, they may remain enrolled in the study as it 
is necessary for completion of the study objectives. If a subject loses the ability to consent due to an 
adverse event/serious adverse event, the subject will remain on study until that event resolves.  
 
Legally Authorized Representative (LAR) 
 
If subjects will remain in the study, a Legally Authorized Representative (LAR) will be identified and 
informed consent obtained from the LAR. Please see sections 10.1.1 and  10.1.4 for consent procedure. 
 
Non-NIH Enrolling Sites 
LAR will be assigned per institution requirements. 
 
NIH Clinical Center  
All subjects will be offered the opportunity to fill in their wishes for research and care, and assign 
a substitute decision maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation” form so that another person can make decisions about their medical care in the event 
that they become incapacitated or cognitively impaired during the course of the study. The PI or 
AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed 
for the following: an independent assessment of whether an individual has the capacity to provide 
consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an 
assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and 
do not have pre-determined substitute decision maker, the procedures described in NIH HRPP 
Policy 403 for appointing a surrogate decision maker for adult subjects who are (a) decisionally 
impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed. 
 
5.4 
LIFESTYLE CONSIDERATIONS 
Study participants should refrain from drinking alcohol. 
Study participants and their partners should avoid pregnancy through abstinence or use of two highly 
effective forms of contraception until 1 month after last day of study drug. 
 

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5.5 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently assigned to the study intervention or entered in the study because the participants did not 
meet the trial eligibility or withdrew consent. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be rescreened 
once. The time interval between the initial screen and the rescreen should be ≥ 1 month. The re-screened 
participant will be assigned a new, unique participant number. 
 
5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Non-NIH Enrolling Sites 
Subjects will be recruited at each participating site in accordance with the site’s recruitment strategy. 
  
NIH Clinical Center  
A Strategic Recruitment Plan (SRP) will be developed with the NHLBI Patient Recruitment Office (PRO) 
and ongoing regular meetings will be held with the PRO to ensure the study is meeting enrolment 
projections.  
Referrals are expected primarily from BMT specialists; however, participants may be recruited via self-
referral. 
The recruitment strategies to be used for this study may include: 
• 
Social media postings on Facebook and Twitter from NIH accounts – these may be paid or 
unpaid. 
• 
Listings on official NIH websites to include: 
1. Clinicaltrials.gov  
2. Clinical Center Recruitment website with dedicated study page mirroring the patient 
recruitment flyer.  Page links to CT.gov and/or Search the Studies. 
3. Clinical Center Research Studies (“Search the Studies”) website 
• 
Clinical Center TV (CCTV) – these large TVs placed all around the NIH Clinical Center will 
rotate through various messages including one for this study. 
• 
The AAMDS website and/or social media accounts (using IRB approved language, flyer, and/or 
social media language with photos.) 
• 
Use of Clinical Center Office of Patient Recruitment Services (OPR) including OPR Listservs 
(Email list of those interested in receiving study recruitment updates.) (Links to one of the above 
mentioned websites or pages). Includes the OPR Protocols and OPR Healthy Volunteers listservs 
and 3 NIH listservs (NIH Post back, NIH Clinical Fellows & NIH Study Volunteers), 
• 
Craigslist & Research Match, NIH Newsletters 
• 
An informational letter to physicians will be available for electronic (and hard copy as 
appropriate) distribution to local and other clinical specialist contacts. 
In addition, to help recruit subjects for the study, a query within the Biomedical Translational 
Research Information System (BTRIS) will be run to help identify persons based on inclusion 
criteria (described in section 5.1). This query will be run bi-weekly where laboratory data is 

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searched for adult subjects who have had allogenic transplant at the NIH within the past 10 
years. The query process will be as follows: 
a) Platelet count: Thrombocytopenia, defined as average platelets count <30 x 109/L for 3 
consecutive available readings at least 2 weeks apart 
b) Hemoglobin:  defined as hemoglobin ≤ 9 g/dL for 3 consecutive available readings at 
least 2 weeks apart 
c) Adults: Ages 18-75 years inclusive 
d) Subjects are  ≥ 60 days post-allogeneic transplant  
 
BTRIS will generate a list of subjects who meet the query criteria including their NIH medical 
record numbers. BTRIS will not include information on a subject’s protocol or principal 
investigator. The following process will be used to obtain that information: 
1. The “Protocol Information” tab within a subjects’ Clinical Research Information System 
(CRIS) entry will be checked to determine the name of the Principal Investigator of that 
patient’s applicable HSCT protocol. 
2. The PI will be contacted by 000758 protocol personnel via secure email informing them 
that their patient may be eligible for our protocol. The email will ask the PI to consider 
sharing information about the protocol with their patient.  
3. The PI will be provided with approved recruitment materials that they may share with 
their patient and provide the patient information about our study, inclusion criteria and 
study contact. 
 
If recruitment projections/goals are not being met, additional strategies will be planned and implemented 
by the PRO. 
 
5.6.1 
Costs 
By virtue of NHLBI sponsorship of clinical research protocols, enrolling sites qualify for Centers 
for Medicare and Medicaid Services (CMS) coverage of associated routine costs of medical care 
under the CMS Clinical Trial Policy (CTP). This policy is detailed at 
https://www.cms.gov/Medicare/Coverage/ClinicalTrialPolicies/index.html. According to this 
policy, CMS is explicitly authorized to provide payment for routine patient care costs and costs 
due to medical complications associated with participation in clinical trials. 
5.6.2 
Compensation 
Study subjects will not be compensated for participation in this study. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTIONS(S) ADMINISTRATION 
6.1.1 
Study Intervention Description 
Eligible subjects will receive oral fostamatinib BID for 12 weeks. with the option to enroll on the 
extended access trial if deemed to be responsive at the end of the study.  

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6.1.2 
Dosing and Administration 
Participants will receive fostamatinib 100 mg BID for 4 weeks.  
6.1.2.1 
Dose Continuation or Dose Escalation 
On the 4-week evaluation,  
a) if cytopenia improves (hemoglobin ≥10 g/dL, platelets ≥ 50 x 109/L), patients will continue the same 
dose for a total of 12 weeks,  
b) if refractory cytopenias persist (hemoglobin < 10 g/dL, platelets < 50 x 109/L), the dose will be 
increased to 150 mg BID. Subjects with persistent (≥2 readings, 2 weeks apart) loss of hematologic 
response after week 5 can increase their dose to 150 mg BID until at end of the study on week 12.     
6.1.2.2 
Dose Limiting Toxicity 
N/A 
6.1.2.3 
Dose Modifications 
Fostamatinib dose modification is recommended based on individual safety and tolerability. Management 
of some adverse reactions may require dose-interruption, reduction, or discontinuation. 
A dose reduction schedule (DRS) is provided below. For example, if a patient is on the maximum (300mg 
total daily dose) at the time of an adverse reaction, the first dose reduction would be from 300mg/day to 
200mg/day. 
 
Dose Reduction Schedule (DSR) 
Total daily dose 
Dosing Schedule 
Morning 
Evening 
300mg 
150mg 
150mg 
200mg 
100mg 
100mg 
150mg 
150mg1 
--- 
100mg2 
100mg1 
--- 
1: Once daily fostamatinib should be taken in the morning. 
2: If further dose reduction below 100mg/day is required, stop fostamatinib 
 
Treatment may be delayed for a maximum of 14 days after holding the treatment for toxicities that 
develop and do not resolve as defined at 6.1.2.3 (neutropenia, LFT elevation, and diarrhea). The timing of 
subsequent lab and the study week are then adjusted to the study week that was stopped. 
 
