Conditions: Chronic Graft-versus-host-disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 159
Healthy volunteers: yes

Brief summary:
This is a Phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025 in subjects with Chronic Graft Versus Host Disease (cGVHD) after at least 2 prior lines of systemic therapy

Detailed description:
Phase 2, open label, randomized, multicenter study in subjects with cGVHD who have previously been treated with at least 2 prior lines of systemic therapy. Approximately 166 subjects with active cGVHD will be randomized (1:1) to receive treatment with one of two belumosudil (formerly known as KD025) regimens:

* Arm A: belumosudil 200 mg QD
* Arm B: belumosudil 200 mg BID

With Amendment 2, the sample size was increased from approximately 126 subjects, with additional subjects to be enrolled as follows:

* 20 adolescents
* 20 adults into a site-specific Companion Study to collect biospecimens

These additional subjects will also be randomized (1:1) to Arm A or Arm B.

Any adolescent taking a proton pump inhibitor (PPI) or a strong CYP3A4 inducer will begin Cycle 1 Day 1 at the escalated dose of belumosudil 200 mg BID.

Randomization will be stratified according to prior cGVHD treatment with ibrutinib (Yes / No) and severe cGVHD at baseline (Yes / No). Subjects may receive treatment in 28-day treatment cycles until clinically significant progression of cGVHD. Subjects who have not achieved a response after 12 cycles of belumosudil should be withdrawn if in the Investigator's judgment there is no evidence of clinical benefit. Subjects will undergo evaluations as outlined in the Study Assessments table (Appendix A). The primary endpoint is the overall response rate (ORR) with responses as defined by the 2014 National Institute of Health (NIH) Consensus Development Project on clinical trials in cGVHD.

Arms:
arm 1: Eligible subjects randomized to arm A will take belumosudil 200 mg once daily arm 2: Eligible subjects randomized to arm B will take belumosudil 200 mg twice daily arm 3: Eligible subjects randomized to arm A will take belumosudil 200 mg once daily arm 4: Eligible subjects randomized to arm B will take belumosudil 200 mg twice daily

Interventions: intervention 1: Belumosudil (KD025)
Intervention descriptions: intervention 1: Belumosudil is an orally available Rho-associated protein kinase-2 (ROCK2) selective inhibitor.

Protocol document:
Prot_000.pdf: 
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AMENDED CLINICAL TRIAL PROTOCOL 05 
A Phase 2, Randomized, Multicenter Study to Evaluate the Efficacy 
and Safety of KD025 in Subjects with Chronic Graft Versus Host 
Disease (cGVHD) After At Least 2 Prior Lines of Systemic Therapy 
(The ROCKstar Study) 
 
Protocol Number: 
KD025-213 (DRI17633) 
Study Drug: 
KD025 (SAR445761) 
INN:  
Belumosudil 
IND Number: 
IND 125890 
NCT Number: 
NCT03640481 
Phase: 
2 
Sponsor: 
Kadmon Corporation, LLC 
 
55 Corporate Drive 
 
Bridgewater, NJ 008807 
Steering Committee: 
 Chair 
, 
 
Co-chair 
, 
 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 05 
United States 
14 March 2023, version 1 (electronic 6.0) 
Clinical Study Protocol, Amendment 4 
United States 
11 April 2022 
Clinical Study Protocol, Amendment 3 
United States 
30 August 2021 
Clinical Study Protocol, Amendment 2 
United States 
01 June 2020 
Clinical Study Protocol, Amendment 1 
United States 
26 June 2019 
Clinical Study Protocol (Original) 
United States 
25 June 2018 
a The name and numbering of the protocol is based on a new numbering system followed by the Sponsor 
AMENDED PROTOCOL 05 (14 March 2023) 
This amended protocol (amendment 05) is considered to be substantial. 
OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of this amendment includes revising the eligibility criterion of AST/ALT increase, 
adjusting the frequency of clinical visits with the aim of reducing patient burden and updating 
the safety and contraception sections as per Sanofi standards. Other changes include 
clarifications or corrections of protocol inconsistencies. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Modified logo, protocol information (ie, “CLINICAL TRIAL 
PROTOCOL” modified to “AMENDED CLINICAL TRIAL 
PROTOCOL 05”), protocol number, study drug, sponsor 
address, and document history text. Added INN. 
Updated per Sanofi standards 
Procedures in Case of 
Emergency 
Removed contact information of Medpace medical monitor and 
modified SAE reporting contact information. 
Updated per Sanofi standards 
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Section # and Name 
Description of Change 
Brief Rationale 
Throughout the document 
Modified header and footer 
Updated per Sanofi standards 
 
Replaced “subject” and “patient” to “participant” as necessary 
Updated per Sanofi standards 
 
Modified text on 12-lead ECG throughout the document, as 
applicable, such that it details that it is a “single” 12-lead ECG, 
and such that text on triplicate measurements are removed, and 
that from Cycle 19, ECG is only done if clinically indicated 
Update 
 
Replaced “Kadmon” or “Kadmon Corporation” with “Sponsor” 
Updated per Sanofi standards 
 
Added “assent” or “assent form” to be associated with informed 
consent or informed consent form wherever relevant 
Updated per Sanofi standards 
Sponsor Approval 
Signature Page 
Removed entirely 
Updated per Sanofi standards 
Investigator Signature Page 
Removed entirely 
Updated per Sanofi standards 
Synopsis 
Modified text, including that ibrutinib is indicated for pediatric 
patients aged 1 year and older and added text on ruxolitinib and 
its indication for cGVHD. 
Modified text to provide 
updated information on FDA 
approved drugs for treatment 
of cGVHD 
 
