A Phase II/III Randomized, Multicenter Trial Comparing Sirolimus Plus Prednisone and Sirolimus/Calcineurin Inhibitor Plus Prednisone for the Treatment of Chronic Graft-versus-Host Disease (BMT CTN Protocol #0801)
Phase: PHASE2
Conditions: Chronic GVHD
Sponsor: Medical College of Wisconsin

 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
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Core Study Participants: 
Affiliate Study Participants: 
Blood and Marrow Transplant at Northside 
Hospital 
Case Western Reserve University Consortia 
  - Oregon Health & Science University 
   - University Hospitals of Cleveland 
City of Hope National Medical Center 
Dana Farber Consortia 
   - Brigham & Women’s Hospital 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center 
Johns Hopkins University 
Memorial Sloan-Kettering Cancer Center 
Ohio State Consortia 
 - Roswell Park Cancer Institute  
 - University of North Carolina at Chapel Hill 
 - Virginia Commonwealth University, MCV 
Hospital  
Pediatric Bone and Marrow Transplant Center 
  - Children’s Healthcare of Atlanta 
  - Cook Children’s Medical Center 
  - Indiana University Medical Center, Riley 
        Hospital 
  - Karmanos Cancer Institute/Children's  
Hospital of Michigan 
  - OHSU, Doernbecher Children’s Hospital 
  - Texas Transplant Institute 
  - Utah BMT/Primary Children's Medical Center 
  - Washington University, St. Louis  Children’s   
        Hospital 
Stanford Hospital and Clinics 
University of Florida Consortia 
 - Emory University 
  - University of Florida/Shands Healthcare 
University of Michigan 
University of Minnesota 
University of Nebraska Consortia 
 - University of Kansas Hospital 
  - University of Nebraska Medical Center 
University of Pennsylvania  
University of Texas, MD Anderson 
Washington University, Barnes Jewish Hospital 
 
Fox Chase Temple University 
Hackensack University 
Jewish Hospital BMT Program 
Mayo Clinic, Rochester 
Medical College of Wisconsin 
Medical University of South Carolina 
Mount Sinai Medical Center 
Rush University 
Texas Transplant Institute 
University of California, San Diego 
University of Chicago 
University of Iowa Hospital & Clinics 
University of Maryland Medical Systems, 
Greenbaum Cancer Center  
University of Oklahoma Health Sciences 
Center 
University of Utah Medical School 
University of Wisconsin Hospital & Clinics 
Wake Forest University Health Sciences 
 

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PROTOCOL SYNOPSIS – BMT CTN PROTOCOL 0801 
 
A Phase II/III Randomized, Multicenter Trial Comparing Sirolimus plus Prednisone and 
Sirolimus/Calcineurin Inhibitor plus Prednisone for the Treatment of Chronic Graft-
versus-Host Disease 
 
Principal Investigators: Paul Carpenter, MB, BS 
 
Mukta Arora, MD 
 
Study Design: 
 
Combined Phase II/III, randomized, open label, multicenter, 
prospective comparative study of sirolimus plus prednisone versus 
sirolimus/calcineurin-inhibitor plus prednisone for the treatment of 
chronic GVHD. 
 
Phase II Component: 
A Phase II randomized trial of sirolimus + prednisone (Arm 1) versus 
sirolimus + calcineurin inhibitor + prednisone (Arm 2). 
The intent is to enroll subjects at the start of initial therapy for 
chronic GVHD, or before their chronic GVHD is refractory to 
glucocorticoid 
therapy, 
or 
is 
chronically 
dependent 
upon 
glucocorticoid 
therapy 
and 
multiple 
secondary 
systemic 
immunosuppressive agents.  Patients will be stratified by transplant 
center and will be randomized to an experimental arm of sirolimus + 
prednisone or the comparator arm of sirolimus + calcineurin inhibitor 
+ prednisone in a 1:1 ratio. 
Phase III Component: 
The Phase II study above will proceed into the Phase III component 
of the protocol if the experimental arm is more efficacious than the 
comparator arm.   
Thus, subjects that were enrolled on the Phase II will continue to be 
followed for the Phase III endpoints. Phase III accrual will then be 
completed by enrolling additional patients.   
 
Primary Objective: 
Phase II Component: 
To estimate the proportion of subjects with complete or partial 
responses after 6 months of therapy in both study arms using an 
intention to treat analysis. 
 
Phase III Component: 
To compare the proportion of subjects with complete resolution of all 
reversible manifestations at 24 months after starting therapy in both 
study arms.   
 

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Secondary Objectives: 
Phase II component estimates among patients receiving SRL 
versus SRL +CNI: the percent reduction in the average daily dose of 
prednisone (or equivalent) by 6 and 12 months; the cumulative 
incidence of treatment failure at 1 year; the prevalence of active 
symptomatic chronic GVHD at 1 and 2 years; the cumulative 
incidence of discontinuation of all systemic immunosuppressive 
therapy at 1 and 2 years; the overall and cancer progression-free 
survival at 1 and 2 years; the candidate serum biomarkers of chronic 
GVHD at baseline, 2 months and 6 months; and, to evaluate NIH and 
other new response instruments in chronic GVHD. 
Phase III component comparisons among patients receiving SRL 
versus SRL +CNI: percent reduction in the average daily dose of 
prednisone (or equivalent) at 6, 12, and 24 months; cumulative 
incidence of treatment failure at 1 and 2 years; prevalence of active 
symptomatic chronic GVHD at 1 and 2 years; cumulative incidence 
of discontinuation of all systemic immunosuppressive therapy at 1 
and 2 years; overall and cancer progression-free survival at 1 and 2 
years; candidate serum biomarkers of chronic GVHD at baseline, 2 
months, and 6 months; and, to evaluate NIH and other new response 
instruments in chronic GVHD. 
3-Year Assessments: All patients except those who are enrolled 
during the last 12 months of accrual will be evaluated at 3 years after 
beginning study therapy for the endpoints above under the Phase III 
component.  Patients enrolled in the last 12 months will not complete 
3 year assessments and will be excluded from the analysis. 
 
Eligibility: 
Inclusions: 
Suitable candidates are patients with classic chronic or overlap 
syndrome (classic chronic plus acute) GVHD that meets NIH 
Consensus Working Group Guidelines in one of the following 
categories: 1 
a) 
Previously untreated (newly diagnosed) as defined by having 
received < 14 days of prednisone (or equivalent) before 
enrollment/randomization to study therapy. 
b) 
Previously treated but inadequately responding after ≤ 16 weeks 
of initial therapy with prednisone and/or CNI ± additional non-
sirolimus agent (started at the time of chronic GVHD 
diagnosis). 
 
Exclusions: 
a) 
Patients with late persistent acute GVHD or recurrent acute 
GVHD only. 

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b) 
Inability to begin prednisone therapy at a dose of > 0.5 
mg/kg/day (or equivalent). 
c) 
Receiving sirolimus for treatment of chronic GVHD (sirolimus 
for prophylaxis or treatment of acute GVHD is acceptable). 
d) 
Already receiving sirolimus (for prophylaxis or treatment of 
acute GVHD) with prednisone at ≥ 0.25 mg/kg/day (or 
equivalent) ± additional agents. 
e) 
Receiving therapy for chronic GVHD for more than 16 weeks. 
f) 
Invasive fungal or viral infection not responding to appropriate 
antifungal or antiviral therapies. 
g) 
Creatinine clearance < 50 mL/min/1.73 m2 or a serum creatinine 
based on the Cockcroft-Gault formula (adults) or Schwartz 
formula (age ≤ 12 years).  
h) 
Inability to tolerate oral medications. 
i) 
Absolute neutrophil count < 1500 per microliter. 
j) 
Requirement for platelet transfusions.  
k) 
Receiving any treatment for persistent, progressive or recurrent 
malignancy. 
l) 
Progressive or recurrent malignancy defined other than by 
quantitative molecular assays. 
m) Known hypersensitivity to sirolimus. 
 
Treatment Description:  
Arm 1: Sirolimus + Prednisone 
Arm 2: Sirolimus + Calcineurin Inhibitor + Prednisone 
Prednisone is administered initially as a single early morning dose of 
1 mg/kg/day [or equivalent (Adults: maximum dose 100 mg, for age 
< 17 years, the use of adjusted body weight as per institutional 
guidelines should be considered to calculate doses for patients who 
weigh > 110% of ideal body weight)].   
If prednisone at a dose of 1 mg/kg/day (or equivalent) is 
contraindicated (e.g. poorly controlled diabetes, hypertension, 
osteoporosis, avascular bone necrosis, major mood disturbance) 
patients may begin prednisone between 0.5 -1 mg/kg/day.   
Prednisone therapy continues at the initial dose until there is 
objective evidence of improvement in manifestations of chronic 
GVHD.  
The initial taper of prednisone from the starting dose of 0.5-1 
mg/kg/every day (or equivalent) is attempted within 2 weeks after the 

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first evidence of improvement in GVHD and takes place over 4-8 
weeks to achieve a dose of 0.5-1 mg/kg/every-other-day.   
Once an alternating-day prednisone (or equivalent) regimen is 
achieved, the dose of prednisone should be held constant for 10-12 
weeks until all reversible manifestations of chronic GVHD resolve, 
after which a second taper is attempted.  The tempo of this second 
taper may follow individual institutional guidelines but it is 
recommended that the extent of the taper be approximately calibrated 
to the magnitude of an individual patient’s alternating-day prednisone 
dose.  For example, a patient whose prednisone dose has been stable 
at 0.5 mg/kg/every-other-day may attempt to taper prednisone 
completely.  However, a patient whose prednisone dose has been 
stable at 1.0 mg/kg/every-other-day is recommended first to taper 
over 4-8 weeks to 0.5 mg/kg/every-other-day, followed by 2-3 
months of further observation before attempting a complete taper.  
Calcineurin inhibitor therapy continues at a dose which achieves 
the following trough serum levels (HPLC/TMS): 
a) Tacrolimus: 5-10 ng/mL 
b) Cyclosporine: 120-200 ng/mL 
Sirolimus therapy begins at 2 mg orally per day (1 mg/m2 per day if 
< 40 kg) to target a trough serum level of 3-12 ng/mL.  
Supportive care will follow institutional guidelines that reflect 
reasonable standard practices appropriate to the patient with chronic 
GVHD as outlined by the Ancillary Therapy and Supportive Care 
Working Group Report of the NIH Consensus Development Project 
on Criteria for Clinical Trials in Chronic GVHD.2  
 
Accrual Objective: 
Phase II Component: One hundred subjects will be randomized 1:1 
across the Phase II study (50 per arm). 
 
Phase III Component: If the Phase II is successful, then 100 patients 
from the Phase II study continue on the Phase III.  Two hundred 
additional subjects will be randomized 1:1 across the Phase III (100 
per arm) for a combined Phase II/III total of 300 subjects.    
 
Accrual Period: 
The estimated accrual period is 3 years for the Phase II, and 4 years 
for the Phase III. 
 
Study Duration: 
The estimated study duration is 3.5 years for the Phase II, and 6 years 
for the Phase III. 
 

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STUDY DESIGN SCHEMATIC 
 
 
If Phase II successful
BMT CTN 0801 – Phase II/III Study in Chronic GVHD (total N=300)
Phase II
Phase III
Randomize
P+SRL
P+SRL+CNI
N=50
N=50
1:1
Accrual of new subjects
P+SRL
P+SRL+CNI
100
100
1:1
50
50
N=150
N=150
End of Study
 
 
 

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TABLE OF CONTENTS 
 
 
1. 
BACKGROUND AND RATIONALE ................................................................................. 1-1 
1.1. 
Chronic Graft-versus-Host Disease (cGVHD) .................................................................... 1-1 
1.2. 
Balancing Experimental Design Purity and Study Accrual ............................................... 1-1 
1.3. 
Sirolimus (rapamycin) in GVHD ......................................................................................... 1-2 
1.4. 
FOXP3+CD4+CD25+ Tregs in Chronic GVHD ...................................................................... 1-2 
1.4.1. 
Inhibition of Tregs by Calcineurin-dependent IL-2 Production ................................................. 1-3 
1.5. 
Calcineurin-Inhibitor Free Immunosuppression ................................................................ 1-3 
1.6. 
Endpoints for Clinical Trials and Response ........................................................................ 1-4 
2. 
STUDY DESIGN .................................................................................................................... 2-1 
2.1. 
Study Overview ...................................................................................................................... 2-1 
2.2. 
Hypothesis and Study Objectives ......................................................................................... 2-2 
2.2.1. 
Primary Objective .................................................................................................................... 2-2 
2.2.2. 
Secondary Objectives ............................................................................................................... 2-2 
2.3. 
Patient Eligibility for Randomization .................................................................................. 2-3 
2.3.1. 
Patient Inclusion Criteria ......................................................................................................... 2-3 
2.3.2. 
Patient Exclusion Criteria ........................................................................................................ 2-4 
2.4. 
Stem Cell Transplantation .................................................................................................... 2-4 
2.5. 
Initiating, Monitoring and Adjusting Study Therapy ........................................................ 2-5 
2.5.1. 
Sirolimus .................................................................................................................................. 2-5 
2.5.1.1. 
Initiating sirolimus therapy (Arms 1 and 2) ....................................................................... 2-5 
2.5.1.2. 
Targeting sirolimus levels, dose adjustment and other considerations ............................... 2-5 
2.5.1.3. 
Sirolimus adverse reactions ................................................................................................ 2-6 
2.5.1.4. 
Management of sirolimus toxicities ................................................................................... 2-7 
2.5.1.5. 
Sirolimus drug interactions ................................................................................................. 2-8 
2.5.2. 
Calcineurin Inhibitor (Tacrolimus or Cyclosporine)................................................................ 2-9 
2.5.2.1. 
Stopping calcineurin inhibitor therapy (Arm 1) ................................................................. 2-9 
2.5.2.2. 
Initiating calcineurin inhibitor therapy (Arm 2) ............................................................... 2-10 
2.5.2.3. 
Targeting CNI levels, dose adjustment and other considerations ..................................... 2-10 
2.5.2.4. 
Tacrolimus adverse reactions ........................................................................................... 2-13 
2.5.2.5. 
Cyclosporine adverse reactions ........................................................................................ 2-14 
2.5.2.6. 
Management of tacrolimus and cyclosporine toxicities ................................................... 2-14 
2.5.2.7. 
Tacrolimus drug interactions ............................................................................................ 2-14 
2.5.2.8. 
Cyclosporine drug interactions ......................................................................................... 2-15 
2.5.3. 
Prednisone .............................................................................................................................. 2-15 
2.5.3.1. 
Initiating prednisone therapy ............................................................................................ 2-15 
2.5.3.2. 
Monitoring ........................................................................................................................ 2-15 
2.5.3.3. 
Prednisone adverse reactions ............................................................................................ 2-15 
2.6. 
Approach to Tapering Immunosuppressive Therapy ...................................................... 2-15 
2.6.1. 
Prednisone Taper ................................................................................................................... 2-16 
2.6.2. 
Sirolimus and Calcineurin Inhibitor Tapers ........................................................................... 2-16 
2.7. 
Supportive Care ................................................................................................................... 2-17 
2.7.1. 
Concomitant Azole Therapy .................................................................................................. 2-17 
2.8. 
Drug Information................................................................................................................. 2-18 
2.8.1. 
Description, Administration and Storage ............................................................................... 2-18 
2.8.1.1. 
Sirolimus (rapamycin, Rapamune®) ................................................................................ 2-18 

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2.8.1.2. 
Tacrolimus (FK-506, Prograf®) ....................................................................................... 2-20 
2.8.1.3. 
Cyclosporine ..................................................................................................................... 2-21 
2.8.1.4. 
Glucocorticoids ................................................................................................................ 2-22 
3. 
STUDY ENDPOINTS ............................................................................................................ 3-1 
3.1. 
Definition of High-Risk vs. Standard-Risk .......................................................................... 3-1 
3.2. 
Primary Endpoint .................................................................................................................. 3-1 
3.3. 
Secondary Endpoints ............................................................................................................. 3-1 
3.3.1. 
Prednisone Sparing .................................................................................................................. 3-2 
3.3.2. 
Use of Secondary Therapy ....................................................................................................... 3-2 
3.3.3. 
Symptomatic Patient-Reported Chronic GVHD ...................................................................... 3-2 
3.3.4. 
Permanent Discontinuation of all Systemic Immunosuppressive Therapy .............................. 3-3 
3.3.5. 
Overall Survival ....................................................................................................................... 3-3 
3.3.6. 
Progression-Free Survival ........................................................................................................ 3-3 
3.3.7. 
Biomarkers ............................................................................................................................... 3-3 
3.3.8. 
NIH and Other New Response Instruments ............................................................................. 3-3 
3.3.9. 
Quality of Life.......................................................................................................................... 3-4 
3.4. 
Safety Endpoints .................................................................................................................... 3-4 
3.4.1. 
Mortality .................................................................................................................................. 3-4 
3.4.2. 
Thrombotic Microangiopathy (TMA) ...................................................................................... 3-4 
3.4.3. 
Pneumonitis (NIP) ................................................................................................................... 3-4 
4. 
PATIENT REGISTRATION, RANDOMIZATION AND ENROLLMENT ................... 4-1 
4.1. 
Approaching Patients, Eligibility Screening and Obtaining Consent ............................... 4-1 
4.2. 
Randomization ....................................................................................................................... 4-1 
4.3. 
Treatment Scheduling ........................................................................................................... 4-1 
4.4. 
Study Monitoring ................................................................................................................... 4-1 
4.4.1. 
Patient Assessments ................................................................................................................. 4-1 
4.4.1.1. 
Pre-study evaluations.......................................................................................................... 4-5 
4.4.1.2. 
Study evaluations................................................................................................................ 4-5 
4.4.2. 
Case Report Forms ................................................................................................................... 4-6 
4.4.3. 
Reporting Patient Deaths ......................................................................................................... 4-6 
4.4.4. 
Reporting Serious Adverse Events .......................................................................................... 4-7 
4.4.4.1. 
Patient SAEs ....................................................................................................................... 4-7 
4.4.5. 
CIBMTR Data Reporting ......................................................................................................... 4-7 
5. 
STATISTICAL CONSIDERATIONS ................................................................................. 5-1 
5.1. 
Study Design ........................................................................................................................... 5-1 
5.1.1. 
Accrual ..................................................................................................................................... 5-1 
5.1.2. 
Randomization ......................................................................................................................... 5-1 
5.1.3. 
Primary Endpoint ..................................................................................................................... 5-1 
5.1.4. 
Primary Hypotheses ................................................................................................................. 5-2 
5.2. 
Details of Study Design and Interim Monitoring Plan for Efficacy and Futility ............. 5-2 
5.2.1. 
Details of Stopping Boundary Calculations ............................................................................. 5-3 
5.3. 
Operating Characteristics and Power Considerations ....................................................... 5-4 
5.4. 
Safety Stopping Guidelines ................................................................................................... 5-5 
5.4.1. 
Mortality .................................................................................................................................. 5-5 
5.4.2. 
Non-hematological Toxicities .................................................................................................. 5-7 
5.5. 
Demographics and Baseline Characteristics ....................................................................... 5-8 
5.6. 
Analysis of Secondary Endpoints ......................................................................................... 5-8 

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5.7. 
Safety Analysis ..................................................................................................................... 5-10 
 
 
LIST OF APPENDICES 
 
APPENDIX A – HUMAN SUBJECTS 
APPENDIX B – INFORMED CONSENTS (CONSENT AND ASSENT) 
APPENDIX C – LABORATORY SAMPLE INFORMATION 
APPENDIX D – DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 
APPENDIX E – END OF PHASE II DECISION MAKING CONSIDERATIONS 
APPENDIX F – REFERENCES 
 
 

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CHAPTER 1 
 
 
1. BACKGROUND AND RATIONALE 
 
1.1. 
Chronic Graft-versus-Host Disease (cGVHD) 
 
Fifteen percent to 80% of patients after allogeneic hematopoietic cell transplantation (HCT) 
develop chronic GVHD depending on stem cell source and donor-host factors.3, 4, 5, 6, 7, 8, 9  
Therefore, it is not surprising that cGVHD is the major complication among patients who survive 
beyond 100 days.  Standard immunosuppressive therapy (IST) for cGVHD using glucocorticoids 
with or without a calcineurin inhibitor has not changed for three decades despite the observation 
that most patients respond inadequately.  If the total time to discontinue all systemic IST is 
measured as a surrogate for graft tolerance, it takes a median of 2-3 years from the onset of 
cGVHD therapy; varying according to stem cell source and other factors.10  Unfortunately, 
despite the association of cGVHD with reduced relapse of malignancy, the protracted duration of 
cGVHD makes it the leading cause of impaired immunity, compromised functional status, and 
late treatment-related deaths.11, 12, 13, 14, 15, 16  The protean and sometimes irreversible organ 
manifestations of cGVHD create a burden of symptoms that may negatively impact quality of 
life even after tolerance is achieved.  New approaches to standard IST for cGVHD are needed to 
achieve early control of cGVHD manifestations and facilitate tolerance. 
 
A hypothesis driven choice of novel IST study agents has been problematic because cGVHD 
pathophysiology has been poorly understood.  As a result, contemporary early therapy trials have 
been extremely limited.  Most therapy trials have been restricted to single arm Phase II studies in 
steroid-refractory cGVHD and preliminary data exists for at least five commercially available 
therapies that have shown some activity.17, 18, 19, 20, 21  However, a renewed interest and 
understanding of the potential role of regulatory T cells (Tregs) in facilitating graft tolerance has 
generated enthusiasm for testing tolerance induction strategies that do not impede the expansion 
of Tregs.  Traditional calcineurin-inhibitor (CNI) based therapy impedes Tregs22 and a subset 
analysis from one study suggested that survival was worse when progressive onset cGVHD was 
treated with cyclosporine plus prednisone compared to prednisone alone.23  In contrast, a more 
recent therapy, sirolimus does not impede Tregs, making it a logical candidate to consider 
further.22, 24, 25, 26, 27  Therefore, this prospective randomized combined Phase II/III study will test 
two arms: 
Arm 1:  
 
 
 
Sirolimus + Prednisone 
Comparator Arm (Arm 2): 
Sirolimus + Calcineurin Inhibitor + Prednisone 
 
1.2. 
Balancing Experimental Design Purity and Study Accrual 
 
Eligibility criteria for this study (Section 2.3.1 and 2.3.2) were designed to avoid major 
heterogeneities in the resistance of individuals to IST yet should be compatible with the need to 
optimize timely accrual for early phase testing.  Experimental therapy has generally been 
reserved for failed primary therapy despite the fact that time to discontinue IST for cGVHD 
usually exceeds several years.  This trial encourages physicians to enroll patients with newly 

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diagnosed cGVHD but also allows the common practice of short term “testing” standard therapy 
and by subsequently allowing the inclusion of patients not responding to less than or equal to 16 
weeks of initial therapy with prednisone ± a CNI ± an additional non-sirolimus agent. 
 