The recommended dose modification for adverse reactions are as the following: 
 
 
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 (refer to 
DRS). 
• Consider cardiology consult 

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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 (refer to DRS). 
• If BP remains 160/100 mmHg or higher for 
more than 4 weeks despite aggressive 
antihypertensive therapy, interrupt or 
discontinue fostamatinib. 
• Consider cardiology consult 
 
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. 
• Consider cardiology consult 
Hepatotoxicity 
 
AST/ALT abnormal at enrollment but < 3x ULN 
Recheck LFTs every week to ensure it is still <3x 
ULN. Patient may have it checked locally and 
have results faxed to the NIH. 
Increase in AST/ALT by x3 from level at the time 
of enrollment but less than 3 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 direct bilirubin (DBL) remains less than 2 x 
ULN. 
• Resume fostamatinib at next lower daily dose 
(refer to DSR). 
If patient is asymptomatic: 
• Recheck LFTs every 72 hours until ALT/AST 
are below 1.5 x ULN) and DBL remains less 
than 2 x ULN. 
• Consider interruption or dose reduction of 
fostamatinib if ALT/AST and DBL remain in 
this category (AST/ALT is less than 3x ULN; 
and DBL remains less than 2 x ULN). 
• If interrupted, resume fostamatinib at next lower 
daily dose (refer to DSR) 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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Increase in AST/ALT by x3 ULN and DBL 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 3 x 
ULN) and total BL remains less than 2 x ULN; 
resume fostamatinib at next lower daily dose 
(refer to DSR). Per PI discretion, subject can be 
re-escalated one level at a time until back to the 
maximum tolerable 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 DBL 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) 
bilirubin may be due to UGT1A1 inhibition or 
active hemolysis  
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 (refer 
to DSR). 
Neutropenia 
 
Neutropenia 
•  If absolute neutrophil count decreases (ANC 
less than 1.0 x 109/L) and remains low after 72 
hours, or the neutropenia can be attributed to 
other causes (see below), patient can receive 
standard dose (5mcg/kg or rounded to the 
closest vial or syringe size) filgrastim at the 
discretion of the primary team and continue 
fostamatinib. If neutropenia responds to 
filgrastim (ANC greater than 1.5 x 109/L), 
patient should continue fostamatinib. 
• If no other causes are identified and the 
neutropenia is attributed to fostamatinib, or 
patient does not respond to, or cannot receive 
filgrastim, temporarily interrupt fostamatinib 
until neutropenia resolves (ANC greater than 1.5 
x 109/L), and resume fostamatinib at the next 
lower daily dose (refer to DSR). 
Febrile neutropenia  
Febrile neutropenia is a life-threatening 
complication and urgent broad-spectrum 

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antibiotics, as well as an aggressive search for the 
source and microbial cause of the episode. 
• First febrile neutropenia: hold fostamatinib then 
restart at the next lower dose level after 
resolution of febrile neutropenia (refer to DSR) 
• Second febrile neutropenia on the next lower 
dose level: stop fostamatinib and remove the 
patient from study 
 
▪ 
In the event that the subject is unable to tolerate 100 mg BID, the dose can be reduced to 150mg daily 
with re-assessment. If intolerable AEs with 150 mg daily, dose can be reduced to 100 mg daily. If 
unable to tolerate 100mg daily, patient will stop fostamatinib and will be off study. Intolerance is 
considered as any grade 3-4 AEs, probably or definitely related to fostamatinib, or any grade AE 
which, at the PI’s discretion, appears to be distressing enough to the patient to lead to the drug’s 
discontinuation. If the adverse events resolved and subject tolerates the dose reduction with no 
recurrence of AE, per PI discretion subject can be re-escalated one level at a time until back to the 
maximum tolerable dose.  
▪ 
Causes of neutropenia in a AHCT recipient may include: infections such as cytomegalovirus infection, 
medication such as ganciclovir or other antibiotics, immunosuppressants such as mycophenolate or 
ruxolitinib, graft failure, relapse of primary disease. If neutropenia occurs, we will perform an 
extensively work up on the patient for the other causes stated above, and/or hold other potential culprit 
medications. We will give filgrastim to patients while doing the above work up. If no other causes are 
found, and the neutropenia does not recover, or recurs, with holding other medications, we will 
conclude that fostamatinib is contributing to the development of neutropenia. 
▪ 
GvHD may mimic adverse events. If holding fostamatinib according to the DSR does not reverse the 
diarrhea, abdominal pain, transaminase elevation, AND there are no other causes (such as infection) 
identified, we will consider the cause of the adverse events to possibly be related to GVHD. In such 
circumstances, we will make every effort possible to perform biopsies of the involved organ systems 
to confirm the diagnosis of GvHD.  
 
Dose adjustment for platelet counts and hemoglobin are as the following: 
 
Thrombocytosis  
 
PLT ≥200 x 109 /L to ≤400 x 109 /L at any time 
• Decrease the dose to the next lower dose level. 
Wait 2 weeks to assess the effects of this and 
any subsequent dose adjustments.  
PLT >400 x 109 /L at any time 
• Stop fostamatinib. Increase the frequency of 
platelet monitoring to twice weekly. 
• Once the platelet count is <150 x 109 /L, resume 
fostamatinib at the next lower dose level 
PLT >400 x 109 /L after 2 weeks of therapy at the 
lowest dose of fostamatinib 
• Discontinue fostamatinib 
Polycythemia 
 
Hb ≥ 13 g/dL to ≤ 15 g/dL at any time 
• Decrease the dose to the next lower dose level. 
Wait 2 weeks to assess the effects of this and 
any subsequent dose adjustments.  

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Hb > 15 g/dL at any time 
• Stop fostamatinib. Increase the frequency of 
platelet monitoring to twice weekly. 
• Once the Hb <13 g/dL, resume fostamatinib at 
the next lower dose level 
Hb > 15 g/dL after 2 weeks of therapy at the 
lowest dose of fostamatinib 
• Discontinue fostamatinib 
 
6.1.2.4 
Drug Administration 
Fostamatinib may be taken with or without food. In the case of a missed dose of fostamatinib subjects 
should take their next dose at its regularly scheduled time. For subjects able to swallow medication should 
be taken orally. For subjects who are unable to swallow, drug should be crushed and provided via feeding 
tube access. Tablets should be crushed until granular with an approximate particle size <2 mm, added to 
approximately 10 mL of water, and stirred to mix before administration through the orogastric or 
nasogastric tube. 
Subject who are on a strong CYP3A4 inhibitor and unable to switch to a moderate or low CYP3A4 
inhibitor, the starting dose for the 1st 4 weeks would be 150 mg daily and can be escalated to 100 mg BID 
if refractory cytopenias and able tolerate the treatment at the 4-week assessment visit. Subject who are on 
a weak or moderate CYP3A4 inhibitor can start at the routine dose of 100mg BID and follow closely for 
adverse events. See appendix A for a full list of CYP3A4 inhibitors.  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 
Acquisition and Accountability 
Investigational product (IP) will be shipped to the site either directly from Rigel Pharmaceuticals, or from 
other regional or local drug repositories. All other supplies should be provided by the site. Multiple lots of 
IP may be supplied.  
The site PI is responsible for study product distribution and disposition and has ultimate responsibility for 
study product accountability. The PI may delegate to the research pharmacist responsibility for study 
product accountability. The site’s research pharmacist will be responsible for maintaining complete 
records and documentation of study product receipt, accountability, dispensation, storage conditions, and 
final disposition of the study product(s).  
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
Fostamatinib will be provided by Rigel Pharmaceuticals and stored in the pharmacy of each participating 
site. The drug product consists of 2 strengths of orange film-coated, plain, bioconvex tablets. The 150-mg 
tablet is oval and the 100-mg tablet is round.  The tablets are supplied in white opaque high-density 
polyethylene bottles capped with white polypropylene child resistant closures with foil induction seals. 
6.2.3 
Product Storage and Stability 
Store at room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C 
(59°F to 86°F). Do not remove desiccants.  
6.2.4 
Preparation 
For patients who are able to take oral medication there is no preparation of the tablets. For patients who 
are unable to take oral medication tablets should be crushed until granular with an approximate particle 
size <2 mm, added to approximately 10 mL of water, and stirred to mix before administration through the 
feeding tube. 