Modified text as follow: “20 adults into a site-specific 
Companion Study to collect biospecimens (Appendix 
OSection 21.13 Appendix M), these participants will also be 
randomized (1:1) to Arm A or Arm B” 
Updated study design 
Synopsis, 2.1 Primary 
objectives 
Safety of belumosudil was changed from a primary objective to 
a secondary objective and sections were updated accordingly 
Clarification to be aligned with 
the study endpoints 
Synopsis, 3.1 Study design 
Removed “Subjects who have not achieved a response after 12 
cycles of belumosudil should be withdrawn if in the 
Investigator’s judgment there is no evidence of clinical benefit.” 
Also removed “(Section 4.7)” from section 3.1. 
Clarification to be aligned with 
the United States Prescription 
Information (USPI) 
 
Schema was updated 
Updated schema to reflect 
update made in the study 
design 
Synopsis, 3.1 Study design, 
5.2 Dosage and 
Administration 
Text was updated with a modified version of removed Appendix 
N text 
Clarification 
Synopsis, 1.5 Study 
rationale, 3.1 Study design, 
4.1 Number of participants, 
5.2 Dosage and 
administration, 5.3 
Treatment assignment, 22.1 
Appendix A: Schedule of 
assessments, Appendix N  
Removed appendix N (ie, Adolescent Cohort Addendum) and 
subsequent appendices were renumbered accordingly. Text 
referring to appendix N was removed throughout the document.  
Removed to complement 
update in the study design, 
which took part of appendix N 
text in this update  
Synopsis, 4.3 Inclusion 
criteria, 4.4 Exclusion 
criteria 
Replaced inclusion criteria #3 with modified version of exclusion 
criteria #1 (ie, removed “not”). Added to exclusion criteria #1 
“E01 is no longer applicable per amended protocol 05” 
Updated inclusion and 
exclusion criteria as current 
standard of care may not 
include steroid therapy, which 
has been identified as a 
barrier to enrollment 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, 4.3 Inclusion 
criteria 
Added “(≤5 × ULN if due to cGVHD)” to inclusion criteria #8 
Clarification 
 
For inclusion criteria 11-13, added a statement that they are no 
longer applicable per amended protocol 05 and added entire 
subsection on “Sex, contraceptive/barrier method and 
pregnancy testing requirements/breastfeeding” 
Updated per Sanofi standards 
Synopsis, 4.4 Exclusion 
criteria 
Removed the following subheading “General Criteria” 
Removed since this 
subheading is not necessary 
Synopsis 
Updated text on safety variables (ie, removed PEs and modified 
text on AE reporting period) 
Physical exam was removed 
since it is not mandatory and 
updated text to improve clarity 
of language 
Synopsis, 3.1 Study design 
Updated text such that sparse PK sample is to be performed for 
the whole population, including the adolescent participants 
Update 
1.4 Belumosudil 
Background (Clinical) 
Modified text to highlight that Phase 2 studies of belumosudil 
are now either ongoing or completed. Removed study numbers, 
added diffuse cutaneous systemic sclerosis, and updated the 
number of study participants from 300 to 750.  
Updated text to align with the 
stage of, and the information 
based on, completed and 
ongoing belumosudil studies. 
Removed study numbers to 
improve clarity.  
 
Removed “Data from the KD025 208 study in subjects with 
cGVHD are summarized in Section 1.4.1.”  
Removed since extensive 
study details were removed 
from Section 1.4.1 per Sanofi 
standards 
1.4.1 KD025-208 
Replaced “an ongoing” with “a completed” 
Updated text to align with the 
stage of KD025-208 study, 
which has been completed 
 
Replaced “Data from this ongoing study, with a data cut-off date 
of 19-Feb-2020, are presented below. This data was reported 
out in a Clinical Study Report (dated 07-Jul-2020).” with “Refer 
to the belumosudil IB for more detailed information.” 
Updated per Sanofi standards 
and removed extensive study 
details from the protocol 
1.4.1.1 Demographics and 
Baseline Characteristics, 
1.4.1.2 Subject Disposition, 
1.4.1.3 Efficacy, 1.4.1.4 
Safety 
Removed entire sections 
Removed extensive study 
details from the protocol per 
Sanofi standards 
1.6 Summary of Known and 
Potential Risks and Benefits 
to Human Participants 
Added text that details marketing authorization of belumosudil 
in Australia, Canada, and UK. 
Update 
2.1 Primary objectives 
Removed “and safety” 
Clarification to be aligned with 
the study endpoints 
3.1 Study design 
Added: “Following Protocol Amendment 5, in adolescent 
participants still to be enrolled, response criteria will be 
assessed after Cycles 1, 2, 4, and 6 and then after every third 
cycle (Day 1 of cycles 2, 3, 5, 7, 10, 13, etc.).” 
Update 
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Section # and Name 
Description of Change 
Brief Rationale 
4.7 Withdrawal Criteria 
Added “, at the Investigator’s discretion”  
Update 
 
Removed “In addition, subjects should be withdrawn from the 
study if there has been no response after 12 cycles of 
treatment, if in the judgement of the Investigator there has been 
no clinical benefit for the subject, eg, in terms of organ score 
improvements, improvements in Lee symptom scores or 
reductions of corticosteroid / tacrolimus doses.” 
Update 
4.8.1 Treatment 
Discontinuation 
Added “pregnancy” 
Correction 
 