1.3. 
Sirolimus (rapamycin) in GVHD 
 
Sirolimus (rapamycin) is a naturally occurring macrolide that has immunosuppressive, 
antifungal, and antitumor properties.  Although structurally similar to tacrolimus, sirolimus 
binds uniquely to FK binding protein 12 (FKBP12) and then complexes with mammalian target 
of rapamycin (mTOR) rather than with calcineurin.  The FKBP12-mTOR complex affects 
upstream and downstream signaling that ultimately leads to T and B cell suppression.28, 29  
Downstream there is reduced DNA transcription, translation, protein synthesis and cell cycling. 
Upstream interactions with mTOR include the PTEN/pI3 kinase/Akt and Janus kinase pathways, 
which importantly include the mediation of IL-2 driven signaling from the T cell receptor.30  
This contrasts with the calcineurin inhibitors, which more directly inhibit cytokine production, 
particularly IL-2.  Sirolimus may also act by inhibiting antigen uptake, cellular maturation, 
intracellular signaling and induction of apoptosis in dendritic cells. 31, 32, 33, 34, 35, 36 
 
Phase II data indicates activity of sirolimus in over one hundred patients with steroid-refractory 
cGVHD and overall response rates of 63% to 94%.17, 37, 38 [P. Carpenter unpublished]  Sirolimus 
has also been reported to improve the efficacy of acute GVHD prophylaxis regimens although 
this did not extend to a reduced incidence of cGVHD.39, 40  In all these studies sirolimus was 
combined with a CNI and the side effect profile of combination therapy is now well delineated 
and generally manageable with close attention to therapeutic drug monitoring to avoid renal 
dysfunction that includes: thrombotic microangiopathy, hemolytic uremic syndrome and 
thrombotic thrombocytopenic purpura.  Nephrotoxicity is rare when sirolimus is used without 
CNIs.  
 
Of central interest to this study is the recent understanding that sirolimus might facilitate 
tolerance when used in CNI-free regimens via preferential expansion of Tregs. 22, 41  
 
1.4. 
FOXP3+CD4+CD25+ Tregs in Chronic GVHD 
 
Although IL-2 is important for the development and expansion of conventional effector T cells 
(Tconv), IL-2 is also critical for establishing and maintaining immune tolerance.42, 43, 44  The 
principal mechanism whereby IL-2 promotes immune tolerance appears to be via its roles in the 
preferential generation and maintenance of FOXP3CD4+CD25+ Tregs compared to Tconv.  In one 
study, the frequency of CD4+CD25 Tregs and median FOXP3 values in patients with cGVHD was 
about half that of the non-cGVHD group but the suppressive function of these cells remains 
normal.45  This reduction was thought to be physiologically relevant given the low naturally 
occurring frequency of Tregs in the blood of healthy individuals yet the critical role in controlling 
a wide range of immune responses.  This is perhaps best illustrated by the clinical severity of the 
IPEX syndrome which is caused by specific mutations of FOXP3 that result in a functional 
deficiency of Tregs.46  Interestingly, sirolimus therapy was able to abrogate severe manifestations 
of the IPEX syndrome in 3 children.47  
 

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1.4.1. 
Inhibition of Tregs by Calcineurin-dependent IL-2 Production 
 
Several recent data suggest that it is time to reevaluate the role of calcineurin-inhibitors (CNIs) 
for the treatment of GVHD and induction of tolerance.  Murine Tregs are able to suppress 
experimental acute GVHD and murine Tregs share functional characteristics with their human 
counterparts.  Because IL-2 signaling is critical for the survival of FOXP3+ Tregs in vivo it is 
important to understand the implications of commonly used IST on Treg function in vivo.  Zeiser 
et al compared cyclosporine and sirolimus as IST in an MHC class I and II mismatch T cell 
depleted bone marrow transplant model with T cell add-back in a 1:2 ratio of Tregs /Tconv.22  
Cyclosporine significantly reduced Treg function in vivo as assessed by increased proliferation of 
Tconv, GVHD severity, and reduced survival.  The reduced suppressor function of cyclosporine-
exposed Tregs was IL-2 dependent and correlated with a reduced number of FOXP3+ T cells in 
vitro and in vivo, suggesting the critical importance of calcineurin-dependent IL-2 production.  
In contrast sirolimus did not inhibit the expansion of donor derived FOXP3 Tregs.22  This data is 
in keeping with other in vitro studies showing that sirolimus selectively expands murine Tregs as 
well as functional Tregs in both healthy and diabetic human subjects.48, 49  Both thymic generation 
and peripheral preservation of FOXP3 Tregs appear to be negatively regulated by cyclosporine 
and facilitated by sirolimus.26  Interestingly, the frequency of CD4+CD25+ does not track with 
the total CD4+ cells suggesting that Tregs are an independently regulated subset among CD4+ 
cells.45  The differential impact of sirolimus on Tregs compared to Tconv appears to result from 
reduced usage of the mTOR pathway in Tregs compared with Tconv and explains the synergistic 
effect of sirolimus and Tregs in GVHD protection.  The mechanism is complex but appears to 
involve increased usage of the STAT5 pathway over the PI3K pathway in response to IL-2 and, 
together with sirolimus-induced mTOR inhibition, the differentiation of CD4 T cells is skewed 
toward a FOXP3-expressing phenotype.25, 45  In addition, activation of Tconv induces rapid down-
regulation of PTEN which does not occur in Tregs.25  T cell compartment targeted PTEN knock-
out mice have Tregs that are rendered susceptible to mTOR inhibition.  
 
1.5. 
Calcineurin-Inhibitor Free Immunosuppression 
 
Data from a randomized primary therapy study in cGVHD23 and recent empirical data from four 
centers suggest that it is not unsafe to discontinue a CNI in the treatment of cGVHD. The 
cGVHD study comparing cyclosporine plus prednisone to prednisone required 79 of the 145 
patients who were randomly assigned to prednisone to discontinue cyclosporine shortly after 
beginning the study.  The cumulative incidence of secondary therapy was not increased in the 
prednisone only arm arguing that removal of cyclosporine is safe.  A subset analysis suggested 
that survival was worse when progressive onset cGVHD was treated with cyclosporine plus 
prednisone compared to prednisone alone which is of interest from the context that CNI-based 
therapy impedes Tregs.22  Previous randomized trials had also suggested that the incidence of 
cGVHD was not affected by early discontinuation of cyclosporine in patients who did not have 
acute GVHD on Day 60 after transplantation50 or by prolongation of cyclosporine in patients 
who did not have cGVHD on Day 80 after transplantation.51  A combined total of approximately 
30 patients from Stanford, MD Anderson, NIH/NCI, and FHCRC have received a cGVHD 
therapy change that involved stopping a CNI and adding sirolimus or, in a few cases, 
mycophenolate mofetil. CNIs were mostly discontinued abruptly or after a brief taper.  Major 
flares of acute inflammatory GVHD manifestations were not observed.    

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1.6. 
Endpoints for Clinical Trials and Response 
 
The cGVHD field has been hampered by difficulties in being able to objectively measure 
complete and partial responses to therapeutic interventions.  However, short term endpoints like 
CR+PR are necessary because long term, albeit more objective endpoints like survival, or 
discontinuation of all systemic IST, are impractical for early phase testing.  To begin to address 
this obstacle, the NIH Consensus Development Project for Clinical Trials in cGVHD has 
published study design concepts aimed at improving the quality of response data to allow 
objective evaluation of new cGVHD therapies.52, 53  Central to the design of response criteria is 
that measurements need only capture the most important cGVHD manifestations that reflect 
clinically relevant (functional) benefit for an individual patient.  Measurements should avoid 
detecting trivial responses that arise from crossing thresholds defined by categorical scoring. 
Ideally, instruments should measure a meaningful change calibrated as a percentage of baseline 
abnormality or function, and based upon statistical considerations or clinical perception.  
Clinically meaningful changes might include the measurement of self-reported observations of 
the way a patient feels or functions before and after treatment.  Organ manifestations that might 
not be reversible (dry eye, fasciitis, bronchiolitis obliterans with fibrosis) need to be handled 
differently from manifestations that are expected to fully reverse.  Alternatively, potentially 
irreversible manifestations should be included only for progression.  The Working Group 
recognized that central review of clinical grading and response may improve reproducibility in 
multi-center trials. 
 
A detailed performance analysis of the newly designed GVHD response instruments will be 
possible from the extensive data that will be generated by comprehensive measurements taken at 
baseline and after study interventions.  The goal will be to develop a set of more objective, 
clinically relevant response criteria that could be used in future studies. 

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CHAPTER 2 
 
 
2. STUDY DESIGN 
 
2.1. 
Study Overview 
 
Combined Phase II/III, randomized, open label, multicenter, prospective comparative study of 
sirolimus plus prednisone versus sirolimus/calcineurin-inhibitor plus prednisone for the 
treatment of chronic GVHD. 
 
Phase II Component: 
Phase II will be a randomized trial of Sirolimus (SRL) + Prednisone (PDN) vs SRL + calcineurin 
inhibitor (CNI) + PDN. 
 
The intent is to enroll subjects at the start of initial therapy for chronic GVHD, or before their 
chronic GVHD is refractory to glucocorticoid therapy, or is chronically dependent upon 
glucocorticoid therapy and multiple secondary systemic immunosuppressive agents.  Patients 
will be stratified by transplant center and will be randomized to an experimental arm of SRL + 
PDN [Arm 1] or the comparator arm of SRL + CNI + PDN [Arm 2] in a 1:1 ratio. 
 
Each study arm will include prednisone (or equivalent) and sirolimus.  The experimental arm 
will avoid a calcineurin inhibitor.  
 
If Phase II successful
BMT CTN 0801 – Phase II/III Study in Chronic GVHD (total N=300)
Phase II
Phase III
Randomize
P+SRL
P+SRL+CNI
N=50
N=50
1:1
Accrual of new subjects
P+SRL
P+SRL+CNI
100
100
1:1
50
50
N=150
N=150
End of Study
 
 
Phase III Component: 
If the result of Phase II confirms the hypothesis that the CNI free Arm (SRL +PRN) appears to 
be superior to the CNI containing Arm (SRL +CNI +PDN) then the trial will proceed into the 
Phase III component.  Thus, subjects that were enrolled on the Phase II will continue to be 
followed for the Phase III endpoints.  Phase III accrual will then be completed by enrolling 
additional patients.   
 

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2.2. 
Hypothesis and Study Objectives 
 
The primary purpose of the Phase II component is to compare a treatment regimen that contains 
sirolimus without a calcineurin inhibitor, to a comparator regimen of sirolimus with a calcineurin 
inhibitor.  The goal is to determine if sirolimus plus prednisone is a sufficiently promising 
treatment regimen for further comparison in the Phase III trial.  
 
The primary hypothesis is that avoidance of a calcineurin inhibitor in the treatment of chronic 
GVHD might facilitate the development of tolerance and improve the GVHD response rates at 6 
months, and ultimately the 24 month complete response rates compared to immunosuppressive 
therapy regimens that contain a calcineurin inhibitor (the comparator arm, SRL + CNI + PDN).  
 
2.2.1. 
Primary Objective 
 
Phase II Component:  The primary objective is to estimate in patients with recently diagnosed 
chronic GVHD the rates of complete plus partial responses at 6 months after randomization in 
both study arms using an intention to treat analysis. 
 
Phase III Component:  To compare the proportion of subjects with complete resolution of all 
reversible manifestations at 24 months after starting therapy in both study arms.   
 
2.2.2. 
Secondary Objectives 
 
Phase II Component: 
1. To estimate the percent reduction in the average daily prednisone (or equivalent) dose by 
6 and 12 months, among patients receiving SRL versus SRL + CNI. 
2. To estimate the cumulative incidence of treatment failure at 1 year, among patients 
receiving SRL versus SRL + CNI. 
3. To estimate the prevalence of active symptomatic chronic GVHD at 1 and 2 years, 
among patients receiving SRL versus SRL + CNI. 
4. To 
estimate 
the 
cumulative 
incidence 
of 
discontinuation 
of 
all 
systemic 
immunosuppressive therapy at 1 and 2 years, among patients receiving SRL versus SRL 
+ CNI. 
5. To estimate overall and cancer progression-free survival at 1 and 2 years, among patients 
receiving SRL versus SRL + CNI. 
6. To evaluate candidate serum biomarkers of chronic GVHD at baseline, 2 months, and 6 
months, among patients receiving SRL versus SRL + CNI. 
7. To evaluate NIH and other new response instruments in chronic GVHD.  
 
Phase III Component: 
1. To compare the percent reduction in the average daily dose of prednisone (or equivalent) 
at 6, 12, and 24 months, among patients receiving SRL versus SRL+CNI. 

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2. To compare the cumulative incidence of treatment failure at 1 and 2 years, among 
patients receiving SRL versus SRL+CNI. 
3. To compare the prevalence of active symptomatic chronic GVHD at 1 and 2 years, 
among patients receiving SRL versus SRL+CNI. 
4. To 
compare 
the 
cumulative 
incidence 
of 
discontinuation 
of 
all 
systemic 
immunosuppressive therapy at 1 and 2 years, among patients receiving SRL versus 
SRL+CNI. 
5. To compare overall and cancer progression-free survival at 1 and 2 years, among patients 
receiving the SRL versus SRL+CNI. 
6. To compare candidate serum biomarkers of chronic GVHD at baseline, 2 months, and 6 
months, among patients receiving SRL versus SRL+CNI.  
7. To evaluate NIH and other new response instruments in chronic GVHD. 
 
3-Year Assessments: 
All patients except those who are enrolled during the last 12 months of accrual will be evaluated 
at 3 years after beginning study therapy for the endpoints 1 through 5 listed above under the 
Phase III component (also see Section 3.2).  Patients enrolled in the last 12 months will not 
complete 3 year assessments and will be excluded from the analysis. 
 
2.3. 
Patient Eligibility for Randomization 
 
2.3.1. 
Patient Inclusion Criteria 
 
Patients may be included in this trial if they meet all of the following criteria: 
1. Suitable candidates are patients with classic chronic GVHD or overlap syndrome 
(classic chronic plus acute GVHD) that meets NIH Consensus Working Group 
Guidelines in one of the following categories: 
a) Previously untreated (newly diagnosed) as defined by having received < 14 days of 
prednisone (or equivalent) before enrollment/randomization to study therapy. 
b) Previously treated but inadequately responding after ≤ 16 weeks of initial therapy 
with prednisone and/or CNI ± additional non-sirolimus agent (started at the time of 
chronic GVHD diagnosis). 
2. Patient or guardian willing and able to provide informed consent. 
3. Stated willingness to use contraception in women of childbearing potential. 
4. Stated willingness of patient to comply with study procedures and reporting 
requirements. 
 

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2.3.2. 
Patient Exclusion Criteria 
 
Patients will be excluded from this trial if they meet any of the following criteria: 
1. Patients with late persistent acute GVHD or recurrent acute GVHD only. 
2. Inability to begin prednisone therapy at a dose of ≥ 0.5 mg/kg/day (or equivalent). 
3. Receiving sirolimus for treatment of chronic GVHD (sirolimus for prophylaxis or 
treatment of acute GVHD is acceptable). 
4. Already receiving sirolimus (for prophylaxis or treatment of acute GVHD) with 
prednisone at ≥ 0.25 mg/kg/day (or equivalent) ± additional agents. 
5. Receiving therapy for chronic GVHD for more than 16 weeks. 
6. Invasive fungal or viral infection not responding to appropriate antifungal or antiviral 
therapies. 
7. Creatinine clearance < 50 mL/min/1.73 m2 based on the Cockcroft-Gault formula (adults) 
or Schwartz formula (age ≤ 12 years): 
 
Adults:  eCCr (mL/min) = (140 – age) x mass (kg) x (0.85 if female) / 
72 x serum creatinine (mg/dL)  
Creatinine clearance (mL/min/1.73m2) = eCCr x 1.73 / BSA (m2) 
 
Children: eCCr (mL/min/1.73 m2) = k x height (cm) / serum creatinine (mg/dL) 
k = 0.33 (pre-term), 0.45 (full term to 1 year old), 0.55 (age 1-12 years) 
8. Inability to tolerate oral medications. 
9. Absolute neutrophil count < 1500 per microliter. 
10. Requirement for platelet transfusions. 
11. Pregnancy (positive serum β-HCG) or breastfeeding. 
12. Receiving any treatment for persistent, progressive or recurrent malignancy. 
13. Progressive or recurrent malignancy defined other than by quantitative molecular assays.  
14. Known hypersensitivity to sirolimus. 
 
2.4. 
Stem Cell Transplantation 
 
Patients may have received any type of transplant conditioning, any type of stem cell source and 
donors may be HLA-matched or mismatched. 
 

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2.5. 
Initiating, Monitoring and Adjusting Study Therapy 
 
2.5.1. 
Sirolimus 
 
2.5.1.1. 
Initiating sirolimus therapy (Arms 1 and 2) 
 
Formulation 
Route 
Adult 
Child < 17 yr 
Rapamune® 
Oral 
2 mg daily 
1 mg/m2 daily 
 
Initial doses are calculated using actual body weight except for those patients who are greater 
than 100% of ideal body weight in which case calculation of dose using adjusted body weight is 
recommended. 
 
There is generally no loading dose for patients with classic chronic GVHD.  For patients with 
chronic GVHD and acute overlap syndrome, physicians may elect to administer a loading dose 
of 6 mg (3 mg/m2 for children < 17 yr) followed by a daily maintenance dose of 2 mg. 
 
2.5.1.2. 
Targeting sirolimus levels, dose adjustment and other considerations 
 
The target serum level for sirolimus is 3-12 ng/mL 
 
Oral solution and tablets are available for incremental dosing.  Dose adjustments are based upon 
clinical judgment of the managing physician after considering clinical toxicity, serum levels, 
GVHD, concomitant drug use and the rate of rise or decline of the serum level (see Table 2.5b 
and “Sirolimus & CNI Therapy Physician Guide”). Sirolimus blood levels will be measured 
by either HPLC or immunoassay.  
 
Other Important Considerations: 
• To minimize the variability of exposure to sirolimus, it should be taken at a consistent 
time of day and consistently with or without food.  
• Sirolimus should not be taken within 4 hours after administration of Neoral® (or 
Gengraf®) cyclosporine oral solution and/or cyclosporine gelatin capsules because 
premarketing studies in healthy volunteers demonstrated 116%-512% elevations of mean 
Cmax and 148%-230% elevations in AUC when sirolimus oral solution or tablets were 
simultaneously administered with Neoral but not when the doses were separated by 4 
hours.  
• Grapefruit juice reduces CYP3A4-mediated metabolism of sirolimus and must not be 
administered with sirolimus or used for dilution. 
• Extreme caution when subject is on voriconazole therapy (See Section 2.7.1). 
• Emesis: The sirolimus dose may be repeated within 15 minutes of a vomited dose.  
• Impaired renal function does not mandate dosage adjustment.   

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• Impaired hepatic function should prompt consideration for sirolimus maintenance doses 
to be reduced but no dose adjustment of the loading dose is necessary. Maintenance 
doses of sirolimus may be reduced by approximately one third in patients with hepatic 
impairment (Child-Pugh Score of ≥ 7/15 based on the sum of 1, 2 and 3 points 
respectively for each of: serum bilirubin in mg/dL (< 2, 2-3, > 3), serum albumin in 
mg/dL (> 3.5, 2.8-3.5, < 2.8), INR (< 1.7, 1.71-2.2, >2.2), hepatic encephalopathy (none, 
grade I-II, grade III-IV), or ascites (none, slight, moderate/refractory).  
• Interchangeability of oral solution and tablets: Two-milligram Rapamune Oral 
Solution is clinically equivalent to 2-milligram Rapamune oral tablets; hence, are 
interchangeable on a milligram to milligram basis.  However, it is not known if higher 
doses of Rapamune Oral Solution are clinically equivalent to higher doses of tablets on a 
milligram to milligram basis (see Section 2.7.1). 
 
2.5.1.3. 
Sirolimus adverse reactions 
 
Most side-effects of sirolimus occur with prolonged use, especially when used in combination 
with CNIs like tacrolimus and cyclosporine.  Sirolimus alone is not associated with neurotoxicity 
or nephrotoxicity because of its inability to inhibit calcineurin.  Adverse reactions that resulted in 
rates of sirolimus discontinuation > 5% were increased creatinine, hypertriglyceridemia and 
thrombotic thrombocytopenic purpura.  
 
TABLE 2.5a.  SIROLIMUS TOXICITIES 
 
Common 
>20% 
Occasional 
5-20% 
Rare 
<5% 
Immediate 
Within 1-2 days of 
receiving drug 
Headache (L), 
hypertension (L), nausea, 
diarrhea, immuno-
suppression (L), fever, 
constipation 
Chest pain, insomnia, 
dyspepsia, vomiting, dyspnea 
Hypotension, asthma, increased 
cough, flu like syndrome, 
tachycardia, anorexia, 
hypersensitivity reactions 
(exfoliative dermatitis, 
angioedema) 
Prompt 
Within 2-3 weeks, 
prior to the next 
course 
Tremor (L), renal 
dysfunction, elevated 
creatinine/BUN, anemia, 
pain (abdominal, back, 
pain), hyperlipidemia, 
hypercholesteremia, 
hypertrigylceridemia, 
hyperglycemia, peripheral 
edema, weight gain, 
arthralgia 
Elevated LFTs (with elevated 
sirolimus levels), stomatitis, 
urinary tract infections, URIs, 
mild thrombocytopenia, 
leukopenia, 
hyper/hypokalemia (L), 
hypophosphatemia, rash, 
hives, pruritis, delayed 
wound healing or dehiscence 
(L), hypomagnesaemia (L), 
proteinuria 
Opportunistic infections, pleural 
and pericardial effusions, non-
infectious pneumonitis or 
bronchiolitis-obliterans 
organizing pneumonia and 
pulmonary fibrosis, thrombosis, 
myalgias, increased risk of CNI-
induced HUS/TTP/TMA (L) 
  
Delayed 
Any time later 
during therapy, 
excluding the 
above conditions 
Acne 
 
Chronic renal dysfunction, renal 
tubular necrosis, CHF, ascites, 
arthrosis, bone necrosis, 
osteoporosis 

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Common 
>20% 
Occasional 
5-20% 
Rare 
<5% 
Late 
Any time after 
completion of 
treatment 
 
 
Lymphoproliferative disorders, 
skin malignancies 
Unknown 
Frequency and 
Timing 
Sirolimus was embryo/fetotoxic in rats at dosages of approximately 0.2 to 0.5; clinical doses 
were adjusted for body surface area. It is not known whether sirolimus is excreted in human 
milk. 
(L) Toxicity may also occur later. 
 
2.5.1.4. 
Management of sirolimus toxicities 
 
Toxicities will be scored as per the NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 (see http://ctep.cancer.gov/forms/CTCAEv3.pdf).  
 
• Hyperlipidemia: In the Phase III studies, treatment of new-onset hypercholesterolemia 
with lipid-lowering agents was required in 42-52% of patients enrolled in the sirolimus 
arms.  Concomitant administration of sirolimus and HMG-CoA reductase inhibitors 
(statins) and/or fibrates appeared to be well tolerated.  However, statins or fibrates should 
only be administered with caution to patients being treated with sirolimus and a CNI, at 
doses which are reduced according to label recommendations.  Treated patients should be 
monitored for the development of rhabdomyolysis.  Sirolimus should be continued during 
therapy for hypercholesterolemia and hypertriglyceridemia unless the lipid levels are 
uncontrollable with standard therapy and are deemed to be at risk to the subject, per the 
treating physician. 
 
