A Pilot Study of Belimumab (Benlysta) for Prevention of Chronic Graft-versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation
Phase: PHASE1
Conditions: Graft Vs Host Disease, Graft-versus-host-disease
Sponsor: Washington University School of Medicine

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A Pilot Study of Belimumab (Benlysta) for Prevention of Chronic Graft-versus-Host 
Disease Following Allogeneic Hematopoietic Cell Transplantation 
  
  
Washington University School of Medicine 
Department of Internal Medicine, Section of Bone Marrow Transplant 
660 S. Euclid Ave., Campus Box 8007 
St. Louis, MO 63110 
 
Protocol #: 201709068 
Version date: 08/01/22 
 
Principal Investigator: 
Iskra Pusic, M.D. 
Phone: (314) 454-8304 
Email: iskrapusic@wustl.edu 
 
Sub-Investigators 
 
 
Modality 
Tanner M. Johanns, M.D., Ph.D. 
Medical Oncology 
John F. DiPersio, M.D., Ph.D. 
Medical Oncology 
Feng Gao, Ph.D. 
 
 
Biostatistics 
 
Study Drug:  
Belimumab (Benlysta) 
 
IND #:   
 
136433 
Clinicaltrials.gov #:  NCT03207958 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to another party unless law or 
regulations require such disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them 
 
 
 

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A Pilot Study of Belimumab (Benlysta) for Prevention of Chronic Graft-versus-Host 
Disease Following Allogeneic Hematopoietic Cell Transplantation 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
08/24/17 
Amendment #1 Version 
 
 
 
 
 
 
02/22/18 
Amendment #2 Version 
 
 
 
 
 
 
01/14/19 
Amendment #3 Version 
 
 
 
 
 
 
01/08/20 
Amendment #4 Version 
 
 
 
 
 
 
05/29/20 
Amendment #5 Version 
 
 
 
 
 
 
08/01/22 
 
 

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SYNOPSIS 
 
Background:  
• 
Chronic graft-versus-host disease (GvHD) is the leading cause of late morbidity and non-
relapse mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT), 
occurring in 40-60% long-term survivors 
• 
Chronic GvHD occurs due to the dysfunctional peripheral tolerance during post-transplant 
hematopoietic reconstitution that allows the development and persistence of alloreactive 
donor-derived T and B cells   
• 
Prednisone is the front-line therapy, however about 50% of persons have steroid-refractory 
disease and there is no standard second line therapy 
• 
The most attractive approach for controlling chronic GvHD would be the prevention of the 
most severe and irreversible clinical manifestations while maintaining Graft-versus-Leukemia 
effect 
 
Objectives: 
• 
Primary: To evaluate safety and tolerability of belimumab as prophylaxis of chronic GvHD in 
subjects following alloHCT. 
 
• 
Secondary:  
o To evaluate the impact of prophylactic belimumab on the incidence and severity of chronic 
GvHD at 6, 12 and 24 months after alloHCT 
o To evaluate the impact of prophylactic belimumab on the incidence and severity of acute 
GvHD at 3 and 6 months after alloHCT 
o To evaluate the impact of prophylactic belimumab on overall survival at 6, 12 and 24 
months after alloHCT 
o To evaluate the impact of prophylactic belimumab on relapse rate at 6, 12 and 24 months 
after alloHCT 
o To evaluate the impact of prophylactic belimumab on overall corticosteroid requirement 
(dose and duration) for treatment of chronic GvHD at 6, 12 and 24 months after alloHCT 
o To evaluate the impact of prophylactic belimumab on the necessity to use alternative 
treatment modalities for chronic GvHD at 6, 12 and 24 months after alloHCT 
 
• 
Exploratory: 
o To evaluate the effect of prophylactic belimumab on post-transplant immune cell 
reconstitution. 
o To explore candidate biomarkers (i.e. BAFF level, BAFF:B cell ratio; B cell subpopulation 
frequency) that could predict subjects who may benefit from prophylactic administration of 
belimumab to prevent chronic GvHD.  
 
Eligibility:  
Key Inclusion criteria: 
1. At least 18 years of age 
2. ECOG performance status ≤ 2 
3. Diagnosis of hematologic malignancy (i.e. acute myeloid leukemia, acute lymphoblastic 
leukemia, 
chronic 
lymphocytic 
leukemia, 
myelodysplastic 
syndrome, 
chronic 
myelogenous leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma)  
4. Use of myeloablative or non-myeloablative conditioning regimen 
5. Use of mobilized peripheral blood stem cells from fully HLA-matched related or unrelated 
donor as a graft source 

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6. Acute GvHD prophylaxis with methotrexate and tacrolimus 
7. Documented complete remission with full donor engraftment (by STR identity testing) on 
Day +30 bone marrow biopsy 
8. Adequate end organ function: 
• 
Serum bilirubin ≤ 1.5 x ULN 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN 
• 
Creatinine clearance ≥ 40 mL/min/1.73 m2 by the Cockcroft-Gault formula 
 
9. Women of childbearing potential must agree to use adequate contraception (hormonal or 
barrier method of birth control, abstinence) prior to study entry, for the duration of study 
participation, and for 16 weeks after the last dose of study drug.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she must inform her 
treating physician immediately. 
10. Able to understand and willing to sign an IRB-approved written informed consent 
 
Key Exclusion Criteria:  
1. Active grade III-IV classic acute GvHD; subjects with prior resolved acute GvHD on stable 
doses of immunosuppression at time of enrollment will be permitted 
2. Evidence of classic chronic GvHD or overlap chronic GvHD at time of enrollment 
3. Subjects who participated in a clinical trial of acute GvHD prophylaxis in which chronic 
GvHD was a secondary end point 
4. Donor lymphocyte infusion administered to treat relapse or loss of donor chimerism 
5. Treatment with rituximab or other anti-B cell specific antibodies within previous 3 months  
6. History of other malignancy ≤5 years previous with the exception of basal cell or squamous 
cell carcinoma of the skin which were treated with local resection only or carcinoma in situ 
of the cervix 
7. Currently receiving any other investigational agents 
8. Known allergy or intolerance to any component of belimumab, including human or murine 
proteins or monoclonal antibodies 
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations (including current drug or alcohol abuse or 
dependence, or history of drug or alcohol abuse or dependence within the last year) that 
would limit compliance with study requirements 
10. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-
parasitic agents) within 14 days prior to planned start of therapy 
11. Evidence of serious suicide risk including any history of suicidal behavior in the last 6 
months and/or any suicidal ideation in the last 2 months and/or poses a significant suicide 
risk in the judgment of the investigator 
12. History of pre-existing immunodeficiency disorder, autoimmune condition, or chronic 
infection 
13. Known HIV positivity 
14. Serologic evidence of current or past hepatitis B infection based on the results of testing 
for HBsAg and anti-HBc – Patients positive for HBsAg or HBcAb are excluded 
15. Positive test for hepatitis C antibody (patients with documented clearance of hepatitis C 
by PCR following treatment will be permitted)  
16. Currently on therapy for active chronic infection (such as tuberculosis, pneumocystis, 
cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria). 
Prophylactic therapy is allowed.  
17. Has any other clinically significant abnormal laboratory value in the opinion of the 
investigator  
 

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Design:  
This is a single center, open-label pilot and feasibility study of prophylactic belimumab for the 
prevention of chronic GvHD following alloHCT at Washington University School of Medicine in St. 
Louis.  
 
The study will include Screening Phase, Treatment Phase, and Follow-up Phase. Subjects will be 
screened for the study after obtaining the results from their standard-of-care Day +30 bone 
marrow biopsy. Those subjects meeting the Inclusion and Exclusion Criteria will be enrolled in 
the study and start treatment between Day +30 and Day +80 after alloHCT. The study population 
will include 10 subjects. Planned duration of treatment is 7 cycles (6 months; see study schema).  
Subjects will be followed for 24 months.   
 
Subjects may be on steroids that were used to treat acute GvHD and then developed chronic 
GvHD before completing a taper. At the time of enrollment subject should be responding to 
therapy with severity of acute GvHD grade II or less, and the dose of steroid should be ≤0.5 
mg/kg/day of prednisone equivalent with no dose increase in the preceding 1 week. Subjects may 
also remain on other systemic immunosuppressive drugs that were used to prevent acute GvHD. 
Subjects diagnosed with or treated for chronic GvHD prior to study enrollment will be excluded 
from the study.  
 
The subjects who develop chronic GvHD while receiving treatment with the study drug, 
belimumab, may continue on the study with the careful documentation of their GvHD severity and 
treatments used for it. 
 
The primary endpoint is safety and tolerability of belimumab. Subjects who receive at least one 
dose of belimumab will be eligible for primary endpoint analysis and it will be performed according 
to the CTCAE v4.03.  
 
Documentation of chronic GvHD will be per NIH criteria (Appendix B). Those subjects diagnosed 
with chronic GvHD will have organ specific staging and global scoring according to the NIH criteria 
(Appendix D and Appendix E).  
 
