Randomized Feasibility Study of Discontinuation Versus Continuation of Immunosuppressive Therapy (IST) in Patients With Chronic Graft Versus Host Disease (GVHD)
Phase: PHASE2
Conditions: Chronic Graft Versus Host Disease
Sponsor: Fred Hutchinson Cancer Center

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Randomized feasibility study of discontinuation versus continuation of 
immunosuppressive therapy (IST) in patients with chronic Graft Versus Host 
Disease (GVHD) (Protocol 9962) 
Current Version Date: 24 October 2020 
Principal Investigator 
Stephanie Lee, MD, MPH 
Member, FHCRC 
1100 Fairview Ave. N., D5-290 
Seattle, WA 98109 
Phone: 206.667.6190 
E-mail: sjlee@fredhutch.org 
 
Sub-Investigators 
Mary Flowers, MD 
Member, FHCRC 
 
Paul Carpenter, MD 
Member, FHCRC 
 
Paul Martin, MD 
Member, FHCRC 
 
Leslie Kean, MD 
Joint Associate Member 
FHCRC 
 
Rachel Salit, MD 
Assistant Member 
 
Dan Egan, MD 
Assistant Member 
 
Elizabeth Krakow, MD  
Assistant Member 
 
Lauri Burroughs, MD 
Associate Member 
 
Kanwaldeep Mallhi, MD 
Assistant Member 
 
Corinne Summers, MD 
Assistant Member 
Project Manager 
Julianne Dunlap 
FHCRC 
1100 Fairview Ave. N., LF-230 
Seattle, WA 98109 
Phone: 206.667.4160 
E-mail: jdunlap@fredhutch.org 
 
Biostatistician 
Qian Vicky Wu, PhD 
FHCRC 
1100 Fairview Ave. N., M2-B820 
Seattle, WA 98109 
Phone: 206.667. 3358 
E-mail:  qwu@fredhutch.org 
IRO received 09/24/20
FHCRC IRB Approval  
10/08/2020 
Document Released Date

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1 
Protocol Synopsis 
Title 
Randomized feasibility study of discontinuation versus continuation 
of immunosuppressive therapy (IST) in patients with chronic Graft 
Versus Host Disease (GVHD) 
Short Title 
Functional Tolerance after Allo HCT 
Study 
Design 
Randomized prospective study 
Study 
Objectives 
Primary Objective.  Assess feasibility of enrolling and randomizing 
patients with chronic GVHD to discontinuation versus continuation of 
IST.  
 
Secondary Objectives.  
- Assess feasibility of enrolling and randomizing patients who are not 
local, and evaluate the quality of data received for those patients. 
- Assess whether prolonged IST decreases the need for pulses of 
high dose IST.  
- Evaluate the effect of prolonged IST on chronic GVHD 
manifestations and severity, risk of relapse, infection and organ 
toxicity.  
 
Study 
Endpoints 
Primary Endpoints.  
- Number of patients enrolled on the study (signed consent) in 2 
years 
 
Secondary Endpoint.  
- Successful randomization of patients 
- Compliance with treatment and data collection as outlined in the 
protocol 
- Rate of IST resumption (discontinuation arm)/increase IST dose 
(continuation arm) by 12 months after randomization 
- New chronic GVHD manifestations and/or worsening of existing 
manifestations, recurrent malignancy by 12 months after 
randomization, grade ≥ 3 infections, and grade ≥ 3 organ toxicity.   
 
Accrual 
Objective 
40 (20 patients on each arm) 
Study 
Duration 
2 year accrual period; 12 month active follow-up after randomization; 
Long term annual follow up via chart review. 
Stopping 
Rules 
Accrual of less than 12 patients in the first year 
 
Treatment 
Description  
 IST continuation for 9 months on the continuation arm. Taper IST to 
off as planned in the discontinuation IST arm. 
Inclusion 
Criteria 
1. Prior allogeneic stem cell transplant, with any graft source, donor 
type, and GVHD prophylaxis. 