• Thrombotic Microangiopathy (TMA): Studies in adult transplant patients have shown an 
increase in TMA from 4.2% when patients were treated with tacrolimus or cyclosporine 
alone compared to 10.8% in patients treated with the tacrolimus/sirolimus combination.54  
TMA may occur both in the setting of sirolimus and/or CNI levels being above the 
therapeutic range or when levels are within desired ranges.  Although complete renal 
recovery occurred in 92% of these patients, the potential seriousness of this complication 
requires careful monitoring and early therapy.  
 
To meet the definition for TMA a patient must have all of the following: 
1. Increased percentage (> 4%) of schistocytes in the blood 
2. De novo, prolonged, or progressive thrombocytopenia (platelet count < 50x109/L 
or 50% or greater reduction from previous counts) 
3. Sudden and persistent increase in LDH 
4. Decrease in hemoglobin concentration or increased red blood cell transfusion 
requirement 
5. Decrease in serum haptoglobin 
 

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The following criteria are supportive of this diagnosis: 
1. Sudden and persistent increase in BUN and Creatinine 
2. Neurological symptoms 
 
TMA should be managed preventively and conservatively.  Prevention involves 
monitoring and keeping CNI and sirolimus levels within the target ranges.  When CNI 
and sirolimus levels are high, doses need to be held for hours to days until levels in the 
therapeutic range are measured.  High levels should prompt closer scrutiny of the 
patient’s laboratory studies for a drop in hematocrit, presence of schistocytes, rise in 
serum LDH, BUN or creatinine, or drop in haptoglobin and in platelet count.  Any 
changes in these measures should warrant close scrutiny of the patient with tight control 
of levels of tacrolimus and sirolimus.  Immediate reporting of TMA to the Protocol 
Principal Investigators is required.  
 
If TMA develops then the CNI should be discontinued and one of the Protocol Principal 
Investigators should be contacted to discuss the case.  If a systemic agent is substituted for 
the discontinued CNI, then treatment failure should be designated.  Sirolimus should be held 
if serum levels are supratherapeutic and restarted once in the target range at an 
appropriate dose.  The use of plasmapheresis and plasma exchange does not appear to be of 
significant clinical utility in the management of transplant-associated microangiopathy, but 
may be used at the discretion of the treating physician. 
 
• Hematological Toxicity: It is recommended that the ANC, hematocrit and platelet counts 
will be monitored at the frequencies described in Table 2.5b, Section 2.5.1.3.  A thorough 
investigation should be made to assess for possible causes of the cytopenia (recurrent 
disease, infection, drug effect other than sirolimus, TMA, autoimmune hemolytic 
anemia/thrombocytopenia, GVHD, late engraftment of platelets in cord blood transplant, 
etc.).  If other causes have been ruled out and cytopenias are significant (ANC<500, 
platelets <20K) sirolimus doses may be decreased by 50%.  If the cytopenia does not 
resolve after two weeks, sirolimus may be held.  If counts improve, restart sirolimus at 
50% of dose and titer to full dose as tolerated. 
 
• Other Toxicities: Patients with toxicities such as lower extremity edema, arthralgias, and 
aphthous ulcers, should have a thorough assessment to rule out other causes of these 
symptoms (medications, heart failure, GVHD, etc.).  If the toxicity is thought to be 
caused by sirolimus and is significant, sirolimus dosing may be decreased by 50%.  If the 
symptoms do not stabilize, improve, or resolve after two weeks then sirolimus may be 
held. In some cases, interstitial lung disease has resolved upon discontinuation or dose 
reduction of sirolimus.  The risk may be increased as the sirolimus concentration 
increases. 
 
2.5.1.5. 
Sirolimus drug interactions 
 
Sirolimus is a substrate for cytochrome CYP 3A4 and a P-glycoprotein (P-gp).  
 
 

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Drugs that may increase sirolimus blood concentrations include CYP 3A4, 5, or P-gp inhibitors:  
• Calcineurin inhibitors: Simultaneous administration of cyclosporine soft gelatin capsules 
(Neoral®) results substantial increases in the sirolimus Cmax and AUC.  This is avoided 
if administration of cyclosporine and sirolimus is taken 4 hours after administration 
of cyclosporine. 
• Calcium Channel Blockers: diltiazem, nicardipine, nifedipine, verapamil and amlodipine. 
Sirolimus should be monitored and a dose adjustment may be necessary.  
• Triazole antifungal agents: fluconazole, itraconazole, clotrimazole, posaconazole, 
voriconazole, ketoconazole. The magnitude of increases sirolimus Cmax, tmax, and AUC is 
such that sirolimus should be administered cautiously together with fluconazole, 
itraconazole, or posaconazole, and with extreme caution if administered together 
with voriconazole.  If co-administration is unavoidable, then the dose of sirolimus 
should be greatly reduced at the time of initiation of the antifungal medication as 
recommended in Table 2.7a. and that there should be very frequent monitoring of trough 
concentrations of sirolimus in whole blood.  Sirolimus concentrations should be 
measured upon initiation, during co-administration, and at discontinuation of antifungal 
treatment, with sirolimus doses adjusted accordingly. 
• Macrolide antibiotics: clarithromycin, erthyromycin, telithromycin, troleandomycin (but 
NOT azithromycin). 
• Gastrointestinal prokinetics: cisapride, metocloproramide. 
 
Drugs that may decrease sirolimus blood concentrations include CYP 3A4, 5, 7 or P-gp inducers:  
• Anticonvulsants: carbamazepine, Phenobarbital, phenytoin. 
• Antibiotics: Rifampin, rifanpentine. 
• Herbs: St. John’s Wort (Hypericum perforatum). 
 
Care should be taken when other drugs or substances that are metabolized by CYP3A4 or P-
glycoprotein are administered concomitantly with sirolimus.  Grapefruit juice reduced CYP3A4 
mediated metabolism of sirolimus and must not be used for dilution. 
 
2.5.2. 
Calcineurin Inhibitor (Tacrolimus or Cyclosporine) 
 
2.5.2.1. 
Stopping calcineurin inhibitor therapy (Arm 1) 
 
It is suggested that patients who are randomized to a CNI-free regimen and are already taking a 
CNI discontinue their CNI therapy by rapid taper over 1-2 weeks.  The initial dose reduction 
should be at least 50% of the current dose. 
 

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2.5.2.2. 
Initiating calcineurin inhibitor therapy (Arm 2) 
 
Formulation 
Route 
Adult 
Child < 17 yr 
Tacrolimus 
(Prograf®) 
oral 
0.01-0.02 mg/kg 
twice daily 
0.05-0.08 mg/kg  
twice daily 
Cyclosporine 
(Neoral® or Gengraf®) 
oral 
1-2 mg/kg  
twice daily 
3.75 mg/kg  
twice daily 
 
Initial doses are calculated using actual body weight except for those patients who are greater 
than 100% of ideal body weight in which case calculation of dose using adjusted body weight is 
recommended. 
 
2.5.2.3. 
Targeting CNI levels, dose adjustment and other considerations 
 
The target serum level for tacrolimus is 5-10 ng/mL                
 
The target serum level for cyclosporine is 120-200 ng/mL 
 
Dose adjustments are based upon clinical judgment of the managing physician after considering 
clinical toxicity, serum levels, GVHD, concomitant drug use and the rate of rise or decline of the 
serum level.  A reasonable approach that incorporates these principles into a management 
algorithm is suggested in Table 2.5b. and “Sirolimus & CNI Therapy Physician Guide” 
which attempts to target steady state blood trough levels within relatively narrow therapeutic 
ranges with the goal of preventing combined toxicities of sirolimus and calcineurin inhibitors. 
 
The suggested frequency for monitoring sirolimus and CNI blood levels varies from monthly to 
twice weekly based upon the guidance provided in Table 2.5b.  Monitoring frequency takes into 
consideration changes in renal function and changes in concomitant medications which are 
known to affect levels by altering the metabolism of either sirolimus or CNIs.  It is important to 
recognize that drug-related toxicities occur with greater frequency when sirolimus and CNIs are 
given concomitantly (also see Sections 2.5.1.3-2.5.1.5).  
 
Whole blood levels of CNIs will be measured by high performance liquid chromatography 
(HPLC) or HPLC with tandem mass spectrometric detection (preferred methods) or equivalent 
method with correlation coefficient ≥ 0.90.  

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TABLE 2.5b. RECOMMENDED MONITORING AND DOSE MODIFICATION OF THERAPY WITH  
SIROLIMUS, CYCLOSPORINE OR TACROLIMUS 
Parameter 
Target Range 
Result 
Action 
Test Frequency on Therapy 
< 1 month 
 1 month 
Neutrophils 
>3000L 
<1300/L 
Stop sirolimus4 
weekly 
weekly 
 
 
1300-1999/L 
none 
weekly 
weekly 
 
 
2000-3000/L 
none 
weekly 
every 2 weeks 
 
 
>3000/L 
none 
weekly 
Monthly2 
Platelets  
> 100,000L 
<30,000/L 
Stop sirolimus4 
weekly 
weekly 
 
 
30,000-49,999/L 
none 
weekly 
weekly 
 
 
50,000-100,000/L 
none 
weekly 
every 2 weeks 
 
 
>100,000/L 
none 
weekly 
monthly 
Hyperlipidemia1 
age normal 
< 2.5 x upper N 
Consider dietary manipulations 
weekly 
monthly 
 
 
> 2.5 x upper N 
Consider appropriate drug therapy 
weekly 
weekly 
 
 
>800 mg/dL 
Start appropriate lipid lowering agent 
weekly 
weekly 
Sirolimus 
3-12 ng/mL 
> 15 ng/mL3 
Stop sirolimus; monitor for HUS 
every 3-4 days 
every 3-4 days 
with CNI 
 
12-15 ng/mL 
Reduce sirolimus 20-25% 
every 3-4 days 
every 3-4 days 
(trough levels) 
 
10 – 12 ng/mL & serum Cr > 2 x N 
Reduce sirolimus 20-25% 
every 3-4 days 
every 3-4 days 
 
 
3-12 ng/mL on > 3 successive tests 
Less frequent monitoring 
weekly 
monthly 
 
 
< 3 ng/mL & serum Cr < 2 x N 
Increase sirolimus 20-25% 
weekly 
weekly 
Sirolimus 
3-12 ng/mL 
> 12-18 ng/mL 
Reduce sirolimus by 20-25% 
weekly 
weekly 
without CNI 
 
3 – 12 ng/mL on > 3 successive tests 
Less frequent monitoring 
weekly 
monthly 
(trough levels) 
 
< 3 ng/mL 
Increase sirolimus 20-25% 
weekly 
weekly 
Cyclosporine 
120-200 ng/mL  
> 360 ng/mL  
Stop/reduce CSP, recheck level & serum Cr 
every 1-3 days 
every 3-4 days 
(trough level) 
 
>200 & serum Cr normal  
reduce dose of cyclosporine 
every 3-4 days 
every 3-4 days 
 
 
120-200 ng/mL & serum Cr < 2.5 x N 
continue same dose 
every 1-2 wks 
monthly 
 
 
80-200 ng/mL & serum Cr > 2.5 x N 
monitor for HUS 
every 3-4 days 
every 3-4 days 
Tacrolimus  
5-10 ng/mL 
>20 ng/mL  
Stop/reduce TAC, recheck level & serum Cr 
every 1-3 days 
every 3-4 days 
(trough level) 
 
>10 ng/mL and serum Cr normal  
reduce dose of tacrolimus 
every 3-4 days 
every 3-4 days 
 
 
5-10 ng/mL & serum Cr < 2.5 x N 
continue same dose 
every 1-2 wks 
monthly 
 
 
5-10 ng/mL & serum Cr > 2.5 x N 
monitor for HUS 
every 3-4 days 
every 3-4 days 
Notes: 1 Fasting serum triglycerides. 2 Every 2 weeks if on ganciclovir or valganciclovir. 3 Hold dose and recheck level before readministering sirolimus at lower dose. 4 If 
patients develop neutropenia, thrombocytopenia or hyperlipidemia while taking sirolimus please consult Section 2.8 of protocol for further details on management. HUS; 
Hemolytic Uremic Syndrome. [See also Section 2.5.1.4 (TMA/HUS/TTP) and “Sirolimus & CNI Therapy Physician Guide”] 

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Other Important Considerations:  
• Children generally require a larger total daily dose of CNI by weight than adults. If aged 
< 6 years, every 8 hour administration may be required to maintain desirable serum 
trough levels. For those patients in whom adequate serum trough levels cannot be 
maintained using intermittent oral or IV dosing, continuous IV infusion may be 
warranted.  
• Review of concomitant medications for potential interactions that may significantly 
alter serum CNIs levels (see Section 2.5.2.7-2.5.2.8) is essential because CNIs undergo 
extensive metabolism by the hepatic and intestinal cytochrome P-450 system which may 
impact toxicity and efficacy of CNIs.   
• Although elevated CNI blood levels are more frequently associated with toxicity 
(especially renal or hepatic), “therapeutic” CNI blood levels may also be associated with 
toxicity (e.g. significant tremors). Therefore, dose decreases are recommended for 
significant organ toxicities that manifest despite a “therapeutic” CNI level. 
• Emesis: A repeat dose of CNI may be given if emesis occurs within 15 minutes of a 
dose.  
• CNIs should be administered at a consistent time each day and in relation to meals.  
Neoral oral solution should be administered in orange or apple juice at room temperature.   
• Subjects should avoid beverages containing the enzyme bergamottin (grapefruit juice, 
Sunny Delight, Fresca, and Squirt) when taking CNIs.  
• Distal paraesthetic pain or burning during the infusion may be alleviated by extending 
the IV infusion time for Sandimmune from the standard of 1 hour to as long as 6 hours. 
Alternatively, cyclosporine may be administered as a continuous infusion over 24 hours 
for patients intolerant of intermittent administration.  
• Monitor closely for an acute allergic reaction for the first 30 minutes after starting 
tacrolimus IV infusion and at frequent intervals thereafter.   
• Intravenous route of administration is preferred for patients with progressive GVHD 
of the liver or gastro-intestinal tract until GVHD is clinically improved and the oral 
route reliable. 
• If the oral route becomes temporarily unfeasible and conversion to the intravenous 
formulation is required the following recommendations are made: 
Starting Oral 
Formulation 
Conversion to IV formulation 
Prograf® 
IV Prograf = 0.25 x total daily dose of oral Prograf but should be 
given as continuous daily infusion 
Neoral® 
IV Sandimmune = 0.4 x total daily dose of Neoral 
Gengraf® 
IV Sandimmune = 0.4 x total daily dose of Gengraf 
Sandimmune® 
IV Sandimmune = 0.25 x total daily dose of oral Sandimmune 
 
 

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2.5.2.4. 
Tacrolimus adverse reactions 
 
The primary toxicities in large controlled trials were reversible renal insufficiency, hypertension, 
hyperglycemia, hypomagnesemia, hyperkalemia, and neurological toxicity (tremor and 
headache).  With the IV formulation, there is also an infusional toxicity of the cremaphor diluent.  
There is increased risk of opportunistic infections and secondary malignancies.  Some of these 
toxicities are recognized complications of transplantation. 
 
TABLE 2.5c.  TACROLIMUS TOXICITIES 
 
Common 
>20% 
Occasional 
5-20% 
Rare 
<5% 
Immediate 
Within 1-2 days 
of receiving drug 
Headache (L), 
hypertension (L), nausea, 
vomiting, anorexia 
immunosuppression (L), 
diarrhea, constipation, 
fever 
Chest pain 
Anaphylaxis with the injection, allergic 
reaction, hypotension, asthma, dyspnea, 
increased cough, flu like syndrome, pleural 
effusion, seizure (L), tachycardia, angina 
Prompt 
Within 2-3 weeks, 
prior to the next 
course 
Tremor (L), decrease in 
GFR, elevated 
creatinine/BUN, anemia, 
insomnia, asthenia, pain 
(abdominal, back, pain), 
hyperglycemia, 
hypomagnesemia (L), 
hyper-/hypokalemia (L), 
hypophosphatemia, 
paresthesiae, 
opportunistic infections 
Alopecia, dizziness, 
elevated LFTs, UTI, 
peripheral edema, rash, 
pruritis, hyperlipidemia, 
hypercholesterolemia, 
leukocytosis, 
thrombocytopenia 
Dyspepsia, dysphagia, gastritis, esophagitis, 
flatulence, CNS abnormalities (confusion 
(L), somnolence (L), depression (L), anxiety, 
anxiousness, abnormal dreams, emotional 
labiality, hallucinations, psychosis, 
hypertonia, incoordination,  neuropathy, 
nervousness encephalopathy, abnormal 
vision, tinnitus, coagulation disorder, 
leukopenia (L), polycythemia, anemia, 
leukocytosis, thrombosis, phlebitis, 
arthralgia, myalgia, electrolyte abnormalities 
Delayed 
Any time later 
during therapy, 
excluding the 
above conditions 
 
 
Acne, exfoliative dermatitis, skin 
discoloration, photosensitivity reaction, skin 
ulcer, delayed wound healing, hirsutism 
(hypertrichosis) (L), gingival hyperplasia, 
abnormal vision, amblyopia, ear pain, otitis, 
tinnitus, GI hemorrhage, GI perforation, 
cholelithiasis, cholestatic jaundice, chronic 
renal dysfunction, renal failure, post 
transplant diabetes mellitus (L), Reversible, 
concentration dependent myocardial 
hypertrophy (L), elevated liver function 
tests, liver damage, ascites 
Late 
Any time after 
completion of 
treatment 
 
 
Lymphoproliferative disorders, skin 
malignancies 
Unknown 
Frequency and 
Timing 
Fetal toxic effects of tacrolimus have been noted in animals.  Tacrolimus is transported across the 
placenta and its use during pregnancy has been associated with neonatal hyperkalemia and renal 
dysfunction.  Tacrolimus is excreted in human milk, nursing should be avoided. 
(L) Toxicity may also occur later. 
 

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2.5.2.5. 
Cyclosporine adverse reactions 
 
The toxicities of cyclosporine are similar to tacrolimus but not overlapping (see Section 2.5.2).  
Common toxicities include: hypertension, tremor, hirsuitism, hyperlipidemia, hyperkalemia, 
hypomagnesemia, elevated creatinine/BUN, hyperglycemia, paraesthesiae, gingival hyperplasia, 
abnormal LFTs, acne, reduced bicarbonate, abdominal discomfort, anorexia, nausea, vomiting, 
CNS disturbances and potential for TTP/HUS/TMA similar to tacrolimus and exacerbated by 
sirolimus (see Section 2.5.2.4), gynecomastia, and with the IV form: flushing, erythema, skin 
bullae. 
 
2.5.2.6. 
Management of tacrolimus and cyclosporine toxicities 
 
Please see Section 2.5.1.4 and Table 2.5b for management of nephrotoxicity, Thrombotic 
Microangiopathy and hyperlipidemia. 
 
2.5.2.7. 
Tacrolimus drug interactions 
 
Tacrolimus is a substrate for cytochrome CYP 3A4 enzyme systems.  
 
Drugs that may increase tacrolimus blood concentrations include CYP 3A4 inhibitors:  
• Calcium Channel Blockers: diltiazem, nicardipine, nifedipine, verapamil. Tacrolimus 
should be monitored and a dose adjustment may be necessary.  
• Triazole antifungal agents: fluconazole, itraconazole, clotrimazole, posaconazole, 
voriconazole, ketoconazole.  See Section 2.7.1 for recommendations for preemptive dose 
reduction of CNI doses when initiating triazole antifungal therapy (Table 2.7a.) and 
anticipated need to increase CNI doses after triazole antifungal therapy is discontinued 
(Table 2.7b.). 
• Macrolide antibiotics: clarithromycin, troleandomycin. 
• Gastrointestinal prokinetics: cisapride, metocloproramide. 
• Other: cyclosporine, ethinyl estradiol, omperazole, lansoprazole, methylprednisolone. 
 
Drugs that may decrease tacrolimus blood concentrations include CYP 3A4 inducers:  
• Anticonvulsants: carbamazepine, Phenobarbital, phenytoin. 
• Antimicrobials: Rifampin, rifabutin, caspofungin. 
• Herbs: St. John’s Wort (Hypericum perforatum). 
 
Due to potential for additive or synergistic impairment of renal function, care should be taken 
when administering tacrolimus with drugs that may be associated with renal dysfunction.  These 
include but are not limited to amphotericin B products, aminoglycosides, vancomycin, 
trimethoprim with sulfamethoxazole, fenofibrate, gemfibrozil, statins, angiotensin II receptor 
antagonists, and diuretics. 
 

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2.5.2.8. 
Cyclosporine drug interactions 
 
The drug interactions for cyclosporine are similar or identical to tacrolimus (see Section 2.5.2.7).  
Postmarketing cases of myositis, myopathy and rhabdomyolysis have been reported with 
concomitant administration of cyclosporine with HMG-CoA reductase inhibitors (statins) which 
should be used with caution and at doses which are reduced doses according to label 
recommendations. 
 
2.5.3. 
Prednisone 
 
2.5.3.1. 
Initiating prednisone therapy 
 
Prednisone is administered initially as a single early morning dose of 1 mg/kg/day [or equivalent 
(adults: maximum dose 100 mg, age < 17 years: adjusted body weight as per institutional 
guidelines for patients who weigh > 110% of ideal body weight)].   
 
If prednisone (or equivalent) at a dose of 1 mg/kg/day is contraindicated (e.g. poorly controlled 
diabetes, hypertension, osteoporosis, avascular bone necrosis, major mood disturbance) patients 
may begin prednisone between 0.5 -1 mg/kg/day.   
 
Prednisone therapy continues at the initial dose until there is objective evidence of improvement 
in manifestations of chronic GVHD.  
 
2.5.3.2. 
Monitoring 
 
Prednisone therapy will be monitored according to institutional guidelines. 
 
2.5.3.3. 
Prednisone adverse reactions 
 
The side effects of prednisone are broad and well recognized.  They include but are not limited 
to: fluid and sodium retention, hypokalemia, hypertension, myopathy, muscle wasting, altered 
body habitus with cushingoid appearance, osteoporosis, tendon rupture, pancreatitis, peptic ulcer, 
impaired wound healing, thin fragile skin, petechiae and ecchymoses, ruddy facies, negative 
nitrogen balance, pseudotumor cerebri, headache, secondary adrenal insufficiency, suppression 
of growth in children, hyperglycemia, diabetes mellitus, posterior subcapsular cataracts, 
glaucoma, euphoria, insomnia, mood swings, personality changes, severe depression, emotional 
instability, and frank psychosis. 
 
2.6. 
Approach to Tapering Immunosuppressive Therapy 
 
The recommended sequence is to taper prednisone, then CNI (for study subjects on Arm 2) and, 
finally sirolimus.  The suggestions for taper schedules are explained in Sections 2.1 (schematic 
overviews) and 2.6.1 - 2.6.2 below.  Minor variations in these tapers are expected based on the 
physician discretion which considers individual clinical circumstances.  
 