 
 

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A Pilot Study of Belimumab (Benlysta) for Prevention of Chronic Graft-versus-Host Disease Following Allogeneic 
Hematopoietic Cell Transplantation 
 
SCHEMA 
 
 

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Table of Contents 
SYNOPSIS ................................................................................................................................ 3 
1 
BACKGROUND AND RATIONALE ................................................................................ 9 
1.1 
Graft-versus-Host Disease.......................................................................................... 9 
1.2 
Belimumab ................................................................................................................11 
1.3 
Study Rationale .........................................................................................................13 
2 
STUDY OBJECTIVES ...................................................................................................13 
2.1 
Primary Objective ......................................................................................................13 
2.2 
Secondary Objectives ................................................................................................13 
2.3 
Exploratory Objectives ...............................................................................................14 
3 
PATIENT SELECTION AND ENROLLMENT .................................................................14 
3.1 
Inclusion Criteria ........................................................................................................14 
3.2 
Exclusion Criteria .......................................................................................................14 
3.3 
Inclusion of Women and Minorities ............................................................................15 
4 
REGISTRATION PROCEDURES ..................................................................................15 
4.1 
Confirmation of Patient Eligibility................................................................................16 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ......................16 
4.3 
Assignment of UPN ...................................................................................................16 
5 
TREATMENT OF SUBJECTS AND STUDY DESIGN ...................................................16 
5.1 
Baseline Evaluations .................................................................................................17 
5.2 
Study Drug Administration .........................................................................................19 
5.3 
Premedication............................................................................................................19 
5.4 
Duration of Therapy ...................................................................................................19 
5.5 
Duration of Follow-up .................................................................................................19 
5.6 
Concomitant Medication and Supportive Care Guidelines .........................................20 
5.7 
Management of Adverse Clinical Events and Dose Modification Guidelines ..............20 
5.8 
Acute GvHD ..............................................................................................................22 
5.9 
Women of Childbearing Potential...............................................................................22 
5.10 
Study Stopping Rule ..................................................................................................23 
6 
PHARMACEUTICAL INFORMATION ............................................................................23 
6.1 
Belimumab (Benlysta) Description .............................................................................23 
6.2 
Clinical Pharmacology ...............................................................................................23 
6.3 
Pharmacokinetics and Drug Metabolism ....................................................................23 
6.4 
Supplier(s) .................................................................................................................23 
6.5 
Dosage Form and Preparation ...................................................................................23 
6.6 
Storage and Stability..................................................................................................24 
6.7 
Administration ............................................................................................................24 
6.8 
Special Handling Instructions .....................................................................................24 
7 
ADVERSE EVENTS REPORTING ................................................................................24 
7.1 
Sponsor-Investigator Reporting Requirements ..........................................................25 
7.2 
Exceptions to Expedited Reporting ............................................................................27 
8 
MEASUREMENT OF EFFECT ......................................................................................27 
8.1 
Primary Endpoint: Safety and Tolerability ..................................................................27 
8.2 
Secondary Endpoints .................................................................................................27 
8.3 
Exploratory Endpoints/Correlative Studies .................................................................28 
9 
CORRELATIVE STUDIES .............................................................................................28 
10 
STUDY CALENDAR ......................................................................................................30 
10.1 
Screening and Treatment Calendar ...........................................................................30 
10.2 
Follow-Up Calendar ...................................................................................................31 
11 
DATA AND SAFETY MONITORING .............................................................................32 

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12 
DATA SUBMISSION SCHEDULE .................................................................................32 
12.1 
Adverse Event Collection in the Case Report Forms .................................................33 
13 
STATISTICAL ANALYSIS .............................................................................................34 
14 
REFERENCES ..............................................................................................................35 
APPENDIX A. Clinical Differentiation of Acute and Chronic GvHD ............................................38 
APPENDIX B. Diagnostic Criteria for Chronic GvHD .................................................................39 
APPENDIX C. Performance Status Criteria ...............................................................................43 
APPENDIX D. Organ Specific Staging of Chronic GvHD ..........................................................44 
APPENDIX E. Global Scoring of Chronic GvHD ........................................................................47 
APPENDIX F. Minnesota-CIBMTR Staging and Grading for Acute GVHD ................................48 
APPENDIX G: Definitions for Adverse Event Reporting ............................................................49 
APPENDIX H: Reporting Timelines ...........................................................................................51 
 
 
 

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1 
BACKGROUND AND RATIONALE 
 
Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative therapy for 
subjects with aggressive or relapsed/refractory hematologic malignancies. In 2013, the Center for 
International Blood and Marrow Transplant Research (CIBMTR) estimated approximately 8,000 
alloHCT were performed in the US (www.cibmtr.org). Unfortunately, the high non-relapse 
mortality (NRM) associated with alloHCT significantly limits the number of subjects who undergo 
this treatment modality.  
 
1.1 
Graft-versus-Host Disease 
 
Chronic graft-versus-host disease (GvHD) is the most common cause of late morbidity 
and non-relapse mortality following alloHCT, occurring in roughly 40-60% of long-term 
survivors [1-3]. Risk factors for developing chronic GvHD include older patient age, use of 
peripheral blood stem cells versus bone marrow, and lack of T-cell depletion [4, 5]. Chronic 
GvHD is a multisystem, debilitating, immune-mediated disorder characterized by 
immunosuppression and immune dysregulation, resulting in increased risk of infections, 
impaired organ function and reduced quality of life (QOL). Importantly, the incidence of 
GvHD is on the rise due to multiple factors, including more transplantation of older adults, 
increased use of mobilized peripheral blood as a stem cell source, increased use of 
alternative donors (i.e., unrelated or haploidentical donors), and improved early post-
transplant survival. Symptoms of chronic GvHD occur gradually, starting on average at 6 
months after transplantation. Chronic GvHD targets skin, mouth, eyes, gut, liver, lungs, 
joints, and genitourinary system; it may be restricted to a single site, but more frequently 
several organ-sites are included.  
 
1.1.1 Chronic GVHD diagnosis and classification  
 
One of the major obstacles to clinical research in chronic GvHD has been the lack 
of standardized criteria for the diagnosis, staging, and measurements of response 
to therapy. In 2005 the National Institutes of Health (NIH) Consensus Conference 
consolidated expert opinions and standardized recommendations for diagnosis 
and staging, histopathology, biomarkers, response criteria, ancillary therapy and 
supportive care, and design of clinical trials. The Chronic GvHD Consortium was 
subsequently established to conduct multicenter studies on chronic GvHD and 
many retrospective and prospective longitudinal studies have been published over 
the last nine years further validating the NIH Consensus Conference criteria [6-
15]. In 2014, now with 9-years of experience, the experts met again to update and 
improve on the original recommendations and clarify controversies [16-21]. The 
2014 NIH criteria provide greater specificity and more accurate measures of the 
disease burden. According to the NIH criteria, the diagnosis of chronic GvHD 
requires at least one diagnostic manifestation (establish the diagnosis of chronic 
GvHD without the need for further testing) or at least one distinctive (highly 
suggestive of chronic GvHD but insufficient alone to establish the diagnosis) 
confirmed by biopsy, laboratory test, or by radiology in the same or another organ. 
Other features can be recognized as part of chronic GvHD only if the diagnosis is 
confirmed and common features are found in both acute and chronic GvHD and 
cannot be used to distinguish between the two disorders. Chronic GvHD is 
separated from acute GvHD not by time since HCT, but by the presence of 
diagnostic and distinctive clinical manifestations. The NIH Consensus Conference 
recognizes two major categories of GvHD - acute and chronic, each one with 2 

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subcategories: (1) “classic” acute GvHD, (2) “persistent, recurrent or late” acute 
GvHD, (3) “classic” chronic GvHD and (4) an “overlap syndrome” (Appendix A).  
Early diagnosis is important because the goal of treatment is control of symptoms 
and the prevention of irreversible organ damage.  
 
1.1.2 Pathophysiology of chronic GvHD 
 
Although the precise pathophysiology of chronic GvHD is not known, recent 
advances have been made in understanding the disease process [22]. In contrast 
to acute GvHD, which results from activation of adoptively transferred host-reactive 
donor T cells, chronic GvHD occurs due to dysfunctional peripheral tolerance 
during post-transplant hematopoietic reconstitution that allows the development 
and persistence of autoreactive donor-derived T and B cells. Though a pathologic 
role for T cells in both acute and chronic GvHD has long been recognized [23, 24], 
a significant role of B cells in the pathogenesis of chronic GvHD has more recently 
been appreciated [2, 25]. Augmented B-cell responses in chronic GvHD result in 
marked abnormalities in B-cell homeostasis and signaling pathways, but the 
mechanisms responsible for aberrant B-cell homeostasis and the inability to 
establish B-cell tolerance in patients with chronic GvHD have not been fully 
elucidated [26]. Alloreactive B-cells are associated with chronic GvHD, in 
particular, antibodies against minor histocompatibility antigens (mHAs) correlated 
with chronic GVHD incidence. HY antibodies develop in male patients who receive 
their alloHCT from a female donor [27]. HY antigens are mHAs found on the Y 
chromosome with homologous proteins on the X chromosome, and by looking at 
the HY antigens in sex-mismatched transplants an allo-immune response 
representing chronic GVHD was studied. The rationale is that lymphocytes from 
the female donor graft, which lack a Y chromosome, recognize the HY mHAs as 
foreign, thus producing HY specific antibodies. In support of this hypothesis, 
rituximab, a monoclonal antibody targeting CD20-expressing cells such as B cells, 
infused 2-3 months after alloHCT in male patients with female donors prevented 
development of HY antigen-specific alloreactive B-cells and IgM antibodies. 
Rituximab has been used both for prevention and treatment of established chronic 
GvHD supporting the role of B cell-directed therapy as a plausible treatment 
strategy [28, 29]. Another potential mechanism to impair abnormal B cell function 
is through the inhibition of B-cell activating factor (BAFF), which is a homeostatic 
cytokine important for survival of autoreactive B cells and has been shown to be 
elevated in serum of patients after alloHCT [30, 31]. Moreover, prolonged elevation 
of BAFF serum levels in the post-transplant environment has been implicated in 
the development of chronic GvHD. As such, patients with chronic GvHD have 
delayed normal B-cell reconstitution associated with elevated BAFF:B-cell ratios 
compared to patients without chronic GvHD. In contrast, chronic GvHD patients 
who demonstrate clinical improvement and positive response to treatment have 
robust recovery of the peripheral naive B-cell pool, though it is unclear what role 
BAFF has on this clinical scenario.  
 
1.1.3 Treatment and Prevention of Chronic GvHD 
 
Approaches to the treatment of chronic GvHD are complex and the field is rapidly 
advancing. While there have been a number of effective strategies to prevent and 
treat acute GvHD, prophylactic and treatment options for chronic GvHD remain 
limited. Currently there is no FDA-approved therapy for chronic GvHD, and 

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development of well-designed prospective therapeutic studies for chronic GvHD is 
an urgent unmet clinical need. Successful management and supportive care of 
patients with chronic GvHD require close follow-up to identify complications before 
they limit organ function or threaten mortality. Chronic GvHD and its treatment 
further results in increased risk of infection, impaired organ function, and reduced 
QOL. The goal of therapy is to stop destructive immunological processes, improve 
symptoms, and eventually establish immunological tolerance with ultimate 
withdrawal of immunosuppressive therapy. Approximately 85% of patients who 
survive beyond five years after diagnosis are able to stop systemic therapy [32]. 
 