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6.2.5 
Return and Reconciliation  
The number of tablets dispensed and returned is to be documented on the accountability log and 
reconciled by site personnel. The study monitor will review both the dispensing and dosing administration 
record to verify the drug accountability 
6.2.6 
IP Destruction   
At the end of the trial all used and unused drug need to be destroyed by the site or designee.  The CRA 
will complete the final accountability and ensure a Proof of Destruction is obtained. 
 
Records of the destruction of any unused study drug must be kept and filed in the Pharmacy Binder and 
written confirmation must be provided to Rigel at the end of the trial to confirm destruction of surplus IP. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
N/A 
6.4 
STUDY INTERVENTION COMPLIANCE 
The research team will review the medication pill count upon follow up visits and document any missing 
doses.   
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the CRF are concomitant 
prescription medications used for the treatment of posttransplant cytopenias.  
For patients that are eligible for the study, other therapy received prior to enrollment with any other 
experimental treatment or off-label use of marketed medications or currently stable dose for 15 days prior 
to enrollment is not an exclusion criterion of the trial.  
Do not report vitamins, herbal supplements, or topical medications. Do not report over-the- counter 
medicines that the subject reportedly took at home prior to enrollment.  
Please refer to section 2.3.1 for drug-drug interactions. 
6.6 
TRANSFUSIONS 
During the study period, packed RBC transfusion should be administered when hemoglobin <7g/dL, or 
<9g/dL with symptoms; platelet transfusion should be administered when platelet count <10g/dL. 
Additional transfusions may be administer per the discretion of the PI or the local HCT provider. The 
number of units transfused should be documented.   
Transfusions between scheduled study visits can be done locally or at the sites per institutional standards. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
See section 6.1.2.3 for information on dosing modifications or discontinuation rules based on laboratory 
abnormalities or other adverse events. 

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Subjects who have the study product stopped for safety related issues will not continue with dosing. In 
addition, subjects who have an allergic reaction that is temporally associated with study product 
administration and the PI believes it to be related to study product will not receive any more study 
product.  
In addition, a subject in this clinical study may discontinue study drug at their request for any reason. 
Every effort should be made to encourage subjects to remain in the study for the duration of their planned 
outcome assessments. Subjects should be educated on the continued scientific importance of their data, 
even if they discontinue study drug.  
Discontinuation from the study drug does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be recorded as an adverse event (AE). 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Reason for discontinuation 
• 
Any adverse event  
• 
Patients will be followed for clinical data required for the duration of the study  
Participants are free to withdraw from participation in the study at any time upon request. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Investigator discretion 
• 
Positive pregnancy test 
• 
Participant unable to receive study drug 
• 
Participant non-compliance, defined as missing >20% of the study drug during any 4-week study 
interval 
• 
If participant has drug interruptions more than 14 days due to toxicity (as defined at 6.1.2.3), 
participants will be withdrawn from the study. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY   
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 14 days following the last dose of study therapy. 
 
• 
Participants are free to withdraw from participation in the study at any time upon request.  
• 
Participants can be taken off study at any time per site principle investigator discretion (e.g. for 
significant noncompliance or if the PI believes it would be in the subject’s best interest).  
• 
Patients rolled over to Extended Access protocol 000760 will be discontinued from this protocol. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the  Case 
Report Form (CRF). Subjects who sign the informed consent form but do not receive the study 
intervention may be replaced.   
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for a scheduled visit and is 
unable to be contacted by the study site staff.  

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The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within one week 
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. 
• 
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 or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record or study file.  
• 
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. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
SCREENING PROCEDURES 
8.1.1 
Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• 
Email, written, in person or telephone communications with prospective subjects.  
• 
Review of existing medical records to include H&P, laboratory studies, etc.   
• 
Review of existing MRI, x-ray, or CT images. 
• 
Review of existing photographs or videos. 
• 
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes. 
8.1.2 
Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the consent for this study.  
• 
Physical examination 
• 
Pregnancy test (for female subjects of childbearing age) 
• 
Clinical labs (CBC, liver enzymes panel, basic metabolic panel, lactate dehydrogenase, , HIV 
testing, absolute reticulocyte count, haptoglobin, stool occult blood, urinalysis ), if not available 
The overall eligibility of the subject to receive the study drug will be assessed once all screening values 
are available and completion of an eligibility checklist. 
8.2 
EFFICACY ASSESSMENTS 
For all baseline assessments and follow-up visits, refer to the Schedule of Assessments (SOA) for 
procedure to be done, and details below for each assessment.  
The subject’s clinical status will be captured on each study biweekly follow up visit through the end of 
the study. 
8.2.1 
Clinical Evaluations 
Physical examination A targeted physical examination will be performed at baseline prior to initial study 
product administration on Day 1. The baseline physical examination can be one that is conducted from 
screening to Day 1. Post-baseline physical examinations will be done only when needed to evaluate 
possible adverse event(s) (i.e. any new signs or symptoms). WHO bleeding assessment should be done on 
each follow up visit. No routine physical exam is needed for study visits after Day 1.  

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Radiographic or other imaging assessments.  
N/A 
8.2.2 
Biospecimen Evaluations 
Research bloods will be sent to the NIH for processing in either the clinical laboratory or in a NHLBI 
research lab.  
The amount of blood that may be drawn from adult patients (i.e., those persons 18 years of age or older) 
for research purposes shall not exceed  300 mL over any eight-week period.  
Please refer to laboratory manual for further information about processing and shipment. 
 