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2. On only one systemic immunosuppressive agent for chronic 
GVHD with a plan to stop all systemic IST. Hydrocortisone or 
prednisone continued for treatment of adrenal insufficiency is not 
considered a systemic IST. 
3. No evidence of malignancy at the time of enrollment. 
4. Agreement for evaluation at the transplant center at the time of 
study enrollment, and then every 3 months at the transplant center 
or by local provider for 12 months after randomization 
5. Agreement to be contacted by phone or e-mail for health status 
evaluation for up to 3 years 
6. Signed, informed consent 
Exclusion 
Criteria 
1. Inability to comply with study procedures 
2. Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1. 
Background and Rationale .................................................................................... 4 
2. 
Objectives ............................................................................................................... 5 
3. 
Endpoints ............................................................................................................... 5 
4. 
Stopping Rules ....................................................................................................... 6 
5. 
Subject Selection ................................................................................................... 6 
5.1 Inclusion criteria .................................................................................................. 6 
5.2 Exclusion criteria ................................................................................................. 6 
6. 
Study Procedures .................................................................................................. 6 
6.1 Study Design ........................................................................................................ 6 
6.2 Study Design Rationale ....................................................................................... 9 
6.3 Subject Registration and Informed Consent ..................................................... 9 
6.4 Data Collection ................................................................................................... 10 
6.5 Study Procedures .............................................................................................. 10 
6.6 Adverse Reactions and their Management ..................................................... 12 
6.7 Data and Specimen Storage ............................................................................. 12 
7. 
Statistical Considerations ................................................................................... 12 
7.1. Statistical Analysis Plan .................................................................................. 12 
7.1.1. Primary Endpoint .......................................................................................... 12 
7.1.2. Secondary Endpoints ................................................................................... 13 
7.1.3. Methods ....................................................................................................... 13 
7.2. Sample Size and Power .................................................................................... 13 
8. Risks and Discomforts ........................................................................................... 13 
9. 
Potential Benefits ................................................................................................. 14 
10. Adverse Events/Serious Adverse Events ........................................................... 14 
10.1 Adverse Events ................................................................................................ 14 
10.2 Serious Adverse Events .................................................................................. 15 
10.3 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as SAEs .................................................................................................................... 15 
10.4 Unexpected Adverse Event............................................................................. 16 
10.5 Monitoring and Recording Adverse Events .................................................. 16 
10.6 Grading Adverse Event Severity .................................................................... 16 
10.7 Attribution of an Adverse Event ..................................................................... 17 
10.8 Adverse Event Recording Period ................................................................... 17 
11. 
Data and Safety Monitoring Plan ..................................................................... 17 
12. 
References ........................................................................................................ 19 
11. Appendix ................................................................................................................ 21 
Appendix A. Patient Survey .................................................................................... 21 
 

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1. Background and Rationale 
Patients who received allogeneic hematopoietic cell transplantation (HCT) typically 
require administration of immunosuppressive treatment (IST) for at least 6 months in 
order to prevent or treat graft-versus-host disease (GVHD). GVHD is the most serious 
and common complication of allogeneic HCT. Significant acute GVHD occurs in 20-50% 
of patients,(1-3) and chronic GVHD occurs in 30-60% of patients who survive more than 
100 days after transplantation.(3, 4) Duration of IST is typically prolonged once patients 
develop GVHD. Particularly, duration of IST in patients who have chronic GVHD is 
reported to exceed 2-3 years.(5, 6) While IST is important to reduce mortality and 
morbidity associated with GVHD, it may increase risks of infection, recurrent malignancy 
and secondary malignancy.(7)  
“Immunologic tolerance” may be defined as the absence of immune-mediated injury 
when immunosuppressive medications are no longer given. Unlike solid organ 
transplantation,(8) many patients after allogeneic HCT can achieve sufficient 
“functional” tolerance even after development of GVHD, and can eventually stop all IST 
permanently without developing active manifestations of GVHD. However, many 
patients, especially those with chronic GVHD, develop GVHD exacerbation and require 
resumption of IST. Currently, there are no clinical or biological predictors for successful 
IST discontinuation, and management of chronic GVHD patients consists of repeated 
attempts to taper and stop IST.  
A recent retrospective evaluation of 250 adult patients who received systemic treatment 
for chronic GVHD at the Fred Hutchinson Cancer Research Center (FHCRC)/Seattle 
Cancer Care Alliance (SCCA) demonstrated that although 51% patients were able to 
stop IST at least one time, 46% of these patients required resumption of IST after a 
median of 3.4 months off therapy (IQR 2.1-8.0), due to GVHD exacerbation (9). Among 
patients stopping IST a second time, 30% restarted at a median of 6 months.  
Resumption of IST for chronic GVHD exacerbation may increase the morbidity and 
mortality of patients, since common practice is to reinstitute high doses of IST initially, 
followed by a taper again to the lowest dose. Additionally, GVHD may fail to be 
controlled after resumption of IST, or irreversible organ damage may occur each time 
GVHD symptoms flare. 
A potential alternative approach to the current practice of repeated attempts to taper 
and stop IST is continuation of IST.  
The purpose of this study is to enroll a cohort of patients with chronic GVHD whose their 
treating physician is planning to taper their IST to off, and to randomize them to either 
discontinuation of IST (standard approach) or continuation of IST for another 9 months 
(investigational approach), in order to evaluate the effect of prolonged IST on chronic 
GVHD control, with the hypothesis that this approach would decrease the risk of GVHD 
exacerbation and decrease the need to resume high doses of IST. The rational for the 9 
months extended IST in the continuation IST arm is retrospective data demonstrating 

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that >75% of patients who resumed IST after discontinuation, restarted within 9 months 
of IST discontinuation.   
The rationale for the feasibility study is that a large sample size is needed to 
demonstrate statistically significant differences between the two treatment approaches.  
Thus, prior to proceeding with a large study we need to conduct a feasibility study to 
evaluate whether patients can be enrolled, randomized, and follow their assigned 
treatment, and to assess whether the observations about IST resumption in the 
retrospective study appear accurate.  We acknowledge the heterogeneity among the 
target patient population (e.g. donor and stem cell source, time since transplant, and 
IST), but despite this heterogeneity when patients are ready to taper IST they are more 
similar than different in their clinical status. Information from this feasibility study are 
necessary to help us design a larger study and apply for external funding. In the larger 
study, we plan to use stratified randomization to help balance underlying patient and 
transplant characteristics.    
Biological samples will be collected during the study to analysis of blood profiles and 
cellular signatures of “functional” tolerance and biomarkers of GVHD exacerbation. 
 