Added “In case a participant wants to permanently discontinue 
the treatment (ie, withdrawal of consent for the intervention), the 
participant will be asked if a final assessment is possible to be 
performed using the procedure normally planned for the last 
dosing day (EOT and at 28-day follow up visit) with the IMP 
prior to consent of the withdrawal. See the SoA (Section 6.1) for 
the data to be collected at the time of the study treatment 
discontinuation, for information on the follow-up, and for any 
further evaluations that would need to be completed.” 
Update 
5.2 Dosage and 
Administration 
Updated dosage and administration text regarding the cycles 
for PK/PD sampling, and regarding when and where 
belumosudil should be taken (ie, home or clinic). 
Updated PK/PD sampling 
schedule. Updated text to 
allow increased flexibility in 
terms of where doses can be 
taken to reduce participant 
burden. 
5.2.1 Belumosudil Tapering 
Guidance 
Replaced “Belumosudil will be tapered” with “Tapering of 
belumosudil is allowed” and added “at the Investigator’s 
discretion”  
Updated text to improve clarity 
of language and also to clarify 
that tapering of belumosudil 
and cessation of all other 
immunosuppressants should 
be determined at the 
discretion of the Investigator. 
5.6 Missed Doses 
Added “Participants should make every effort to take the study 
drug at the same time every day with their morning/evening 
meal.” 
Update 
5.9 Treatment of Overdose 
Updated first sentence as “Any dose of belumosudil >1000 mg 
within a 24-hour period will be considered an overdose.” 
Update in overdose definition 
5.10 Dose Modification 
Guidelines 
Modified Guidelines for Management of Treatment Emergent 
Toxicities table (ie, Table 2) 
Update 
 
Removed Belumosudil Dose Decrements table (ie, Table 5 
previously), the text below the table (ie, “If the reduced dose is 
tolerated for 1 complete cycle, the dose may be escalated to 
the previous dose.”), and the statement referencing this table 
(ie, “When dose reduction is necessary, the dose should be 
decreased as shown in Table 5) 
Update 
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Section # and Name 
Description of Change 
Brief Rationale 
6.2.1 Screening, 6.2.2 
Cycle 1, Day 1 (Baseline), 
6.2.4 Cycle 2 and Beyond, 
Day 1 (±3 days), 6.2.5 End 
of Treatment (EOT), 6.2.6 
28-Day Follow-Up Visit 
Modified text on pregnancy test to state as follows: Highly 
sensitive urine or serum pregnancy test (for females of 
childbearing potential). Positive urine results are to be 
confirmed with serum testing. 
Updated text to clarify the type 
of test required to assess 
pregnancy and to improve 
clarity of language 
6.2.4 Cycle 2 and Beyond, 
Day 1 (±3 days) 
Modified text, expanding upon the cycles beyond Cycle 2 
Modified text to clarify the 
cycles that participants will 
need to be back at the clinics 
for 
 
Modified text such that single 12-lead ECG is to be done on 
C2D1, C3D1, C5D1, C7D1, and Day 1 of every 3rd cycle 
thereafter through C19D1, and only if clinically indicated from 
C19D1 and onward for pre-dose 
Update 
 
Changed cycle number such that full PFT is required after 
Cycle 2 (ie, Day 1 of Cycle 3) instead of after Cycle 3 (ie, Day 1 
of Cycle 4) 
Update 
 
Replaced “These items must be completed on Day 1 of Cycles 
2-5, then on Day 1 of every other Cycle thereafter, (i.e. Day 1 of 
Cycles 2, 3, 4, 5, 7, 9, 11 etc.)” with “These items must be 
completed on Day 1 of Cycles 2, 3, 5, 7, then on Day 1 of every 
3 cycles thereafter, (Day 1 of Cycles 10, 13, 16, 19 etc.)” 
 
 
Replaced “From Cycle 19, Day 1 (C19D1), subjects may 
receive 2 cycles worth of study drug along with 2 diaries and 
return to the clinic every other cycle for assessments and 
investigational product accountability.” with “On Cycle 2 Day 1 
(C2D1) participants will receive study drug for 1 cycle along 
with 1 diary. On Cycle 3 and 5 Day 1 (C3D1 and C5D1), 
participants will receive the study drug for the next 2 cycles 
along with 2 diaries, and from cycle 7 onwards (C7D1, C10D1, 
C13D1 etc.) participants will receive the study drug for 3 cycles 
along with 3 diaries and return to the clinic every 3 cycles for 
assessments and investigational product accountability.” 
Update 
6.2.4 Cycle 2 and Beyond, 
Day 1 (±3 days), 7.2 Full 
PK, 21.1 Appendix A: 
Schedule of Assessments 
Text on Sparse PK was updated to reflect change of sparse PK 
sampling from Cycle 4 to Cycle 7 and removal of sparse PK 
sampling 5 hours post dose. 
Updated PK sampling 
6.4.5 Pregnancy Testing 
Modified text on pregnancy such that it details that pregnancy 
tests are to be done using highly sensitive urine or serum test at 
timepoints specified in the SoA, and that Sponsor will continue 
to collect pregnancy data until after the birth of the baby to 
assess pregnancy outcome and status of newborn, as well as, 
collecting data on the participant’s partner’s pregnancy, birth, 
and condition of newborn. 
Updated per Sanofi standards 
6.5 Use of Biological 
Samples and Data for 
future Research 
Added entire section 
Updated per Sanofi standards 
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Section # and Name 
Description of Change 
Brief Rationale 
9.1 Safety Parameters 
Removed urinalysis results from safety parameters, replaced 
“serum” chemistry with “clinical” chemistry, and added “Adverse 
events will be recorded after the ICF/assent form is signed until 
28 days after the last dose of belumosudil.” 
Update 
9.2 Adverse Event 
Definition 
Modified entire section 
Updated per Sanofi standards 
9.3 Evaluating Adverse 
Events 
Replaced “intensity” with “severity” 
Updated text to improve clarity 
of language 
9.3.1 Serious Adverse 
Events 
Modified entire section 
Updated per Sanofi standards 
9.3.2 Recording and follow-
up of AE and/or SAE 
Replaced entire section with the following section: “Recording 
and follow-up of AE and/or SAE” 
Updated per Sanofi standards 
9.3.3 Reporting 
Requirements for SAEs 
Replaced entire section with the following section: “Reporting 
Requirements for SAEs” 
Updated per Sanofi standards 
9.3.4 Relationship to 
cGVHD or Underlying 
Disease 
Removed entire section 
Updated per Sanofi standards 
9.3.5 Recording Adverse 
Events 
Removed entire section 
Updated per Sanofi standards 
9.3.6 Serious Adverse 
Event Reporting 
Removed entire section 
Updated per Sanofi standards 
9.4.2 Follow-Up of Adverse 
Events 
Removed entire section 
Updated per Sanofi standards 
14.4 Future Use of Subject 
Samples 
Removed entire section 
Updated per Sanofi standards 
20 Publication of Data and 
Protection of Trade Secrets 
Added “For those journals that request sharing of the 
analyzable data sets that are reported in the publication, 
interested researchers are directed to submit their request to 
vivli.org. 
Individual anonymized participant data and supporting clinical 
documents are available for request at vivli.org. While making 
information available we continue to protect the privacy of 
participants in our clinical trials. Details on data sharing criteria 
and process for requesting access can be found at this web 
address: vivli.org.” 
Updated per Sanofi standards 
21.1 Appendix A: Schedule 
of Assessments 
Replaced “Pregnancy test (urine)” with “Highly sensitive urine or 
serum pregnancy test” 
Updated per Sanofi standards 
 