Table of samples to be collected* 
Test/assay 
Volume 
blood 
(approx.) 
Type of tube 
Frequency 
Location of 
specimen analysis 
Routine*  
• 
CBC 
• 
Absolute 
reticulocyte count 
 
• 
BMP 
• 
Hepatic pane 
• 
Lactate 
dehydrogenase 
• 
haptoglobin 
 
 
3 mL 
 
 
 
4 mL 
 
EDTA tube 
 
 
 
Lithium Heparin 
tube (light green)  
 
 
Baseline (prior to 
treatment) and 
then biweekly on 
follow up visits  
 
 
NIH clinical lab or  
Clinical Lab 
At participating 
sites  
 
Research* 
• 
STR Chimerism, 
CD19 
 
 
6 ml 
 
 
 
 
EDTA tube 
 
 
 
 
 
Baseline, then 
W4,8,12 
 
NHLBI Research 
Lab (Childs), NIH 
Clinical Lab 
(Molecular 
Hematology, 
2C324) 
Research* 
• 
Type and screen 
 
 
6 mL 
 
EDTA tube 
 
Baseline, then 
W4, 8, 12 
 
NIH Clinical Lab 
or, Clinical Lab 
At participating 
sites** 
 
 

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Table of samples to be collected* 
Test/assay 
Volume 
blood 
(approx.) 
Type of tube 
Frequency 
Location of 
specimen analysis 
Research* 
• 
Immunoglobulins, 
quantitative (IgA, 
IgG, IgM)  
 
 
3.5 mL 
 
Lithium Heparin 
tube (light green) 
 
Baseline, then 
W4, 8, 12 
 
NIH Clinical Lab 
Or, 
Clinical Lab 
At participating 
sites*** 
 
 
Research* 
• 
HLA antibodies 
(Class 1 A, B, C 
and Class 2 
DRB1, DQB1) 
• 
MFI 
 
 
10 mL 
 
EDTA tube 
 
Baseline, then 
W4, 8, 12  
 
NIH Clinical Lab  
Research* 
• 
CRP  
 
4 mL 
 
Lithium Heparin 
tube (light green)  
 
Baseline, then 
W4, 8, 12 
 
NIH Clinical Lab 
or   
Clinical Lab 
At participating 
sites  
 
Research* 
• 
Erythropoietin  
• 
 
 
3.5 mL 
 
Red top tube 
(SST3.5) 
 
Baseline, then 
W4, 8, 12 
 
NIH Clinical Lab  
 
Research* 
• 
IL-6 
 
6 mL 
 
EDTA (lavender) 
 
Baseline, then 
W4, 8, 12 
 
NHLBI Research 
Lab (Childs) 
Research* 
• 
Expanded 
cytokine panel  
• 
Thrombopoietin 
 
 
16 mL 
 
Red top tube 
(serum) 
 
Baseline, then 
W4, 8, 12 
 
NHLBI Research 
Lab (Childs) 
Research* 
• 
Lymphocyte 
subsets 
• 
PBMC 
 
 
20 mL 
 
Sodium Heparin 
(green top) 
 
Baseline, then 
W4, 8, 12 
 
NHLBI Research 
Lab (Childs) 
* Residual bloods from clinical care can be transferred to the NHLBI research lab for storage 

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In addition to the research blood requested above, we will request residual blood from clinical labs for 
research purposes, as available for research purposes. 
** If baseline testing is negative, this test can be performed at participating sites. If baseline testing is 
positive, send it to NIH clinical lab for quantification  
*** If clinical lab at participating sites cannot process the listed tests, samples can be sent to NIH clinical 
lab 
8.2.3 
Correlative Studies for Research/Pharmacokinetic Studies 
N/A  
8.2.4 
Samples for Genetic/Genomic Analysis 
N/A 
8.3 
SAFETY AND OTHER ASSESSMENTS 
Physical examination A targeted physical examination will be performed at baseline prior to initial study 
product administration on Day 1. The baseline physical examination can be one that is conducted from 
screening to Day 1. Post-baseline physical examinations will be done only when needed to evaluate 
possible adverse event(s) (i.e. any new signs or symptoms). WHO bleeding assessment should be done on 
follow up visits. No routine physical exam is needed for study visits after Day 1.  
Vital signs Vital signs will be done on each follow up visit and include temperature, blood pressure, heart 
rate, respiratory rate, O2 saturation. 
Assessment of adverse events.  
Assessment of adverse events will be performed at each follow up visit  
The results of the research studies will not be mandatorily revealed to the patients but can be provided to 
the patients upon request. 
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.4.1 
Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.4.2 
Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse. 

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8.4.3 
Classification of an Adverse Event 
8.4.3.1 
Severity of Event 
This study will utilize the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) 
for toxicity and adverse event reporting.  A copy of the CTCAE v5.0 can be downloaded from the 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
AEs will be recorded, verified, and followed until satisfactory resolution or stabilization.   
Severity definitions found in the CTCAE v5.0 will be used for grading the severity (intensity) of AEs: 
1) Mild (Grade 1):  Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2) Moderate (Grade 2):  Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL* 
3) Severe (Grade 3):  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
4) Life- threatening (Grade 4):  Life-threatening consequences; urgent intervention indicated. 
5) Death (Grade 5):  Death related to AE. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
8.4.3.2 
Relationship to Study Intervention 
All grade 3 and 4 AEs, clinically significant laboratory abnormalities, and all SAEs occurring from the 
time of study drug initiation through the end of the 16th week must have their relationship to study 
intervention assessed by the investigator who examines and evaluates the participant based on temporal 
relationship and his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (de-challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (rechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 

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• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship improbable 
(e.g., the event did not occur within a reasonable time after administration of the study 
intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.] 
8.4.3.3 
Expectedness  
The site principal investigator will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  The determination will be made only for grade 3 and 4 AE, clinically significant 
laboratory abnormalities, and all SAEs. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the study 
intervention in the package insert or investigator’s brochure. 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
Grade 3 and 4 AE, clinically significant laboratory abnormalities, and all SAEs occurring from the 
initiation of the study drug through the last visit will be will be captured on the appropriate case report 
form (CRF). All grade 3-4 AEs and all SAEs will be followed to adequate resolution, or until the 
investigator deems the event to be chronic or the participant is stable. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates and that 
event reaches grade 3 and above, or becomes an SAE at any time after the first dose of the study drug, it 
will be recorded as an AE. For the purposes of baseline documentation, a medical condition is described 
as a group of signs and symptoms clearly related to a disease, illness or injury; any physiologic, mental or 
psychological condition or disorder and will be captured as a single event. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
8.4.5 
Adverse Event Recording  
Information on grade 3 and 4 AEs, clinically significant laboratory abnormalities, and all SAEs, occurring 
from the initiation of the study drug through the last visit will be recorded on the appropriate CRF. All 
clearly related signs, symptoms, and results of diagnostic procedures performed because of an AE should 
be grouped together and recorded as a single diagnosis. If the AE is a laboratory abnormality that is part 
of a clinical condition or syndrome, it should be recorded as the syndrome or diagnosis rather than the 
individual laboratory abnormality. Each AE will also be described in terms of duration (start and stop 
date), severity, association with the study product, action(s) taken, and outcome. Clinician’s assessment of 
severity, relationship to study product should be assessed only by those with the training and authority to 
make a diagnosis.  
8.4.6 
Serious Adverse Event Reporting  
The study investigator will report any SAE to the Data Coordinating Center (DCC)/study sponsor 
(NHLBI) no later than 72 hrs after the investigator becomes aware of the SAE, whether or not considered 

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study-intervention related, including those listed in the protocol or package insert and must include an 
assessment of whether there is a reasonable possibility that the study intervention caused the event.  
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the participant is stable. Other supporting documentation of the event may be requested by the 
Data Coordinating Center (DCC)/study sponsor and should be provided as soon as possible. 
SAEs from all sites will be reported to the IRB of record (NIH IRB) in accordance with the Policy 801. 
The sites should report SAE locally in accordance with institutional requirements. 
IND safety reports will be submitted to FDA by the IND sponsor in accordance with 21 CFR 312. 
Rigel Pharmaceuticals:  
Data Coordinating Center (DCC)/study sponsor (NHLBI) will provide Rigel with copies of SAEs as per 
the schedule in the following table.  
 