2. Objectives 
 
2.1 Primary Objective  
Assess feasibility of enrolling and randomizing patients with chronic GVHD to 
discontinuation (standard of care) versus continuation (investigation) of IST.  
 
2.2 Secondary Objectives  
- Assess feasibility of enrolling and randomizing patients who are not local, and evaluate 
the quality of data received for those patients. 
- Assess whether prolonged IST decreases the need for pulses of high dose IST.  
- Evaluate the effect of prolonged IST on chronic GVHD manifestations and severity, 
risk of relapse, infection and organ toxicity.  
 
 
3. Endpoints 
 
3.1 Primary Endpoint  
- Number of patients enrolled on the study (signed consent) in 2 years 
 
3.2 Secondary Endpoint  
- Successful randomization of patients 
- Compliance with treatment and data collection as outlined in the protocol 
- Evaluate enrollment rate and quality of data of patients who are not local 
- Rate of IST resumption (discontinuation IST arm)/increase IST dose (continuation IST 
arm) by 12 months after randomization 

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- New chronic GVHD manifestations and/or worsening of existing manifestations, 
recurrent malignancy by 12 months after randomization, grade ≥ 3 infections, and grade 
≥ 3 organ toxicity.   
 
 
4. Stopping Rules 
 
1. Accrual of less than 12 patients in the first year 
 
5. Subject Selection 
 
5.1 Inclusion criteria 
1.  Prior first allogeneic stem cell transplant, with any graft source, donor type, and 
GVHD prophylaxis. 
2. Patients who are on one systemic immunosuppressive agent for chronic GVHD 
with a plan to withdraw all systemic IST. Hydrocortisone or prednisone continued 
for treatment of adrenal insufficiency are not considered a systemic IST. 
3. No evidence of malignancy at the time of enrollment. 
4. Agree to be evaluated at the transplant center or by local provider every 3 months 
for 12 months after randomization. 
5. Agreement to be contacted by phone or e-mail for health status evaluation for up 
to 3 years. 
6. Signed, informed consent 
 
5.2 Exclusion criteria 
1. Inability to comply with study procedures 
2. Pregnancy 
 
6. Study Procedures 
 
6.1 Study Design  
We plan to enroll 40 patients in 2 years. Patients are eligible for enrollment at any time 
after an allogeneic transplant, as long as they were diagnosed with chronic GVHD, are 
on one immunosuppression agent, and are planning to withdraw all IST. Patients will be 
randomized to either IST discontinuation (following standard of care practice) or 
continuation of IST for an additional 9 months (investigational). If patients are enrolled 
on the study prior to reaching the IST dose that the attending physician recommends 

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they continue should they be randomized to the continuation IST arm, randomization 
will take place before the patient gets to the IST dose that would be continued if they 
are randomized to the IST continuation arm (investigational arm). If patients are enrolled 
on the study while they are already taking the IST dose that the attending physician 
recommends they continue should they be randomized to the continuation IST arm, 
randomization will take place at time of enrollment (Figure 1). Randomization will occur 
within three months of study enrollment. Patients will be actively followed for 12 months 
after randomization. After active participation will continue long term annual follow up 
via chart review.  
Patients on the discontinuation IST arm will have their IST tapered and discontinued per 
the plan of the treating physician, while patients on the continuation IST arm will 
continue a fixed dose IST for an additional 9 months with no taper. After 9 months, IST 
may be tapered.  
The dose of IST to be continued, if a patient is randomized to the continuation IST arm, 
will be determined by the attending physician at the time of enrollment based on the 
following overarching guidelines in the table below:  
Immunosuppressive 
therapy 
Age  18 years 
Age <18 years 
Cyclosporine 
Continuation dose should result in a level < 120 ng/mL 
Tacrolimus 
Continuation dose should result in a level < 5 ng/mL 
Sirolimus 
Continuation dose should result in a level < 3 ng/mL 
Mycophenolate mofetil 
Continuation dose 
≤ 500 mg BID 
Continuation dose 
≤ 7.5 mg/kg BID 
Prednisone 
< 20 mg/day or  
< 40 mg every other day 
< 0.25 mg/kg/day or  
< 0.5 mg every other day 
Any other agent 
Defined by the treating physician at the time of 
enrollment 
 
For further evaluation of adult patients’ health status, adult participants will be asked to 
complete a survey (Appendix A) based on the PROMIS-29 and Lee Symptom Scale. 
Please note that patient surveys might be reformatted for ease of completion and to 
ensure uniform font and style in the two documents or to correct any formatting or 
typographical errors. However, no questions will be added without IRB approval. 
 