Removed footnote d and reorganized subsequent footnotes and 
updated annotations accordingly 
Updated to clarify changes in 
assessment schedules 
 
Modified footnote e 
Updated adolescent height 
measurement schedule 
 
Modified footnote j 
Updated study drug 
administration schedule 
 
Modified footnote l 
Updated text to clarify 
changes in assessment 
schedules 
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Section # and Name 
Description of Change 
Brief Rationale 
 
In table 10, added “3, 5” to “Cycle 2” and for Cycle 19 and 
onward, modified text such that From Cycle 19 and onward, 
ECG assessments are only to be performed if clinically 
indicated 
Updated ECG assessment 
schedule 
22.9 Appendix I: 
Determining Relationship of 
AEs to Study Drug 
Removed entire appendix 
Updated per Sanofi standards 
22.10 Appendix J: PFT 
Assessments 
Updated “response” timepoints and footnote (ie, footnote a) 
Updated PFT assessment 
schedule 
 
Updated footnote b and moved ‘X’ from C4 to C3 for full PFT 
Updated PFT assessment 
schedule 
 
Updated “Spirometry” timepoints 
Updated PFT assessment 
schedule 
21.14 Appendix N: 
Contraceptive and Barrier 
Guidance 
Added entire appendix 
Updated per Sanofi standards 
21.15 Appendix O: Protocol 
Amendment History  
Added entire appendix 
Updated per Sanofi standards 
In addition, other minor editorial changes (eg, grammatical, stylistic, references, minor typographical error corrections) were 
implemented throughout the protocol. Also, abbreviations, section/table/figure/appendix numbers or letters, and dates were 
updated as needed. 
 
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Procedures in Case of Emergency 
Serious Adverse Events  
Any serious adverse event (SAE)* occurring in a participant while receiving study drug or within 
28 days of receiving their last dose of study drug, even though the event may not appear to be 
study drug related, must be promptly reported (within 24 hours) by telephone, e-mail, or telefax 
to the sponsor (or designee).  
Emergency Contact Information  
 