The most attractive approach for controlling chronic GvHD would be the prevention 
of the most severe and irreversible clinical manifestations [33, 34].  Selective 
modulation of alloreactive response and inflammation, rather than general 
immunosuppression, might be a promising mechanism for reducing GvHD while 
preserving GvL effect. Inhibitors of specific B-cell signaling pathways, both small 
molecules and monoclonal antibodies, are now available for clinical use and are 
being applied in the treatment of B-cell malignancies. These new agents can also 
be used to identify and potentially modify specific abnormalities of B-cell 
homeostasis. Development of clinical trials using these agents in patients 
undergoing allogeneic HCT will enable the development of new strategies to target 
B-cell responses for prevention and treatment of chronic GvHD. 
 
1.2 
Belimumab  
 
1.2.1  Clinical Pharmacology 
 
Belimumab (Benlysta) is a recombinant, human immunoglobulin G 1 lambda 
(IgG1λ) monoclonal antibody that blocks the binding of soluble human B 
lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B) to 
its receptors on B cells [35]. Belimumab does not bind B cells directly, but by 
binding BLyS it inhibits the survival of B cells and reduces the differentiation of B 
cells into immunoglobulin-producing plasma cells. Belimumab has a molecular 
weight of approximately 147 kDa and is produced by recombinant DNA technology 
in a mammalian cell expression system [36]. In humans with systemic lupus 
erythematosus (SLE) and rheumatoid arthritis (RA), elevated BLyS levels have 
been found to be positively correlated with elevated autoantibody levels, 
immunoglobulin IgG, and disease activity [37]. By neutralizing the activity of BLyS, 
belimumab inhibits survival of B cells. 
 
1.2.2 Preclinical Experience 
 
Please refer to Investigators Brochure for experience in preclinical studies. 
 
1.2.3 Clinical Experience and Toxicology 
 
Over 3,000 individuals with SLE have been treated with belimumab in clinical 
studies. Two Phase 3 studies of belimumab in SLE were completed in 2009. 
Results of these studies showed that belimumab treatment (10 mg/kg IV every 2 
weeks for 3 doses and every 4 weeks thereafter) was effective in reducing disease 
activity as measured by the SLE responder index (SRI) at Week 52, the primary 
efficacy endpoint of both trials [38, 39]. The data suggested that belimumab 

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treatment may be associated with reduced steroid use and risk of severe flare.  
Belimumab is currently FDA approved for the treatment of systemic lupus 
erythematosus and another trial assessing the efficacy in rheumatoid arthritis has 
recently been completed. Furthermore, clinical trials in other rheumatologic 
conditions, such as scleroderma and Sjögren’s syndrome [40] are underway 
[www.clinicaltrials.gov]. Treatment with belimumab plus standard of care was 
generally well tolerated with no apparent dose response in the safety profile. Rates 
of adverse events (AEs), severe AEs, serious adverse events (SAEs), AEs leading 
to discontinuation, and serious/severe infections were generally comparable to the 
rates observed in the placebo plus standard of care group. When used as a single 
agent there were rare grade ≥3 adverse events with the most common grade 1 or 
2 adverse events involving infectious complications (i.e., upper respiratory 
infections, gastroenteritis, urinary tract infection), headaches, and neutropenia [37, 
40]. Moreover, when belimumab was combined with standard of care 
immunosuppressive therapy in subjects with lupus, there was no increased rate of 
adverse events of any grade compared to standard of care plus placebo 
suggesting an acceptable benefit/risk balance of belimumab when combined with 
additional immune modulating agents [38, 39]. Psychiatric events, including 
depression and suicide, were observed more frequently with belimumab, although 
it is unknown if belimumab treatment is associated with increased risk for these 
events. Although no increase in the rate of serious infections or malignancies was 
observed, as with other immunomodulating therapies the mechanism of action of 
belimumab could increase the risk for these events. Hypersensitivity and infusion 
reactions were observed more frequently with belimumab, with anaphylaxis 
observed ≤ 1% of subjects. The most commonly-reported adverse reactions, 
occurring in ≥ 3% of patients receiving 10 mg/kg belimumab in clinical trials (and 
at a ≥ 1% greater rate than placebo) were nausea, diarrhea, pyrexia, 
nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, 
pharyngitis, cystitis, leucopenia, and gastroenteritis viral. Experience from open-
label, long-term continuation trials of belimumab in SLE patients confirms 
prolonged treatment with belimumab remains generally well tolerated, with no 
apparent increase in the incidence rate of AEs or SAEs over time, including 
important events such as infections and malignancies [37, 41]. Long term 
belimumab treatment appears to provide sustained improvement in SLE disease 
activity and reduction of flares. Please refer to the investigator’s brochure for 
summaries of clinical trials of belimumab.  
 
The observation that antagonism of BLyS by treatment with belimumab results in 
reductions of B cells, serum immunoglobulins and in particular, reduction of a 
variety of serum autoantibodies suggests that belimumab may have therapeutic 
benefit in other B cell-mediated autoimmune diseases in which BLyS may have a 
role [42]. Diseases which are characterized by autoantibody production or excess 
antibody levels in which elevated levels of BLyS have been observed, and in some 
cases, shown to be correlated with disease activity include: Sjogren’s Syndrome, 
idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasmic antibodies 
(ANCA)-associated vasculitides, chronic graft versus host disease (GvHD), 
chronic 
antibody-mediated 
allograft 
rejection, 
and 
Waldenstrom's 
macroglobulinemia.  
 
 

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1.2.4 Pharmacokinetics and Drug Metabolism 
 
Pharmacokinetic Parameter 
Population Estimates 
(n = 563) 
Peak concentration (Cmax, mcg/mL) 
313 
Area under the curve (AUC, day · mcg/mL) 
3,083 
Distribution half-life (t½, days) 
1.75 
Terminal half-life (t½, days) 
19.4 
Systemic clearance (CL, mL/day) 
215 
Volume of distribution (Vss, L) 
5.29 
 
1.3 
Study Rationale 
 
Given the role of B cells in the pathophysiology of chronic GvHD, the association between 
elevated BAFF levels post-transplant in abnormal B-cell homeostasis and chronic GvHD, 
and the efficacy of belimumab in the inhibition of BAFF signaling, these proof-of-principle 
findings support the rational for use of belimumab as prophylaxis of chronic GvHD. We 
propose a pilot and feasibility study to assess the safety and tolerability, as well as 
preliminary efficacy, of belimumab as prophylaxis of chronic GvHD following alloHCT. Our 
central hypothesis is that belimumab will be well tolerated and have a favorable effect on 
incidence and severity of chronic GvHD. 
 
 
2 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
To evaluate safety and tolerability of belimumab as prophylaxis of chronic GvHD in 
subjects following alloHCT.  This will be assessed by CTCAE v. 4.03. 
 
2.2 
Secondary Objectives 
 
1. To evaluate the impact of prophylactic belimumab on the incidence and severity of 
chronic GvHD at 6, 12 and 24 months after alloHCT 
2. To evaluate the impact of prophylactic belimumab on the incidence and severity of 
acute GvHD at 3 and 6 months after alloHCT 
3. To evaluate the impact of prophylactic belimumab on overall survival at 6, 12 and 24 
months after alloHCT 
4. To evaluate the impact of prophylactic belimumab on relapse rate at 6, 12 and 24 
months after alloHCT 
5. To evaluate the impact of prophylactic belimumab on overall corticosteroid 
requirement (dose and duration) for treatment of chronic GvHD at 6, 12 and 24 months 
after alloHCT 
6. To evaluate the impact of prophylactic belimumab on the necessity to use alternative 
treatment modalities for chronic GvHD at 6, 12 and 24 months after alloHCT 
  
 
 

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2.3 
Exploratory Objectives 
 
1. To evaluate the effect of prophylactic belimumab on post-transplant immune cell 
reconstitution. 
2. To explore candidate biomarkers (i.e. BAFF level, BAFF:B cell ratio; B cell 
subpopulation frequency) that could predict subjects who may benefit from 
prophylactic administration of belimumab to prevent chronic GvHD.  
 
 
3 
PATIENT SELECTION AND ENROLLMENT 
 
3.1 
Inclusion Criteria 
 
1. At least 18 years of age 
2. ECOG performance status ≤ 2 
3. Diagnosis of hematologic malignancy (i.e. acute myeloid leukemia, acute 
lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous 
leukemia, 
Hodgkin’s 
lymphoma, 
non-Hodgkin’s 
lymphoma, 
myelodysplastic 
syndrome, chronic myelomonocytic leukemia) 
4. Use of myeloablative or non-myeloablative conditioning regimen 
5. Use of mobilized peripheral blood stem cells from fully HLA-matched related or 
unrelated donor as a graft source 
6. Acute GvHD prophylaxis with methotrexate and tacrolimus 
7. Documented complete remission and full donor engraftment (by STR identity testing) 
on Day +30 bone marrow biopsy 
a. Complete remission:  less than 5% blasts in an aspirate bone marrow sample 
with a count of at least 200 nucleated cells, no blasts with Auer rods or 
persistence of extramedullary disease PLUS absolute neutrophil count (ANC) > 
1,500/μL, platelet count ≥ 50,000/μL and no leukemic blasts in the peripheral 
blood.  
b. Negative minimal residual disease  
c. Full donor engraftment by STR testing (either by bone marrow or peripheral 
blood testing)  
8. Adequate end organ function: 
a. Serum bilirubin ≤ 1.5 x ULN 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x 
ULN 
c. Creatinine clearance ≥ 40 mL/min/1.73 m2 by the Cockcroft-Gault formula  
9. Women of childbearing potential must agree to use adequate contraception (hormonal 
or barrier method of birth control, abstinence) prior to study entry, for the duration of 
study participation, and for 16 weeks after the last dose of study drug.  Should a 
woman become pregnant or suspect she is pregnant while participating in this study, 
she must inform her treating physician immediately. 
10. Able to understand and willing to sign an IRB-approved written informed consent. 
 