Patients will be asked to complete the survey at enrollment, randomization, every 3 
months after randomization, at the end of the active study participation (12 months after 
randomization), and if IST resumed/dose increased (if still during the active study 
participation period).  
 
The Patient-Reported Outcomes Measurement Information System (PROMIS®), is a 
set of person-centered measures developed with NCI support (10). The PROMIS-29 
profile contains 7 PROMIS domains with 4 questions each (short-forms using Likert 
scales), and one pain intensity (0-10) question. All PROMIS scores use a standardized 
t-score metric against normative data for the U.S. general population (11, 12). The scale 
takes less than 5 minutes to complete.  

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The Lee cGVHD symptom scale is a 30 item measure with 7 domains capturing 
bothersome symptoms from chronic GVHD (13). The Lee cGVHD symptom scale is 
sensitive to change in patient status with 6-7 point differences being clinically 
meaningful (14, 15). The scale takes 2-5 minutes to complete. 
 
Pediatric patients will not be asked to complete the surveys, which were designed to the 
adult population. No Patient-Reported Outcomes Measurement or symptom scale 
surveys have been validated for transplant pediatric population. Thus, pediatric 
participants would not be asked to complete surveys.     
 
Whole blood samples will be collected for research. All effort will be made to collect 40 
mL blood samples (see table for children <40 kg) at enrollment, randomization, and 
monthly until one year after randomization, and at times of IST resumption or dose 
increase.  
 
 
25-40 kg 
10-24.99 kg 
<10 kg 
Maximum volume of each blood draw 
20 mL 
10 mL 
5 mL 
Maximum volume in 1 year 
260 mL 
130 mL 
65 mL 
  
Patients may participate without donating blood but every effort will be made to collect 
the samples, including use of remote draw and overnight shipping. 
 
 
 
Figure 1. Study design 

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6.2 Study Design Rationale 
Need for a feasibility study: This study is based on the hypothesis that prolonged low 
dose IST will prevent GVHD exacerbation and need to resume of high doses of IST. 
Preliminary data in support of this hypothesis are derived from a retrospective study 
demonstrating that approximately half of patients with chronic GVHD who stop IST need 
to restart treatment after a median of 3-6 months. The only way to test this hypothesis is 
with a randomized trial but the sample size for such a study is prohibitive without 
evidence that patients can be enrolled and randomized, that they will follow their 
assigned treatment, and that the observations about IST resumption in the retrospective 
study appear accurate. 
 
Justification for allowing heterogeneity in last agent, tapering schedules, and dose to 
continue in the intervention arm: As patients with chronic GVHD respond to a variety of 
immunosuppressive agents and doses, there is no unified treatment protocol for chronic 
GVHD. Similarly there are no uniform criteria when attempts to stop IST should be 
initiated. In our retrospective study the last immunosuppressive regimen to be 
discontinued was variable, including calcineurin inhibitors (43%), prednisone (28%), 
sirolimus (19%), or mycophenolate mofetil (10%). Thus, after discussion with the LTFU 
attendings, we elected to allow heterogeneity in plans for IST taper timing and speed. 
This study design mirrors routine clinical practice and allows us to capture data about 
the most common practices regarding IST discontinuation.  At the time of enrollment, 
physicians must specify the dose/schedule at which they are comfortable randomizing a 
patient to possibly continue stable treatment for an additional 9 months. Ideally, this 
would be a dose that does not cause toxicity and also controls GVHD. 
 
Enrollment time: We will enroll patients at the time when they are only taking one 
immunosuppressive agent, chronic GVHD is under control and the plan is to start 
tapering IST, or when patients are already tapering IST. Patients may be enrolled on the 
study before or at the time they are taking the IST dose that the attending physician 
recommends they continue should they be randomized to the continuation IST arm. 
Enrolling patients before or at the time they reach the IST dose that may be continued 
should they be randomized to the continuation IST arm (Figure 1) allows us to present 
the protocol to patients when they are seen in the clinic, which will increase the chance 
of enrolling patients on the study (Patients with well controlled GVHD are seen in clinic 
infrequently and thus may be seen before or at the time they have already reached the 
lower IST dose to be continued).  
 
6.3 Subject Registration and Informed Consent  
 
Eligible subjects will be identified by the SCCA LTFU or SCH providers and the study 
staff. A complete, signed, study informed consent is required for registration. 
 
Before enrollment, the study investigator or sub-investigators will discuss the study and 
consent form thoroughly with the potential participant. The study will be presented as 
objectively as possible and the potential risks and hazards of the study explained to the 

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subject. Consent will be obtained using forms approved by the Institutional Review 
Board of the Fred Hutchinson Cancer Research Center (FHCRC).  
 
The study and consent form will be discussed with potential participants at their LTFU at 
the SCCA or SCH visits. However, if the patient requests to think about the study prior 
to making final decision, the study PI or sub-PI will call the patient about a week after 
his/her appointment, will review the study and consent form again, answer any 
questions the patient might have, and if the patient is interested he/she will sign consent 
over the phone.  The rational for the telephone follow-up and not in person follow-up is 
that many of the patients are not local, and the phone follow-up will decrease burden on 
the patient. If patient would like to have in person follow-up this option would be 
available.  
 