SAE CRITERIA 
* A SAE is any untoward medical occurrence that at any dose results in any of the following 
outcomes, regardless of relationship to study drug (see Section 9.3.1, Serious Adverse Events, 
for additional information): 
• Death. 
• Life-threatening adverse drug event. 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• A persistent or significant disability/incapacity. 
• A congenital anomaly/birth defect. 
• 
An important medical event that may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
For SAE reporting, send the SAE form, pregnancy form or follow-up within 24 hours of 
becoming aware to:  
Sanofi Pharmacovigilance 
KDM-ClinicalSAEReporting@Sanofi.com 
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SYNOPSIS 
Study Title 
A Phase 2, Randomized, Multicenter Study to Evaluate the 
Efficacy and Safety of KD025 in Subjects with Chronic Graft 
Versus Host Disease (cGVHD) After At Least 2 Prior Lines of 
Systemic Therapy 
Clinical Phase 
2 
Study Background 
Chronic graft versus host disease (cGVHD) remains a major 
complication of allogeneic hematopoietic cell transplantation 
(HCT) occurring in approximately 50% of transplant recipients and 
involving multiple organs. Patients with cGVHD require prolonged 
immunosuppressive treatment for an average of 2 to 3 years from 
the initial diagnosis, with 10% of those surviving for at least 
7 years still requiring immunosuppressive treatment at that time 
and beyond. 
Glucocorticoids, with or without calcineurin inhibitors, remain the 
standard initial treatment, but are associated with significant side 
effects and unsatisfactory outcomes, particularly for patients with 
high-risk features of cGVHD.  
Based upon data from this Study, KD025-213, the Food and Drug 
Administration (FDA) approved REZUROCK (belumosudil) for the 
treatment of adult and pediatric patients 12 years and older with 
cGVHD after failure of at least 2 prior lines of systemic therapy. 
The other FDA approved drugs for the treatment of cGVHD are 
ibrutinib and ruxolitinib. Ibrutinib is indicated for the treatment of 
adults and pediatric patients aged 1 year and older with cGVHD 
after failure of one or more lines of systemic therapy. Ruxolitinib is 
indicated for the treatment of adults and pediatric patients aged 
12 years and older with cGVHD after failure of one or two lines of 
systemic therapy. 
Belumosudil (formerly known as KD025) is an orally available 
Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor. 
Belumosudil has been shown to downregulate pro-inflammatory 
T helper 17 cells and T follicular helper cells while upregulating 
anti-inflammatory regulatory T cells, which may potentially correct 
the immunological imbalance seen in cGVHD. 
Furthermore, belumosudil has been shown to be active and well-
tolerated in cGVHD. Study KD025-208 enrolled participants with 
active cGVHD who had previously received no more than 3 prior 
lines of treatment. Approximately two-thirds of cGVHD patients 
treated with belumosudil 200 mg QD (Cohort 1) and 200 mg BID 
(Cohort 2) achieved clinical responses.  
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Study Objective(s) / 
Purpose 
The objective of this study is to evaluate the efficacy of 
belumosudil at dose levels of 200 mg QD and 200 mg BID in 
participants with cGVHD who have previously been treated with at 
least 2 prior lines of systemic therapy. 
Study Design 
Phase 2, open label, randomized, multicenter study in participants 
aged ≥12 with cGVHD who have previously been treated with at 
least 2 prior lines of systemic therapy.  
Approximately 166 participants with active cGVHD will be 
randomized (1:1) to receive treatment with one of two belumosudil 
regimens: 
• 
Arm A: belumosudil 200 mg QD 
• 
Arm B: belumosudil 200 mg BID 
With Amendment 2, the sample size was increased from 
approximately 126 participants, with additional participants to be 
enrolled as follows: 
• 
20 adolescents  
• 
20 adults into a site-specific Companion Study to collect 
biospecimens (Section 21.13 Appendix M), these participants 
will be randomized (1:1) to Arm A or Arm B. 
With amendment 4, eligible adolescent participants were enrolled 
into the study at the belumosudil 200 mg QD dose. Since 
amendment 4, there are no more randomization and stratification 
factors applied for this group. The expected sample size in each 
Arm is therefore: Arm A, N = 93 with addition of 20 adolescents 
and 10 adults and Arm B, N = 73 with addition of 10 adults. 
Randomized participants withdrawn from the study before 
receiving any study drug will be replaced. Randomization will be 
stratified according to prior cGVHD treatment with ibrutinib (Yes / 
No) and severe cGVHD at baseline (Yes / No).  
Participants may receive treatment in 28-day treatment cycles until 
clinically significant progression of cGVHD.  
Participants will undergo evaluations as outlined in the Schedule 
of Assessments (APPENDICES). 
The primary endpoint is the overall response rate (ORR) with 
responses as defined by the 2014 National Institutes of Health 
(NIH) Consensus Development Project on clinical trials in cGVHD. 
Responses are assessed with respect to baseline. 
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Number of Study 
Centers 
Approximately 30 
Number of 
Participants 
Approximately 166 
Approximate Duration 
of Participant 
Participation 
Up to 2 weeks for screening, treatment until clinically significant 
progression of disease, and 4 weeks of follow-up. 
Study Treatment 
Belumosudil will be provided as 200 mg tablets to be taken with 
food either QD (Arm A) or BID (Arm B).  
Criteria for Inclusion 
and Exclusion  
Inclusion Criteria 
1. Male and female participants at least 12 years of age who 
have had allogeneic hematopoietic cell transplant (HCT). 
2. Previously received at least 2 and not more than 5 lines of 
systemic therapy for cGVHD. 
3. Participant has been on a stable dose/regimen of systemic 
cGVHD treatments for at least 2 weeks prior to screening. 
Note: Concomitant corticosteroids, calcineurin inhibitors, 
sirolimus, MMF, methotrexate, rituximab, and extracorporeal 
photopheresis (ECP) are acceptable. Systemic investigational 
GVHD treatments are not permitted.  
4. Have persistent cGVHD manifestations and systemic therapy 
is indicated. 
5. Karnofsky (if aged ≥16 years) / Lansky (if aged <16 years) 
Performance Score of ≥60.  
Laboratory Parameters 
6. Absolute neutrophil count ≥1.5 × 109/L.  
7. Platelet count ≥50 × 109/L with no transfusions within 72 hours. 
8. ALT and AST ≤3 × ULN (≤5 × ULN if due to cGVHD). 
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9. Total bilirubin ≤1.5 × ULN. 
10. Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 using the 
MDRD-4 variable formula (if aged ≥18 years) or using the 
Bedside Schwartz formula (if aged <18 years). 
General Criteria 
11. I11 is no longer applicable per amended protocol 05. 
12. I12 is no longer applicable per amended protocol 05. 
13. I13 is no longer applicable per amended protocol 05. 
14. Participant (or the participant’s legally authorized 
representative) is able to provide written informed consent / 
assent prior to the performance of any study-specific 
procedures. 
15. Weight ≥40 kg. 
16. It is in the best interest of the participant to participate in the 
study. 
 