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2.6.1. 
Prednisone Taper 
 
The initial taper of prednisone (or equivalent) from the starting dose of 0.5-1 mg/kg/every day is 
attempted within 2 weeks after the first evidence of improvement in GVHD and takes place over 
4-8 weeks to achieve a dose of 0.5-1 mg/kg/every-other-day.   
 
Every-other-day dosing, in which twice the usual daily dose of prednisone is administered every 
other morning provides the patient requiring long-term pharmacologic dosing with the beneficial 
effects of glucocorticoids while minimizing certain undesirable effects, including pituitary-
adrenal suppression, the cushingoid state, glucocorticoid withdrawal symptoms, and growth 
suppression in children.  Note that this approach may not be appropriate for every patient 
because of complications associated with large swings in prednisone dose.  
 
Once an alternating-day prednisone regimen is achieved, it is recommended that the dose of 
prednisone be held constant for 10-12 weeks until all reversible manifestations of chronic GVHD 
have resolved, after which a second taper may be attempted.  The tempo of this second taper may 
follow individual institutional guidelines but it is recommended that the extent of the taper be 
approximately calibrated to the magnitude of an individual patient’s alternating-day prednisone 
dose.  For example, a patient whose prednisone dose has been stable at 0.5 mg/kg/every-other-
day may attempt to taper prednisone completely.  However, a patient whose prednisone dose has 
been stable at 1.0 mg/kg/every-other-day is recommended first to taper over 4-8 weeks to 0.5 
mg/kg/every-other-day, followed by 2-3 months of further observation before attempting a 
complete taper.  
 
2.6.2. 
Sirolimus and Calcineurin Inhibitor Tapers 
 
Arm 1 (Prednisone + Sirolimus):  
Sirolimus may be tapered at the discretion of the managing physician over 1-3 months after 
prednisone has been discontinued.  The recommended approach is to monitor and confirm the 
stability of GVHD response for 1-3 months before tapering sirolimus.  Please see Section 2.6.1 
regarding the taper of prednisone. 
 
Arm 2 (Prednisone + Sirolimus + Calcineurin Inhibitor):  
After prednisone is discontinued, the order and approach for tapering sirolimus or the CNI 
occurs at the discretion of managing physician.  The recommended approach is to monitor and 
confirm the stability of GVHD response for 1-3 months before tapering the CNI over 3-6 
months.  A similar 1-3 month period of monitoring to confirm the stability of GVHD response to 
stopping the CNI is recommended prior to attempting taper or discontinuation of sirolimus.  
Please see Section 2.6.1 regarding the taper of prednisone. 
 

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2.7. 
Supportive Care 
 
All supportive care will be in keeping with BMT CTN Manual of Procedures and local 
institutional guidelines that reflect reasonable standard practices appropriate to the patient with 
chronic GVHD as outlined by the Ancillary Therapy and Supportive Care Working Group 
Report of the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic 
GVHD.2  Supportive care should be administered in a similar fashion to subjects randomized to 
both arms of the study. 
 
2.7.1. 
Concomitant Azole Therapy 
 
Antifungal prophylaxis: Triazole antifungal medications are expected to increase serum CNI and 
sirolimus levels, therefore, dosages of CNIs and sirolimus, should be adjusted accordingly using 
the guidelines recommended in Table 2.7a. and 2.7b.  Due to extreme interactions with 
sirolimus, voriconazole is contraindicated during sirolimus therapy.  In the event of 
suspected or documented fungal infection, alternative antifungal therapy should be used 
wherever possible.  
 
TABLE 2.7a. - PRE-EMPTIVE DOSE REDUCTION OF SIROLIMUS OR CNIs WHEN 
AZOLES ARE INITIATED AT STEADY STATE LEVELS OF SIROLIMUS OR CNIs 
Antifungal 
Cyclosporine 
Tacrolimus 
Sirolimus 
 
Dose 
 
Comment 
Dose  
Comment 
Dose 
 
Comment 
Voriconazole 
50% 
Strongly 
advised 
67% 
Strongly 
advised 
90% 
Essential* 
Posaconazole 
25% 
Consider 
67% 
Advised 
67% 
Advised 
Itraconazole 
50% 
Advised 
50% 
Advised 
ND 
ND 
Fluconazole 
25% 
Consider 
25% 
Consider 
50% 
If > 400 mg QD 
*Notes: 
1. Voriconazole should not be used unless deemed absolutely clinically necessary. 
2. If an voriconazole must be added to control fungal infection then following the 90% reduction in 
sirolimus dosing55 and/or 50%-67% reduction in CNI dosing SRL and/or CNI serum levels 
should be measured 24-48 hours later and then every 3-4 days until levels are stable and in the 
desired range.  If voriconazole is given intravenously or if voriconazole and sirolimus are not 
given together, these guidelines may not apply because the effect on bioavailability of sirolimus 
will be weaker. 
3. Note that sirolimus tablets should not be split or crushed.  Fractional dose of sirolimus may be 
achieved by drawing an appropriate volume of the 1 mg/mL oral liquid formulation into a 1 mL 
syringe and swallowed directly (or mixed with water or orange juice; no other liquids, including 
grapefruit juice, should be used for dilution). 
4. If posaconazole or itraconazole or high-dose fluconazole are added then SRL and/or CNI serum 
levels should be followed 48-72 hours later and then every 3-5 days until levels are stable and in 
the desired range. 
 

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TABLE 2.7b. - ANTICIPATE DOSE INCREASE OF SIROLIMUS OR CNIs WHEN 
AZOLES ARE STOPPED DURING CONCOMITANT SIROLIMUS OR CNI THERAPY 
Antifungal 
Cyclosporine 
Tacrolimus 
Sirolimus 
 
Dose  
Comment 
Dose  
Comment 
Dose  
Comment 
Voriconazole 
2-fold 
Dose increase 
may not be 
necessary for    
5-10 days 
3-fold 
Dose increase 
may not be 
necessary for    
5-10 days 
10-fold 
Dose increase 
may not be 
necessary for     
5-10 days 
Posaconazole 
1.3-
fold 
3-fold 
ND 
Itraconazole 
2-fold 
2-fold 
ND 
Fluconazole 
1.3-
fold 
1.3-
fold 
2-fold 
Note:  Although sirolimus and CNI doses may need to be substantially increased when azole therapy is 
stopped, the azole mediated inhibition of cytochrome CYP 3A4 (and other) and P-glycoprotein may take 
5-10 days to abate and therefore immediate dose increases are not advised.  Rather, sirolimus and CNI 
dose increases should be cautious and based on more frequent monitoring of the sirolimus and/or CNI 
levels as appropriate.   
 
2.8. 
Drug Information 
 
2.8.1. 
Description, Administration and Storage 
 
2.8.1.1. 
Sirolimus (rapamycin, Rapamune®) 
 
Sirolimus is a naturally occurring compound produced by Streptomyces hygroscopicus.  In 
addition to its immunosuppressive properties, sirolimus has antifungal, antiviral and 
antineoplastic properties (see also Section 1.3). 
 
1) Oral solution:  
Sirolimus oral solution is supplied in cartons of 2 oz (60 mL fill) or 5 oz (150 mL fill) 
amber glass bottles, or foil pouches.  The oral solution contains sirolimus at a 
concentration of 1 mg/mL and the following inactive ingredients: Phosal 50 PG 
(phosphatidylcholine, propylene glycol, monodiglycerides, ethanol, soy fatty acids, and 
ascorbyl palmitate) and polysorbate 80.  The oral solution also contains 1.5% - 2.5% 
ethanol.  The appropriate dose of sirolimus oral solution should be measured using the 
provided amber colored oral syringe and is diluted in at least 2 oz (1/4 cup) of water or 
orange juice to improve palatability.  No other liquids, including grapefruit juice, 
should be used for dilution.  After vigorous mixing, the diluted dose should be taken 
immediately.  Refill the container with an additional volume (recommended minimum of 
4 oz (1/2 cup) of water or orange juice, stir vigorously, and drink or administer at once to 
assure delivery of all of the medication.  Small children may not be able to consume the 
recommended volumes of water or orange juice suggested for dilution and may need 
lesser volumes. 
 
Sirolimus oral solution provided in bottles may develop a slight haze when refrigerated.  
If such a haze occurs allow the product to stand at room temperature and shake gently 

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until the haze disappears.  The presence of this haze does not affect the quality of the 
product. Rapamune® Oral Solution bottles and pouches should be stored protected from 
light and refrigerated at 2C to 8C (36F to 46F).  The syringe should be discarded after 
one use.  After dilution, the preparation should be used immediately. 
 
2) Tablets:  
Sirolimus tablets are available as white, tan or yellow-to-beige triangular-shaped tablets 
marked “RAPAMUNE 1 mg,” “RAPAMUNE 0.5 mg” or “RAPAMUNE 2 mg” 
respectively, in bottles containing 100 tablets or cartons containing 10 blister cards each 
with 10 tablets (0.5 mg and 1 mg formulations only).  Each tablet contains sirolimus and 
the following inactive ingredients: sucrose, lactose, polyethylene glycol 8000, calcium 
sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, 
magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl 
monooleate, carnauba wax, and other ingredients.  The 0.5 mg and 2 mg tablets also 
contain yellow iron (ferric) oxide and brown iron (ferric) oxide.  Sirolimus tablets should 
be stored at 20 to 25C (68 - 77F).  Cartons should be used to protect blister cards and 
strips from light.  Sirolimus tablets should be dispensed in a tight, light-resistant 
container.  Sirolimus tablets should not be split or crushed. 
 
3) Pharmacology: 
The absorption of sirolimus is rapid after administration of Rapamune Oral Solution, 
with a mean Tmax of 1-2 hours in different study populations. Oral bioavailability is only 
14% in stable renal transplant patients due to first pass metabolism in the liver and the 
intestinal wall, plus countertransport in the gut lumen by P-glycoprotein. Mean 
bioavailability of sirolimus after administration of the tablet is about 27% higher relative 
to the oral solution. However, clinical equivalence has been demonstrated for the 2-mg 
dose.  Coadministration with high fat meals leads to reduced Cmax, prolonged Tmax and 
increased AUC, meaning that sirolimus should be taken consistently with or without 
food. The distribution of sirolimus is notable for extensive partitioning into blood cells 
and approximately 92% is bound to human plasma proteins.  Sirolimus is a substrate for 
CYP3A4 and P-glycoprotein, and is extensively metabolized by O-demethylation and/or 
hydroxylation to at least 7 major metabolites.  The parent compound contributes to more 
than 90% of the immunosuppressive activity.  The excretion of Sirolimus is 91% fecal 
and only 2.2% via the urine. 
 
Whole blood sirolimus trough levels in renal transplant recipients who were administered 
daily doses of 2 mg or 5 mg at 4 hours after Neoral®) were 8.59 ± 4.01 ng/mL and 17.3 ± 
7.4 ng/mL, respectively, as measured by LC/MS/MS.  Whole blood trough levels 
significantly correlated with steady state AUC (r2=0.96).  Six days of multiple dosing 
were required to achieve steady state.  Alternatively, a loading dose of three times the 
maintenance dose will provide near steady state concentrations within one day in most 
patients.  
 
The mean  SD terminal elimination half life (T1/2) of sirolimus after multiple dosing in 
stable renal transplant patients was 62  16 hours.  The mean T1/2 increased from 79  12 

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hours in subjects with normal hepatic function to 113  41 hours in patients with 
impaired hepatic function.  Dosage reduction is recommended for patients with mild to 
moderate hepatic impairment.  Limited pharmacokinetic data are available in pediatric 
patients with chronically impaired renal function but indicates similar Tmax (0.62-1.6 h) 
and T1/2 (31-111h).  Clearance is slower in males compared to females but dose 
adjustments based on gender are not recommended.  There were no differences between 
African Americans and non-African Americans. 
 
2.8.1.2. 
Tacrolimus (FK-506, Prograf®) 
 
Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis that 
inhibits T-lymphocyte activation, although the exact mechanism of action is not known.  
Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A 
complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the 
phosphatase activity of calcineurin inhibited.  This effect may prevent the dephosphorylation and 
translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to 
initiate gene transcription for the formation of lymphokines like interleukin-2 and gamma 
interferon.  The net result is the inhibition of T-lymphocyte activation.  Tacrolimus may also 
inhibit cellular activities such as nitric oxide synthetase activation and apoptosis, and may 
potentiate the action of corticosteroids in these processes. 
 
1) Oral capsules:  
Tacrolimus (Prograf®) is available as oblong shaped, light yellow (0.5 mg), white (1 
mg), or grayish-red (5 mg) capsules supplied in bottles containing 100 capsules or cartons 
containing 10 blister cards each with 10 capsules.  Capsules should be stored at 25C 
(77F). 
 
2) IV solution:  
Tacrolimus IV solution is supplied in 1 mL ampoules that contain 5 mg of anhydrous 
tacrolimus (concentration of 5 mg/mL) and should be stored between 5C to 25C (41F 
– 77F). 
 
Tacrolimus Injection must be diluted with 0.9% Sodium Chloride Injection or 5% 
Dextrose Injection before use to a concentration between 0.004 mg/mL and 0.02 mg/mL. 
Diluted infusion solution should be stored in glass or polyethylene containers and should 
be discarded after 24 hours.  The polyoxyethylated castor oil contained in the concentrate 
for intravenous infusion can cause phthalate stripping from PVC.  It is strongly 
recommended that glass bottles and non-PVC tubing be used to minimize patient 
exposure to phthalates.  Due to the chemical instability of tacrolimus in alkaline media, 
Tacrolimus Injection should not be mixed or co-infused with solutions of pH 9 or greater 
(e.g., ganciclovir or acyclovir).  
 
3) Pharmacology: 
The absorption of tacrolimus after oral administration is incomplete and variable and 

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absolute bioavailability was 17-23% and the Tmax was 1.5-3 hours in different study 
populations.  The rate and extent was greatest under fasted conditions and least with high 
fat or high carbohydrate meals.  Tacrolimus binding to plasma proteins is 99% which is 
independent of concentrations ranging from 5-50 ng/mL.  Tacrolimus is also highly 
associated with erythrocytes.  Tacrolimus is a substrate for mixed-function oxidase 
system, primarily CYP3A4, and is extensively metabolized by demethylation and 
hydroxylation to a possible 8 major metabolites.  The parent compound is primarily 
responsible for the immunosuppressive activity.  The excretion of orally administered 
tacrolimus is 92% fecal and 2.3% via the urine.  Typical whole blood tacrolimus trough 
levels after the recommended oral doses of 0.1-0.2 mg/kg/day were 5-20 ng/mL as 
measured by LC/MS/MS.  The mean terminal elimination half life (T1/2) of tacrolimus 
after multiple dosing in different study populations was 11-34 hours.  The T1/2 in children 
was generally at the lower range and showed that children needed higher doses than 
adults to achieve similar trough concentrations.  The mean T1/2 was reduced by 2-3-fold 
in patients with impaired hepatic function.  Dosage reduction is recommended for 
patients with mild to moderate hepatic impairment.  A retrospective comparison of 
African American and Caucasian kidney transplant patients indicated that African 
American patients required higher tacrolimus doses to attain similar trough 
concentrations; there were no gender-based differences. 
 
2.8.1.3. 
Cyclosporine 
 
Cyclosporine is a cyclic polypeptide immunosuppressant agent produced by the fungus species 
Beauveria nivea.  While the molecular structure of cyclosporine is distinct from tacrolimus, their 
mechanism of action is almost indistinguishable and involves inhibition of calcineurin and the 
resulting activation cascade leads to inhibition of T cell signaling (see Section 2.8.1.2).  
Cyclophilin is the cytosolic binding protein for cyclosporine that is distinct from FK-binding 
protein. 
 
1) Oral formulations:  
Cyclosporine is most commonly prescribed as soft gelatin capsules (Neoral®) or 
modified oral solution (Neoral® Oral Solution) that have increased bioavailability in 
comparison to the less commonly used Sandimmune formulations.  Neoral® and 
Sandimmune® cannot be used interchangeably and care must be exercised when 
converting from high doses of Sandimmune® to Neoral®.  Neoral® capsules are 
available in two strengths: 25 mg (oval, blue-gray) or 100 mg (oblong, blue-gray) 
imprinted in red. Neoral® Oral solution is available in 50 mL bottles of yellow liquid 
containing 100 mg/mL of cyclosporine.  Both Neoral® formulations contain 11.9% v/v 
alchohol.  Neoral® capsules and oral solution should be stored at 20-25C (68F -77F) 
and not in the refrigerator.  Sandimmune® capsules are available in two strengths: 25 mg 
(oblong, pink) or 100 mg (oblong, dusty rose), in unit dose packages of 30 capsules that 
should be stored at 25C (77F).  Sandimmune® Oral solution is available in 50 mL 
bottles of yellow liquid containing 100 mg/mL of cyclosporine.  Both Sandimmune® 
formulations contain ~12.5% v/v alcohol.   
 

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2) IV solution:  
Sandimmune® IV solution is supplied in 5 mL ampoules that contain 50 mg of 
cyclosporine per mL, Cremaphor and 32.9% alcohol v/v.  It should be stored at 
temperatures below 30C (86F) but not in the refrigerator and should be protected from 
light.  
 
3) Pharmacology: 
The absorption of cyclosporine after oral administration is incompletely dependent on the 
individual patient, patient population and the formulation.  Cyclosporine is excreted in 
human milk.  The absolute oral bioavailability of Sandimmune® was 10%-89% in adults 
and had not been determined for Neoral®.  Mean cyclosporine AUC is generally 20%-
50% greater, and Cmax 40%-106% greater, with Neoral® compared to Sandimmune®, 
respectively.  The Tmax following oral administration of Neoral® is 1.5-2 hours.  The rate 
and extent of absorption were lower with low or high fat meals.  Cyclosporine binding to 
plasma proteins is 90%, primarily lipoproteins.  Cyclosporine is 33%-47% in the plasma, 
4%-9% in lymphocytes, and 41%-58% in erythrocytes.  Cyclosporine is extensively 
metabolized CYP3A4 and to a lesser extent in the gastrointestinal tract and kidney.  At 
least 25 metabolites have been identified in bile, feces, blood and urine but the parent 
compound is primarily responsible for the immunosuppressive activity.  Elimination is 
primarily biliary with only 6% of the dose excreted in urine. The mean terminal 
elimination half life (T1/2) of cyclosporine is 8.4 hours (range 5-18 hours).  The T1/2 in 
children was generally at the lower range and showed that children needed higher doses 
than adults to achieve similar trough concentrations.  The mean T1/2 was reduced by 2-3-
fold in patients with impaired hepatic function.  Dosage reduction is recommended for 
patients with mild to moderate hepatic impairment.  A retrospective comparison of 
African American and Caucasian kidney transplant patients indicated that African 
American patients required higher tacrolimus doses to attain similar trough 
concentrations; there were no gender-based differences. 
 
2.8.1.4. 
Glucocorticoids 
 
Naturally occurring glucocorticoids cause profound and varied metabolic effects which include 
modification of the body’s immune system. 
 
The most commonly used glucocorticoid formulations for the treatment of chronic GVHD are 
prednisone tablets which are available in a variety of strengths ranging from 1 mg up to 50 mg. 
The most commonly used intravenous formulation is methylprednisolone. 
 
 

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CHAPTER 3 
 
 
3. STUDY ENDPOINTS 
 
3.1. 
Definition of High-Risk vs. Standard-Risk  
 
The definition of high-risk and standard-risk patients is as follows: 
1) High-risk defined as meeting one or more of the following criteria: 
a) Patients with platelets < 100,000 
b) Patients > 50% skin involvement 
c) Patients with bronchiolitis obliterans 
d) Patients receiving prednisone ≥ 0.5 mg/kg/day (or equivalent) at the time of cGVHD 
diagnosis 
2) Standard-risk not meeting the high-risk criteria above. 
 
3.2. 
Primary Endpoint 
 
Treatment success will be defined according to the local physician’s response. 
 
Phase II Endpoint 
The primary endpoint is a comparison of the proportion of treatment successes in patients at 6 
months after randomization in both study arms.  Treatment success is defined as a study subject 
who is alive and who achieved a complete or partial response.  The subject did not receive 
secondary systemic immunosuppressive therapy and had no subsequent progression or 
additional secondary immunosuppressive therapy added through 6 months after 
randomization.  Relapse is considered a competing risk and is not included in the primary 
endpoint definition. 
 
Phase III Endpoint 
The primary endpoint is a comparison of the proportion of treatment success in patients at 24 
months after randomization in both study arms.  Treatment success is defined as a study subject 
who is alive and who achieved complete resolution of all reversible manifestations at 24 
months after randomization and did not receive secondary systemic immunosuppressive 
therapy.   
 
3.3. 
Secondary Endpoints 
 
The secondary endpoints will explore clinically relevant presumed associations with the primary 
endpoint of response.  These will be evaluated at baseline, and between 2 months and 3 years 
after the start of therapy depending on the specific endpoint.   
 

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3.3.1. 
Prednisone Sparing 
 
The percent reduction in the average daily dose of prednisone (or equivalent) will be calculated 
at 6 and 12 months (Phase II/III) and, additionally at 24 and 36 months (Phase III) after study 
entry based upon the prednisone doses that will be captured on case report forms up to 36 
months from randomization.  
 
3.3.2. 
Use of Secondary Therapy 
 
Treatment failure is defined at the time any secondary systemic therapy is added to control 
manifestations of chronic GVHD.  Secondary systemic therapy includes any intervention 
intended to control chronic GVHD through an immunosuppressive effect from oral or parenteral 
administration of any systemic medication not originally given under the auspices of this 
protocol for treatment of chronic GVHD.  Examples include, but are not limited to the following:  
cyclosporine or tacrolimus(Study Arm 1 only), and extracorporeal photopheresis, mycophenolate 
mofetil, azathioprine, rituximab, infliximab, daclizumab, etanercept, antithymocyte globulin, 
pentostatin, thalidomide, and hydroxychloroquine (Arms 1 and 2). 
 
Any increase in the dose of prednisone (or equivalent) and any resumption of treatment with 
prednisone, after previous discontinuation following the diagnosis of chronic GVHD for any 
reason is not considered as secondary systemic therapy.  However, prednisone pulses exceeding 
2 mg/kg/day are considered secondary therapy. 
 
Any increase in the dose of CNI or sirolimus, or resumption of treatment with CNI or sirolimus 
after previous discontinuation for any reason is not considered as secondary systemic therapy, if 
the drug in question was included in the immunosuppressive regimen when treatment for chronic 
GVHD was started.  
 
A change in treatment from cyclosporine to tacrolimus or vice versa because of drug toxicity is 
not considered as secondary treatment, but any such change made because of uncontrolled 
chronic GVHD is considered as secondary treatment.  Sirolimus may be discontinued for 
toxicities without counting as treatment failure unless a new systemic therapy is added for 
control of GVHD. 
 
Topical therapy, including glucocorticoid creams, topical tacrolimus, oral beclomethasone or 
budesonide, topical azathioprine and ophthalmic glucocorticoids, is not considered as secondary 
systemic therapy. 
 