If subject signs the informed consent at home (after discussing the study procedure and 
its potential risk with the study investigator or sub-investigator), he/she will mail the 
signed informed consent form (ICF) to the FHCRC and the document will be signed by 
the person who obtained the consent over the phone. The investigator/sub-investigator 
will document the consent discussion in the medical record.  A copy of the ICF will be 
provided to the subject. Signed ICFs will remain in each subject’s chart. 
 
6.4 Data Collection  
Provider and patient assessments will be collected in the form of study surveys at 
enrollment, and if possible at randomization, and every three months for 12 months and 
at times of IST resumption or increased dose, if still during the period of active study 
participation. If patients cannot be seen at the SCCA or SCH clinic at these time points, 
an effort will be made to collect the pertinent information from the patients’ local 
providers. The study team will contact participants monthly via phone or email to check 
on each patient’s status. Additional information (e.g. laboratory test results) would be 
obtained from the patients’ records.  
 
For further evaluation of patients’ health status, adult participants will be asked to 
complete a survey based on the PROMIS-29 and Lee symptoms scale (Appendix A). 
Patients will be asked to complete the survey at enrollment, randomization, every 3 
months after randomization, at the end of the active study participation (12 months after 
randomization) and if IST resumed/dose increased (if still during the active study 
participation period). If a patient is not seen in clinic, questionnaires will be mailed to the 
patient.  
 
Following the 12 months active participation period, participants will be followed by chart 
review annually to determine disease status, GVHD status, IST status, and survival. 
 
6.5 Study Procedures 
Eligible patients will be identified at Seattle Cancer Care Alliance or Seattle Children’s 
Hospital by clinicians. Signed informed consent will be obtained by clinicians. All 

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females of childbearing potential will have a pregnancy test at enrollment. Pregnant 
women will be excluded from the study.  
After consent, the clinician will complete the provider survey, the patient will complete 
the patient self-assessment survey, and an effort will be made to have a research blood 
sample drawn.  
If patients are enrolled on the study prior to reaching the IST dose the attending 
physician recommends they continue should they be randomized to the continuation 
IST arm, then randomization will take place before the patient gets to the IST dose that 
would be continued if they are randomized to the IST continuation arm (investigational 
arm). If patients are enrolled on the study while they are already taking the IST dose 
that the attending physician recommends they continue should they be randomized to 
the continuation IST arm, randomization will take place at time of enrollment (Figure 1). 
The clinician and the patient will be informed about the randomization, and further IST 
management would be according to the study arm the patient was randomized to, as 
described above.  
There is no financial compensation to patients for participating in this study.  
Participants will be contacted by the study coordinator via phone or email (according to 
their preference) monthly, if they are not seen at the LTFU clinic. The study coordinator 
will review health status, confirm future clinic schedules and check whether IST was 
restarted for GVHD. Following the 12 months active participation period, participants will 
be followed by chart review annually to determine disease status, GVHD status, IST 
status, and survival. 
Research blood samples will be collected from patients at time of enrollment, and 
potentially several time points after enrollment as discussed above in section 6.1.  
Data will be entered electronically into a password-protected database using only the 
participant study ID. All data will be maintained in secured areas (locked file cabinets 
and password-protected electronic databases).  
If a patient relapses with their primary disease and requires systemic anti-cancer 
treatment, data collection from the patient and clinician will cease and no additional 
research samples will be taken. The patient will continue to be followed via chart review. 
The intent is to randomize patients within three months of enrollment. If a patient has 
not been randomized within three months of enrollment, data collection from the patient 
and clinician will cease and no additional research samples will be taken. The patient 
will continue to be followed via chart review. 
If a participant or the partner of a research participant becomes pregnant during the 
study, the principal investigator will follow the pregnant female for pregnancy outcome. 
 

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6.6 Adverse Reactions and their Management 
Prolonged IST on the continuation IST arm may result in increased risk of infection, 
treatment related organ toxicity, and increased risk for relapse. Earlier discontinuation of 
IST on the discontinuation arm may result in increased risk for GVHD exacerbation, 
required initiation of high dose immunosuppression, which again may result in increased 
risk of infection, treatment related organ toxicity, and increased risk for relapse. 
Treatment of any complication will be at the discretion of the patient’s provider.  
Blood collection for research purposes will usually be done at the same time as clinical 
sampling.  
If an adverse event occurs as a result of study participation, the PI will ensure 
appropriate follow-up is carried out until the effects of the adverse event are resolved.  If 
the study staff becomes aware of any unanticipated severe adverse reactions due to 
study participation, the circumstances will be reported to the IRB. To note, clinical 
events and/or laboratory findings related to IST will not be reported as adverse events, 
since both discontinuation or prolonged continuation of IST are used in practice.  
 
6.7 Data and Specimen Storage 
Blood samples will be collected for future laboratory studies. Participants will donate 
whole blood at enrollment and additional time points as detailed in section 6.1. Samples 
will be processed according to standard procedures and labeled with a sample 
identification number. Samples will be stored in a repository and may be used to study 
chronic GVHD and/or other transplant complications. 
 