NHLBI Clinical Director: Data Coordinating Center (DCC)/study sponsor (NHLBI) will refer to 
NHLBI DIR Policy to determine Clinical Director reporting requirements and timelines. 
8.4.7 
Events of Special Interest  
The following clinical and laboratory characteristics will be followed closely: blood pressure, diarrhea, 
hemoglobin, ANC, platelet count, AST, ALT, total bilirubin, direct bilirubin, LDH. 
8.4.8 
Reporting of Pregnancy  
Pregnancy is not an AE. However, any pregnancy that occurs during study participation should be 
reported to the IND Sponsor on the appropriate CRF (see 8.4.6). Pregnancy should be followed to 
outcome.  
8.5 
UNANTICIPATED PROBLEMS 
8.5.1 
Definition of Unanticipated Problems (UP) 
Any incident, experience, or outcome that meets all of the following criteria: 
Type of Report 
Timeline (Calendar Days from 
Awareness Date) 
Format 
Means of Exchange 
Fatal or life threatening 
Suspected Unexpected 
Serious Adverse 
Reactions (SUSARs) using 
Rigel Compound  
Copies of all IND Safety Reports will 
be submitted to Rigel concurrently 
with their submission to the FDA.  
Medwatch Form  
 
 
Email: clinsafety@rigel.com 
Fax: +1.650.745.0971 
 
Other SUSARs using Rigel 
Compound  
Copies of all IND Safety Reports will 
be submitted to Rigel concurrently 
with their submission to the FDA. 
Medwatch Form 
Pregnancy reports 
30 Days 
Medwatch Form 
All other SAEs using Rigel 
Compound 
Promptly, but no later than 15 
Days 
Medwatch Form 

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• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; and 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others (which many include research staff, family 
members or other individuals not directly participating in the research) at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or 
expected. 
8.5.2 
 Unanticipated Problem Reporting  
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board (IRB) as 
per Policy 801. 
8.5.3 
NIH IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to 
the NIH IRB according to Policy 801. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESIS AND SAMPLE SIZE DETERMINATION 
This study will use a Simon two-stage minimax design [23] to test the null hypothesis (H0) that the 
response rate after 12 week (primary endpoint defined in Section 3) is ≤10% versus a one-side alternative. 
If the true response rate, meaning the rate of meeting the primary endpoint at 12 weeks, is 35% , the 
following two-stage design would have a power of 86% with a type 1 error of 0.05. 
In the first stage, the study will enroll 11 subject. If ≤ 1 subjects achieve a response, the study will stop for 
futility and H0 is not rejected.  If 2 or more subjects achieve a response, the study will proceed to the second 
stage and enroll an additional 9 subjects for a total of 20 evaluable subjects. The H0 will be rejected, meaning 
that the study is not futile, if more than 4 responses are observed in 20 subjects. 
Subjects who discontinue treatment before completing 4 weeks, with discontinuation being unrelated to 
the treatment-related adverse event or disease progression will not be evaluated for the primary endpoint. 
Early discontinuation within 12 weeks due to toxicity or AE related to the study drugs or disease 
progression is counted as non-response towards the primary endpoint and these subjects will not be 
replaced. Safety will be assessed in subjects who received at least one dose of fostamatinib. Up to 8 
additional subjects may be enrolled to account for treatment discontinuations before completing 4 weeks 
for reasons unrelated to treatment or disease progression. Early discontinuation within 12 weeks due to 
toxicity or AE related to the study drugs is counted as non-response towards the primary endpoint and 
these subjects will not be replaced. 
 

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9.2 
POPULATIONS FOR ANALYSES 
9.2.1 
Evaluable for response  
Only those patients who have completed at least 4 weeks of fostamatinib treatment will be considered 
evaluable for response. These patients will have their response classified according to the definitions in 
section 3). Subjects who discontinue treatment before completing 4 weeks  (unrelated to treatment or 
disease progression) will not be evaluated for treatment response. Early discontinuation within 12 weeks 
due to toxicity or AE related to the study drug will be considered as evaluable and counted as non-
response. 
9.3 
STATISTICAL ANALYSES 
9.3.1 
General Approach 
Descriptive statistics will be used to summarize baseline characteristics, adverse events and outcomes 
from the study treatment.  For continuous measures, the mean (standard deviation) or median 
(interquartile range) will be presented. For categorical variables, the frequency and the percentage in each 
category will be presented.  
9.3.2 
Analysis of the Primary Endpoints 
The primary endpoint (see Section 3) is the proportion of subjects with stable hematologic recovery (2 
consecutive readings) without recent blood product transfusion support (in the past 7 days).  
Hematologic recovery is defined as: 
Hemoglobin ≥10 g/dL (or at least ≥2 g/dL above baseline) in subjects with posttransplant anemia. In 
subjects with symptomatic anemia, a hemoglobin increase of at least ≥2 g/dL above baseline is required 
OR 
Platelets ≥ 50 x 109/L (or at least ≥20 x 109/L above baseline) in subjects with posttransplant 
thrombocytopenia  
OR  
Both of the above criteria in subjects with posttransplant Evans syndrome 
The proportion of people who meet the above response criteria will be estimated using sample 
proportions, and their inferences including confidence intervals and hypothesis testing will be evaluated 
using binomial distributions. 
9.3.3 
Analysis of the Secondary and Exploratory Endpoint(s) 
Secondary and exploratory endpoint(s) are listed in Section 3. The analysis of these endpoint will include 
the descriptive statistics as describe in the general approach (Section 8.3.1). In addition,  time-to-event 
analysis will be performed using appropriate tools in survival analysis such as Kaplan-Meier estimates 
and cumulative incidence estimates. Paired analysis and regression analysis may be used to analyze 
certain continuous variables as appropriate. Graphical tools will be used to display the appropriate 
estimates. 
9.3.4 
Interim Analyses and stopping rules  
A. Interim analysis for futility: By the study design, there is a planned interim analysis after 11 
subjects have been evaluated for the response for the primary endpoint (see section 9.1) . If ≤1 
subject achieve a response in the first 11 subjects, the study will stop for futility.   
 
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We wish to assure that this procedure has less than 25% treatment related SAE (TRSAE) by 12 
weeks. We will use a Bayesian approach by Geller et al. [24]. The stopping boundary is reached 
if the Bayesian posterior probability that the true probability of TRSAE exceeds 0.25 is at least 
90%. We take our prior distribution to be a beta distribution so that our prior clinical opinion is 
worth 20% of the weight we will place on the new data. This gives prior parameters alpha = 1, 
beta =3. We will begin monitoring when 2 subjects are evaluable for TRSAE by 12 weeks. The 
following table summarizes the threshold numbers for the boundary, which would lead to a 
recommendation to stop the study due to excess TRSAE. 
 
 
Number of subjects in the 
study 
Stop if the number of subjects 
who have developed TRSAE by 
12 weeks 
3 - 4 
3 
5 - 7 
4 
8 - 10 
5 
11 - 13 
6 
14 - 16 
7 
17 - 20 
8 
We investigated the performance of the above stopping rule by a simulation study. In each 
simulation run, we generated a study with 20 independent Bernoulli trials; each had a probability 
p for having TRSAE by 12 weeks, and compared the TRSAE outcomes with the above stopping 
boundary to determine whether the study was stopped.  We repeated the simulation 100,000 times 
and computed the proportion of stopped studies using the above stopping rule.  The following 
table summarizes the performance of the stopping rule under a number of scenarios for TRSAE 
probability p: 
Probability of TRSAE = p 
0.1 
0.2 
0.25 
0.3 
0.4 
0.5 
Proportion of Stopped Studies 
1% 
8% 
19% 
33% 
67% 
90% 
Average number of subjects 
19.9 
19.1 
18.1 
16.7 
13.1 
9.4 
Average number TRSAEs 
2 
3.8 
4.5 
5 
5.2 
4.7 
These simulation results suggest that our stopping rule has a low probability stopping a study when the 
proportion of TRSAE events is below 25%, and the probability of stopping a study is high when the true 
proportion of TRSAE events exceeds 25%. There, we believe that our Bayesian stopping rule for TRSAE 
has satisfactory statistical properties. 
 