3.3.3. 
Symptomatic Patient-Reported Chronic GVHD  
 
Symptomatic chronic GVHD will be defined as severity of chronic GVHD symptoms as reported 
by patients on the Patient Surveys. Prevalence rates will be calculated and compared between 
groups at 1 and 2 years (Phase II/III) and, additionally at 3 years for Phase III component.  
 

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3.3.4. 
Permanent Discontinuation of all Systemic Immunosuppressive Therapy 
 
Cumulative incidence curves of discontinuation of all systemic IST at 1 and 2 years (Phase II/III) 
and, additionally at 3 years for the Phase III component, will be calculated based upon the time 
that all systemic IST has been discontinued after resolution of all reversible manifestations of 
chronic GVHD.  Death or drop out with lack of follow-up information after resolution of all 
reversible manifestations of chronic GVHD and discontinuation of all systemic IST but before 
the final analysis is expected to occur infrequently and will be categorized as successful 
discontinuation of IST for the purposes of this study since the treatment had been successful in 
controlling chronic GVHD.  Discontinuation of immunosuppressive medications for the purpose 
of inducing an anti-tumor response after the development of recurrent or secondary malignancy 
will not be counted as successful discontinuation of IST.  If a patient requires only physiological 
doses of glucocorticoid to treat adrenal insufficiency when the final immunosuppressive agent is 
discontinued then it is acceptable to assign the designation: “permanent discontinuation of all 
systemic immunosuppressive therapy”. 
 
3.3.5. 
Overall Survival 
 
Overall survival probabilities will be compared between treatment arms adjusting for 
significantly imbalanced covariates.  Patients are considered a failure of this endpoint if they die 
from any cause.  The time to this event is the time from randomization to death, loss to follow up 
or end of study whichever comes first.  Overall survival will be assessed 1 and 2 years from the 
time of randomization (Phase II/III) and, additionally at 3 years for the Phase III component.   
 
3.3.6. 
Progression-Free Survival 
 
Progression-free survival will be assessed 1 and 2 years from the time of randomization (Phase 
II/III) and, additionally at 3 years for the Phase III component.  Progression of a cancer is 
defined as any clinical evidence of progression or relapsed disease, or any therapy used to treat 
persistent, progressive, or relapsed disease including withdrawal of immunosuppressive therapy 
or DLI.    
 
3.3.7. 
Biomarkers 
 
T-regs, B-cell and plasma BAFF levels will be enumerated at baseline and months two and six 
after randomization as long as patients do not start secondary therapy.  If secondary systemic 
immunosuppressive therapy is prescribed, samples should be drawn for T regs, B cell, and 
plasma BAFF levels prior to initiation of secondary therapy. 
  
3.3.8. 
NIH and Other New Response Instruments 
 
An important secondary endpoint of this study will be to test more objective, clinically relevant 
CR and PR criteria using instruments that have been recommended along the lines of the NIH 
Consensus guidelines52  A comprehensive assessment of organ involvement using the NIH 
Consensus response assessment tools and other study instruments will be performed at baseline, 

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2 months, 6 months, 1 year and 2 years (Phase II/III) and additionally at 3 years (Phase III), and 
in the event that a subject prematurely discontinues the study. 
 
3.3.9. 
Quality of Life 
 
Health Related Quality of Life will be described prior to the initiation of therapy for patients 
utilizing the FACT-BMT self report, transplant specific questionnaire and the generic quality of 
life tool, the SF-36.  The questionnaires will be scored according to standard procedures.  They 
will be due at baseline and months 2, 6, 12, 24, and 36. 
 
3.4. 
Safety Endpoints 
 
Monitoring of several safety endpoints will be conducted monthly and be used to form the basis 
of the stopping guidelines detailed in Section 5.4.  The key safety endpoint is mortality at 56 
days after randomization.  Two additional non-hematological toxicities will also be monitored: 
Thrombotic Microangiopathy (TMA) and Pneumonitis (NIP).  
 
3.4.1. 
Mortality 
 
The rate of mortality will be monitored up to 56 days post-randomization.  Monitoring will be 
performed monthly beginning after the third month of enrollment until enrollment is closed.  At 
least three events must be observed in order to trigger review. 
 
3.4.2. 
Thrombotic Microangiopathy (TMA) 
 
This complication might be expected to occur more frequently in the sirolimus and calcineurin-
inhibitor containing arm than in the other arm (see Section 2.5.1.4). 
 
3.4.3. 
Pneumonitis (NIP) 
 
Sirolimus associated NIP is poorly understood but has been reported after solid organ 
transplantation.  NIP appears to be uncommon although the exact incidence is unknown.  NIP 
should be suspected if a patient develops fatigue, fever and/or dyspnea within weeks to months 
after starting sirolimus; especially in patients > age 40 years, when patients have been converted 
from CNI-based IST to sirolimus-based IST, and when sirolimus levels have exceeded 
12 ng/mL.  Radiological pulmonary infiltrates are invariably observed and often resemble 
bronchiolitis obliterans-organizing pneumonia (BOOP), more currently referred to as crytogenic 
organizing pneumonia (COP).  Sirolimus associated NIP symptoms are generally readily 
reversible within 14-28 days when sirolimus is stopped; although, pulmonary infiltrates may take 
3-6 months to resolve.  Sirolimus should not be restarted if sirolimus-associated NIP is 
diagnosed. 
 
 

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CHAPTER 4 
 
 
4. PATIENT REGISTRATION, RANDOMIZATION AND ENROLLMENT 
 
4.1. 
Approaching Patients, Eligibility Screening and Obtaining Consent 
 
Subjects will be approached for this protocol after they have developed chronic GVHD. 
Transplant physicians will evaluate patient eligibility for randomization on to this protocol (see 
Section 2.3).  If the patient has already been discharged from the transplant center, the patient’s 
current managing physician may contact the transplant center to determine patient eligibility for 
randomization.  Eligibility criteria will be verified and ineligible patients will proceed off study 
and no further follow-up will be obtained.  Eligible patients willing to potentially participate in 
the trial will have a thorough discussion about the protocol with a transplant center physician 
who is an investigator or sub-investigator.  If necessary, this discussion may take place by 
telephone.  The patient (or guardian) will be given a copy of the IRB-approved consent 
document to review before this discussion.  During the discussion, the purposes of the study, 
procedures and alternative forms of therapy will be presented as objectively as possible, and the 
potential benefits and risks of participation will be explained.  The patient (or guardian) will be 
given a copy of the entire signed consent document to keep.  The last page of the consent 
document must be signed by the patient (or guardian) and by the physician who discussed the 
protocol.  Transplant center personnel will record the documentation of patient consent in 
EMMES AdvantageEDCSM (Electronic Data Capture, an Internet-based data entry system) and 
patients will be enrolled through AdvantageEDC.  
 
4.2. 
Randomization 
 
Once the subject is deemed eligible and has given written informed consent, and the transplant 
center has confirmed patient eligibility in AdvantageEDC, randomization occurs.  See Section 
5.1.2 for further details on the randomization process. 
 
4.3. 
Treatment Scheduling 
 
Treatment scheduling begins as soon as possible after a patient has undergone baseline screening 
evaluations and randomization in AdvantageEDC (see Section 4.4, and in particular, baseline 
screening Section 4.4.1.1). 
 
4.4. 
Study Monitoring 
 
4.4.1. 
Patient Assessments 
 
A) Study Endpoint Assessments are study specific and include comprehensive NIH style 
evaluations of chronic GVHD and blood for biomarkers as shown in Table 4.4a.  Results of 
these assessments will be recorded on Case Report Forms. A recommended target day range for 
these visits (Table 4.4b.) is computed based on date of signed written consent and is displayed 
for printing in AdvantageEDC. 

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Patients who discontinue therapy early will still be followed through the duration of the study for 
the scheduled Study Endpoint Assessments (Table 4.4a.) and Clinical Assessments (Table 4.4b) 
relevant to analysis of secondary endpoints. 
 
B) Clinical Assessment Visits that are considered standard care for the average patient being 
treated with CNI and/or sirolimus based therapy for chronic GVHD.  Assessments include 
history, physical exam, height, weight, directed evaluation of GVHD/toxicity, CBC and platelets, 
blood chemistry panel, serum lipids, pulmonary function tests, drug levels, and prednisone dose 
as shown in Table 4.4a.  A recommended target day range for these visits (Table 4.4c.) is 
computed based on date of signed written consent and is displayed for printing in 
AdvantageEDC.  However, the visit frequency and target day range should be dictated mainly by 
good clinical practice with a focus on safe delivery of immunosuppressive therapy as 
recommended by the monitoring approach in Table 2.5b. and/or the form entitled: “Sirolimus & 
CNI Therapy Physician Guide.”   
 
 
 
 

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TABLE 4.4a. STUDY ASSESSMENT SCHEDULE 
BASELINE through END OF STUDY 
Baseline 
Months Post-Study Entry 
1 
2 
3 
6 
12 
24 
36 
Study Endpoint Assessments/Testing 
Comprehensive Chronic GVHD Assessment1 
X 
 
X 
 
X 
X 
X 
X 
Required Peripheral Blood Sample 
(Biomarkers: BAFF, T-cell and B-cell) 
X 
 
X 
 
X 
 
 
 
And at initiation of secondary immunosuppressive therapy 
Optional Peripheral Blood Sample (Future 
Testing of Biomarkers) 
X 
 
X 
 
X 
 
 
 
Optional Buccal Swab (Future Testing of 
Biomarkers) 
X 
 
 
 
 
 
 
 
Clinical Assessments/Testing 
History, Physical Exam, Weight, Height2 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy Test (if applicable) 
X 
 
 
 
 
 
 
 
Toxicity Assessment 
 
 
X 
X 
X 
X 
 
 
Prednisone Dose at end of Month3 
X 
X 
X 
X 
X 
X 
X 
X 
Pulmonary Function Tests 
X 
 
 
X 
X 
X 
 
 
CBC, Differential, Platelet Count4 
X 
X 
X 
X 
X 
X 
 
 
Serum Cholesterol/Triglycerides4 
X 
X5 
X 
X 
X 
X 
 
 
Blood Chemistry Panel4 
X 
X 
X 
X 
X 
X 
 
 
Sirolimus Level4 
 
X 
X 
X 
X 
X 
 
 
Cyclosporine or Tacrolimus Level4 
 
X 
X 
X 
X 
X 
 
 
Notes: 
1 Comprehensive cGVHD assessment includes Provider Survey, Patient Survey, 2 minute walk (optional), grip test (optional), and 
Schirmer’s eye exam (optional).  Per institutional standards for other times between visits. 
2 Height is only required at baseline. 
3 Q monthly (4-12 mo) then every other mo. (12-36 mo). 
4 Frequency of labs not recorded on CRF at times indicated follows the recommendations outlined in “Sirolimus & CNI Therapy Physician 
Guide.   
5 Cholesterol at 1 month.  
 

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TABLE 4.4b. TARGET DAY RANGE FOR STUDY ENDPOINT ASSESSMENT 
Study Visit 
Target Day post  
Study Entry 
Baseline 
See Section 4.4.1.1 
Month 2 
60 ± 10 days 
Month 6 
180 ± 30 days 
Month 12 
365 ± 45 days 
Month 24 
730 ± 60 days 
Month 36 
1095 ± 90 days 
 
 
TABLE 4.4c. TARGET DAY RANGE FOR CLINICAL ASSESSMENT 
Study Visit 
Target Day post  
Study Entry 
Baseline 
See Section 4.4.1.1 
Month 1 
30 ± 5 days 
Month 2 
60 ± 10 days 
Month 3 
90 ± 14 days 
Month 4 
120 ± 14 days 
Month 5 
150 ± 14 days 
Month 6 
180 ± 14 days 
Month 7 
210 ± 14 days 
Month 8 
240 ± 14 days 
Month 9 
270 ± 14 days 
Month 10 
300 ± 14 days 
Month 11 
330 ± 14 days 
Month 12 
365 ± 30 days 
Month 14 
425 ± 30 days 
Month 16 
485 ± 30 days 
Month 18 
545 ± 45 days 
Month 20 
605 ± 45 days 
Month 22 
665 ± 45 days 
Month 24 
730 ± 60 days 
Month 26 
795 ± 60 days 
Month 28 
855 ± 60 days 
Month 30 
915 ± 90 days 
Month 32 
975 ± 90 days 
Month 34 
1035 ± 90 days 
Month 36 
1095 ± 90 days 
 

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4.4.1.1. 
Pre-study evaluations 
 
The following observations should be made at enrollment/randomization ± 14 days: 
1. Pregnancy test (if applicable). 
2. History, physical examination, height and weight. 
3. Comprehensive Chronic GVHD assessment [to include provider survey, patient survey, 
2 minute walk (optional), grip test (optional) and Schirmer’s eye exam (optional)]. 
4. Complete blood count (CBC) with differential and platelet count, blood chemistry panel 
to include serum creatinine, bilirubin (total), alkaline phosphatase, AST, ALT, LDH. 
5. Peripheral blood (18 mL) for plasma BAFF levels and regulatory T-cell and B-cell 
immunophenotyping.  This should be collected and processed according to instructions 
summarized in Appendix C and detailed in the BMT CTN 0801 Laboratory Sample 
Guide. 
6. (OPTIONAL) If consent for optional future research sample was obtained, patient buccal 
swabs, and an additional peripheral blood sample (10 mL, or 6 mL for patients < 40 kg) 
should be collected and stored for the future undefined testing of biomarkers related to 
cGVHD.  These samples should be collected and processed according to instructions 
summarized in Appendix C and detailed in the BMT CTN 0801 Laboratory Sample 
Guide. 
7. Fasting serum cholesterol and triglycerides. 
8. Pulmonary function tests including full spirometry are required (DLCO is recommended 
although not required). 
 
4.4.1.2. 
Study evaluations 
 
The following observations should be made according to Tables 4.4a or 4.4c: 
1. History, physical examination, and weight at months 2, 3, 6, 12, 24, and 36. 
2. Comprehensive Chronic GVHD assessment [to include provider survey, patient survey, 
2 minute walk (optional), grip test (optional) and Schirmer’s eye exam (optional)] for 
assessment of response at months 2, 6, 12, 24, and 36. 
3. Toxicity assessments at months 2, 3, 6, and 12. 
4. CBC with differential and platelet count, blood chemistry panel to include serum 
creatinine, bilirubin (total), alkaline phosphatase, AST, ALT, LDH, at least weekly for 
the first 4 weeks.  CBCs are also indicated at other times during the course of monitoring 
sirolimus therapy based on the frequencies recommended in Table 2.5b or Sirolimus & 
CNI Therapy Physician Guide.  Data will be collected on Case Report Forms at months 
1, 2, 3, 6, 12, but not necessarily at other times except in the event of Adverse Event 
Reporting. 
5. Fasting serum cholesterol and triglycerides at months 2, 3, 6, and 12. 

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6. Pulmonary function tests including full spirometry are required (DLCO is recommended 
although not required) at months 3, 6, and 12. 
7. Sirolimus levels are done at the frequencies recommended in Table 2.5b or Sirolimus & 
CNI Therapy Physician Guide.  Sirolimus levels are recorded on the Case Report Forms 
at months 1, 2, 3, 6, and 12.  Levels are unnecessary during taper. 
8. Tacrolimus or cyclosporine levels at the frequencies recommended in Table 2.5b or 
Sirolimus & CNI Therapy Physician Guide.  Tacrolimus or cyclosporine levels are 
recorded on the Case Report Forms at months 1, 2, 3, 6, and 12.  Levels are unnecessary 
during taper. 
9. Peripheral blood (18 mL) for plasma BAFF levels and regulatory T-cell and B-cell 
immunophenotyping at 2 months and 6 months and initiation of secondary systemic 
immunosuppressive therapy, if applicable.  This should be collected and processed 
according to the instructions summarized in Appendix C and detailed in the BMT CTN 
0801 Laboratory Sample Guide. 
10. (OPTIONAL) If consent for optional future research sample was obtained, an additional 
peripheral blood sample (10 mL, or 6 mL for patients < 40 kg) should be collected at 2 
months and 6 months and stored for the future undefined testing of biomarkers related to 
cGVHD (see instructions summarized in Appendix C and detailed in the BMT CTN 
0801 Laboratory Sample Guide). 
 
4.4.2. 
Case Report Forms 
 
A description of the forms, the procedures required for forms completion and timeliness of 
submission can be found in the Data Management Handbook and User’s Guide. Forms that are 
not received within the specified time are considered delinquent.  Transplant centers can view 
submitted, past due, and expected forms via AdvantageEDC.  A missing form will continue to be 
requested either until the form is reported, or until an exception is granted. 
 
4.4.3. 
Reporting Patient Deaths 
 
Deaths must be reported to the BMT CTN Data and Coordinating Center (DCC) within one 
business day of the event notification to the transplant center.  If the cause of death is unknown, 
it need not be recorded at the time of the initial reporting.  However, once the cause of death is 
known, the form must be updated.  
 

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4.4.4. 
Reporting Serious Adverse Events 
 
4.4.4.1. 
Patient SAEs 
 
Reporting of patient serious adverse events (SAE) will be consistent with standard BMT CTN 
procedures.  Unexpected, grades 3-5 adverse events (AEs) will be reported through an expedited 
AE reporting system via the web-based electronic data capture system, AdvantageEDC. 
Unexpected, grades 4-5 AEs must be reported within 24 hours of the event.  Unexpected, grade 3 
AEs must be reported within three business days of knowledge of the event.  Unexpected, grade 
3-5 AEs will be reported using NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0.  Other SAEs will be tracked periodically as defined in the Form 
Submission Schedule, staged according to NCI Common Terminology Criteria for Adverse 
Events (CTCAE), Version 3.0.  The Data and Safety Monitoring Board will receive summary 
reports of all adverse experiences on at least an annual basis.  
 
4.4.5. 
CIBMTR Data Reporting 
 
Centers participating in BMT CTN trials must register pre and post-transplant outcomes on all 
consecutive hematopoietic stem cell transplants done at their institution during their time of 
participation to the Center for International Blood and Marrow Transplant Research (CIBMTR).  
Registration is done using procedures and forms of the Stem Cell Transplant Outcomes 
Database (SCTOD).  (Note: Federal legislation requires submission of these forms for all US 
allotransplant recipients.)  Additionally, CIBMTR pre- and post- transplant Report Forms must 
also be submitted for all patients enrolled on this trial according to the randomization assigned 
to the patient at the time of initial registration with the CIBMTR according to the randomization 
assigned to the patient at the time of initial registration with the CIBMTR.   
 

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CHAPTER 5 
 
 
5. STATISTICAL CONSIDERATIONS 
 
5.1. 
Study Design 
 
The protocol is designed as a combined Phase II/III, randomized, open label, multicenter, 
prospective comparative study of sirolimus plus prednisone (SP) versus sirolimus/calcineurin-
inhibitor plus prednisone (SPC) for the treatment of chronic GVHD.  The target enrollment is 
300 patients across both phases of the study.   
 
After 50 patients per study arm in the Phase II study have been accrued (100 total) and followed 
for the 6 month CR+PR rate, a decision will be made about whether to continue in the Phase III 
study.  At this point an additional 200 patients will be randomized on the Phase III study, so that 
the final sample size for the Phase III comparison will be 300 patients.  A schema illustrating this 
study design is given in the Protocol Synopsis. 
 
5.1.1. 
Accrual 
 
It is estimated that 7 years of accrual (3 years for phase II study) will be necessary to enroll the 
targeted sample size.  Both Core and Affiliate Centers will enroll patients on this study.  Accrual 
will be reported by race, ethnicity, gender, age (children defined as < 17 years).  Accrual will not 
be halted while waiting for the 6-month response assessment on the last patient enrolled in the 
Phase II study; over-run of the Phase II accrual target is considered acceptable as long as there 
are no safety concerns. 
 
5.1.2. 
Randomization 
 
All patients will be randomized in a 1:1 ratio using random block sizes for the two arms.  
Randomization will be stratified by transplant center.   
 
5.1.3. 
Primary Endpoint 
 
Treatment success will be defined according to the local physician’s response. 
 
Phase II Endpoint: 
The proportion of subjects with complete or partial responses after 
6 months of therapy.   
 
Phase III Endpoint: 
The proportion of subjects with complete resolution of all 
reversible manifestations at 24 months after starting therapy in 
both study arms.   
 
The primary analysis will be performed using the intent-to-treat principle so that all randomized 
patients will be included in the analysis.   
 

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5.1.4. 
Primary Hypotheses 
 
The primary hypothesis is that avoidance of a calcineurin inhibitor in the treatment of chronic 
GVHD might facilitate the development of tolerance and improve the CR/PR rates at 6 months 
and ultimately the 24 month CR rates compared to immunosuppressive therapy regimens that 
contain a calcineurin inhibitor (the comparator arm, denoted SPC).  We are testing the null 
hypothesis.  
 
H0:pSP= pSPC  
 
Against the alternatives  
 
H1: pSP >pSPC 
 
Where p refers to the CR/PR rate at 6 months in the initial Phase II study and to the CR rate at 
24 months for the subsequent Phase III study. 
 
5.2. 
Details of Study Design and Interim Monitoring Plan for Efficacy and Futility 
 
The primary objective of the Phase II component is to estimate the CR/PR rate for each treatment 
arm, and determine whether the SP arm is sufficiently promising to expand the trial into a Phase 
III study.  In the Phase II trial, the Z statistic for comparing the CR/PR rates at 6 months between 
the two treatments will be computed.  The SP treatment will not be considered further if the Z 
statistic comparing its CR/PR rate to the SPC arm is ≤ 0.9.  This is approximately equivalent to 
rejecting the SP treatment for further consideration if its CR/PR rate is not at least 9% better than 
the SPC arm, assuming an approximately 40% baseline CR+PR rate.  If the Z statistic comparing 
the CR/PR rates at 6 months is at least 3.53, then we will consider this sufficient evidence of 
efficacy that we will not continue randomizing patients in a Phase III trial, but will just follow 
the patients already enrolled for the 2-year CR rate.  This corresponds approximately to a 35% 
observed improvement in CR+PR rates compared to the SPC arm.   
 
If the Phase II study progresses to Phase III, the primary endpoint of the study will be switched 
to the proportion of patients in CR at 24 months.  Additional interim analyses based on this new 
primary endpoint are planned, after approximately 50 and 100 patients per arm have been 
followed for two years, and the target final sample size is 150 patients per arm.  Although these 
interim analyses will likely not have an effect in terms of stopping accrual to the study, they are 
put into place to monitor whether the study results are sufficiently strong or futile to indicate 
early presentation of study results.  This is especially important if accrual is lagging.  The 
stopping boundaries to be used and the decision algorithm for this study are given in Table 5.2. 
 