3.2 
Exclusion Criteria 
  

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1. Active grade III-IV classic acute GvHD; subjects with prior resolved acute GvHD on 
stable doses of immunosuppression at time of enrollment will be permitted 
2. Evidence of classic chronic GvHD or overlap chronic GvHD at time of enrollment 
3. Subjects who participated in a clinical trial of acute GvHD prophylaxis in which chronic 
GvHD was a secondary end point 
4. Donor lymphocyte infusion administered to treat relapse or loss of donor chimerism 
5. Treatment with rituximab or other anti-B cell specific antibodies within previous 3 
months 
6. History of other malignancy ≤ 5 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
carcinoma in situ of the cervix 
7. Currently receiving any other investigational agents 
8. Known allergy or intolerance to any component of belimumab, including human or 
murine proteins or monoclonal antibodies 
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations (including current drug or alcohol 
abuse or dependence, or history of drug or alcohol abuse or dependence within the 
last year) that would limit compliance with study requirements 
10. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or anti-
parasitic agents) within 14 days prior to planned start of therapy 
11. Evidence of serious suicide risk including any history of suicidal behavior in the last 6 
months and/or any suicidal ideation in the last 2 months and/or poses a significant 
suicide risk in the judgment of the investigator 
12. History of pre-existing immunodeficiency disorder, autoimmune condition, or chronic 
infection 
13. Known HIV positivity 
14. Serologic evidence of current or past hepatitis B infection based on the results of 
testing for HBsAg and anti-HBc – Patients positive for HBsAg or HBcAb are excluded 
15. Positive test for hepatitis C antibody (patients with documented clearance of hepatitis 
C by PCR following treatment will be permitted) 
16. Currently on therapy for active chronic infection (such as tuberculosis, pneumocystis, 
cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria). 
Prophylactic therapy is allowed. 
17. Has any other clinically significant abnormal laboratory value in the opinion of the 
investigator  
  
3.3 
Inclusion of Women and Minorities 
 
Men and women as well as members of all races and ethnic groups are eligible for this 
trial. 
 
 
4 
REGISTRATION PROCEDURES 
 
Subject must not start any protocol intervention prior to registration through the Siteman Cancer 
Center. The subject must read, understand and sign the Institutional Review Board approved 
consent form. The following steps must be taken before registering subjects to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 

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3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
All necessary procedures and evaluations must be performed to document that the subject 
meets all of the inclusion criteria and none of the exclusion criteria prior to first dose on 
Day 1. Adult subjects must read, understand, and sign the Institutional Review 
Board/Research Ethics Board/Independent Ethics Committee (IRB/REB/IEC) approved 
informed consent form (ICF) confirming his or her willingness to participate in this study 
before any study-specific screening procedures are performed. Subjects less than 18 
years of age will not be enrolled on this study. Subjects must also grant permission to use 
protected health information per the Health Insurance Portability and Accountability Act 
(HIPAA).  
 
Confirm patient eligibility by collecting the information listed below: 
 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed informed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All subjects must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a UPN for this study.  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
 
5 
TREATMENT OF SUBJECTS AND STUDY DESIGN 
 
This is a single center, open-label pilot and feasibility study of prophylactic belimumab for the 
prevention of chronic GvHD following alloHCT at Washington University School of Medicine in St. 
Louis. The study will include Screening Phase, Treatment Phase, and Follow-up Phase. 
 
Subjects will be screened for the study after obtaining the results from their standard-of-care Day 
+30 bone marrow biopsy. Those subjects meeting the Inclusion and Exclusion Criteria will be 
enrolled in the study and start treatment between Day +30 and Day +80 after alloHCT. At 
enrollment, subjects may continue on steroids that were used to treat acute GvHD. At the time of 
enrollment, however, subjects should be responding to therapy and the dose of steroid should be 
≤0.5 mg/kg/day of prednisone equivalent with no dose increase in the preceding 1 week. Subjects 
may also remain on other systemic immunosuppressive drugs that were used to prevent or treat 
acute GvHD. At the time of enrollment, acute GvHD should be grade II or less. Subjects diagnosed 
with or treated for chronic GvHD will be excluded from the study. The study population will include 
10 subjects. Planned duration of treatment is for 7 cycles (6 months; see study schema). Subjects 
will be followed for 24 months. One of the secondary endpoints is to evaluate the impact of 

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belimumab on incidence and severity of chronic GvHD. The subjects who develop chronic GvHD 
while receiving treatment with the study drug, belimumab, may continue on the study at the 
discretion of treating transplant physician with careful documentation of their GvHD severity and 
treatments used for it. If at any point it is considered that the study drug may be contributing to 
chronic GvHD it will be discontinued.  
 
The primary endpoint is safety and tolerability of belimumab. Subjects who receive at least one 
dose of belimumab will be eligible for primary endpoint analysis and it will be performed according 
to the CTCAE v4.03.  
 
Diagnosis of chronic GvHD will be per NIH criteria (Appendix B). Those patients diagnosed with 
chronic GvHD will have organ specific staging and global scoring according to the NIH criteria 
(Appendices D and E). 
 
5.1 
Baseline Evaluations 
 
5.1.1 Medical History and Demographics 
 
The subject’s relevant medical history through review of medical records and by 
interview will be collected and recorded. Concurrent medical signs and symptoms 
must be documented to establish baseline severities. A disease history and the 
date of initial diagnosis will be recorded. 
 
5.1.2 Prior and Concomitant Medications 
 
All active medications from 30 days prior to signing of ICF through 30 days after 
the last dose of study drug will be documented. All prior and current treatments for 
acute and chronic GvHD will be documented.  
 
5.1.3 History and physical neurological, and psychiatric exam, vital signs 
and ECOG performance score 
 
The physical examination will include the general appearance of the subject, height 
(Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, 
lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and 
lymphatic system. Vital signs will include blood pressure, heart rate, respiratory 
rate, and body temperature. ECOG performance score will be recorded (Appendix 
C). 
 
5.1.4 Laboratory 
 
5.1.4.1 Bone Marrow Biopsy 
 
Remission will be assessed as defined in the Inclusion Criteria. It will be 
evaluated using a local laboratory and include pathology review, minimal 
residual disease and engraftment testing.  
 
 
 

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5.1.4.2 Hematology 
 
Hematology will be evaluated using a local laboratory and parameters will 
include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils. 
 
5.1.4.3 Chemistry 
 
Serum chemistry will be evaluated using a local laboratory and parameters 
will include sodium, potassium, chloride, blood urea nitrogen (BUN)/Urea, 
creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline 
phosphatase, total bilirubin, LDH, phosphate, uric acid, magnesium and 
bicarbonate. 
 
 
5.1.4.4 Hepatitis Serologies 
 
Hepatitis serologies will be evaluated using a local laboratory and include 
hepatitis C antibody, hepatitis B surface antigen, and hepatitis B core 
antibody. If hepatitis B core antibody, hepatitis B surface antigen, or 
hepatitis C antibody is positive, then PCR to quantitate hepatitis B DNA or 
hepatitis C RNA must be performed.   
 
 
5.1.4.5 Serum Immunoglobulins  
 
Serum immunoglobulins will be evaluated using a local laboratory and 
include IgA, IgG and IgM levels. 
 
5.1.4.6 Pregnancy test 
 
Serum pregnancy test is required at Screening using a local laboratory and 
only for women of childbearing potential. 
 
5.1.5 ECG 
 
At Screening, 12-lead ECG is required and will be done in triplicate (≥1 minute 
apart). Any clinically significant abnormalities noted at Screening should be 
included in the medical history. 
 
 
 
ECGs should be performed at the investigator’s discretion, particularly in subjects 
with arrhythmic symptoms (e.g. palpitations, lightheadedness) or new onset of 
dyspnea.   
 
5.1.6 Chronic GvHD Assessment 
 
Patients should be assessed for chronic GvHD and no active chronic GvHD should 
be present. Please see Diagnostic Criteria for Chronic GvHD (Appendix B). 
 
5.1.7 Correlative pharmacodynamics and immunology studies 
 
Refer to Section 9.0.  

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5.2 
Study Drug Administration  
 
Belimumab will be administered intravenously at 10 mg/kg over 1 hour. Enrollment and 
the first dose of belimumab (Cycle 1) will be administered between Day +30 and Day +80 
after alloHCT, after reviewing bone marrow biopsy results and confirming eligibility. 
Subjects will receive belimumab every 2 weeks for 3 cycles and then every 4 weeks for a 
total of 7 cycles (6 months of therapy).   
 
Therefore: Cycle 1 of belimumab will be administered between Day +30 and +60 after 
alloHCT, Cycle 2 will be administered 2 weeks later (+/- 3 days), Cycle 3 will be 
administered two weeks after Cycle 2 (+/- 3 days), and each subsequent cycle will be 
given every 4 weeks thereafter (+/- 1 week) for total of 7 cycles (6 months of therapy).  
This dosing and schedule of belimumab administration is similar to prior phase III studies 
for systemic lupus erythematous [38, 39]. Subjects will continue to adjust their standard of 
care immunosuppressive medications at the discretion of treating physician.  
 
5.3 
Premedication  
 
Premedication with an oral antihistamine, with or without an antipyretic, may be 
administered before the infusion of belimumab. 
 
5.4 
Duration of Therapy 
 
Treatment may continue for six months, or until one of the following criteria applies: 
• 
Documented and confirmed original hematologic disease relapse 
• 
Death 
• 
Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• 
General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• 
Grade III-IV acute GvHD not responding to therapy after 2 weeks 
• 
Serious noncompliance with the study protocol 
• 
Lost to follow-up 
• 
Patient withdraws consent 
• 
Investigator removes the patient from study 
• 
The Siteman Cancer Center decides to close the study 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation 
documented in the case report forms. Subjects who prematurely discontinue treatment for 
any reason will be followed as indicated in the study calendar. 
 
5.5 
Duration of Follow-up 
 
Subjects will be followed after discontinuation of treatment every 3 months during the first 
2 years post-C1D1 and then annually for 5 years post-C1D1 or until death, whichever 
occurs first. Subjects removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. 