C. Stopping rule for secondary graft failure 
 
In this study, we would not enroll patients with evidence of graft failure (sections 5.2). Therefore, in this 
study any graft failure that occurs would be secondary graft failure, which is a known complication of 
allogeneic stem cell transplantation. Secondary graft failure rates vary in incidence according to the type 
of transplant, but in general would not be expected to occur in more than 10% of patients [25, 26]. 
Secondary graft failure is defined as initial blood or marrow donor myeloid chimerism ≥5% declining to 
<5% on subsequent measurements. If chimerism assays are technically not possible in the setting of 
declining blood count in a subject with prior neutrophil recovery and the absolute neutrophil count is 
sustained at <500/mm3, in the absence of other causes, this will be counted as secondary graft failure.  
 
We wish to assure that the rate of secondary graft failure of this study is no more than 10%. We will use a 
Bayesian approach by Geller et al. [24]. The stopping boundary is reached if the Bayesian posterior 
probability that the true probability of secondary graft failure exceeds 0.10 is at least 90%. We take our 

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prior distribution to be a beta distribution so that our prior clinical opinion is worth 20% of the weight we 
will place on the new data. This gives prior parameters alpha = 0.4, beta =3.6. The following table 
summarizes the threshold numbers for the boundary, which would lead to a recommendation to stop the 
study due to excess graft failure. 
 
 
Number of subjects in the 
study 
Stop if the number of subjects 
who have developed graft 
failure 
2 - 4 
2 
5 - 11 
3 
12 - 17 
4 
18 - 20 
5 
 
We investigated the performance of the above stopping rule by a simulation study. In each 
simulation run, we generated a study with 20 independent Bernoulli trials; each had a probability 
p for having graft failure, and compared the graft failure outcomes with the above stopping 
boundary to determine whether the study was stopped.  We repeated the simulation 100,000 times 
and computed the proportion of stopped studies using the above stopping rule.  The following 
table summarizes the performance of the stopping rule under a number of scenarios for secondary 
graft failure probability p: 
 
Probability of secondary graft failure = p 
0.05 
0.10 
0.15 
0.2 
0.25 
0.3 
Proportion of Stopped Studies 
3% 
14% 
34% 
55% 
73% 
86% 
Average number of subjects 
19.6 
18.4 
16.3 
13.9 
11.5 
9.4 
Average number graft failures 
1 
1.8 
2.4 
2.8 
2.9 
2.8 
 
These simulation results suggest that our stopping rule has a low probability stopping a study when the 
proportion of secondary graft failure events is below 10%, and the probability of stopping a study is high 
when the true proportion of secondary graft failure events exceeds 10%. There, we believe that our 
Bayesian stopping rule for secondary graft failures has satisfactory statistical properties. 
 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
 
10.1 INFORMED CONSENT PROCESS 
10.1.1 Consent/Assent Procedures and Documentation 
Non-NIH Enrolling Sites 
Informed consent shall be documented using the current IRB-approved consent form. The investigational 
nature and objectives of this trial, the procedures and treatments involved, and their attendant risks and 
discomforts and potential benefits will be carefully explained in person to the patient, and a signed 
informed consent document will be obtained by the PI or any person authorized to consent. 
When consent is obtained, the consent document(s) must be signed and dated by the subject, and the 
person obtaining consent. Telephone or any institution-approved electronic consent process can be used. 
The original, signed informed consent document will be placed in the medical record, and the subject will 
receive a signed copy of the informed consent document. Documentation of informed consent and the 
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NIH Clinical Center  
Informed consent will be conducted following OHSRP Policy 301- Informed Consent. An IRB-approved 
consent form will be provided to the participant  or consent designee(s) (legally authorized [LAR] if 
participant is an adult unable to consent) electronically or by hard copy for review prior to consenting. 
The initial consent process as well as re-consent, when required, may take place in person or remotely 
(e.g., via telephone or other NIH approved platforms). The investigational nature and objectives of this 
trial, the procedures, and their attendant risks and discomforts and potential benefits will be carefully 
explained to the participant in a private setting. The participant will be given as much time as they need to 
review the document and to consult with their family, friends, and personal health care providers. In 
addition, a study team member will be available to answer any questions. A signed and dated informed 
consent document will be obtained by any investigator authorized to consent prior to entry onto the study. 
Consent may be obtained with required signatures on the hard copy of the consent or on the electronic 
document. When a document that is in electronic format is used for obtaining consent, this study may use 
the iMed platform which is 21 CFR, Part 11 compliant, to obtain the required signatures. During the 
consent process, participants and investigators may view the same approved consent document 
simultaneously when participant is being consented in person at the Clinical Center or both may view 
individual copies of the approved consent document on screens in their respective locations remotely. 
Signatures may be obtained either by both directly signing on the device that the consenting investigator 
is using (when in person) or through iMed Mobile Signature Capture (remotely) which allows texting or 
emailing a link to the participant. That link allows the participant to review the consent, then proceed to 
sign on the device they are using. Whether hard copy or electronic, both the investigator and the 
participant will sign the document with a hand signature using a pen (if using hard copy), finger, stylus, or 
mouse (if electronic). When done remotely, if the participant prefers to sign a hard copy, they may be 
instructed to sign and date the consent document during the discussion and mail, secure email or fax the 
signed document to the consenting investigator. Whether in person or remotely, the privacy of the 
participant will be maintained. Finally, the fully signed informed consent document will be stored in the 
electronic medical record, and the participant will receive a copy of the signed informed consent 
document. 
Telephone consent: When appropriate, the consent will be sent to the subject to be executed by 
telephone.  The investigational nature of the protocol will be carefully explained to the subject.  An 
investigator with consenting rights will lead this discussion.  The subject will be directed to sign and 
date the consent . The original informed consent document will then be sent back to the principal or 
associate investigator who led the discussion, who will sign and date the consent form with the date it 
was returned.  A fully executed copy will be returned via mail for the subject’s records. The informed 
consent process will be documented in the medical record. The investigator will confirm that, when 
required, written legally effective consent has been obtained prior to initiating any study 
interventions. 
 
10.1.2 Consent for minors when they reach the age of majority  
N/A 
10.1.3 Participation of Subjects who are/become Impaired in Decision Making  
For participants addressed in section 5.4, an LAR will be identified consistent with Policy 403 and 
informed consent obtained from the LAR, per section 10.1. 
10.2 .STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be provided 

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by the suspending or terminating party to study participants, investigator, the Investigational New Drug 
(IND) sponsor and regulatory authorities.  If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), 
and sponsor and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
10.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the NHLBI OCD. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by clinical 
sites will be secured and password protected. At the end of the study, all study databases will be de-
identified and archived at the NHLBI OCD. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies by 
helping assure confidentiality and privacy to participants. 