All study data will be stored in the master database using only the participant’s unique 
identifier.  The link to the participant’s identity will be maintained separately from the 
study data.  
 
7. Statistical Considerations 
 
7.1. Statistical Analysis Plan 
7.1.1. Primary Endpoint 
The primary objective of this study is to assess feasibility of enrolling and randomizing 
patients with chronic GVHD to discontinuation (discontinuation IST arm; standard of 
care) versus prolonged continuation of IST (continuation IST arm; investigational arm).  
 
Feasibility will be assessed by accrual rate of 20 patients per year. Early stopping of the 
accrual to the study is low accrual rate defined as less than 12 patients enrolled in the 
first year.  

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7.1.2. Secondary Endpoints 
The secondary objective of this study includes three parts: 1) treatment compliance 
including rate of patient reaching randomization and rate of patients following study 
specific IST management based on study arm; 2) assess feasibility (enrollment and 
data collection) for patients who are not local; and 3) assess whether continuation IST 
decreases the need for pulses of high does IST and efficacy and safety evaluation of 
continuation IST arm  
 
Secondary endpoint analyses will be descriptive.  The analyses will be conducted by 
overall population, patients who are not local, and by arm, as applicable.  
 
The summary statistics for continuous variables will include sample size, mean, 
standard deviation (SD), median, minimum and maximum for both baseline and post-
baseline measurements (if applicable). The summary statistics for categorical variables 
will include sample size, frequency and percentages.  The difference between two arms 
will be examined if applicable. Fisher’s exact test will be proposed to test the difference 
between two arms for categorical variables. 
7.1.3. Methods 
Descriptive summary table will be provided for overall study population, and by each arm, 
respectively.  The summary statistics for continuous variables will include sample size, 
mean, standard deviation (SD), median, minimum and maximum for both baseline and 
post-baseline measurements (if applicable). The summary statistics for categorical 
variables will include sample size, frequency and percentages.  The difference between 
the two arms will be examined if applicable. Fisher’s exact test will be proposed to test 
the difference between two arms for categorical variables.  
 
7.2. Sample Size and Power 
This feasibility study is to assess the ability to enroll and randomize patients with 
chronic GVHD to discontinuation versus continuation of IST.  Sample size of 40 patients 
is based on the anticipated availability of eligible patients. Although the study is not 
powered based on a specific null hypothesis, if 20 patients are enrolled in each arm, we 
will have 83% power to see statistically significant difference between two arms (at the 
two-sided level of 0.1) if the true 12 months rate of IST resumption in discontinuation 
IST arm is 75% and true 12 months rate of increase IST dose in investigation arm is 
30%. 
 
8. Risks and Discomforts 
Prolonged IST on the continuation IST arm (investigational arm) may result in increased 
risk of infection, treatment related organ toxicity, and increased risk for relapse. Earlier 
discontinuation of IST on the discontinuation arm (standard of care) may result in 
increased risk for GVHD exacerbation, required initiation of high dose 
immunosuppression, which again may result in increased risk of infection, treatment 

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related organ toxicity, and increased risk for relapse. Treatment of any complication will 
be at the discretion of the patient’s provider.  
Blood collection for research purposes will usually be done at the same time as clinical 
sampling.  
9. Potential Benefits 
Based on retrospective data demonstrating that approximately 50% of patients who stop 
IST require resumption of IST due to GVHD exacerbation, the continuation arm of this 
study (investigational arm) offers potential benefit of decreasing the risk of chronic 
GVHD exacerbation and decreasing the need for resuming high-dose IST. 
 
10. Adverse Events/Serious Adverse Events  
 
10.1 Adverse Events  
According to ICH guidelines (Federal Register. 1997; 62(90):25691-25709) and 21 CFR 
312.32, IND Safety Reports, and ICH E2A, Definitions and Standards for Expedited 
Reporting, an adverse event is defined as follows: 
An adverse event is any untoward medical occurrence in a clinical investigation 
subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
Abnormal laboratory values for laboratory parameters specified in the study 
should not be recorded as an adverse event unless an intervention is required 
(repeat testing to confirm the abnormality is not considered intervention), the 
laboratory abnormality results in a serious adverse event or the adverse event 
results in study termination or interruption/discontinuation of study treatment. 
Medical conditions present at screening (i.e., before the study treatment is 
administered) are not adverse events and should not be recorded on adverse 
event pages of the CRFs.  These medical conditions should be adequately 
documented on the subject chart.  However, medical conditions present at 
baseline that worsen in intensity or frequency during the treatment or post-
treatment periods should be reported and recorded as adverse events. 
Events that do not meet the definition of an AE or SAE include:  
• 
Any clinically significant abnormal laboratory finding or other abnormal 
safety assessments that is associated with the underlying disease, unless 