Sex, contraceptive/barrier method and pregnancy testing 
requirements/breastfeeding 
17.  All 
Contraceptive use by men and women should be consistent with 
local regulations regarding the methods of contraception for those 
participating in clinical studies.  
a) Male participants 
Male participants are eligible to participate if they agree to 
the following during the study intervention period and for at 
least 90 days after the last administration of study 
intervention:  
- 
Refrain from donating sperm or cryopreserving sperm; 
PLUS, either: 
- 
Be abstinent from heterosexual intercourse as their 
preferred and usual lifestyle (abstinent on a long term 
and persistent basis) and agree to remain abstinent; 
OR 
- 
Must agree to use contraception/barrier as detailed 
below 
- 
A male condom and an additional highly effective 
contraceptive method as described in Section 21.14 
(Appendix N: Contraceptive and Barrier Guidance) 
when having sexual intercourse with a woman of 
childbearing potential (WOCBP) who is not currently 
pregnant. 
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b) Female participants 
A female participant is eligible to participate if she is not 
pregnant or breastfeeding, and one of the following 
conditions applies: 
- 
Is a woman of nonchildbearing potential (WONCBP) as 
defined in Section 21.14 Appendix N: Contraceptive 
and Barrier Guidance. 
OR 
- 
Is a woman of childbearing potential (WOCBP) and 
agrees to use a contraceptive method that is highly 
effective (with a failure rate of <1% per year), 
preferably with low user dependency, as described in 
Section 21.14 (Appendix N: Contraceptive and Barrier 
Guidance) during the study intervention period (to be 
effective before starting the intervention) and for at 
least 90 days after the last administration of study 
intervention and agrees not to donate or cryopreserve 
eggs (ova, oocytes) for the purpose of reproduction 
during this period. 
- 
A WOCBP must have a negative highly sensitive 
pregnancy test (urine or serum as required by local 
regulations) within 28 days before the first 
administration of study intervention, see Section 6.4.5 
Pregnancy testing. If a urine test cannot be confirmed 
as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the 
participant must be excluded from participation if the 
serum pregnancy result is positive. 
Exclusion Criteria 
1. E01 is no longer applicable per amended protocol 05. 
2. Histological relapse of the underlying cancer or post-transplant 
lymphoproliferative disease at the time of screening. 
3. Current treatment with ibrutinib. Prior treatment with ibrutinib is 
allowed with a washout of at least 28 days prior to 
randomization. 
4. Female participant who is pregnant or breastfeeding. 
5. History or other evidence of severe illness or any other 
conditions that would make the participant, in the opinion of the 
Investigator, unsuitable for the study (such as malabsorption 
syndromes, poorly controlled psychiatric disease or coronary 
artery disease). 
6. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
or history of human immunodeficiency virus (HIV). 
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7. Diagnosed with another malignancy (other than malignancy for 
which transplant was performed) within 3 years of enrollment, 
with the exception of: 
• 
Completely resected basal cell or squamous cell carcinoma 
of the skin. 
• 
Carcinoma in situ of the cervix. 
• 
Resected breast ductal carcinoma in situ. 
• 
Prostate cancer with Gleason score <6 and stable PSA 
over 12 months. 
8. Has had previous exposure to belumosudil. 
9. Known allergy/sensitivity to belumosudil or any other ROCK2 
inhibitor. 
10. Participant has QTc(F) >480 ms. 
11. Participant has FEV1 ≤39% or has lung score of 3. 
12. Participant considered unlikely to adhere to treatment and / or 
follow protocol in the opinion of the Investigator. 
13. Treatment with any non-GVHD investigational agent, or any 
investigational device or procedure, within 28 days (or 5 half- 
lives, whichever is greater) of enrollment. 
Efficacy Variables 
 