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10.4 FUTURE USE OF STORED SPECIMENS AND DATA 
We may share specimens and data with other researchers for future research to better understand post 
transplant cytopenia(s).  
Following analyses of biospecimens for primary research purposes as described in the protocol, remaining 
samples suitable for future research will be stored in manner that conforms with DIR policy (such as BSI) 
or in a publicly accessible research biospecimen repository following IRB approval. Currently there is no 
plan to perform genetic testing on the samples. Collected samples will be de-identified prior to storage 
following current NHLBI DIR BSI Policy. An electronic database is used to store patient information 
related to the coded samples. Hard copy records or electronic copies of documents containing patient 
information are kept in the locked laboratory or other controlled access locations. 
Coded biospecimens may be sent to collaborators outside of the NIH with IRB approval in accordance 
with applicable NIH and DIR Policy for sharing research resources, including an executed material 
transfer agreement (MTA). Biospecimens may be destroyed only when permitted by the clinical director 
and approved by the IRB.  Any future research use of identifiable biospecimens not defined in the 
research protocol will occur only after IRB review and approval. 
10.5 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including hematology and oncology Members of the DSMB 
should be independent from the study conduct and free of conflict of interest, or measures should be in 
place to minimize perceived conflict of interest.  The DSMB will meet at least semiannually to assess 
safety and efficacy data on each arm of the study. The DMSB will operate under the rules of an approved 
charter that will be written and reviewed at the organizational meeting of the DSMB. At this time, each 
data element that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to 
Dr. Richard Childs, who is the sponsor’s authorized representative for the NHLBI Office of the Clinical 
Director 
10.6 CLINICAL MONITORING 
As per ICH-GCP 5.18 and FDA 21 CFR 312.5 clinical protocols are required to be adequately monitored 
by the study sponsor. The monitoring of this study will be conducted by Clinical  Research Associates 
(CRAs)/Monitors employed by an independent contract organization working under an agreement with 
NHLBI to monitor aspects of the study in accordance with the appropriate regulations and the approved 
protocol. The objectives of a monitoring visit will be: 1) to verify the existence of signed informed 
consent form (ICF) and documentation of the ICF process for each monitored subject; 2) to verify the 
prompt and accurate recording of all monitored data points, and prompt reporting of all SAEs; UPs, and 
deviations, 3) to compare abstracted information with individual subjects’ records and source documents 
(subject’s charts, laboratory analyses and test results, physicians’ progress notes, nurses’ notes, and any 
other relevant original subject information); and 4) to help ensure investigators are in compliance with the 
protocol and with the appropriate regulations. The monitors also will inspect the clinical site regulatory 
files to ensure that regulatory requirements (Office for Human Research Protections-OHRP) and 
applicable guidelines (ICH-GCP) are being followed.  During the monitoring visits, the investigator 
(and/or designee) and other study personnel will be available to discuss the study progress and monitoring 
visit. 
The investigator (and/or designee) will make study documents (e.g., consent forms and pertinent hospital 
or clinical records) readily available for inspection by the local IRB, the site monitors, and the NHLBI 
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10.7 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), 
Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
10.8 DATA HANDLING AND RECORD KEEPING 
10.8.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report form 
(eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
Clinical data (including inpatient concomitant medications and clinical laboratory data) will either be 
entered into CTDB, a 21 CFR Part 11-compliant data capture system, and/or will be imported on Excel 
file(s) from the site’s electronic health records system. Adverse events (AEs) grade 3 and above will be 
entered into CTDB. 
10.8.2 Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention, or as per the NIH Intramural 
Records Retention Schedule. No records will be destroyed without the written consent of the sponsor. It is 
the responsibility of the sponsor to inform the investigator when these documents no longer need to be 
retained. 
10.9 PROTOCOL DEVIATIONS 
It is the responsibility of the investigator to use continuous vigilance to identify and report deviations to 
the NIH Institutional Review Board as per Policy 801.  All deviations must be addressed in study source 
documents, reported to Data Coordinating Center. The investigator is responsible for knowing and 
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10.9.1 NIH Definition of Protocol Deviation 
A protocol deviation is any changed, divergence, or departure from the IRB-approved research protocol.  
• 
Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to substantially 
negatively impact the scientific integrity or validity of the study. 
• 
Minor deviations: Deviations that do not have the potential to negatively impact the rights, safety 
or welfare of subjects or others, or the scientific integrity or validity of the study. 
10.10 PUBLICATION AND DATA SHARING POLICY 
10.10.1 Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from 
this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results 
in peer-reviewed journals.  Data from this study may be requested from other researchers after the 
completion of the primary endpoint by contacting Dr. Richard Childs, who is the accountable 
investigator. 
10.10.2 Genomic Data Sharing Plan 
N/A 
10.11 COLLABORATIVE AGREEMENTS  
10.11.1 Agreement Type 
A Clinical Research and Development Agreement (CRADA) or a Clinical Trial Agreement (to be 
determined) between NHLBI and Rigel Pharmaceutics for the conduct of this study is being executed. 
10.12 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed by each site. 
Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts 
managed in a way that is appropriate to their participation in the design and conduct of this trial.  The 
study leadership in conjunction with NHLBI has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
11 ABBREVIATIONS 
 
AE 
Adverse Event 
AIHA  
Autoimmune Hemolytic Anemia 

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CFR 
Code of Federal Regulations 
cGVHD  
Chronic Graft Versus Host Disease 
CONSORT 
Consolidated Standards of Reporting Trials 
CRADA 
Clinical Research and Development Agreement 
CRF 
Case Report Form 
DAG 
Diacyl Glycerol 
DCC 
Data Coordinating Center 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
EPAG 
Eltrombopag 
EPO 
Erythropoietin 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GVHD 
Graft Versus Host Disease 
HCT  
Hematopoietic Stem Cell Transplantation 
HLH 
Hemophagocytic Lymphohistiocytosis 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug Application 
IP3 
Inositol Triphosphate 
IRB 
Institutional Review Board 
ITP  
Idiopathic Thrombocytopenic Purpura 
IVIG  
Intravenous Immunoglobulin 
MAPK 
Mitogen Activated Protein Kinase 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NHLBI 
National Heart, Lung, and Blood Institute 
OCD 
Office of the Clinical Director 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PRO 
Patient Recruitment Office 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red Blood Cell  
SAE 
Serious Adverse Event 
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus-2 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SYK 
Spleen Tyrosine Kinase 
TPO  
Thrombopoietin 
UP 
Unanticipated Problem 
US 
United States 
WHO  
World Health Organization 
 
 
 