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5.6 
Concomitant Medication and Supportive Care Guidelines 
 
5.6.1 Permitted Concomitant Medications   
 
All systemic immunosuppressive medications with exact doses and additional   
treatment modalities for chronic GvHD will be recorded at time of every visit. 
Adjustment to immunosuppressive medications or initiation of additional treatment 
modalities for treatment of chronic GvHD will be at the discretion of the treating 
transplant oncologist. Systemic immune suppressive medications that the patient 
is already receiving at the time of enrollment will be tapered at the discretion of the 
treating transplant oncologist.  
 
Infectious prophylaxis should follow institutional guidelines. All patients should 
continue on prophylaxis against viral, fungal and pneumocystis infections.  
 
5.6.2 Prohibited Medications  
 
After prior B-cell therapy, there must be a wash-out of 5 therapeutic half-lives, 
when pharmacodynamic effect would be minimal (e.g., one year following 
rituximab). 
 
From the time of initiation of conditioning regimen subjects must not have received 
any biologic investigational agent (i.e. any drug not approved for sale in the country 
in which it is being used). 
 
For 30 days prior to administration of belimumab (or 5 half-lives, whichever is 
greater) subjects must not have received any non-biologic investigational agent 
(i.e. any drug not approved for sale in the country in which it is being used).  
 
Live vaccines should not be given within 30 days prior to administration of 
belimumab or concurrently with belimumab.  
 
5.6.3 Supportive Care Guidelines 
 
Supportive medications in accordance with standard practice (such as for emesis, 
diarrhea, etc.) are permitted. Use of neutrophil growth factors and red blood cell 
growth factors is permitted per institutional policy and in accordance with the 
ASCO guidelines. Transfusions may be given in accordance with institutional 
policy.  
 
5.7 
Management of Adverse Clinical Events and Dose Modification Guidelines 
 
Belimumab is generally a well-tolerated agent.  Most common adverse reactions are: 
nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, depression, migraine. 
Management guidelines for some potential events are outlined below. Further details are 
available in the Investigator’s Brochure. All serious AEs, including AEs of Special Interest, 
i.e., serious hypersensitivity or infusion reactions; serious infections, including herpes 
zoster and opportunistic infections; malignancy; and/or Suicidal thought, intent or 
behaviour must be reported to GSK within 24 hours of awareness. 
 

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Hypersensitivity and Infusion Reactions 
Site personnel will be aware of the risk of hypersensitivity reactions, which may present 
as infusion reactions, and monitor subjects closely. Subjects should remain under clinical 
supervision for 3 hours after completion of the first 2 infusions.  The infusion rate may be 
slowed or interrupted if the patient develops an infusion reaction.  Should symptoms of 
acute hypersensitivity occur, an extended period of monitoring may be appropriate based 
on clinical judgment. This may include, but is not limited to, monitoring vital signs and 
observing any untoward reactions. Beyond the first 2 infusions, subjects should be 
monitored during infusion and for 30 minutes after infusion according to standard 
operating procedure for IV infusions.  Infusion reactions occurred more frequently on the 
first two infusion days and tended to decrease with subsequent infusions. Delay in the 
onset of acute hypersensitivity reactions has been observed with recurrence of clinically 
significant reactions after initial resolution of symptoms following appropriate treatment. 
Therefore, subjects should be monitored during and for an appropriate period of time after 
administration of belimumab. Delayed-type, non-acute hypersensitivity reactions have 
also been observed and included symptoms such as rash, nausea, fatigue, myalgia, 
headache, and facial edema. 
 
Serious infections 
Serious infections, including herpes zoster and opportunistic infections are rare, but 
possible. Infection prophylaxis should follow institutional guidelines.  If patient develops 
infection requiring intravenous or intramuscular antibiotics, belimumab may be held for up 
to two weeks and will then be administered.  If a patient needs a dose held for more than 
two weeks, the PI will be contacted to determine suitability for further study participation.  
 
Rash with or without pruritus 
Rash should be managed symptomatically according to standard medical practice. Patient 
should be evaluated for presence of acute GvHD (see guidelines below). 
 
Elevation of liver enzymes 
Elevation of liver enzymes is not listed as an expected adverse event with belimumab. 
However, elevated liver enzymes can occur in the context of acute GvHD and such 
patients should be evaluated for presence of acute GvHD.  
 
Nausea and/or vomiting 
Standard anti-emetics may be used for prophylaxis and treatment of nausea or vomiting. 
 
Diarrhea 
Diarrhea should be managed according to clinical practice. Patient should be evaluated 
for presence of acute GvHD (see guidelines below).  
 
Depression and suicidality 
Some autoimmune diseases have an increased risk of depression and suicidal behavior 
and/or ideation [Bachen, 2009; Timonen, 2003; Stenager, 1992].  For this reason, in 
studies of subjects with autoimmune disease, subjects should be assessed for depression, 
suicidal ideation and/or behavior at each visit by the treating physician (to be recorded in 
a physician note). 
 
Progressive Multifocal Leukoencephalopathy (PML) 
PML resulting in neurological deficits, including fatal cases, has been reported in SLE 
subjects receiving immunosuppressant pharmacotherapy, including belimumab.  A 

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diagnosis of PML should be considered in any subject presenting with new-onset or 
deteriorating neurological signs and symptoms.  The subject should be referred to a 
neurologist or other appropriate specialist for evaluation.  If PML is confirmed, belimumab 
should 
be 
discontinued 
and 
consideration 
should 
be 
given 
to 
stopping 
immunosuppressant therapy. 
 
5.8 
Acute GvHD 
 
Any patient with new rash, diarrhea or elevated liver enzymes should be evaluated for 
presence of acute GvHD.  In the event a study participant were to develop acute GvHD 
grade III-IV after initiating belimumab therapy, belimumab treatment will be held. 
Belimumab administration can be delayed for up to two weeks, however, if the grade of 
acute GvHD does not improve to grade II or less by that time, belimumab will be 
discontinued indefinitely and patient will be taken off study.  
 
5.9 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 7 days prior to the first dose of belimumab.  
 
Women of childbearing potential must agree to one of the following: 
• 
Complete abstinence from intercourse from 2 weeks prior to administration of the first 
dose of belimumab until 16 weeks after the last dose of belimumab (if consistent with 
the preferred and usual lifestyle of the patient).  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
• 
Consistent and correct use of one of the following acceptable methods of birth control 
for one month prior to the start of the study agent, during the study, and 16 weeks after 
the last dose of study agent: 
• 
Oral contraceptive, either combined or progestogen alone 
• 
Injectable progestogen 
• 
Implants of levonorgestrel or etonogestrel 
• 
Estrogenic vaginal ring 
• 
Percutaneous contraceptive patches 
• 
Intrauterine device (IUD) or intrauterine system (IUS) with < 1% failure rate as stated 
in the product label 
• 
Male partner sterilization (vasectomy with documentation of azoospermia) prior to the 
female subject’s entry into the study, and this male is the sole partner for that subject.  
For this definition, “documented” refers to the outcome of the investigator’s/designee’s 
medical examination of the subject or review of the subject’s medical history for study 
eligibility, as obtained via a verbal interview with the subject or from the subject’s 
medical records. 
• 
Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) 
plus spermicidal agent (foam/gel/film/cream/suppository) 
 
If a patient is suspected to be pregnant, belimumab should be immediately discontinued.  
In addition, a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing.  If a female 

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patient or female partner of a male patient becomes pregnant during therapy or within one 
month after the last dose of belimumab, the investigator must be notified in order to 
facilitate outcome follow-up. 
 
5.10 
Study Stopping Rule 
 
As this is a pilot study enrolling 10 eligible participants, the study will be suspended if any 
death considered at least possibly related to study treatment occurs during participation.  
The suspension may be lifted only if review of the event by the PI and QASMC results in 
a recommendation to permit further study enrollments.  
 
 
6 
PHARMACEUTICAL INFORMATION 
 
6.1 
Belimumab (Benlysta) Description 
 
Benlysta (belimumab) is a human IgG1λ monoclonal antibody specific for soluble human 
B lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B).  
Belimumab has a molecular weight of approximately 147 kDa.  Belimumab is produced 
by recombinant DNA technology in a mammalian cell expression system. 
 
6.2 
Clinical Pharmacology 
 
Please refer to Section 1.2. 
 
6.3 
Pharmacokinetics and Drug Metabolism 
 
Please refer to Section 1.2. 
 
6.4 
Supplier(s) 
 
Belimumab will be provided free of charge by GSK. 
 
6.5 
Dosage Form and Preparation 
 
Belimumab will be supplied as a sterile, white to off-white, preservative-free, lyophilized 
powder for intravenous infusion.  It will be provided in single-use glass vials with a rubber 
stopper and a flip-off seal.  Each 5-mL vial contains 120 mg of belimumab and each 20-
mL vial contains 400 mg of belimumab.  Upon reconstitution with Sterile Water for 
Injection, USP, each single-use vial delivers 80 mg/mL belimumab in 0.16 mg/mL citric 
acid, 0.4 mg/mL polysorbate 80, 2.7 mg/mL sodium citrate, and 80 mg/mL sucrose, with 
a pH of 6.5. 
 
Dilution Instructions: 
1. Dextrose intravenous solutions are incompatible with BENLYSTA. BENLYSTA should 
only be diluted in 0.9% Sodium Chloride Injection, USP. Dilute the reconstituted 
product to 250 mL in 0.9% Sodium Chloride Injection, USP (normal saline) for 
intravenous infusion. From a 250-mL infusion bag or bottle of normal saline, withdraw 
and discard a volume equal to the volume of the reconstituted solution of BENLYSTA 
required for the patient’s dose. Then add the required volume of the reconstituted 

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solution of BENLYSTA into the infusion bag or bottle. Gently invert the bag or bottle to 
mix the solution. Any unused solution in the vials must be discarded.  
2. Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Discard 
the solution if any particulate matter or discoloration is observed.  
3. The reconstituted solution of BENLYSTA, if not used immediately, should be stored 
protected from direct sunlight and refrigerated at 2° to 8°C (36° to 46°F). Solutions of 
BENLYSTA diluted in normal saline may be stored at 2° to 8°C (36° to 46°F) or room 
temperature. The total time from reconstitution of BENLYSTA to completion of infusion 
should not exceed 8 hours.  
4. No incompatibilities between BENLYSTA and polyvinylchloride or polyolefin bags 
have been observed.  
 