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5-3 
TABLE 5.2: BOUNDARY VALUES FOR INTERIM MONITORING 
 
Interim 
Analysis 
Number of 
patients 
evaluable per 
treatment arm 
Boundary 
Decision 
1 
50 evaluable at 6 
months 
Z6 ≤ 0.9 
SP not sufficiently promising in terms of 6-
month CR+PR rate; stop study 
 
 
Z6 ≥ 3.53 
Stop for efficacy based on a large observed 
difference in 6-month CR+ PR rates; stop 
study but continue to follow-up enrolled 
patients for two-year outcomes  
 
 
0.9 < Z6 <3.53 
Treatment is promising based on 6 month 
outcomes, and continue enrolling to the 
Phase III part of the study 
2 
50 evaluable at 2 
years 
Z24 >= 3.12 
Stop for efficacy: study has demonstrated 
sufficient evidence of an improvement in 
two year outcomes 
 
 
Z24 < 3.12 
Continue 
3 
100 evaluable at 
2 years 
Z24 ≤ 0.88 
Stop for futility; study is not likely to 
demonstrate an improvement in two year 
outcomes 
 
 
Z24 ≥ 2.46 
Stop for efficacy; study has demonstrated 
sufficient evidence of an improvement in 
two year outcomes 
 
 
0.88 < Z24 <2.46 
Continue 
4 
150 
Z24 < 2.01 
No evidence of an improvement in two year 
outcome 
 
 
Z24 ≥ 2.01 
Statistically significant improvement in two 
year outcome 
 
 
5.2.1. 
Details of Stopping Boundary Calculations 
 
Stopping boundaries for the comparison of 24 month CR rates are based on an error spending 
approach, using the error spending function 
3
( )
min(
, )
t
t




, which is similar to an O’Brien-
Fleming boundary.  These will be conservative since they ignore the impact of the aggressive 
futility boundary in the phase II trial on the overall type I error rate.  However, they provide 
control of the type I error rate even if the futility boundary is not followed exactly.  We also add 
an option for stopping the study early for efficacy at the end of the phase II study.  This is meant 
to account for unexpectedly large differences in the 6 month CR+PR rate, which are unlikely to 
disappear when looking at the 24 month CR rate.  This additional stopping rule is designed very 
conservatively, and therefore has negligible impact on the type I error rate under the overall null 
hypothesis that there is no difference between the treatments on either outcome. 
 

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For the futility boundary after the initial Phase II look, we use a stopping rule based on 
conditional power of less than 5% at the estimated effect size. 
 
These boundary values are shown in Table 5.2 above for the proposed monitoring schedule using 
Monte Carlo integration, but they may be recalculated using the error spending function if the 
timing of the analyses do not match up with the planned schedule.   
 
5.3. 
Operating Characteristics and Power Considerations 
 
Simulations were performed to study the operating characteristics of the study design and 
monitoring algorithm.  Binary observations modeling the 6-month CR+PR rate for the first 100 
patients were generated according to the vector of probabilities in each group 
p(6)=(pSPC(6),pSP(6)).  Binary observations for all 300 patients analyzed in the Phase III trial 
were generated according to 24-month CR probabilities p(24)=(pSPC(24),pSP(24),).  Note that 100 
patients will have both the 6-month and the 24-month binary outcomes, so that a model for the 
association between these must be postulated.  Odds ratios (OR) between these outcomes ranging 
from 1 (independent) to 5 to 100 (strongly positively associated) were used in simulations.  
Baseline 6-month CR+PR rates were expected to be approximately 40%, while baseline 24-
month CR rates were expected to be around 28%, although we also considered rates as high as 
40%.  Several type I error rate scenarios were investigated to demonstrate control at a 2.5% one-
sided level, in which p(6), p(24), and the odds ratio were modified.  For each scenario in Table 
5.3a. the stopping probabilities for futility or efficacy at each interim analysis, as well as the 
overall type I error rate, are given.  Note that the type I error rate is maintained conservatively in 
all situations as expected.  Also worth noting is that if there is no difference in 6-month CR+PR 
rates, there is an 82% chance that the study will stop at the end of the Phase II component and an 
18% chance that the study will proceed to Phase III. 
 
 
TABLE 5.3a.: SIMULATION RESULTS FOR TYPE I ERROR RATE 
 
p(6) 
p(24) 
OR 
P(stop for futility) 
at look 
P(stop for efficacy) at look 
Overall 
Power 
Phase II 
3 
Phase II 
2 
3 
4 
(0.4,0.4) (0.4,0.4) 
1 
0.821 
0.146 
0.000 
0.000 
0.001 
0.003 
0.005 
  
  
5 
0.822 
0.126 
0.000 
0.001 
0.003 
0.005 
0.009 
  
  
100 
0.818 
0.096 
0.001 
0.001 
0.006 
0.009 
0.016 
(0.4,0.4) (0.28,0.28) 
1 
0.820 
0.145 
0.000 
0.000 
0.001 
0.003 
0.005 
  
  
5 
0.819 
0.126 
0.000 
0.001 
0.003 
0.005 
0.009 
  
  
100 
0.821 
0.100 
0.000 
0.001 
0.005 
0.008 
0.015 
 
 
Next we simulated the power to identify a true difference.  Note that for a difference in outcomes 
to be detectable, it needs to be present in both the 6-month CR+PR rate and the 24-month CR 
rate.  The power to detect a 20% improvement in both outcomes is given in Table 5.3b. below 

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for several configurations of outcome proportions and odds ratios measuring association between 
outcomes.  This study design has at least 80% power to identify a 20% improvement in both 6-
month CR+PR rates and 24-month CR rates between the SP arm and the SPC arm.  Also worth 
noting, if the SP arm is 20% better than the SPC arm on the 6-month CR+PR rate, there is only a 
13% chance of stopping the study for futility at the first Phase II analysis. 
 
TABLE 5.3b.: SIMULATION RESULTS FOR POWER UNDER THE ALTERNATIVE 
HYPOTHESIS 
 
p(6) 
p(24) 
OR 
P(stop for futility) at look 
P(stop for efficacy) at look 
Overall Power 
Phase 2 
3 
Phase  
2 
2 
3 
4 
(0.6,0.4) (0.6,0.4) 
1 
0.131 
0.021 
0.093 
0.137 0.369 0.212 
0.810 
  
  
5 
0.131 
0.018 
0.090 
0.137 0.380 0.208 
0.815 
  
  
100 
0.130 
0.010 
0.090 
0.105 0.429 0.203 
0.828 
(0.6,0.4) (0.48,0.28) 
1 
0.130 
0.015 
0.090 
0.141 0.409 0.186 
0.826 
  
  
5 
0.131 
0.013 
0.091 
0.136 0.420 0.183 
0.829 
  
  
100 
0.132 
0.008 
0.092 
0.117 0.453 0.174 
0.836 
 
 
5.4. 
Safety Stopping Guidelines 
 
Monitoring of several safety endpoints will be conducted monthly, and if rates significantly 
exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB can be advised.  
Policies and composition of the DSMB are described in the BMT CTN's Manual of Procedures.  
The stopping guidelines serve as a trigger for consultation with the DSMB for additional review. 
The key safety endpoint to be monitored is mortality.  Two additional non-hematological 
toxicities also will be monitored: Thrombotic Microangiopathy (TMA) and Pneumonitis (NIP).  
Each outcome will be monitored using a Sequential Probability Ratio Test (SPRT) as described 
below.  A version for censored exponential data will be used for monitoring mortality up to 56 
days, while a version for binary data will be used for monitoring the incidence of the other 
outcomes by 56 days.  The SPRT conserves type I error at 5% across all of the monthly 
examinations.  No additional control of the type I error across multiple toxicity outcomes or 
across multiple treatment groups will be used. 
 
5.4.1. 
Mortality 
 
The rate of mortality will be monitored up to 56 days post-randomization.  Monitoring will be 
performed monthly beginning after the third month of enrollment until enrollment is closed.  At 
least three events must be observed in order to trigger review.  Each month, the null hypothesis 
that the 56-day mortality rate is less than or equal to 20% is tested, separately for each of the 
treatment arms.  This is based on a cohort of 76 high-risk patients (thrombocytopenia and 
progressive onset) out of 170 patients with cGVHD at the University of Minnesota.  An 

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extension of the SPRT for censored exponential data will be used for monitoring, as described in 
greater detail below and in Appendix D. 
 
This sequential testing procedure conserves type I error at 5% across all of the monthly 
examinations.  The SPRT can be represented graphically.  At each monthly interim analysis, the 
total time on study is plotted against the total number of endpoints (e.g., patients experiencing 
death).  The continuation region of the SPRT is defined by two parallel lines.  Only the lower 
boundary will be used for monitoring to protect against excessive 56-day mortality.  If the graph 
falls below the lower boundary, the SPRT rejects the null hypothesis, and concludes that there 
are more events than predicted by the observed time on study.  Otherwise, the SPRT continues 
until enrollment reaches the maximum of 150 patients for a treatment continuing in Phase III. 
 
This procedure assumes a censored exponential distribution for the time until death during the 
first 56 days, and censors follow-up time after 56 days.  Only deaths that occur on or before the 
patient has been followed for 56 days are counted.  Total time on study is computed as time from 
registration to death, or to 56 days, whichever comes first, summed for all patients on study. 
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size 
E(N|i).  The test for overall mortality was developed from the following SPRT:   
• A SPRT contrasting 20% versus 35% 56-day rate of mortality results in decision 
boundaries with a common slope of 6.336 and a lower intercept of –24.049, with nominal 
type I and II errors of 7% and 15%, respectively. 
 
The actual operating characteristics of the truncated test, shown in Table 5.4.a, were determined 
in a simulation study that assumed uniform accrual of 150 individuals over a seven-year time 
period, and exponential time to failure after randomization.   
 
TABLE 5.4.a:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 10,000 REPLICATIONS 
  
Day 56 Mortality 
 
True 56-Day Rate 
20% 
30% 
35% 
40% 
Probability Reject Null after 
50 patients 
0.034 
0.379 
0.660 
0.868 
Probability Reject Null after 
150 patients 
0.052 
0.756 
0.971 
0.999 
Mean Month Stopped 
82.7 
45.5 
26.4 
17.0 
Mean # Endpoints in 56 Days 
28.9 
23.9 
16.0 
11.7 
Mean # Patients Enrolled 
144.6 
80.7 
47.4 
30.6 
 

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For example, the testing procedure for a treatment which continues into Phase III testing rejects 
the null hypothesis in favor of the alternative 5% of the time when the true 56-day mortality rate 
is 20%, and 76% of the time when the rate is 30%.  This corresponds to a type I error rate of  = 
0.05 and a type II error rate of  = 0.24.  When the true 56-day mortality rate is 30%, on average, 
the DSMB will be consulted 45 months after opening, when 24 events have been observed in 81 
patients.  For a treatment arm which only enrolls up to 50 patients, the stopping rule will have 
87% power to reject the null hypothesis when the Day 56 mortality rate is 40%. 
 
5.4.2. 
Non-hematological Toxicities 
 
The cumulative incidences (C.I.) of Thrombotic Microangiopathy (TMA) and Pneumonitis (NIP) 
at Day 56 will be monitored separately for each arm.  Definitions of TMA and NIP are detailed 
in Section 3.3 (Safety Endpoints).  Each month, the null hypothesis that the cumulative 
incidences of TMA or NIP is  10% will be tested against the alternative that it is > 10%.  This 
will be done using a SPRT for binary outcomes.  As above, the SPRT can be represented 
graphically.  At each interim analysis, the total number of patients enrolled is plotted against the 
total number of patients who have experienced toxicity.  The continuation region of the SPRT is 
defined by two decision boundaries.  Only the upper boundary will be used for monitoring the 
study to protect against high incidences of toxicity.  If the graph falls above the upper boundary, 
the SPRT rejects the null hypothesis, and concludes that the toxicity rate is higher than predicted 
by the observed number of patients enrolled on study.  Otherwise, the SPRT continues until 
enrollment reaches the target goal.   
 
The tests for TMA and NIP are identical and were developed from the following SPRT:   
• A SPRT contrasting 10% versus 25% 56-day incidence, which results in decision 
boundaries with a common slope of 0.166 and an upper intercept of 2.413, with nominal 
type I and II errors of 6% and 15%, respectively. 
 
The actual operating characteristics of this truncated test, shown in Table 5.4.b, were determined 
in a simulation study that assumed uniform accrual of 150 individuals over a seven-year time 
period.   
 

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5-8 
TABLE 5.4.b:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 10,000 REPLICATIONS 
  
Day 56 Incidence of TMA 
 
True 56-Day Rate 
10% 
15% 
20% 
25% 
Probability Reject Null after 
50 patients 
0.038 
0.226 
0.546 
0.818 
Probability Reject Null after 
150 patients 
0.049 
0.379 
0.856 
0.991 
Mean Month Stopped 
82.8 
64.6 
36.3 
19.9 
Mean # Endpoints in 56 Days 
14.4 
16.8 
12.4 
8.2 
Mean # Patients Enrolled 
144.3 
112.0 
61.8 
32.8 
 
For example, the testing procedure for a treatment which continues into Phase III testing rejects 
the null hypothesis in favor of the alternative 5% of the time when the true 56-day TMA rate is 
10%, and 86% of the time when the rate is 20%.  This corresponds to a type I error rate of  = 
0.05 and a type II error rate of  = 0.14.  When the true 56-day TMA rate is 20%, on average, the 
DSMB will be consulted 36 months after opening, when 12 events have been observed in 62 
patients.  For a treatment arm which only enrolls up to 50 patients, the stopping guidelines will 
have 82% power to reject the null hypothesis when the Day 56 TMA rate is 25%.  Operating 
characteristics for NIP are identical, since the monitoring guidelines are the same. 
 
5.5. 
Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, primary disease, risk status, 
donor age, and donor gender, conditioning intensity, donor type, peripheral blood versus marrow, 
time from transplant to enrollment, time from start of immunosuppressive therapy to enrollment, 
and percent of patients with high risk cGVHD.  Between group comparisons will be performed 
for continuous variables via a Kruskal-Wallis Test and for categorical variables, via the Chi-
Square Test. 
 
5.6. 
Analysis of Secondary Endpoints 
 
1. Prednisone Sparing: The median percent reduction in average daily dose among 
survivors will be estimated for each treatment with a 95% confidence interval by 6 and 
12 months after transplant for the Phase II component and additionally by 24 and 36 
months for the Phase III component.  These will be compared between treatments using 
the Kruskal-Wallis Test. 
2. Use of Secondary Therapy: The proportion of patients who received secondary therapy 
at months 6, 12, 24, and 36 will be computed and compared using a Chi-Square test.   

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3. Patient-Reported Symptomatic Chronic GVHD Symptoms: The proportion of 
patients with symptomatic chronic GVHD will be estimated for each treatment with a 
95% confidence interval at 1 and 2 years for the Phase II component and additionally at 
3 years for the Phase III component.  These proportions will be compared between 
groups using the Chi-Square Test. 
We will also estimate the correlation between patient-reported symptoms on the Patient 
Survey and physician-reported symptoms on the Provider Survey. 
4. Discontinuation of all Systemic Immunosuppressive Therapy: The cumulative 
incidence of discontinuation of all systemic IS therapy will be estimated by treatment 
with a 95% confidence interval at 1 and 2 years for the Phase II component and 
additionally at 3 years for the Phase III component.  Death will be considered the 
competing risk.  Cumulative incidence curves will be compared between groups using 
Gray’s Test.   
5. Survival and Progression-free Survival: Survival and progression-free survival from 
time of randomization will be computed using the Kaplan-Meier estimates along with a 
95% confidence interval for each group at 1 and 2 years for the Phase II component and 
additionally at 3 years for the Phase III component.  Survival curves will be compared 
across treatment using the Logrank Test.   
6. Biomarkers: T regulatory cell numbers, B cell numbers, and plasma BAFF levels will 
be enumerated.  BAFF to B cell ratios will also be computed.  T reg numbers and BAFF 
to B cell ratios will be compared to respective values within groups using the Paired T-
Test, or between groups using the Two Sample T-Test.  Biomarker data will also be 
correlated with CR+PR status at 6 months using logistic regression. 
7. NIH Consensus Clinically Relevant Adjudicated CR and PR Rates: The proportion 
of patients experiencing a CR or PR according to the NIH consensus definition will be 
estimated for each treatment with a 95% confidence interval.  They will be compared 
between treatment arms similar to the comparison of the primary endpoint.  Agreement 
between the NIH consensus guidelines CR/PR evaluation and the CR/PR outcome based 
on the primary endpoint will be computed using the Kappa statistic.  As feasibility of 
this outcome is also of interest, the proportion of patients with complete data for this 
evaluation will also be estimated.   
Two-sided tests will be used throughout.  A p-value of 0.05 or less will be considered 
statistically significant. 
8. Health Quality of Life: Health quality of life will be compared between both treatment 
groups utilizing the FACT-BMT self report, transplant specific questionnaire and the 
generic quality of life tool, the SF-36.  Only English speaking patients are eligible to 
participate in the HQL component of this trial.  The HQL assessments will be performed 
at baseline, months two and six, then at one, two and three years after randomization.  
Pairwise t-tests at each time point will be used as a descriptive analysis.  Reasons for 
missing data will be explored, and linear mixed models will be used to model QOL after 
accounting for data missing at random.  We will also consider missing data models for 
QOL conditional on survival at each time point, using methods of Kurland and 
Heagerty.56  

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5-10 
 
5.7. 
Safety Analysis 
 
The reporting of serious adverse events will be consistent with standard BMT CTN procedures.  
The type and severity of adverse events will be described. 
 

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APPENDIX A 
 
HUMAN SUBJECTS 

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A-1 
APPENDIX A 
 
HUMAN SUBJECTS 
 
 
Subject consent: Candidates for the study will be identified as described in Chapter 4 of the 
protocol.  The Principal Investigator or his/her designee at each transplant center will contact the 
candidates and enroll them onto the study.  The study coordinator at each center will provide the 
patient with information about the purpose of the study and obtain consent.  The Network will 
provide a template of the consent form to each center.  Each center will customize the template 
according to their local requirements and submit it for review by the local Internal Review Board 
(IRB).  The DCC will verify the adequacy of the consent forms.  Each center must provide 
evidence of IRB approval.  
 
Confidentiality: Confidentiality will be maintained by individual names being masked and 
assigned a patient identifier code.  The code relaying the patient’s identity with the ID code will 
be kept separately at the center.  The ID code will be transmitted to the network.   
 
Participation of women, children, minorities and other populations: Women, children and 
ethnic minorities will be included in this study. 
 
Accrual will be monitored within each center with the expectation that the enrolled patient 
population is representative of the transplanted patient population at each center.  Representation 
will be examined by comparing gender, race, ethnicity and age distributions.  Accrual of 
minority patients will be expected to be in proportion to the number of minority patients 
transplanted at each center.  The DCC and NHLBI will discuss enrollment anomalies with the 
centers. 
 
 

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Information & Informed Consent Form 
 
Initials 
 
 
APPENDIX B 
 
INFORMED CONSENTS 
 
 
 
PATIENT CONSENT  
PATIENT ASSENT  
 
 

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Information & Informed Consent Form 
 
Initials 
 
B-2 
Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
Your Name: 
 
 
 
 
 
 
 
 
 
 
 
 
Study Title: 
A Phase II/III Randomized, Multi-center Trial Comparing Sirolimus plus 
Prednisone and Sirolimus/Calcineurin Inhibitor plus Prednisone for the 
Treatment of Chronic Graft-versus-Host-Disease. 
Protocol: 
0801 
Co-Investigator: Paul Carpenter, M.B., B.S.  
Fred Hutchinson Cancer Research Center  
1100 Fairview Avenue North 
Mailstop D5-290 
Seattle, WA 98109-1024 
Phone: (206) 667-5191. 
Co-Investigator: Mutka Arora, M.D. 
University of Minnesota 
420 Delaware Street S.E. 
MMC 803  
Minneapolis, MN 55455 
Phone: 612-626-4105 
Transplant Center 
Investigator: 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
The National Institutes of Health (NIH) gave financial support for this 
research study through the Blood and Marrow Transplant Clinical Trials 
Network (BMT CTN).  
 
Therakos, a company that manufactures the CELLEXTM extracorporeal 
photopheresis device, has provided some financial support to help pay the 
costs of this study.  This company did not plan or design this study.  Therakos 
will not have a part in analyzing the results of this study. 

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Information & Informed Consent Form 
 
Initials 
 
B-3 
Introduction 
You are invited to join a research study.  The primary goals of this study are to compare two 
treatments for chronic graft-versus-host disease (GVHD), and evaluate how well your chronic 
GVHD responds to treatment.   
 
This study will be done over three years.  One hundred people will participate at up to 50 clinics.  
Each clinic in this study will offer two study treatments.  We will explain the two study 
treatments for your clinic in this Consent Form.  Every clinic will report their results, so we can 
compare the two treatments at the end of the study.  
 
The standard treatment for chronic GVHD is a corticosteroid (such as prednisone) and a 
calcineurin inhibitor (cyclosporine or tacrolimus).  Patients who have chronic GVHD that is not 
controlled by the standard treatment usually have other drugs added to their treatment.  Or less 
often, they may receive other drugs instead of standard treatment. 
 
In this study chronic GVHD will be treated with another drug (sirolimus) in addition to either: 
▪ A corticosteroid, or 
▪ A corticosteroid and a calcineurin inhibitor, such as cyclosporine or tacrolimus  
 
Sirolimus will be added to both treatments because research suggests that it may have positive 
effects on immune cells and improve GVHD treatment. 
 
You will be randomly assigned to receive one of the two following treatments:  
 
2-Drug Treatment 
3-Drug Treatment 
▪ 
A corticosteroid (such as prednisone)  
▪ 
Sirolimus 
▪ 
A corticosteroid 
▪ 
A calcineurin inhibitor (cyclosporine or 
tacrolimus) 
▪ 
Sirolimus  
 
This study will try to learn if it is better to add sirolimus to standard treatment or to replace a 
calcineurin inhibitor with sirolimus. 
 
This Consent Form will tell you about the purpose of the research, its possible risks and benefits, 
other options available to you, and your rights as a participant in the study.  Please take your time 
to make your decision.  
 
Everyone who takes part in research at [insert facility name] should know that: 
▪ Being in any research study is voluntary. 
▪ You may or may not benefit from being in the study.  Knowledge we gain from this study 
may benefit others. 
▪ If you join the study, you can quit the study at any time.   

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Initials 
 
B-4 
▪ If you decide to quit the study, it will not affect your care at [insert name of facility or 
institution]. 
▪ Please ask the study staff questions about anything that you do not understand, or if you 
would like to have more information. 
▪ You can ask questions now or any time during the study. 
▪ Please take the time you need to talk about the study with your doctor, study staff, and 
your family and friends.  It is your decision to be in the study.  If you decide to join, 
please sign and date the end of the Consent Form. 
 
You and your doctor will discuss other treatment choices if you do not want to participate 
in this study. 
 
 
1. Background 
 
This research study is sponsored by The National Institutes of Health (NIH) through the Blood 
and Marrow Transplant Clinical Trials Network (BMT CTN).  This study is being done to 
compare two treatments for chronic GVHD in people who have had an allogeneic transplant.  
 
Chronic GVHD 
Chronic GVHD is a medical condition that can become very serious.  Chronic GVHD is a 
common development after allogeneic transplant.  It happens when the donor cells attack and 
damage your tissues.   
 
Chronic GVHD may cause:  
▪ Skin rashes 
▪ Mouth pain or dryness 
▪ Eye dryness 
▪ Nausea (feeling sick to your stomach) or diarrhea 
▪ Liver inflammation 
▪ Damage to other organs, such as the lungs, throat, and vagina 
 
Treatments for chronic GVHD 
Corticosteroid (or steroid) medications are the most basic treatment for chronic GVHD.  
However, less than half of patients will become free of chronic GVHD when steroid treatment is 
used alone.  Several other drugs are often added to steroids to help treat chronic GVHD, 
including a calcineurin inhibitor (cyclosporine or tacrolimus) and/or sirolimus. 
 