Primary Endpoint 
The primary efficacy endpoint is the ORR [including Partial 
Response (PR) and Complete Response (CR)]. Responses are as 
defined by the 2014 National Institutes of Health (NIH) Consensus 
Development Project on clinical trials in cGVHD, and are assessed 
by Investigators. 
Secondary Endpoints 
• 
Duration of Response (DOR). 
• 
Change in Lee Symptom Scale Score. 
• 
Response rate by organ system. 
• 
Time to Response (TTR). 
• 
Time to Next Treatment (TTNT). 
• 
Percentage of participants who have a best response of PR 
and percentage of participants who have a best response of 
CR. 
• 
Change in corticosteroid dose. 
• 
Change in calcineurin inhibitor dose. 
• 
Failure-free survival (FFS). 
• 
Overall survival (OS). 
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• 
Change in cGVHD global severity rating as based on the 
Clinician-Reported Global cGVHD Activity Assessment.  
• 
Change in symptom activity as based on cGVHD Activity 
Assessment Patient Self-Report.  
• 
Pharmacokinetics. 
Exploratory Endpoints 
• 
PROMIS Global Health subscores for physical and mental 
functioning. 
• 
ORR using Kadmon Algorithmic Response Assessment 
(KARA) for overall response. 
• 
Pharmacodynamics - Changes in the expression of relevant 
biomarkers after belumosudil administration. 
Safety Variables 
Safety is a secondary endpoint. The primary safety outcome will 
be the percent of participants in each arm experiencing AEs. 
Safety assessments include AEs, Grade ≥3 AEs, SAEs, vital sign 
measurements, clinical laboratory evaluations, and ECGs. 
Reasons for treatment discontinuation will be documented.  
Adverse events will be recorded after the ICF/assent form is 
signed and for 28 days after the last dose of belumosudil.  
Pharmacokinetics 
Full PK profiles will be collected for approximately 12 participants 
in each treatment arm at selected sites, and sparse PK sampling 
will be performed for the whole population, including adolescent 
participants. 
Pharmacodynamics 
Samples will be collected for exploratory PD analyses from all 
participants at sites with appropriate capabilities prior to dosing 
with belumosudil on Day 1 of Cycles 1, 2 and 7, and upon 
progression of cGVHD (or flare). PD samples will not be required 
from adolescents if the site has policies limiting the daily volume of 
blood allowed to be drawn as part of a clinical trial. Additional 
samples will be collected from participants enrolled in the site-
specific Companion Study for PD analyses as described in 
Section 21.13 Appendix M. 
Statistical Analysis 
Sample Size: 
Sample size is based on the primary efficacy endpoint of ORR, 
with a target ORR of 55% and with one planned Interim Analysis 
(IA). With 63 participants, and a 10% dropout rate, each treatment 
arm is estimated to have 90% power to yield a 95% confidence 
interval of ORR that excludes 30%. The Hochberg procedure will 
be applied for multiplicity adjustment for the primary efficacy 
endpoint of ORR. 
Analysis Population: 
The modified Intent-to-Treat (mITT) population is defined as all 
participants who are randomized and receive at least one dose of 
study drug. 
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The mITT population is the primary population for the analysis of 
the primary efficacy endpoint. 
Data Presentations/Descriptive Statistics 
Three analyses are planned: 
1. An IA will be conducted approximately 2 months after 
126 participants have been enrolled into the mITT population. 
A nominal 1-sided alpha of 0.0025 will be spent, but there will 
be no early study termination for efficacy.  
2. The primary analysis (PA) will be conducted approximately 
6 months after 126 participants have been enrolled into the 
mITT population, with 1-sided alpha 0.0225 (or 0.025 if the 
ORRs of both arms are significant at interim).  
3. A follow-up analysis will be conducted approximately 
12 months after 126 participants have been enrolled into the 
mITT population. 
4. Additional analyses will be conducted to include adolescent 
participants and Companion Study participants, approximately 
6 months after completion of enrollment of the respective 
participants. 
Alpha will only be allocated to the primary endpoint, ORR. 
Demographics, participant disposition, and screening and baseline 
characteristics will be summarized for the ITT population. 
AEs will be coded using the MedDRA dictionary (Version 20.0 or 
greater). The number and percentages of participants 
experiencing treatment-emergent AEs will be tabulated by system-
organ-class (SOC) and preferred term (PT) and will be presented 
by treatment group. The number of events by preferred term will 
also be summarized. Tabulation by maximum severity and 
relationship to treatment will also be included by treatment group. 
Summary participant listing will be provided for SAEs, AEs 
resulting in study discontinuation, and deaths. 
AEs, SAEs, related AEs, related SAEs, Grade ≥3 AEs, related 
Grade ≥3 AEs, and AEs leading to withdrawal and treatment 
discontinuation will be summarized according to treatment group. 
Laboratory results will be summarized by treatment group. 
Incidence of laboratory abnormalities will be summarized by 
treatment group. The worst on-study grade during the treatment 
period will be summarized. The incidence of ≥Grade 3 laboratory 
abnormalities under treatment and shifts in toxicity grading from 
baseline to highest grade post-baseline will be displayed.  
Vital sign measurements and ECGs will be summarized by 
treatment group at each scheduled time point using descriptive 
statistics and included in data listings.  
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 05 ........................................................................... 1 
TABLE OF CONTENTS ............................................................................................................18 
LIST OF TABLES ......................................................................................................................22 
LIST OF FIGURES ...................................................................................................................23 
LIST OF ABBREVIATIONS .......................................................................................................24 
1 
INTRODUCTION .................................................................................................................27 
1.1 
CHRONIC GRAFT VERSUS HOST DISEASE ...........................................................27 
1.2 
RHO-ASSOCIATED PROTEIN KINASES ..................................................................27 
1.3 
BELUMOSUDIL BACKGROUND (NON-CLINICAL) ...................................................28 
1.4 
BELUMOSUDIL BACKGROUND (CLINICAL) ............................................................28 
1.4.1 KD025-208 .................................................................................................................29 
1.5 
STUDY RATIONALE ..................................................................................................29 
1.6 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS TO HUMAN 
PARTICIPANTS .........................................................................................................30 
2 
STUDY OBJECTIVES / PURPOSE .....................................................................................31 
2.1 
PRIMARY OBJECTIVE ..............................................................................................31 
2.2 
SECONDARY OBJECTIVES ......................................................................................31 
2.3 
EXPLORATORY OBJECTIVES ..................................................................................31 
3 
INVESTIGATIONAL PLAN ..................................................................................................32 
3.1 
STUDY DESIGN .........................................................................................................32 
3.2 
STUDY STEERING COMMITTEE ..............................................................................34 
3.3 
ESTIMATED STUDY DURATION...............................................................................34 
4 
STUDY POPULATION ........................................................................................................35 
4.1 
NUMBER OF PARTICIPANTS ...................................................................................35 
4.2 
STUDY CENTERS .....................................................................................................35 
4.3 
INCLUSION CRITERIA ..............................................................................................35 
4.4 
EXCLUSION CRITERIA .............................................................................................37 
4.5 
PRIOR LINES OF THERAPY .....................................................................................38 
4.6 
SCREENING ..............................................................................................................38 
4.7 
WITHDRAWAL CRITERIA .........................................................................................39 
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4.8 
REPLACEMENTS ......................................................................................................39 
4.8.1 Treatment Discontinuation ..........................................................................................40 
5 
STUDY TREATMENT .........................................................................................................41 
5.1 
INVESTIGATIONAL PRODUCT .................................................................................41 
5.2 
DOSAGE AND ADMINISTRATION ............................................................................41 
5.2.1 Belumosudil Tapering Guidance .................................................................................41 
5.3 
TREATMENT ASSIGNMENT .....................................................................................42 
5.4 
BLINDING ..................................................................................................................42 
5.5 
TREATMENT COMPLIANCE .....................................................................................42 
5.6 
MISSED DOSES ........................................................................................................43 
5.7 
PRODUCT ACCOUNTABILITY ..................................................................................43 
5.8 
CONCOMITANT MEDICATIONS AND PROCEDURES .............................................43 