6.6 
Storage and Stability 
 
Vials of belimumab should be stored refrigerated between 2° and 8°C (36° to 46°F).  Vials 
should be protected from light and stored in the original carton until use; it should not be 
frozen; exposure to heat should be avoided.  It should not be used beyond the expiration 
date. 
 
6.7 
Administration 
 
Belimumab will be given intravenously at a dose of 10 mg/kg over the course of one hour.  
Refer to the package insert for reconstitution instructions. 
 
6.8 
Special Handling Instructions 
 
None. 
 
 
7 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. Please refer to Appendix G for definitions and Appendix H for a grid of reporting 
timelines. 
 
Adverse events will be tracked from C1D1, as soon as the infusion of Belimumab, through 30 
days following the last day of study treatment. All adverse events must be recorded on the toxicity 
tracking case report form (CRF) with the exception of: 
• 
Baseline adverse events, which shall be recorded on the medical history CRF 
• Adverse events that are less than CTCAE grade 3 
• 
AEs not of special interest as defined in Section 7.1.4.1 (special interest AEs will 
be recorded regardless of grade, including those thought to be related to chronic 
GvHD) 
 
Refer to the data submission schedule in Section 12 for instructions on the collection of AEs in 
the EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1. 

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7.1 
Sponsor-Investigator Reporting Requirements 
 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. The PI is required to promptly notify the IRB of the following events: 
 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The Sponsor investigator is required to notify the QASMC of any unanticipated 
problems involving risks to participants or others occurring at WU or any BJH or 
SLCH institution that has been reported to and acknowledged by HRPO.  
(Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu. Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
7.1.3 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the Washington University principal investigator to report to the 
FDA as follows: 
 
• 
Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix G for definitions) no later than 7 calendar days after initial 
receipt of the information.   
• 
Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix G) no later than 15 calendar days it is determined 
that the information qualifies for reporting. Report an adverse event (Appendix 
G) as a suspected adverse reaction only if there is evidence to suggest a 
causal relationship between the drug and the adverse event, such as:   
o A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure  
o One or more occurrences of an event that is not commonly associated with 
drug exposure but is otherwise uncommon in the population exposed to the 
drug 

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o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment group 
than in a concurrent or historical control group  
• 
Report any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies that suggest a significant risk in humans exposed to 
the drug no later than 15 calendar days after it is determined that the 
information qualifies for reporting. 
• 
Report any findings from animal or in vitro testing that suggest significant risk 
in humans exposed to the drug no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  
• 
Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days after 
it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to 
the due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
7.1.4 Reporting to GSK 
 
In addition to events described in Section 7.4 as reportable, all events of possible 
drug-induced liver injury with hyperbilirubinemia defined as ALT ≥ 3x ULN and 
bilirubin ≥ 2x ULN (>35% direct) (or ALT ≥ 3x ULN and INR > 1.5, if the INR is 
measured) termed ‘Hy’s Law’ events (INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants) should 
be reported. 
 
Any pregnancy that occurs during study participation must be reported.  To ensure 
subject safety, each pregnancy must be reported within 2 weeks of learning of its 
occurrence.  The pregnancy must be followed up to determine outcome (including 
premature termination) and status of mother and child.  Pregnancy complications 
and elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE. 
 
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the 
investigator as possibly related to the study treatment, must be promptly reported 
to GSK. 

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Safety information should be sent via email notification within 24 hours of 
awareness for all SAEs and AEs of Interest, and within 60 days for any other 
reportable non-serious events to oax37649@gsk.com (backup fax number +44 208 754 
7822). 
 
7.1.4.1 Adverse Events of Special Interest: 
 
The frequency of all (both serious and non-serious) of the following 
Adverse Events of Special Interest will be assessed and included in the 
final report:   
• Serious Hypersensitivity or Infusion Reactions 
• Serious infections, including herpes zoster and opportunistic infections 
• Malignancy 
• Suicidal thought, intent or behaviour 
 
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 
• 
planned hospitalizations 
• 
hospitalizations < 24 hours 
• 
respite care 
• 
events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
8 
MEASUREMENT OF EFFECT 
 
8.1 
Primary Endpoint: Safety and Tolerability 
 
All subjects who receive any study treatment are evaluable for safety and tolerability. 
Subjects are followed for primary endpoint from first receiving study treatment until a 30-
day follow-up after the last dose. Adverse events will be diagnosed and graded according 
to CTCAE v4.03 as described above.   
 
8.2 
Secondary Endpoints 
 
Subjects who receive at least 2 cycles of belimumab are evaluable for secondary and 
explorative endpoints. 
 
1. Incidence and severity of chronic GvHD at 6, 12 and 24 months after alloHCT 
The presence of chronic GvHD will be determined according to the 2014 NIH Criteria 
(Appendix B). If chronic GvHD is diagnosed, each organ will be scored 0-3 and 
graded, according to the 2014 NIH criteria for Diagnosing and Staging of Chronic 
GvHD (Appendix D).  These data will allow calculation of the NIH global severity score 
of mild, moderate or severe (Appendix E). Data will be collected on forms capturing 
chronic GvHD diagnosis and activity according to the 2014 NIH Criteria for chronic 
GvHD. 

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2. Incidence and severity of acute GvHD at 3 and 6 months after alloHCT 
Acute GvHD will be graded according to modified Minnesota CIBMTR (Appendix F). 
 
3. Overall survival at 6, 12 and 24 months after alloHCT 
Overall survival will be determined from date of belimumab initiation, with death from 
any cause as the event of interest, and censoring at last follow up date for those with 
incomplete observations. 
  
4. Relapse rate at 6, 12 and 24 months after alloHCT 
Relapse rate will be determined from date of belimumab initiation and censoring at 
last follow up date for those with incomplete observations. 
 
5. Overall corticosteroid requirement (dose and duration) for treatment of chronic 
GvHD at 6, 12 and 24 months after alloHCT 
The dose of corticosteroids will be captured at each study visit.  
 
6. Use of alternative treatment modalities for chronic GvHD at 6, 12 and 24 months 
after alloHCT 
The use of additional systemic immune suppressive agents will be captured at each 
study visit. 
 
8.3 
Exploratory Endpoints/Correlative Studies 
 
Subjects who receive at least 2 cycles of belimumab are evaluable for explorative 
endpoints/correlative studies.  
 
Age- and disease-matched controls with matched conditioning regimens and donor 
source/mismatch status will be obtained from the Bone Marrow Transplant Tissue Bank 
at Siteman Cancer Center at Washington University in St. Louis. These patients have had 
peripheral blood samples stored at time of transplant, 30 days post-transplant, 100 days 
post-transplant, 180 days post-transplant, and 360 days post-transplant. Immune 
competence and B cell phenotype subset panels will be performed on these samples. 
Additionally, BAFF levels will be measured and correlated with development of GvHD 
similarly to study cohort. The clinical outcomes including survival, recurrence rate, 
engraftment, incidence of acute and chronic GvHD, and medications list are readily 
available in institutional computerized database.  
 
 
9 
CORRELATIVE STUDIES 
 
All subjects will have blood drawn for correlative studies. Serum will be removed from a serum 
separator tube (SST) containing 10 mL patient blood, and peripheral mononuclear cells (PBMC) 
will be isolated from a 10 mL CPT tube at baseline and first follow-up post-belimumab (+24 wk), 
then every three months thereafter to assess BAFF levels and immune cell reconstitution. An 
additional serum sample will be collected prior to cycle 3 (+4 wk) to assess efficacy of belimumab 
in suppressing BAFF levels. BAFF levels will be quantitated by ELISA and immune cell 
reconstitution will be quantitated by whole blood flow cytometry.  
 
Once there is evidence of B cell reconstitution (anticipate between 18-24 months post-transplant), 
serum (1 x 10 mL SST) and PBMC (5 x 10 mL CPT tubes) will be collected for isolation of the 

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mononuclear cell layer, or buffy coat, by Ficoll-based density separation for additional B cell 
phenotyping by flow cytometry. Similar blood collections will be performed at 1 and 2 years post-
C1D1. Additional optional correlative lab draws will continue to be collected for similar analysis 
yearly thereafter up to 5 years post-C1D1. All samples will be processed and stored in the Dunn 
Lab (7408 BJCIH, 660 S Euclid Ave, St. Louis, Missouri) or Tissue Procurement Center until time 
of analysis.  
 
The following variables will be assessed: 
  
• 
Immune competence panel to quantify the relative frequency and absolute number of T 
cells, B cells, and NK cells which will determine impact of belimumab on immune 
reconstitution following transplantation. 
• 
BAFF levels at baseline and following treatment to assess the efficacy of belimumab in 
suppressing this target cytokine as well as to correlate development of chronic GvHD with 
circulating BAFF levels (i.e. degree of inhibition). 
• 
A B cell phenotype panel will be performed to assess the effect of belimumab on 
reconstitution and homeostasis of B cell subsets after transplant. 
• 
Immunoglobulin subset quantification will be performed to determine the effect of 
belimumab on the functional competency of B cells after transplant. 
 