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judged by the investigator to be more severe than expected for the 
subject’s condition. 
• 
The disease/disorder being studied, or expected progression, signs, or 
symptoms of the disease/disorder being studied, unless more severe than 
expected for the subject’s condition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the 
condition that leads to the procedure is an AE 
• 
Situations where an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the study that do not 
worsen 
• 
Clinical events or laboratory findings related to immunosuppressive 
therapy 
10.2 Serious Adverse Events 
An adverse event should be classified as an SAE if it meets one of the following criteria: 
 
Fatal 
Adverse event results in death. 
Life threatening:  
The adverse events placed the subject at immediate risk of 
death. This classification did not apply to an adverse event that 
hypothetically might cause death if it were more severe.  
Hospitalization:  
It required or prolonged inpatient hospitalization. Hospitalizations 
for elective medical or surgical procedures or treatments planned 
before enrollment in the treatment plan or routine check-ups are 
not SAEs by this criterion. Admission to a palliative unit or 
hospice care facility is not considered to be a hospitalization.  
Disabling/incapacitating  Resulted in a substantial and permanent disruption of the 
subject’s ability to carry out normal life functions.  
Congenital anomaly or 
birth defect:  
An adverse outcome in a child or fetus of a subject exposed to 
the molecule or treatment plan regimen before conception or 
during pregnancy.  
Medically significant:  
The adverse event did not meet any of the above criteria, but 
could have jeopardized the subject and might have required 
medical or surgical intervention to prevent one of the outcomes 
listed above.  
 
10.3 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
SAEs  
An event which is part of the natural course of the disease under study (i.e., disease 
progression) does not need to be reported as an SAE.  However, if the progression of 
the underlying disease is greater than that which would normally be expected for the 
subject, or if the investigator considers that there was a causal relationship between 
treatment with investigational product or protocol design/procedures and the disease 
progression, then this must be reported as an SAE. 

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10.4 Unexpected Adverse Event 
An unexpected adverse event is defined as an event that has a nature or severity, or 
frequency that is not consistent with the applicable investigator brochure, or the prior 
medical condition of the subject or other treatment given to the subject.  “Unexpected,” 
as used in this definition, refers to an adverse drug experience that has not been 
previously observed and reported in preclinical or clinical studies rather than an 
experience that has not been anticipated based on the pharmacological properties of 
the study drug. 
 
10.5 Monitoring and Recording Adverse Events 
All AEs will be assessed by the investigator or qualified designee and recorded in the 
CRFs. The investigator should attempt to establish a diagnosis of the event on the basis 
of signs, symptoms and/or other clinical information. In such cases, the diagnosis 
should be documented as the adverse event and/or serious adverse event and not 
described as the individual signs or symptoms. The following information should be 
recorded: 
• Description of the adverse event using concise medical terminology 
• Description as to whether or not the adverse event is serious, noting all criteria 
that apply  
• The start date (date of adverse event onset) 
• The stop date (date of adverse event resolution) 
• The severity (grade) of the adverse event  
• A description of the potential relatedness of the adverse event to study drug, a 
study procedure, or other causality  
• The action taken due to the adverse event 
• The outcome of the adverse event 
 
If an adverse event occurs as a result of study participation, the PI will ensure 
appropriate follow-up is carried out until the effects of the adverse event are resolved.  If 
the study staff becomes aware of any unanticipated severe adverse reactions due to 
study participation, the circumstances will be immediately reported to the IRB. To note, 
clinical events related to IST will not be reported as adverse events, since both 
discontinuation or prolonged continuation of IST are used in practice. All AEs and SAEs 
will be reported to the DSMC at least annually.  
 
10.6 Grading Adverse Event Severity 
All AEs will be graded in severity according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0. If a CTCAE criterion does not exist, the 
investigator should use the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to describe the maximum 
intensity of the adverse event.  
 

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10.7 Attribution of an Adverse Event 
Association or relatedness to the study agent will be assessed by the investigator as 
follows: 
• Definite: The event follows a reasonable temporal sequence from exposure to 
the investigational agent, has been previously described in association with the 
investigational agent, and cannot reasonably be attributed to other factors such 
as the subject’s clinical state, other therapeutic interventions or concomitant 
medications; AND the event disappears or improves with withdrawal of the 
investigational agent and/or re-appears on re-exposure (e.g., in the event of an 
infusion reaction). 
• Probable: The event follows a reasonable temporal sequence from exposure to 
the investigational agent and has been previously been described in association 
with the investigational agent OR cannot reasonably be attributed to other factors 
such as the subject’s clinical state, other therapeutic interventions or concomitant 
medications. 
• Possible: The event follows a reasonable temporal sequence from exposure to 
the investigational agent, but could be attributable to other factors such as the 
subject’s clinical state, other therapeutic interventions or concomitant 
medications. 
• Unlikely: Toxicity is doubtfully related to the investigational agent(s).  The event 
may be attributable to other factors such as the subject’s clinical state, other 
therapeutic interventions or concomitant medications. 
• Unrelated: The event is clearly related to other factors such as the subject’s 
clinical state, other therapeutic interventions or concomitant medications. 
 
For general AE assessment, an AE is considered related if it is assessed as definitely, 
probably, or possibly related; unrelated if it is assessed as unlikely related or unrelated.  
 