Information from earlier research suggests that different combinations of sirolimus, cyclosporine 
or tacrolimus, and steroids may help to reduce chronic GVHD.   
 
Sirolimus, cyclosporine and tacrolimus all work by blocking the growth of new immune cells 
that can cause chronic GVHD.  Research suggests that sirolimus also supports the growth of 
other immune cells called “T-regs” which limit the immune response that causes GVHD. 

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Cyclosporine and tacrolimus may slow the growth of these immune cells.  eSirolimus, 
cyclosporine and tacrolimus are approved by the U.S. Food and Drug Administration (FDA) to 
prevent rejection after organ transplantation.  They have been used for years as treatments for 
GVHD that do not respond to standard steroid therapy, or to prevent GVHD after allogeneic 
transplant. 
 
 
2. Purpose  
 
You are invited to join this research study because you have chronic GVHD that needs treatment.  
 
The primary goals of this study are to compare two treatments for chronic GVHD and evaluate 
how well your chronic GVHD responds to your treatment.  We will also collect extra blood 
samples for future research on GVHD. 
 
 
3. Right to Ask Questions and/or Withdraw 
 
You have the right to ask questions about the study at any time.  If you have questions about 
your rights as a participant or you want to leave the study, please contact:  
[Insert contact info] 
 
Being in this study is voluntary.  You can choose to not be in this study, or leave this study at 
any time. 
 
If you choose to not take part or to leave this study, your regular medical care will not be 
affected in any way.  This includes standard care for your chronic GVHD.  If you decide to leave 
this study after taking the study treatment, or are asked to leave by your doctor for medical 
reasons, you will be asked to come back to the doctor’s office for tests for your safety.   
 
Even if you withdraw from the study, the information collected from your participation will be 
included in the study evaluation, unless you specifically ask that it not be included. 
 
Your study doctor and study staff will be available to answer any questions that you may have about 
your participation in, or your withdrawal from this study. 
 
 
4. Procedures 
 
Your study participation will last for 3 years, and includes your treatment and follow-up.  One 
hundred patients will participate at up to 50 clinics around the country.   
 
The number of required clinic visits during this time will depend on your treatment and the 
combination of drugs you receive.  You will need to have health evaluations before you start 
treatment and for several years after you finish your treatment.  These tests and examinations are 

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standard care for patients with chronic GVHD and would be done even if you were not part of 
this study. 
 
One of the objectives of this study is to evaluate how the treatment affects the quality of the 
patient’s life and whether there is a difference between the treatment arms.  Therefore, all 
patients will be asked to complete questionnaires asking about their chronic GVHD symptoms 
and quality of life at study entry, 2, 6, 12, 24 and 36 months.  It will take you approximately half 
an hour to complete the questionnaires. 
 
If you decide to join, we will ask you to sign this Consent Form, and you will get a copy of the 
signed form to keep. 
 
Before You Start Your Treatment 
Before you join the study, we will evaluate your general health, medical history, and your current 
medications.  It is important that you do not participate in the study if you suffer from an allergy 
to any of the drugs used in this study; or if you are pregnant, breastfeeding or are likely to 
become pregnant during the study. 
 
You will have at least one clinic visit before you start your treatment for this study.  This visit 
will collect information about your:  
▪ Physical health (including history, height, weight and temperature) 
▪ Comprehensive Chronic GVHD assessment [to include provider survey, patient survey, 2 
minute walk (optional), grip test (optional) and Schirmer’s eye exam (optional)] 
▪ Lung function  
▪ Cancer re-staging (if appropriate) 
▪ Organs affected by GVHD 
▪ Routine blood tests, including cell counts, cholesterol, liver and kidney function, and 
levels of GVHD treatment medications in your blood (if it applies to you) 
▪ Blood samples (4-5 teaspoons, or 3-4 teaspoons for patients under 90 pounds) for 
protocol-defined GVHD studies 
▪ Pregnancy test (if applicable) 
 
Study Participation 
You will receive either the 2-drug treatment or the 3-drug treatment.  
 

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If you are assigned to the 2-drug treatment, you will receive: 
2-Drug Treatment  
▪ Prednisone: once each day until 2 weeks improvement in 
GVHD symptoms is observed, and then slowly lowered and 
then stopped   
▪ Sirolimus: once each day until all prednisone has stopped.  
After up to 3 months of stable improvement is observed, the 
amount of sirolimus will be slowly lowered and then stopped 
 
If you are assigned to the 3-drug treatment, you will receive: 
3-Drug Treatment 
▪ Prednisone: once each day until 2 weeks improvement in 
GVHD symptoms is observed, and then slowly lowered and 
then stopped.   
▪ Sirolimus: once each day.  
▪ CNI: two times each day. 
 
Depending on how well you respond to the treatment, you may need to visit the clinic every 
week for another 24 weeks.  Your visits may drop to once each month, if your doctor feels it is 
appropriate.  You may need to take your assigned treatment for up to two years.  Your doctor 
will lower the amount of drugs you will need to take, as your chronic GVHD symptoms get 
better.   
 
Once you stop taking your assigned treatment, the study team will follow your health for up to 2 
years.  Your total length of study participation may last up to 3 years, including follow-up once 
you finish your treatment. 
 
Study Evaluations 
We will evaluate your health at specific points during your study participation:  
1. History, physical exam, and weight at 2, 3, 6, 12, 24 and 36 months. 
2. Comprehensive Chronic GVHD assessment [to include provider survey, patient survey, 
2 minute walk (optional), grip test (optional) and Schirmer’s eye exam(optional)] to 
measure your response to treatment at 2, 6, 12, 24 and 36 months. 
3. Routine blood tests, including: cell counts, and liver and kidney function, at least weekly 
for the first 4 weeks. 
4. Cholesterol tests at 1, 2, 3, 6, and 12 months. 
5. Lung (pulmonary) function tests at 3, 6 and 12 months. 
6. Blood tests to check sirolimus levels will be done at least every week for the first 4 
weeks and potentially twice a week if you are taking cyclosporine or tacrolimus.  

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Sirolimus levels from Week 5 to the end of your treatment are then done weekly to 
monthly, depending on your treatment. 
7. Blood tests to check cyclosporine or tacrolimus levels are done at least weekly for the 
first 4 weeks and then at least monthly after Week 5 based on your treatment.   
8. Blood samples (4-5 teaspoons, or 3-4 teaspoons for patients under 90 pounds) for 
protocol-defined GVHD studies at 2 months and 6 months or when any new oral or 
injected medication is added to treat your GVHD. 
 
Randomization 
A computer will randomly assign you to receive either the standard treatment or the study 
treatment.  This means that you will be put into a group by chance.  It is like flipping a coin or 
drawing names out of a hat.  You will have an equal chance of being chosen for either treatment. 
 
Additional Health Evaluations and Procedures 
Before and after photographs may be taken to document your chronic GVHD. 
 
 
5. Alternative Treatments 
 
Current available treatments which may be used to treat graft-versus-host disease (GVHD) 
include: 
▪ Corticosteroids (prednisone) with or without cyclosporine or tacrolimus (standard 
treatment for GVHD) 
▪ Other medications 
▪ Participation in another clinical trial (if available, check with your doctor) 
 
Every treatment option has benefits and risks.  Your study doctor will discuss these options with 
you.  If you decide not to participate in this research study, your medical care will not be affected 
in any way. 
 
 
6. Risks and Discomforts 
 
It is very important that you do not eat grapefruit or drink grapefruit juice.  Grapefruit 
has an ingredient called bergamottin, which can affect some of the treatment drugs used in 
this study.  Common soft drinks that have bergamottin are Fresca, Squirt, and Sunny Delight. 
a.) Side Effects of Study Drugs and Treatments 
All drugs can have side effects, including the standard therapy for GVHD (steroids) and 
the other drugs being tested in this study.  Your doctor will watch you carefully and will 
change your treatment if side effects develop.  
Please see Table: Risks and Side Effects of Study Drugs and Treatments at the end of this 
section for more information on the drugs used in the study treatments. 

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b.) Infections 
Because chronic GVHD is caused by an immune attack on your tissues from the 
transplanted donor cells, all treatments for chronic GVHD include drugs to control 
(suppress) that immune attack.  There is a higher risk of infection in patients with chronic 
GVHD and in people who take steroids like prednisone or methylprednisolone, the 
standard therapy for chronic GVHD.   
You will need to take several antibiotics to prevent infection.  You will also be watched 
carefully for any infections while you are being treated for chronic GVHD. Tell your 
doctors promptly if you get a fever, chills, cough or any other symptoms that might be a 
sign of an infection. 
c.) Risks of Other Procedures Including Blood Draws   
There are no major risks associated with drawing blood.  Having your blood drawn can 
be uncomfortable and can sometimes cause a bruise.  In rare cases, a blood draw can 
cause fainting.  Only trained people will draw your blood. 
d.) Reproductive Risks 
The drugs used in this research study, including sirolimus and CNIs may cause injury or 
birth defects if you take them during pregnancy. Because of this, it is important that you 
are not pregnant or breast-feeding and do not become pregnant during the course of the 
study. 
If you are a woman and pregnancy is a possibility, you will need to take a pregnancy test 
before you start the study.  You should discuss ways to not become pregnant while you 
are participating on the study.  
e.) Unforeseen Risks 
New risks might appear at any time during the study that are different from the risks 
listed in this Consent Form. We will promptly tell you of any new information that may 
affect your decision to participate. 
f.) Other Treatments or Medications  
Some medicines react with each other, and it is important that you tell the study doctor or 
staff about any other drugs, treatments, or medicines you are taking.  This includes non-
prescription medications, vitamins and herbal treatments.   
It is also important that you tell the study staff about any changes to these medications 
during your participation in the study. 
 

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Table: Risks and Side Effects of Study Drugs and Treatments 
 
Prednisone 
Sirolimus 
Calcineurin Inhibitor 
(Cyclosporine or 
Tacrolimus) 
Common 
(more 
than 20% 
of 
patients) 
▪ Fluid retention and 
bloating 
▪ Problems with the 
liver, pancreas or 
adrenal glands 
▪ High blood pressure 
▪ Enlarged heart 
▪ Muscle wasting 
▪ Thinning of bones 
▪ Torn tendons 
▪ Stomach ulcers 
▪ Slow wound healing 
▪ Thin fragile skin 
▪ Broken blood 
vessels in the skin, 
esp. face 
▪ Diabetes 
▪ Slowed growth in 
children 
▪ Cataracts 
▪ Mood swings or 
emotional changes 
▪ Insomnia 
▪ High blood pressure 
▪ Nausea (feeling sick 
to your stomach) 
▪ Diarrhea and/or 
constipation 
▪ Infection  
▪ Fever 
▪ Liver or kidney 
problems 
▪ Weight gain 
▪ Muscle pain 
▪ High cholesterol 
▪ Acne 
▪ Headache and/or 
dizziness  
▪ Uncontrollable shaking 
of a part of the body  
▪ Diarrhea and/or 
constipation  
▪ Nausea and/or vomiting  
▪ Heartburn  
▪ Stomach pain  
▪ Loss of appetite  
▪ Difficulty falling asleep 
and/or staying asleep  
▪ Weakness  
▪ Back and/or joint pain  
▪ Burning, numbness, 
pain, or tingling in the 
hands or feet  
▪ Rash 
▪ Itching 
 

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Table: Risks and Side Effects of Study Drugs and Treatments, continued 
 
Prednisone 
Sirolimus 
Calcineurin Inhibitor  
(tacrolimus or 
cyclosporine) 
Less 
Common 
(less than 
20% of 
patients) 
 
▪ Chest pain 
▪ Insomnia (unable to 
sleep) 
▪ Upset stomach or 
vomiting 
▪ Shortness of breath 
▪ Low blood counts 
▪ Skin rashes or hives 
▪ Slow wound healing 
 
Rare but 
Serious 
(less than 
2-3% of 
patients) 
 
▪ Low blood pressure 
▪ Lung problems, 
including asthma 
▪ Loss of appetite 
▪ Serious infections 
▪ Blood clots 
▪ Skin problems 
▪ Kidney failure 
▪ Secondary cancers 
▪ Bone degeneration 
(necrosis) 
▪ Decreased urination  
▪ Pain or burning on 
urination  
▪ Swelling of the arms, 
hands, feet, ankles, or 
lower legs  
▪ Weight gain  
▪ Unusual bleeding or 
bruising  
▪ Seizures  
▪ Coma (loss of 
consciousness for a 
period of time)  
 
 
7. Possible Benefits 
 
Taking part in this study may or may not make your health better. 
 
We do know that the information from this study will help doctors learn more about possible 
therapies for the treatment of chronic GVHD.  This information could help future allogeneic 
transplant patients. 
 
New Information Available During the Study 
During this research study, new information about the study drug or the risks and benefits of the 
study may become known to the study doctors.  If this happens, they will tell you about the new 
information.  The new information may mean that you can no longer participate in the study, or that 
you may not want to continue in the study.   
 
If this happens, the study doctor will stop your participation in the study and you will be offered all 
available care to suit your needs and medical condition. 
 

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8. Privacy, Confidentiality and Use of Information 
 
Your confidentiality is one of our main concerns.  We will do our best to make sure that the 
personal information in your medical record will be kept private.  However, we cannot guarantee 
total privacy.   
 
Your personal information may be given out if required by law.  If information from this study is 
published or presented at scientific meetings, your name and other personal information will not be 
used.  Your study number is not related to your name, social security number or medical record 
number at [insert facility name]. 
 
Information about your transplant from your original medical records may be seen or sent to 
national and international transplant registries, including:  
▪ The Center for International Blood and Marrow Transplant Research (CIBMTR) 
▪ The National Marrow Donor Program (NMDP) 
▪ The Food and Drug Administration (FDA) 
▪ The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI) 
▪ Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN)  
▪ Other authorized study organizations   
 
We will not identify you by name in any publications or reports that come from these organizations 
or groups. 
 
 
9. Ending Your Participation 
 
The study doctor or the study sponsor may stop the study at any time.  We may ask you to leave 
the study if you do not follow directions or if you suffer from side-effects of the treatment.  If 
you are asked to leave the study, the reasons will be discussed with you. 
 
Possible reasons to end your participation in this study include: 
▪ You do not meet the study requirements.   
▪ You need a medical treatment not allowed in this study. 
▪ The study doctor decides that it would be harmful to you to stay in the study. 
▪ You are having serious side-effects. 
▪ You become pregnant. 
▪ You cannot keep appointments or take study drugs as directed. 

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▪ The study is stopped for any reason. 
 
 
10. Physical Injury as a Result of Participation 
 
It is important that you tell your study doctor or study staff if you feel that you have been hurt or 
injured because of taking part in this study.   
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or 
your health plan will be charged for this treatment.  This study will not pay for medical treatment. 
 
In case of injury resulting from this study, you do not lose any of your legal rights to seek payment 
by signing this form. 
 
 
11. Compensation or Payment 
 
You will not be paid for your participation in the research study.  You will not get compensation or 
reimbursement for any extra expenses (travel, meals, etc.) you may have through your participation 
on this trial. 
 
 
12. Costs & Reimbursements 
 
Most of the visits for this research study are standard medical care for patients with GVHD and will 
be billed to your insurance company.  You and/or your health plan/insurance company will need to 
pay for some or all of the costs of standard treatment in this study. 
 
 
13. Ethical Review 
 
The ethical aspects of this research study have been reviewed and approved by  
[name of IRB]. 
 
 
14. Further Information 
 
If you need any information about this study, or if you have any problems while you are 
participating in this study you can contact the study doctor or his/her staff.  They may be contacted 
at the telephone numbers listed here. 
[Insert name and contact details] 
 
 

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15. Independent Contact 
 
If you wish to speak to someone not directly involved in the study, or if you have any complaints 
about any aspect of the project, the way it is being conducted or any questions about your rights as a 
research participant, then you may contact:  
[Insert appropriate contact details] 
 
 
16. 
Web Information 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This web site will not include information that can identify you.  At most, the web site 
will include a summary of the results.  You can search this web site at any time. 
 
 
Health Insurance Portability and Accountability Act 1 (HIPAA1) Authorization to use and 
disclose individual health information for research purposes  
 
A. Purpose   
As a research participant, I authorize the Principal Investigators and the researcher’s staff to use 
and disclose my individual health information for the purpose of conducting the research study:  
 
A Phase II/III Randomized, Multi-center Trial Comparing Sirolimus plus Prednisone and 
Sirolimus/Calcineurin Inhibitor plus Prednisone for the Treatment of Chronic Graft-versus-Host-
Disease. 
 
B. Individual Health Information to be Used or Disclosed  
My individual health information that may be used or disclosed to do this research includes:  
▪ Demographic information (for example: date of birth, sex, weight).  
▪ Medical history (for example: diagnosis, complications with prior treatment). 
▪ Findings from physical exams. 
▪ Laboratory test results obtained at the time of work up and after treatment (for example: 
blood tests, biopsy results).  
 
C. Parties Who May Disclose My Individual Health Information  
The researcher and the researcher’s staff may collect my individual health information from: 
(List hospitals, clinics or providers from which health care information can be requested). 
 
D. Parties Who May Receive or Use My Individual Health Information  
                                                 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 

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The individual health information disclosed by parties listed in item c and information 
disclosed by me during the course of the research may be received and used by the following 
parties: 
▪ Principal Investigator and the researcher’s staff 
 
 
Paul Carpenter, M.B., B.S., Co-Investigator  
Mutka Arora, M.D., Co-Investigator  
▪ Study Sponsors  
National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH); Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN) 
▪ U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research Protections 
(OHRP) 
▪ U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state and local health 
departments. 
 
E. Right to Refuse to Sign this Authorization  
I do not have to sign this authorization.  If I decide not to sign the authorization, I will not be 
allowed to participate in this study or receive any treatment related to research that is 
provided through the study.   
 
My decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits.   
 
F. Right to Revoke   
I can change my mind and withdraw this authorization at any time by sending a written 
notice to the Principal Investigator to inform the researcher of my decision. 
 
If I withdraw this authorization, the researcher may only use and disclose the protected health 
information already collected for this research study.  No further health information about me 
will be collected by or disclosed to the researcher for this study. 
 
G. Potential for Re-disclosure  
My individual health information disclosed under this authorization may be subject to re-
disclosure outside the research study and no longer protected. 
 
Examples include potential disclosures for law enforcement purposes, mandated reporting or 
abuse or neglect, judicial proceedings, health oversight activities and public health measures. 
 
H. This authorization does not have an expiration date. 
 
Blood and DNA Samples for Research  
Please note: This section of the Informed Consent Form is about an additional research 
study that will be done with people who are taking part in the main study.  You may take 

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part in this additional study if you want to.  You can still be a part of the main study even if 
you say ‘no’ to take part in this additional study. 
 
Your blood and cells have a material known as DNA.  This is a molecule that holds a person’s 
genetic information.  
 
We ask for your permission to collect and store extra blood and DNA. These samples will be 
used for future research. 
 
DNA from your stored blood and DNA samples and your health information might be used in 
genome-wide association (GWA) studies for a future project either done or supported by the 
National Institutes of Health (NIH).   
 
Genome-wide association studies are a way for scientists to identify genes involved in human 
disease.  This method searches the genome for small genetic changes that are more common in 
people with a particular disease than in people without the disease.  Each study can look at 
hundreds of thousands of genetic changes at the same time.  Researchers use data from this type 
of study to find genes that may add to a person’s risk of developing a certain disease. 
 
If your coded genetic and clinical information is used in such a study, the researcher is required 
to add the DNA test results and non-identifying information into a public research database.  
This public database is called the NIH Genotype and Phenotype Database and it is managed by 
the National Center for Biotechnology Information (NCBI).  The NCBI will never have any 
information that would identify you, or link you to your information or research samples. 
 
A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA), 
generally makes it illegal for health insurance companies, group health plans, and employers of 
15 or more persons to discriminate against you based on your genetic information.  Health 
insurance companies and group health plans may not request your genetic information that we 
get from this research.  This means that they must not use your genetic information when making 
decisions regarding insurability.  Be aware that this new federal law will not protect you against 
genetic discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance. 
 
Procedures 
▪ We will collect extra blood samples at the same time you have routine blood tests done 
on 3 study visits; before you start treatment (baseline), 2 months and 6 months. 
▪ The amount of blood collected from you is small – about 2 teaspoons (10mL) each time. 
▪ We will also collect samples of your DNA by swabbing four sections of the inside of 
your cheeks with cotton swabs. 
▪ Your blood and DNA samples will be collected confidentially and your name will not be 
on the containers. 
▪ These samples may be stored indefinitely for future research.   
 

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Withdrawal 
If you agree to allow your blood and DNA samples to be used for research, you can change your 
mind at any time.  If you change your mind, please contact [the Principal Investigator at your 
transplant center] in writing to state that you are withdrawing permission for your blood to be 
used for research.  His/her mailing address is on the first page of this Consent Form.  Any unused 
samples will be destroyed if you withdraw your permission.  If you choose not to participate in 
this additional research there will be no change in your care.   
 
Benefits 
You will not benefit directly from providing blood and DNA samples for this study. 
 
Risks 
There are no major risks associated with drawing blood.  Having your blood drawn can be 
uncomfortable and can sometimes cause a bruise.  In rare cases, it can cause fainting.  Only 
trained people will draw your blood.  There are no major risks with swabbing the inside of your 
cheeks. 
 
Confidentiality and Your Medical Information 
The results of GVHD research done with your blood and DNA will not be part of your medical 
record and will not be shared with you.  
 
If you agree to allow your blood and DNA samples to be used for research, they will be collected 
confidentially and your name will not be on the tubes.  Only the study doctors or staff working 
with them will study the results from your blood and DNA samples. 
 
Information gained from research on your blood and DNA may be used to develop diagnostic 
procedures or new treatments for GVHD in the future.  Your blood will not be sold to any 
person, institution, or company for financial gain or profit. 
 

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Making Your Choice 
Please read each sentence below and think about your choice.  After reading each sentence, make 
your selection by checking one of the boxes.  If you have any questions, please talk to your 
doctor or nurse, or call our research review board at [IRB's phone number].  
 
No matter what you decide to do, it will not affect your care. 
 
 I agree to allow my blood and DNA to be used for future research. 
 
 I do not agree to allow my blood and DNA to be used for future research. 
 
 
Signature 
 
 
 
 
 
 
Date____________________ 
 
TITLE: 
A Phase II/III Randomized, Multi-center Trial Comparing Sirolimus plus 
Prednisone and Sirolimus/Calcineurin Inhibitor plus Prednisone for the Treatment of Chronic 
Graft-versus-Host-Disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Name 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Signature  
 
 
 
 
 
Date 
 
 
 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks.  I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Counseling Physician  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Counseling Physician 
 
 
 
 
Date 
 

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Assent to Participate in Research 
 
 
 
 
 
 
 
 
 
Study Title: A Phase II/III Randomized, Multi-center Trial Comparing Sirolimus plus 
Prednisone and Sirolimus/Calcineurin Inhibitor plus Prednisone for the Treatment 
of Chronic Graft-versus-Host-Disease. 
 