 

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10 
STUDY CALENDAR 
 
10.1 
Screening and Treatment Calendar 
 
 
Screening1 
Baseline2 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
+2wk 
+4wk 
+8wk 
+12wk 
+16wk 
+20wk 
Informed consent 
X 
 
 
 
 
 
 
 
 
H&P, ECOG PS 
X 
 
X 
X 
X 
X 
X 
X 
X 
VS 
X 
 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
 
X 
X 
X 
X 
X 
X 
X 
CMP, LDH, phosphate, 
uric acid, magnesium 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test7 
X 
 
X8 
X 
X 
X 
X 
X 
X 
IgG and IgA 
 
X 
 
 
 
 
 
 
 
Hepatitis serologies 
X 
 
 
 
 
 
 
 
 
ECG (triplicate) 
X 
 
As clinically indicated 
Belimumab 
 
 
X5 
X5 
X5 
X6 
X6 
X6 
X6 
Research blood 
 
X2 
 
 
X4 
 
 
 
 
Acute GvHD 
assessment 
 
X 
 
 
X 
X 
X 
X 
X 
Chronic GvHD 
assessment 
 
 
 
 
X 
X 
X 
X 
X 
Immunosuppressive 
medication assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication reconciliation 
 
Monthly 
AE assessment 
 
X --------------------------------------------------------------------------------------------------- X9 
1. 
Screening assessments must take place between 30 and 80 days post-transplant 
2. 
pre-treatment 
3. 
Every 3 months starting at F/U #1 (+24wk) 
4. 
Prior to treatment 
5. 
Dosing window is +/- 3 days 
6. 
Dosing window is +/- 1 week 
7. 
Women of childbearing potential only 
8. 
Pregnancy test need not be repeated on Cycle 1 if conducted within 7 days of Cycle 1 dose 
9. 
AE assessment continues for 30 days post-EOT 
 
 

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10.2 
Follow-Up Calendar 
 
Follow-up visits start 4 weeks after the end of protocol treatment (6-month follow-up is 6 months post-C1D1 and 4 weeks post-
C7D1). 
 
 
+6mo 
+9mo 
+12mo 
+15mo 
+18mo 
+21mo 
+24 mo 
+3 yr 
+4 yr 
+5 yr 
CBC 
X 
 
 
 
 
 
 
 
 
 
CMP, LDH, phosphate, uric 
acid, magnesium 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test1 
X 
 
 
 
 
 
 
 
 
 
Research blood2 
X 
X 
X 
X 
X 
X 
X 
X2 
X2 
X2 
Acute GVHD assessment 
X 
 
 
 
 
 
 
 
 
 
Chronic GVHD assessment 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Immunosuppressive 
medication assessment 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AE assessment 
X 
 
 
 
 
 
 
 
 
 
1. 
Women of childbearing potential only 
2. 
Once there is evidence of B cell reconstitution, additional blood will be drawn (refer to Section 9), and will continue on an optional basis at 3, 4, and 5 
years post-C1D1 

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11 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least 1 patient has been enrolled) or one year 
after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
For phase I dose escalation studies, the Principal Investigator will review all patient data at least 
monthly (or before each dose-escalation if occurring sooner than monthly), and provide a semi-
annual report to the Quality Assurance and Safety Monitoring Committee (QASMC).  For phase 
II or dose expansion cohorts of a phase I study, the Principal Investigator will review all patient 
data at least every six months, and provide a semi-annual report to the QASMC. This report will 
include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• 
History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date 
• 
Average rate of accrual observed in year 1, year 2, and subsequent years 
• 
Expected accrual end date and accrual by cohort 
• 
Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• 
Measures of efficacy (phase I studies only if efficacy is objective of the protocol) 
• 
Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
• 
Power analysis and/or interim analysis (if described in the protocol) 
• 
Summary of toxicities separated by cohorts with the number of dose-limiting toxicities 
indicated 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
12 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
On-Study Form 
Prior to start of study treatment 
Treatment Form 
Medical History Form 
At the end of each cycle 

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Correlatives Form 
Baseline 
Cycle 3 pre-treatment 
6 mos post-C1D1 
9 mos post-C1D1 
1 yr post-C1D1 
15 mos post-C1D1 
18 mos post-C1D1 
21 mos post-C1D1 
Evidence of B-cell reconstitution 
2 yrs post-C1D1 
3 yrs post-C1D1 
4 yrs post-C1D1 
5 yrs post-C1D1 
Treatment Summary Form 
End of treatment 
Acute GvHD Form 
Baseline 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
6 mo f/u 
Chronic GvHD Form 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
6 mo f/u 
9 mo f/u 
12 mo f/u 
15 mo f/u 
18 mo f/u 
21 mo f/u 
24 mo f/u 
Follow-Up Form 
6 mos 
9 mos 
12 mos 
15 mos 
18 mos 
21 mos 
24 mos 
Adverse Event Form 
Immunosuppressive Meds Form 
Continuous 
Progression Form 
Time of progression 
Death Form 
Time of death 
 
 
12.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 

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Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac 
arrest), report as a grade 5 event under that AE.  Participant death must also be 
recorded on the Death Form. 
 
13 
STATISTICAL ANALYSIS 
 
This trial is designed to allow preliminary assessments of safety/tolerability and efficacy of 
belimumab in the post-allogeneic stem cell transplant setting. No pre-specified hypothesis testing 
will be performed. All analyses of demographics, biological activity, and safety will be descriptive. 
A 90% exact binomial confidence interval will be constructed for preliminary efficacy information. 
Data obtained from correlative studies will be used to identify parameters associated with efficacy 
from belimumab treatment that will guide design of subsequent larger clinical trials. Age-, disease-
, and donor-matched subjects will be used as an institutional control. These control subjects will 
be identified within the Bone Marrow Transplant and Lymphoma Tissue Bank (HRPO# 
201103349). Presently, there are roughly 100 subjects with banked specimens and associated 
clinical outcomes data that will serve as the comparator in this study in assessing preliminary 
efficacy. The data from this study will be used for sample size calculation estimates of an 
expansion cohort in a subsequent phase II study. A total of N=10 patients will be enrolled for this 
study. Though the sample size was not determined based on statistical power, this would provide 
us reasonable precision on both safety and feasibility. Based on intensive simulation studies 
regarding the sample size for pilot and translational studies, Piantadosi (2005) recommends that 
a sample size of 10 to 20 patients be adequate to provide preliminary information. For safety 
assessment, for example, there would be 90% chance of observing at least 1 serious adverse 
event if the true rate is at least 20%. Conversely, there would be less than 10% chance that we 
would observe 2 or more serious adverse events if the true rate is less than 5%. 
 
 

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14 
REFERENCES 
 
1. 
Arai, S., et al., Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic 
Transplantation: A Report from the Center for International Blood and Marrow Transplant 
Research. Biology of Blood and Marrow Transplantation, 2015. 21(2): p. 266-274. 
2. 
Socie, G. and J. Ritz, Current issues in chronic graft-versus-host disease. Blood, 2014. 
124(3): p. 374-84. 
3. 
Socie, G., et al., Long-term survival and late deaths after allogeneic bone marrow 
transplantation. Late Effects Working Committee of the International Bone Marrow 
Transplant Registry. N Engl J Med, 1999. 341(1): p. 14-21. 
4. 
Flowers, M.E., et al., Comparative analysis of risk factors for acute graft-versus-host 
disease and for chronic graft-versus-host disease according to National Institutes of 
Health consensus criteria. Blood, 2011. 117(11): p. 3214-9. 
5. 
Anasetti, C., et al., Peripheral-blood stem cells versus bone marrow from unrelated 
donors. N Engl J Med, 2012. 367(16): p. 1487-96. 
6. 
Perez-Simon, J.A., et al., Prognostic factors of chronic graft-versus-host disease 
following allogeneic peripheral blood stem cell transplantation: the national institutes 
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7. 
Kuzmina, Z., et al., Significantly worse survival of patients with NIH-defined chronic graft-
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prospective study. Leukemia, 2012. 26(4): p. 746-56. 
8. 
Arai, S., et al., Global and organ-specific chronic graft-versus-host disease severity 
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9. 
Jacobsohn, D.A., et al., Correlation between NIH composite skin score, patient-reported 
skin score, and outcome: results from the Chronic GVHD Consortium. Blood, 2012. 
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10. 
Inamoto, Y., et al., Validation of measurement scales in ocular graft-versus-host disease. 
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11. 
Arora, M., et al., Impact of prior acute GVHD on chronic GVHD outcomes: a chronic graft 
versus host disease consortium study. Leukemia, 2013. 27(5): p. 1196-201. 
12. 
Pidala, J., et al., Patient-reported quality of life is associated with severity of chronic 
graft-versus-host disease as measured by NIH criteria: report on baseline data from the 
Chronic GVHD Consortium. Blood, 2011. 117(17): p. 4651-7. 
13. 
Pidala, J., et al., Overlap subtype of chronic graft-versus-host disease is associated with 
an adverse prognosis, functional impairment, and inferior patient-reported outcomes: a 
Chronic Graft-versus-Host Disease Consortium study. Haematologica, 2012. 97(3): p. 
451-8. 
14. 
Baird, K., et al., National Institutes of Health chronic graft-versus-host disease staging in 
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15. 
Aki, S.Z., et al., Confounding Factors Affecting the National Institutes ofHealth (NIH) 
Chronic GVHD Organ-Specific Score and Global Severity. BBMT, 2014. 20: p. 265. 
16. 
Jagasia, M.H., et al., National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis 
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17. 
Carpenter, P.A., et al., National Institutes of Health Consensus Development Project on 
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Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant, 
2015. 
18. 
Shulman, H.M., et al., NIH Consensus development project on criteria for clinical trials in 
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19. 
Paczesny, S., et al., National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2014 Biomarker 
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20. 
Lee, S.J., et al., Measuring Therapeutic Response in Chronic Graft-versus-Host 
Disease. National Institutes of Health Consensus Development Project on Criteria for 
Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response Criteria 
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21. 
Martin, P.J., et al., National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical 
Trial Design Working Group Report. Biol Blood Marrow Transplant, 2015. 
22. 
Blazar, B.R., W.J. Murphy, and M. Abedi, Advances in graft-versus-host disease biology 
and therapy. Nat Rev Immunol, 2012. 12(6): p. 443-58. 
23. 
Choi, J., et al., In vivo administration of hypomethylating agents mitigate graft-versus-
host disease without sacrificing graft-versus-leukemia. Blood, 2010. 116(1): p. 129-39. 
24. 
Magenau, J.M., et al., Frequency of CD4(+)CD25(hi)FOXP3(+) regulatory T cells has 
diagnostic and prognostic value as a biomarker for acute graft-versus-host-disease. Biol 
Blood Marrow Transplant, 2010. 16(7): p. 907-14. 
25. 
Sarantopoulos, S. and J. Ritz, Aberrant B-cell homeostasis in chronic GVHD. Blood, 
2015. 125(11): p. 1703-7. 
26. 
Allen, J.L., et al., B cells from patients with chronic GVHD are activated and primed for 
survival via BAFF-mediated pathways. Blood, 2012. 120(12): p. 2529-36. 
27. 
Miklos, D.B., et al., Antibody responses to H-Y minor histocompatibility antigens 
correlate with chronic graft-versus-host disease and disease remission. Blood, 2005. 
105(7): p. 2973-8. 
28. 
Cutler, C., et al., Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD 
after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial. 
Blood, 2013. 122(8): p. 1510-7. 
29. 
Cutler, C., et al., Rituximab for steroid-refractory chronic graft-versus-host disease. 
Blood, 2006. 108(2): p. 756-62. 
30. 
Sarantopoulos, S., et al., High levels of B-cell activating factor in patients with active 
chronic graft-versus-host disease. Clin Cancer Res, 2007. 13(20): p. 6107-14. 
31. 
Socie, G., Chronic GVHD: B cells come of age. Blood, 2011. 117(7): p. 2086-7. 
32. 
Stewart, B.L., et al., Duration of immunosuppressive treatment for chronic graft-versus-
host disease. Blood, 2004. 104(12): p. 3501-6. 
33. 
Inamoto, Y. and M.E. Flowers, Treatment of chronic graft-versus-host disease in 2011. 
Curr Opin Hematol, 2011. 18(6): p. 414-20. 
34. 
Wolff, D., et al., Consensus Conference on Clinical Practice in Chronic GVHD: Second-
Line Treatment of Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant, 
2011. 17(1): p. 1-17. 
35. 
Woodland, R.T., M.R. Schmidt, and C.B. Thompson, BLyS and B cell homeostasis. 
Semin Immunol, 2006. 18(5): p. 318-26. 
36. 
Halpern, W.G., et al., Chronic administration of belimumab, a BLyS antagonist, 
decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus 
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37. 
Andreoli, L., et al., Belimumab for the treatment of refractory systemic lupus 
erythematosus: real-life experience in the first year of use in 18 Italian patients. Isr Med 
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38. 
Furie, R., et al., A phase III, randomized, placebo-controlled study of belimumab, a 
monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic 
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39. 
Navarra, S.V., et al., Efficacy and safety of belimumab in patients with active systemic 
lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet, 2011. 
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40. 
Mariette, X., et al., Efficacy and safety of belimumab in primary Sjogren's syndrome: 
results of the BELISS open-label phase II study. Ann Rheum Dis, 2015. 74(3): p. 526-31. 
41. 
Sabahi, R. and J.H. Anolik, B-cell-targeted therapy for systemic lupus erythematosus. 
Drugs, 2006. 66(15): p. 1933-48. 
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Dorner, T., Crossroads of B cell activation in autoimmunity: rationale of targeting B cells. 
J Rheumatol Suppl, 2006. 77: p. 3-11. 
 