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12 REFERENCES  
 
 
1. 
Page, L.K., et al., The immune thrombocytopenic purpura (ITP) bleeding score: 
assessment of bleeding in patients with ITP. British Journal of Haematology, 2007. 
138(2): p. 245-248. 
2. 
First, L.R., et al., Isolated thrombocytopenia after allogeneic bone marrow 
transplantation: existence of transient and chronic thrombocytopenic syndromes. Blood, 
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3. 
Filipovich, A.H., et al., National Institutes of Health consensus development project on 
criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging 
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4. 
Couriel, D., et al., Ancillary therapy and supportive care of chronic graft-versus-host 
disease: national institutes of health consensus development project on criteria for 
clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive 
Care Working Group Report. Biol Blood Marrow Transplant, 2006. 12(4): p. 375-96. 
5. 
Marotta, S., et al., Eltrombopag for post-transplant cytopenias due to poor graft function. 
Bone Marrow Transplant, 2019. 54(8): p. 1346-1353. 
6. 
Poon, L.M., et al., Romiplostim for delayed platelet recovery and secondary 
thrombocytopenia following allogeneic stem cell transplantation. Am J Blood Res, 2013. 
3(3): p. 260-4. 
7. 
Uday R. Popat, M., Genevieve Ray,  Roland L Bassett, Jr.,  Man-Yin C Poon,  Benigno 
C. Valdez, PhD,  Sergej Konoplev, MD PhD,  Sairah Ahmed, MD, Amin M. Alousi, MD,  
Borje Andersson, MD PhD,  Qaiser Bashir, MD,  Stefan O. Ciurea, MD,  Chitra M. 
Hosing, MD,  Roy Jones, MD PhD, Partow Kebriaei, MD,  Issa F. Khouri, MD,  Stella 
Kim,  Yago Nieto, MD PhD,  Amanda L. Olson, MD,  Betul Oran, MD,  Simrit Parmar, 
MD, Muzaffar H. Qazilbash, MD,  Katy Rezvani, MD PhD,  Nina Shah, MD,  Elizabeth 
J. Shpall, MD,  Richard E. Champlin, MD, Eltrombopag for Post-Transplant 
Thrombocytopenia: Results of Phase II Randomized Double Blind Placebo Controlled 
Trial, in ASH-Blood 2015. 
8. 
Bussel, J., 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(7): p. 921-930. 
9. 
Bruno, B., et al., Secondary failure of platelet recovery after hematopoietic stem cell 
transplantation. Biol Blood Marrow Transplant, 2001. 7(3): p. 154-62. 
10. 
Kuzmina, Z., et al., Significantly worse survival of patients with NIH-defined chronic 
graft-versus-host disease and thrombocytopenia or progressive onset type: results of a 
prospective study. Leukemia, 2012. 26(4): p. 746-56. 
11. 
Audia, S., et al., Immunologic effects of rituximab on the human spleen in immune 
thrombocytopenia. Blood, 2011. 118(16): p. 4394-400. 

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12. 
Mahevas, M., et al., B cell depletion in immune thrombocytopenia reveals splenic long-
lived plasma cells. J Clin Invest, 2013. 123(1): p. 432-42. 
13. 
Fasano, R.M., et al., Persistence of recipient human leucocyte antigen (HLA) antibodies 
and production of donor HLA antibodies following reduced intensity allogeneic 
haematopoietic stem cell transplantation. Br J Haematol, 2014. 166(3): p. 425-34. 
14. 
Blennerhassett, R., et al., Post-allogeneic transplant Evans syndrome successfully treated 
with daratumumab. Br J Haematol, 2019. 187(2): p. e48-e51. 
15. 
Horn, B., et al., Autoimmune hemolytic anemia in patients with SCID after T cell-
depleted BM and PBSC transplantation. Bone Marrow Transplant, 1999. 24(9): p. 1009-
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Hazlehurst, G.R., et al., Haemolysis after T-cell depleted bone marrow transplantation 
involving minor AB0 incompatibility. Scand J Haematol, 1986. 37(1): p. 1-3. 
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Haas, R.J., et al., Acquired immune haemolysis by anti A 1 antibody following bone 
marrow transplantation. Blut, 1986. 53(5): p. 401-4. 
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Gajewski, J.L., et al., Hemolysis of transfused group O red blood cells in minor ABO-
incompatible unrelated-donor bone marrow transplants in patients receiving 
cyclosporine without posttransplant methotrexate. Blood, 1992. 79(11): p. 3076-85. 
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Kaur, M., M. Singh, and O. Silakari, Inhibitors of switch kinase 'spleen tyrosine kinase' 
in inflammation and immune-mediated disorders: a review. Eur J Med Chem, 2013. 67: 
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20. 
Poe, J.C., et al., SYK inhibitor entospletinib prevents ocular and skin GVHD in mice. JCI 
Insight, 2018. 3(19). 
21. 
Clemons Bankston, P. and R.A. Al-Horani, New Small Molecule Drugs for 
Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations. 
Int J Mol Sci, 2019. 20(12). 
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Podolanczuk, A., et al., Of mice and men: an open-label pilot study for treatment of 
immune thrombocytopenic purpura by an inhibitor of Syk. Blood, 2009. 113(14): p. 3154-
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Simon, R., Optimal two-stage designs for phase II clinical trials. Controlled Clinical 
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Geller, N.L., Advances in Clinical Trial Biostatistics. 1st ed. 2003: CRC Press. 271. 
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Kasamon, Y.L., et al., Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-
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Chen, C. and K. Chaloner, A Bayesian stopping rule for a single arm study: With a case 
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APPENDIX A.  INHIBITORS AND INDUCERS OF CYP3A  
Inhibitors of CYP3A  
Strong inhibitors:  
boceprevir  
clarithromycin  
cobicistat  
indinavir 
itraconazole 
ketoconazole 
mibefradil 
nefazodone  
nelfinavir  
posaconazole  
ritonavir  
saquinavir  
suboxone  
telaprevir  
telithromycin  
troleandomycin  
 
Moderate inhibitors:  
amiodarone  
amprenavir  
aprepitant atazanavir  
ciprofloxacin  
crizotinib 
darunavir 
diltiazem  
dronedarone  
erythromycin  
fluconazole  
fosamprenavir  
grapefruit juice  
imatinib 
Seville orange juice  
verapamil  
voriconazole  
 
Weak inhibitors:  
cimetidine  
fluvoxamine  
 
All other inhibitors:  
chloramphenicol  
delaviridine  
diethyl-dithiocarbamate  
gestodene  
mifepristone  
norfloxacin  

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norfluoxetine  
star fruit  
 
Inducers of CYP3A:  
carbamazepine  
barbiturates  
efavirenz  
glucocorticoids  
modafinil  
nevirapine  
oxcarbazepine  
phenobarbital  
phenytoin  
pioglitazone  
rifabutin  
rifampin  
St. John’s Wort  
troglitazone  
 
 
 

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APPENDIX B.  IMMUNE THROMBOCYTOPENIC PURPURA BLEEDING SCORE [1] 
Site  
Bleeding Grade 
0 
1 
2 
Skin (physical 
exam, PE) 
None 
1–5 bruises and/or scattered 
petechiae 
>5 bruises with size >2 cm and/or 
diffuse petechiae 
Oral (PE) 
None 
1 blood blister or >5 petechiae or 
gum bleeding that clears easily 
with rinsing 
Multiple blood blisters and/or gum 
bleeding 
Skin (History, Hx) None 
1–5 bruises and/or scattered 
petechiae 
>5 bruises with size >2 cm and/or 
diffuse petechiae 
Oral (Hx) 
None 
1 blood blister or >5 petechiae 
and/or gum bleeding <5 min 
Multiple blood blisters and/or gum 
bleeding >5 min 
Epistaxis 
None 
Blood when blowing nose and/or 
epistaxis <5 min (per episode) 
Bleeding >5 min (per episode) 
Gastrointestinal 
None 
Occult blood 
Gross blood 
Urinary 
None 
Microscopic (positive dipstick) 
Macroscopic 
Gynecological 
None (normal 
period) 
Spotting not at time of normal 
period 
Bleeding >spotting not at time of period 
or very heavy period 
Pulmonary  
None 
N/A 
Yes 
Intracranial 
hemorrhage 
None 
N/A 
Yes 
Subconjunctival 
hemorrhage 
None 
Yes 
N/A