10.8 Adverse Event Recording Period 
AEs will be monitored and recorded in study-specific case report forms (CRFs) from the 
time of consent through the end of active follow-up (~12 months after randomization).  
 
 
11. Data and Safety Monitoring Plan 
Institutional support of trial monitoring will be in accordance with the FHCRC/University 
of Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under 
the provisions of this plan, FHCRC Clinical Research Support (CRS) coordinates data 
and compliance monitoring conducted by consultants, contract research organizations, 
or FHCRC employees unaffiliated with the conduct of the study.  Independent 
monitoring visits occur at specified intervals determined by the assessed risk level of the 
study and the findings of previous visits per the institutional DSMP.  

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In addition, protocols are reviewed at least annually and as needed by the Consortium 
Data and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee 
(SRC) and the FHCRC/University of Washington Cancer Consortium Institutional 
Review Board (IRB).  The review committees evaluate accrual, adverse events, 
stopping rules, and adherence to the applicable data and safety monitoring plan for 
studies actively enrolling or treating subjects.  The IRB reviews the study progress and 
safety information to assess continued acceptability of the risk-benefit ratio for human 
subjects.  Approval of committees as applicable is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory 
committees and other institutional, state and federal guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12. References 
 
1. 
Champlin RE, Schmitz N, Horowitz MM, Chapuis B, Chopra R, Cornelissen JJ, et 
al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for 
allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working 
Committee and the European Group for Blood and Marrow Transplantation (EBMT). 
Blood. 2000;95(12):3702-9. 
2. 
Castro-Malaspina H, Harris RE, Gajewski J, Ramsay N, Collins R, Dharan B, et 
al. Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome 
analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood. 
2002;99(6):1943-51. 
3. 
Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. 
Comparative analysis of risk factors for acute graft-versus-host disease and for chronic 
graft-versus-host disease according to National Institutes of Health consensus criteria. 
Blood. 2011;117(11):3214-9. 
4. 
Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood 
Marrow Transplant. 2003;9(4):215-33. 
5. 
Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, et al. Duration of 
immunosuppressive treatment for chronic graft-versus-host disease. Blood. 
2004;104(12):3501-6. 
6. 
Vigorito AC, Campregher PV, Storer BE, Carpenter PA, Moravec CK, Kiem HP, 
et al. Evaluation of NIH consensus criteria for classification of late acute and chronic 
GVHD. Blood. 2009;114(3):702-8. 
7. 
Inamoto Y, Flowers ME, Lee SJ, Carpenter PA, Warren EH, Deeg HJ, et al. 
Influence of immunosuppressive treatment on risk of recurrent malignancy after 
allogeneic hematopoietic cell transplantation. Blood. 2011;118(2):456-63. 
8. 
Feng S, Ekong UD, Lobritto SJ, Demetris AJ, Roberts JP, Rosenthal P, et al. 
Complete immunosuppression withdrawal and subsequent allograft function among 
pediatric recipients of parental living donor liver transplants. JAMA. 2012;307(3):283-93. 
9. 
Lee SJ, Nguyen TD, Onstad L, Bar M, Krakow EF, Salit RB, Carpenter PA, 
Rodrigues M, Hall AM, Storer BE, Martin PJ, Flowers ME. Success of 
immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol 
Blood Marrow Transplant. 2017; In press. 
10. 
Cella D, Riley W, Stone A, Rothrock N, Reeve B, Yount S, et al. The Patient-
Reported Outcomes Measurement Information System (PROMIS) developed and tested 
its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin 
Epidemiol. 2010;63(11):1179-94. 
11. 
Liu H, Cella D, Gershon R, Shen J, Morales LS, Riley W, et al. 
Representativeness of the Patient-Reported Outcomes Measurement Information 
System Internet panel. J Clin Epidemiol. 2010;63(11):1169-78. 
12. 
Rothrock NE, Hays RD, Spritzer K, Yount SE, Riley W, Cella D. Relative to the 
general US population, chronic diseases are associated with poorer health-related 
quality of life as measured by the Patient-Reported Outcomes Measurement Information 
System (PROMIS). J Clin Epidemiol. 2010;63(11):1195-204. 

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13. 
Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to 
measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 
2002;8(8):444-52. 
14. 
Pidala J, Kurland BF, Chai X, Vogelsang G, Weisdorf DJ, Pavletic S, et al. 
Sensitivity of changes in chronic graft-versus-host disease activity to changes in patient-
reported quality of life: results from the Chronic Graft-versus-Host Disease Consortium. 
Haematologica. 2011;96(10):1528-35. 
15. 
Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S, et al. Patient-
reported quality of life is associated with severity of chronic graft-versus-host disease as 
measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. 
Blood. 2011;117(17):4651-7. 
 

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11. Appendix 
Appendix A. Patient Survey 
 

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Appendix A. Patient Survey (cont.) 
 

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Appendix A. Patient Survey (cont.) 
 

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Appendix A. Patient Survey (cont.) 
 

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Appendix A. Patient Survey (cont.) 
 
 

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Appendix A. Patient Survey (cont.)