 
 
 
 
 

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APPENDIX A. Clinical Differentiation of Acute and Chronic GvHD 
 
Category 
Time of 
Symptoms After 
alloHSCT or DLI 
Presence of 
Acute GvHD 
Features 
Presence of 
Chronic GvHD 
Features 
Acute GvHD 
 
 
 
Classic acute GvHD 
≤ 100 days 
Yes 
No 
Persistent, recurrent, or late-
onset acute GvHD 
> 100 days 
Yes 
No 
Chronic GvHD 
 
 
 
Classic chronic GvHD 
No time limit 
No 
Yes 
Overlap chronic GvHD 
No time limit 
Yes 
Yes 
 
DLI- donor lymphocyte infusion 
 
 

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APPENDIX B. Diagnostic Criteria for Chronic GvHD  
Organ or Site 
Diagnostic 
Features1 
Distinctive 
Features2 
Others3 
Common 
Features4 
Skin 
Poilkiloderma 
Lichen 
planus-like 
features 
Sclerotic 
features 
Morphea-like 
features 
Lichen 
sclerosis-like 
features 
Depigmentation 
 
Papulosquamous 
lesions 
Sweat impairment 
Ichthyosis 
Keratosis pilaris 
Hypopigmentation 
Hyperpigmentation 
Erythema 
Maculopapular 
rash 
Pruritus 
Nails 
 
Dystrophy 
Longitudinal 
ridging, splitting, 
or brittle features 
Onycholysis 
Pterygium unguis 
Nail loss  
 
 
Scalp and 
body hair 
 
New onset of 
scarring or 
nonscarring scalp 
alopecia  
Loss of body hair 
Scaling 
Thinning scalp hair, 
typically patchy, coarse, 
or dull  
Premature grey hair 
 
Mouth 
Lichen-type 
features 
 
Xerostomia 
Mucocele 
Mucosal atrophy 
Pseudomembranes  
Ulcers  
 
Gingivitis 
Mucositis 
Erythema 
Pain 
 

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Organ or Site 
Diagnostic 
Features1 
Distinctive 
Features2 
Others3 
Common 
Features4 
Eyes 
 
New onset dry, 
gritty, or painful 
eyes  
Cicatricial 
conjunctivitis 
Keratoconjunctivit
is sicca  
Confluent areas of 
punctuate 
keratopathy 
Photophobia 
Periorbital 
hyperpigmentation 
Blepharitis  
 
Genitalia 
Lichen 
planus-like 
features 
Lichen 
sclerosis-like 
features 
Erosions  
Fissures  
Ulcers  
 
 
     Females 
Vaginal 
scarring or 
clitoral/labial 
agglutination 
 
 
 
     Males 
Phimosis or 
urethral/meat
us scarring or 
stenosis 
 
 
 
GI Tract 
Esophageal 
web 
Strictures or 
stenosis in the 
upper to mid-
third of the 
esophagus 
 
Exocrine pancreatic 
insufficiency 
Anorexia 
Nausea 
Vomiting 
Diarrhea 
Weight loss 

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Organ or Site 
Diagnostic 
Features1 
Distinctive 
Features2 
Others3 
Common 
Features4 
Lung 
Bronchiolitis 
obliterans 
diagnosed 
with lung 
biopsy 
BOS 5 
Air trapping and 
bronchiectasis on 
chest CT  
Cryptogenic organizing 
pneumonia 
Restrictive lung disease6 
 
Muscle, 
Fascia, joints 
Fasciitis 
Joint stiffness 
or 
contractures 
secondary to 
sclerosis 
Myositis or 
polymyositis7 
 
Edema 
Muscle cramps 
Arthralgia or arthritis 
 
Hematopoietic 
and immune 
 
 
Thrombocytopenia 
Eosinophilia 
Lymphopenia 
Hypo- or 
hypergammaglobilinemi
a 
Autoantibodies (AIHA 
and ITP) 
Raynaud’s phenomenon 
 
Other 
 
 
Pericardial or pleural 
effusions 
Ascites 
Peripheral neuropathy 
Nephrotic syndrome 
Myasthenia gravis 
Cardiac conduction 
abnormality or 
cardiomyopathy 
 
 
1. Sufficient to establish the diagnosis of chronic GvHD 
2. Seen in chronic GvHD, but insufficient alone to establish a diagnosis of chronic GvHD; In all 
cases, infection, drug effect, malignancy, or other causes must be excluded 

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3. Can be acknowledged as part of the chronic GvHD symptomatology if the diagnosis is 
confirmed 
4. Shared features by both acute and chronic GvHD 
5. BOS can be diagnostic for lung chronic GvHD only if distinctive sign or symptom present in 
another organ 
6. Pulmonary entities under investigation or unclassified 
7. Diagnosis of chronic GvHD requires biopsy 
 
 

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APPENDIX C. Performance Status Criteria 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities.  Up 
and about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX D. Organ Specific Staging of Chronic GvHD 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX E. Global Scoring of Chronic GvHD 
Stage 
Definition 
Mild 
1 or 2 organs involved with no more than score 1 plus Lung score 0 
 
Moderate 
At least 1 organ (not lung) with a score of 2 
or 
3 or more organs involved with no more than score 1 
or 
Lung score 1 
Severe 
At least 1 organ with a score of 3 
or 
Lung score of 2 or 3 
In skin: higher of the 2 scores to be used for calculating global severity 
In lung: FEV1 is used instead of clinical score for calculating global severity 
If the entire abnormality in an organ is noted to be unequivocally explained by a non-cGVHD 
documented cause, that organ is not included for calculation of the global severity 
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the 
score organ will be used for calculation of the global severity regardless of the contributing causes 
(no downgrading of organ severity score). 
 
 

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APPENDIX F. Minnesota-CIBMTR Staging and Grading for Acute GVHD 
 
 
 
 
 
 

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APPENDIX G: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms listed that 
should be used are those provided by the Department of Health and Human Services’ Office for Human 
Research Protections (OHRP).  A copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event.  “Reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  “Suspected adverse reaction” implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-threatening” if, in 
the view of the investigator, its occurrence places the patient at immediate risk of death. It does not 
include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the view of 
the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective IRB 
approval.  The term “research” encompasses all IRB-approved materials and documents including the 
detailed protocol, IRB application, consent form, recruitment materials, questionnaires/data collection 
forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact the 
rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or welfare 
of participants or others or the scientific validity of the study. 
 

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

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Event 
HRPO 
QASMC 
FDA 
Drug/Device Manufacturer 
of that list in the protocol or 
IB 
information qualifies for 
reporting 
Complaints 
If the complaint reveals an 
unanticipated problem 
involving risks to 
participants or others OR 
noncompliance, report 
within 10 working days.  If 
the event results in the 
death of a participant 
enrolled at WU/BJH/SLCH, 
report within 1 working day.  
Otherwise, report at the 
time of continuing review. 
 
 
 
Breach of confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the 
participant poses a safety 
issue, report within 10 
working days.   
 
If withdrawing the 
participant does not 
represent a safety issue 
and the patient will be 
withdrawn, report at 
continuing review. 
 
 
 
 
 
 
 
 

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

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and the patient will be 
withdrawn, report at 
continuing review.