Protocol: 
0801 
 
 
A. Why am I here? 
We are inviting you to join our study because you have chronic graft-versus-host disease 
(GVHD). 
 
Chronic GVHD happens when donor cells from your transplant attack parts of the body like 
your skin, stomach or liver.  Both children and adults can get chronic GVHD.  It can be a 
very serious problem for some people.   
 
 
B. Why are you doing this study? 
We want to compare two ways to treat chronic GVHD.  This will help us learn which may be 
a better treatment. 
 
 
C. What will happen to me? 
If you say you want to be in the study, we will ask you for several things: 
▪ Permission to let us read your medical records and x-rays.  
▪ Check-ups with the study doctors.  
▪ Some blood from you (about 3-5 teaspoons).  A very small needle will be used to get 
blood.  
▪ Answer some questions about how you feel. 
 

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You will be assigned to have either Treatment #1 or Treatment #2. The doctors will use a 
computer to decide who goes into each group.  Each treatment uses a different mix of drugs. 
 
Treatment #1 
Treatment #2 
▪ A steroid 
▪ Cyclosporine or tacrolimus  
▪ Sirolimus 
▪ A steroid 
▪ Sirolimus 
 
We will watch you carefully for fevers, any sign of infection or other problems. 
 
 
D. Will it hurt? 
When you have your blood taken with a needle, it may feel like a pinch.  It will hurt for a 
minute and sometimes the place where the needle went might be red and sore.  You might get 
a little bruise where the blood was taken but it goes away in a few days.  
 
 
E. Will the study help me? 
We don’t know if the study will help you or not.  Your GVHD may stay the same, it may get 
better, or it may get worse. 
 
 
F. What if I have questions? 
You can ask any questions that you have about the study.  If you forget to ask a question and 
think of it later, you can call me [insert office number].  You can also ask your question the 
next time you see me. 
 
You can call the study office at any time to ask questions about the study. 
 
 
G. Do I have to be in this study? 
If you don’t want to be in the study, you need to tell us and your parent or guardian.  Your 
doctor will not be angry or upset if you don’t want to join.   
 
Whether you are in the study or not, you will still need to have treatment for your GVHD. 
 
You can say yes now and change your mind at any time.   
 
Please talk this over with your parent or guardian before you decide if you want to be in the 
study.  We will also ask your parents to give their permission for you to join this study.  
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
Information & Assent Form 
 
Initials 
 
B-21 
Use of Blood and DNA Samples 
 
Some of your blood will be used to test for GVHD.  Additional blood (1-2 teaspoons) and a 
sample of cells from inside your cheek (DNA) will be collected and saved for future studies.  
Your blood has a material known as DNA.  DNA is a molecule that holds your genetic 
information.  We may study your blood and your DNA in future GVHD research. 
 
To be in the study, you must agree to have your blood used for GVHD and other regular 
tests, but you do not have to agree to have your blood or cheek cells (DNA) used in future 
research. 
 
Please check one of the boxes below to show how you want your blood and cheek cells (DNA) 
to be used. 
 
 Yes, you may use my blood and cheek cell (DNA) samples for future research. 
 
 No, you may not use my blood and cheek cell (DNA) samples for future research. 
 
Writing your name on this page means that you agree to be in the study, and know what will 
happen to you.  If you decide to quit the study, all you have to do is tell the person in charge. 
 
You and your parent or guardian will get a copy of this form after you sign it. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant’s Guardian  
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Printed Name of Participant’s Guardian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant (if 18 years old or older) 
 
 
Date 
 
 
 
 
 
 
 
 
 
Printed Name of Participant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Researcher 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Printed Name of Researcher 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
 
 
 
APPENDIX C 
 
LABORATORY SAMPLE INFORMATION  
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
C-1 
APPENDIX C 
 
LABORATORY SAMPLE INFORMATION 
 
 
BIOMARKER BLOOD SAMPLES 
 
Peripheral blood samples (18 mL) will be collected from the patient for T-cell and B-cell 
immunophenotyping and plasma BAFF levels, at baseline prior to initiation of treatment for 
cGVHD, at the 2 months and 6 months post-treatment time points, and at the initiation of 
secondary systemic immunosuppressive therapy.  Additional biomarkers of interest may also be 
evaluated that might be identified via other research reported during the period that this study is 
conducted.  Optional patient buccal swabs and peripheral blood samples (10 mL, or 6 mL for 
patients < 40 kg) may be collected and stored for the future undefined testing of biomarkers 
related to cGVHD.  These samples should be collected and shipped according to the detailed 
instruction in the BMT CTN 0801 Laboratory Sample Guide. 
 
 
SCHEDULE OF LABORATORY EVALUATIONS 
Protocol-Defined Research Testing and for Future, Undefined Research 
 
 
Protocol-Defined cGVHD Assessments 
Research 
Sample 
Type of 
Sample 
Type of Processing 
and Storage 
Dates Samples 
Obtained 
Shipping 
Specifications 
BAFF Levels by 
ELISA 
6 mL peripheral blood 
collected in a 6 mL fill 
EDTA lavender-top 
blood tube. 
 
Centrifuge the EDTA 
containing whole blood 
samples at 1000-1300 x g or 
2100 rpm for 10 minutes 
within 60 minutes of 
collection.  Remove the 
separated plasma.  Transfer 
0.5 mL aliquots to 4-6 
cryovials (depending on 
volume of plasma recovered) 
and freeze at -70ºC in a 
scientific grade freezer. 
At baseline prior to 
initiation of treatment 
for cGVHD, and on 
Day 60 and Day 180 
[or upon initiation of 
secondary systemic 
immunosuppressive 
therapy (whichever is 
sooner)]. 
 
Batch ship yearly, 
frozen on dry ice in a 
provided shipping 
container, FedEx 
priority overnight to the 
BMT CTN Research 
Sample Repository. 
Regulatory  
T-cell and B-cell  
Immunophenotyping 
12 mL peripheral blood 
samples will be 
collected in 6 mL fill 
EDTA lavender top 
blood tubes. 
 
No processing or storage 
required at transplant center. 
At baseline prior to 
initiation of treatment 
for cGVHD, and on 
Day 60 and Day 180 
or upon initiation of 
secondary systemic 
immunosuppressive 
therapy (whichever is 
sooner)]. 
 
Ship blood tubes 
directly to designated 
project lab (DFCI) on 
day of collection by 
priority overnight Fed 
Ex. 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
C-2 
 
Optional Research Samples for Future Undefined Research  
Research 
Sample 
Type of 
Sample 
Type of Processing 
and Storage 
Dates 
Samples 
Obtained 
Shipping 
Specifications 
Baseline, Pre-Treatment  
Patient Plasma 
& 
Patient Whole Blood 
(Source of Donor DN A) 
10 mL peripheral 
blood (6 mL for 
patients < 40 kg) 
collected in an 
EDTA lavender-top 
tube. 
 
Within 60 minutes of collection, 
gently mix the 10 mL blood tube by 
gently inverting the tube for 60 
seconds.  Pipette a 1.0 mL aliquot of 
the whole blood into each of 3 
cryovials and freeze at -70ºC in a 
scientific grade freezer (make three 
0.5 mL whole blood aliquots if the 
alternate 6 mL tube was used).  
Centrifuge the remaining whole blood 
(7 mL) in the EDTA tube (4.5 mL if 6 
mL fill blood tube used) at 1000-1300 
x g or 2100 rpm for 10 minutes.  
Remove the separated plasma.  
Transfer 0.5 mL aliquots to 3-7 
cryovials (depending on volume of 
plasma recovered) and freeze at -70ºC 
in a scientific grade freezer. 
At baseline 
prior to 
initiation of 
treatment for 
cGVHD. 
Batch ship yearly, 
frozen on dry ice in a 
provided shipping 
container, FedEx 
priority overnight to the 
BMT CTN Research 
Sample Repository. 
Baseline, Pre-Treatment  
Patient Buccal Swab 
 (Patient DNA) 
4 buccal swabs 
Transplant centers will have the 
patient collect buccal cell samples per 
instructions.  The 4 swabs should be 
dried for a minimum of 2 hours 
before they are processed for long-
term frozen storage. Each dried swab 
is placed into a separate cryovial (4 
cryovials), the stick cut so that the 
cotton swab tip fits well within the 
cryovial. Secure the cryovial cap. 
Cryovials will need to be promptly 
stored at -70°C in a scientific grade 
freezer until batch-shipped to the 
BMT CTN Research Sample 
Repository. 
At baseline 
prior to 
initiation of 
treatment for 
cGVHD. 
Batch ship yearly, 
frozen on dry ice in a 
provided shipping 
container, FedEx 
priority overnight to the 
BMT CTN Research 
Sample Repository. 
Post-Treatment 
Patient Plasma Samples 
10 mL peripheral 
blood (6 mL for 
patients < 40 kg) 
collected in an 
EDTA lavender-top 
tube. 
 
Within 60 minutes of collection, 
centrifuge the EDTA containing 
whole blood tube at 1000-1300 x g or 
2100 rpm for 10 minutes.  Remove 
the separated plasma.  Transfer 0.5 
mL aliquots to 4-10 cryovials 
(depending on volume of blood 
processed and plasma recovered) and 
freeze at -70ºC in a scientific grade 
freezer. 
Day 60 and 
Day 180  
Batch ship yearly, 
frozen on dry ice in a 
provided shipping 
container, FedEx 
priority overnight to the 
BMT CTN Research 
Sample Repository. 
STANDARD OPERATING PROCEDURES 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
 
APPENDIX D 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 
 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
D-1 
APPENDIX D 
 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED 
EXPONENTIAL DATA 
 
 
Background – The Sequential Probability Ratio Test 
 
Let 
)
(.,
f
be the density function for random variable X.  According to Neyman and Pearson, 
the most powerful test of 
o
H


:
0
 versus
1
1 :


H
 decides in favor of 
1
H  or 
0
H if 

c
Ln 
 
or 

c
Ln 
, respectively, where 


n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1


is the likelihood ratio, and 

c is 
determined to have the size .  When the sample size is not fixed in advance, further 
improvement is possible by using Wald’s Sequential Probability Ratio Test (SPRT).  The SPRT 
continues to sample as long as 
A
L
B
n 

 for some constant 
A
B

1
, stops sampling and 
decides in favor of 
1
H as soon as 
A
Ln 
, and stops sampling and decides in favor of 
0
H as soon 
as 
B
Ln 
. 
 
The usual measures of performance of such a procedure are the error probabilities 

and of 
rejecting 
0
H when 
0


, and of accepting 
0
H when 
1


, respectively, and the expected 
sample size 
)
(
)
|
(
N
E
N
E
j
j 

.  Wald and Wolfowitz showed that among all tests, sequential or 
not, for which 


)
reject 
(
Pr
0
0
H
 and 


)
reject 
(
Pr
0
1
H
, and for which 
)
(N
E j
 are finite, j=0,1, 
the SPRT with error probabilities 

 and minimizes 
)
(
0 N
E
 and 
)
(
1 N
E
.  If, in addition, the 
,...
2
,1 x
x
 are independent and identically distributed (i.i.d.) with density function 
)
,
( 
x
f
, with 
monotone likelihood ratio in 
)
(x

, then any SPRT for testing 
0
against 
)
(
0
1



 has non-
decreasing power function. 
 
For the SPRT with error probabilities 

and , the SPRT boundaries are given approximately 
by 

/)
1( 

A
 and 
)
1
/(




B
.  The operating characteristics of the SPRT are given by 
)
/(
)1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0








h
h
h
B
A
A
O



 where 
)
(
h
is the non-trivial solution to the equation 

1
)
;
(
))
,
(
/)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h




.   
 
The formula 
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(




z
E
B
O
A
O
N
E



provides the average sample number 
for an arbitrary .  The sample size distribution is very highly skewed, 
2
)]
(
[
)
(
N
E
N
Var

.  Thus 
we will consider a truncated test with maximum sample size of 
0
N  and simulate to obtain the 
operating characteristics of the test. 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
D-2 
Derivation of the SPRT for Uncensored Exponential Survival Times 
 
For example, we wish to construct a sequential test for the composite null hypothesis that the rate 
of treatment-related mortality (TRM) at 100 days is less than or equal to 30% versus the 
alternative hypothesis that it is greater than or equal to 50%.  For the derivation of the 
uncensored SPRT, we will require that the type I error of the test be less than 5%, and that the 
test provide 80% power to reject the null hypothesis under a specified alternative that the true 
rate is 50%.  A maximum sample size of 50 patients will be permitted. 
 
Let us assume that the survival times, 
nT
T
T
,...,
,
2
1
, are completely observed (uncensored) and are 
i.i.d. with exponential density function 
T
e
T
f





)
,
(
.  These assumptions will be relaxed to 
incompletely observed data subsequently.  In the exponential parameterization, a 100-day 
survival rate of 70% translates into a mean survival of 0.768 years (

0

1.303), and 50% 
translates into a mean survival of 0.395 years (

1

2.532). 
 
The SPRT is derived with reference to a simple null and alternative hypothesis, in this case, 


o
H


:
0
 1.303 versus
1
1 :


H
 = 2.532.  However, since the log-likelihood ratio for the 
exponential, 








n
i
n
i
n
i
i
i
i
T
n
x
f
x
f
)
(
))
log(
)
(log(
)
,
(
log
)
;
(
log
0
1
0
1
0
1






, 
is 
a 
monotone function of 
n
i
iT , the power of the test is non-decreasing in .  Thus the SPRT is a 
one-sided level .05 test of a composite null (
303
.1
:
0


o
H


) versus a composite alternative 
(
303
.1
:
1


o
H


), with power of 
80
.
1


 at the selected alternative 


1


2.532. 
 
The SPRT can be represented graphically.  The continuation region is bounded by two parallel 
lines with common slope 



)
/(
)
log
(log
1
0
1
0




0.541, and intercepts 


)
/(
log
1
0


A
-2.256 
and 


)
/(
log
1
0


B
1.270, for the lower and upper bounds, respectively.  As each individual unit 
is put on trial and observed to fail, the cumulative sum of failure times,
n
i
iT , is recomputed, and 
plotted against the current sample size, n .  When this graph crosses the lower boundary, the null 
hypothesis is rejected. 
 
The maximum sample size of 50 patients requires that the SPRT be truncated.  We choose to 
truncate the SPRT by declaring that if the test has failed to terminate after 50 patients, that the 
null hypothesis will be accepted.  Since the probability that the untruncated SPRT would reject 
the null at a sample size of 50 is negligible, it makes little difference how the final boundary 
value is selected, and this rule is chosen for simplicity.   
 
Derivation of a Modified SPRT for Censored Exponential Data 
 
The assumption of uncensored exponential survival times is flawed.  However, we consider it 
reasonable to assume the hazard for TRM is constant over the first 100 days post-transplant, and 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
D-3 
we will restrict our attention to this time interval.  Furthermore, it is not practical to conduct a 
clinical study by putting each individual on trial, and waiting until that individual is observed to 
fail.  We relax our assumptions as follows.  Firstly, each individual’s time on study will be 
computed as time from transplant to failure, or to the 100 day time point, whichever comes first.  
Secondly, we will put individuals on trial as soon as they become available, without waiting for 
the previous individual to fail. 
 
Let us consider the impact of relaxing these assumptions one at a time.  In a fixed sample size 
trial with uncensored exponential failure times, mean survival time is estimated by the sample 
mean of the failure times, or total time on study divided by the number of individuals enrolled.  
When censoring is introduced, the estimate becomes the total time on study divided by the 
number of observed (non-censored) failures.  This suggests that in an exponential SPRT test 
modified to incorporate censoring, we replace the observed failure times, 
nT
T
T
,...,
,
2
1
, with 
censored failures times, 
nx
x
x
,...,
,
2
1
, and the current sample size, n , with the number of observed 
failures, d .   
 
Now we relax the second assumption, and put individuals on trial as soon as they become 
available, without waiting for the previous individual to fail.  Assume that three years are 
required for accrual of 50 patients to the study, and that the final analysis takes place 100 days 
after the last patient is entered.  Putting all of this together, we propose a modified truncated 
SPRT, where at any interim time point, s , ranging from 0 to 3 years 100 days, the sum of 
observed time on study, 
n
i
i s
X
)
(
is plotted against the number of observed failures, 
)
(s
d
.  In 
practice, monitoring will be scheduled monthly after the start of enrollment to the study.  A 
further modification to the SPRT was to only use the lower boundary for stopping since the 
primary focus of the monitoring is to protect against unacceptable 100-day TRM rates. 
 
Operating Characteristics of the Modified SPRT Test for Censored Exponential Data 
 
Recall that the uncensored SPRT targeted a drop in survival at Day 100 from 70% to 50%, with 
type I and II errors of 5% and 20%.  Since only the lower boundary is used for monitoring, the 
continuation region of the test was bounded below by a line with a slope of 0.541 and intercept 
of –2.256.  The effect of truncation is to reduce the power of the test.  In order to compensate for 
this, we raise the lower boundary to make it easier to cross.  Under the further assumption of 
uniform accrual over a three year period, and monthly interim analyses over the course of the 
study, the operating characteristics of the modified SPRT were obtained from a simulation study.  
These simulation show that an intercept of –1.741, corresponding to setting parameters  and 
to 10% and 15%, result in empirical type I and II error rates of  about 5% and 20%.   
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
D-4 
Table D-1   Operating Characteristics of Sequential Testing Procedures from a 
Simulation Study with 100,000 Replications 
 
Treatment-Related Mortality (TRM) 
True 100-Day Rate 
30% 
35% 
40% 
45% 
50% 
Probability Reject Null 
0.07 
0.20 
0.41 
0.66 
0.86 
Mean Month Stopped 
34.5 
32.3 
28.5 
23.5 
18.5 
Mean # Endpoints in 100 Days 
13.8 
15.0 
15.1 
14.0 
12.1 
Mean # Patients Enrolled 
48 
45 
40 
33 
26 
 
While the motivation for this testing procedure is largely heuristic rather than theoretical, the 
simulation results validate the approach.  When the true rate of TRM on or before Day 100 was 
30%, the test crossed the lower boundary in 7119 of 100,000 replications, for an estimated type I 
error rate of 7%.  When the true rate of TRM on or before Day 100 was 50%, the test failed to 
cross the boundary in 14226 of 100,000 replications, for an estimated type II error rate of 14%.  
And on average, the boundary will be crossed at 18.5 months, when 26 patients will be enrolled 
to the study. 
 
It is interesting to note that the SPRT derived above for exponential failure times with censoring 
at 100 days, has operating characteristics which are similar to those of a more traditional SPRT, 
derived for binomial variates with success probability equal to the 100 day failure rate.  Using 
time to failure rather than a simple binary indicator of failure, leads to little improvement in 
power when failure times are censored relatively soon after entry on study.  We speculate that if 
the constant hazard rate over the first 100 days were high, the exponential test would reject faster 
than the binomial test, but have not conducted simulation studies to demonstrate this. 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
 
APPENDIX E 
 
END OF PHASE II DECISION MAKING CONSIDERATIONS 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
E-1 
APPENDIX E 
 
END OF PHASE II DECISION MAKING CONSIDERATIONS 
 
 
The adaptive Phase II/III design of Protocol 0801 allows efficient transition from Phase II to 
Phase III, given certain outcomes in the Phase II stage of the trial.  The Phase II stage may result 
in a variety of outcomes, not all of which would favor proceeding directly to the Phase III as 
written.  This Appendix outlines the principles that will be used to determine how to proceed at 
the end of Phase II.  Overall response rates (CR+PR) at 6 months for the experimental arm (SP) 
will be plotted (see examples plotted as  below) relative to the respective comparator arm 
(SPC) as shown in the figures below.  Assumptions include: 1) the overall response rate for SPC 
is about 40%; and, 2) overall response rates in the experimental arm (SP) < 40% are not of 
interest to pursue further. 
 
Scenario 1: The Phase III trial as written is not worth pursuing 
 
SP is inferior to comparator (SPC) and the trial ends at Phase II. 
 
CR+PR rate in SP Arm (%)
90
80
70
60
50
40
30
20
30
40
70
50
60
80
20
Trial ends 
in Phase II
Phase III 
Follow
Arms 
for 
Phase III 
End-points Phase III
Defer to 
DSMB
CR+PR rate in SPC Arm (%)
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
E-2 
Scenario 2: The Phase II study is possibly worth pursuing after further follow-up 
 
The SP arm might be of sufficient interest to continue into a future Phase III trial but Phase II 
short term outcome data does not warrant proceeding directly to Phase III.  In this scenario, both 
arms would have similar CR+PR rates higher than the estimated 40% benchmark for the SPC 
arm.  In this situation, how to proceed may require more information on longer term endpoints.  
Considerations would also include, in rank order, toxicity, convenience and cost of both study 
arms, as well as BMT CTN priorities and other available therapies at the time.   
 
CR+PR rate in SP Arm (%)
90
80
70
60
50
40
30
20
30
40
70
50
60
80
20
Trial ends 
in Phase II
Phase III 
Follow
Arms 
for 
Phase III 
End-points Phase III
Defer to 
DSMB
CR+PR rate in SPC Arm (%)
 
 
 
Scenario 3: Proceed to Phase III as written 
 
This is a scenario in which the experimental arm (SP) is superior to the comparator (SPC) and 
has a CR+PR rate of at least 40%.  
 
CR+PR rate in SP Arm (%)
90
80
70
60
50
40
30
20
30
40
70
50
60
80
20
Trial ends 
in Phase II
Phase III 
Follow
Arms 
for 
Phase III 
End-points Phase III
Defer to 
DSMB
CR+PR rate in SPC Arm (%)
 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
E-3 
Scenario 4: Experimental Arm (SP) is substantially superior (≥ 35%) to SPC  
 
In this example, while the comparator arm (SPC) exceeds the 40% benchmark, the experimental 
arm (SP) is considered sufficiently more superior over SPC that proceeding directly to Phase III 
(SP versus SPC) may not be justified.  The DSMB would advise whether SP and SPC should be 
tested head-to-head in Phase III or if SP should be tested against a novel therapy of interest.  
Considerations would also include, in rank order, toxicity, convenience and cost of all study 
arms, as well as BMT CTN priorities and other available therapies at the time.   
 
CR+PR rate in SP Arm (%)
90
80
70
60
50
40
30
20
30
40
70
50
60
80
20
Trial ends 
in Phase II
Phase III 
Follow
Arms 
for 
Phase III 
End-points
Phase III
Defer to 
DSMB
CR+PR rate in SPC Arm (%)
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
 
APPENDIX F 
 
REFERENCES 
 
 

BMT CLINICAL TRIALS NETWORK 
 
Chronic GVHD Therapy – Protocol 0801 
Version 6.0 dated July 9, 2012 
 
 
F-1 
APPENDIX F 
 
REFERENCES 
 
                                                 
1  Filipovich AH, Weisdorf D, Pavletic S et al. National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: I. 
Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2005; 11: 945-
956. 
2  Couriel D, Carpenter PA, Cutler C et al. Ancillary therapy and supportive care of chronic 
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