5.8.1 Corticosteroids............................................................................................................44 
5.8.2 Systemic cGVHD Therapies .......................................................................................44 
5.8.3 Topical / Organ Specific Therapies for cGVHD ...........................................................44 
5.8.4 CYP3A4 Inducers and Proton Pump Inhibitor .............................................................44 
5.8.5 Prohibited Concomitant Medications ...........................................................................45 
5.9 
TREATMENT OF OVERDOSE ...................................................................................45 
5.10 DOSE MODIFICATION GUIDELINES ........................................................................45 
6 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................46 
6.1 
SCHEDULE OF ASSESSMENTS...............................................................................46 
6.2 
STUDY VISITS ...........................................................................................................46 
6.2.1 Screening ...................................................................................................................46 
6.2.2 Cycle 1, Day 1 (Baseline) ...........................................................................................47 
6.2.3 Cycles 1, Day 15 (±3 days) .........................................................................................48 
6.2.4 Cycle 2 and Beyond, Day 1 (±3 days) .........................................................................49 
6.2.5 End of Treatment (EOT) .............................................................................................50 
6.2.6 28-Day Follow-Up Visit ...............................................................................................52 
6.2.7 Unscheduled Visits .....................................................................................................52 
6.2.8 Long-Term Follow-Up .................................................................................................52 
6.3 
EFFICACY ..................................................................................................................53 
6.3.1 Efficacy Endpoints ......................................................................................................53 
6.3.2 Overall Response Rate ...............................................................................................53 
6.3.3 Patient Reported Outcomes........................................................................................54 
6.3.4 Change in Corticosteroid Dose ...................................................................................55 
6.3.5 Failure Free Survival ..................................................................................................55 
6.4 
SAFETY .....................................................................................................................55 
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6.4.1 Safety Endpoints ........................................................................................................55 
6.4.2 Vital Signs ..................................................................................................................55 
6.4.3 Twelve-lead ECG .......................................................................................................55 
6.4.4 Clinical Laboratory Parameters ...................................................................................56 
6.4.5 Pregnancy Testing ......................................................................................................57 
6.5 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ...............57 
7 
PHARMACOKINETICS .......................................................................................................59 
7.1 
SPARSE PK ...............................................................................................................59 
7.2 
FULL PK .....................................................................................................................59 
8 
PHARMACODYNAMICS .....................................................................................................60 
9 
SAFETY ..............................................................................................................................61 
9.1 
SAFETY PARAMETERS ............................................................................................61 
9.2 
ADVERSE EVENT DEFINITION ................................................................................61 
9.3 
EVALUATING ADVERSE EVENTS ............................................................................63 
9.3.1 Serious Adverse Events .............................................................................................63 
9.3.2 Recording and follow-up of AE and/or SAE ................................................................64 
9.3.3 Reporting Requirements for SAEs ..............................................................................67 
9.4 
OTHER SAFETY CONSIDERATIONS .......................................................................69 
9.4.1 Laboratory Data ..........................................................................................................69 
10 STUDY STOPPING RULES ................................................................................................70 
11 STATISTICAL CONSIDERATIONS .....................................................................................71 
11.1 HYPOTHESIS ............................................................................................................71 
11.2 SAMPLE SIZE AND POWER CALCULATION............................................................71 
11.2.1 Efficacy Decision Rules with Multiplicity Adjustment ...................................................72 
11.3 ANALYSIS POPULATIONS ........................................................................................74 
11.4 SUBGROUP ANALYSES ...........................................................................................74 
11.5 DATA ANALYSIS .......................................................................................................74 
11.6 INTERIM ANALYSIS ..................................................................................................74 
11.7 EFFICACY ANALYSES ..............................................................................................75 
11.7.1 Primary Efficacy Endpoint ...........................................................................................75 
11.7.2 Secondary Efficacy Endpoints ....................................................................................75 
11.8 EXPLORATORY ANALYSES .....................................................................................76 
11.9 SAFETY ANALYSES ..................................................................................................76 
11.10 PHARMACOKINETIC ANALYSES .............................................................................77 
11.11 PHARMACODYNAMIC ANALYSES ...........................................................................77 
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12 DATA QUALITY ASSURANCE ...........................................................................................78 
13 REGULATORY OBLIGATIONS...........................................................................................79 
13.1 COMPLIANCE STATEMENT .....................................................................................79 
14 ETHICAL ASPECTS ...........................................................................................................80 
14.1 LOCAL REGULATIONS .............................................................................................80 
14.2 INFORMED CONSENT ..............................................................................................80 
14.3 RESEARCH ETHICS COMMITTEES .........................................................................80 
15 CONDITIONS FOR MODIFYING THE PROTOCOL ...........................................................81 
16 CONDITIONS FOR TERMINATING THE STUDY ...............................................................82 
17 STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING ..........................................83 
17.1 INVESTIGATOR’S FILES AND RETENTION OF DOCUMENTS ...............................83 
17.2 SOURCE DOCUMENTS AND BACKGROUND DATA ...............................................83 
17.3 AUDITS AND INSPECTIONS .....................................................................................84 
17.4 ELECTRONIC CASE REPORT FORMS ....................................................................84 
18 MONITORING OF THE STUDY ..........................................................................................85 
19 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PARTICIPANT RECORDS ................86 
20 PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ...............................87 
21 APPENDICES .....................................................................................................................88 
21.1 APPENDIX A: SCHEDULE OF ASSESSMENTS .......................................................88 
21.2 APPENDIX B: CGVHD ACTIVITY ASSESSMENT FOR CLINICIAN ..........................92 
21.3 APPENDIX C: CGVHD RESPONSE ASSESSMENT .................................................97 
21.4 APPENDIX D: LEE CGVHD SYMPTOM SCORE .......................................................98 
21.5 APPENDIX E: PROMIS GLOBAL HEALTH SCORE...................................................99 
21.6 APPENDIX F: CGVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT .......... 100 
21.7 APPENDIX G: KARNOFSKY PERFORMANCE SCALE ........................................... 101 
21.8 APPENDIX H: EQUATIONS TO PREDICT GLOMERULAR FILTRATION RATE ..... 101 
21.9 APPENDIX I: DRUGS THAT INDUCE CYP3A4 ....................................................... 102 
21.10 APPENDIX J: PFT ASSESSMENTS ........................................................................ 103 
21.11 APPENDIX K: PREDNISONE DOSE EQUIVALENTS .............................................. 104 
21.12 APPENDIX L: CENTRAL LAB AND CRO CONTACT INFORMATION ..................... 104 
21.13 APPENDIX M: COMPANION STUDY FOR BIOSPECIMEN COLLECTION ............. 105 
21.13.1 
Purpose .............................................................................................................. 105 
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21.13.2 
Summary ............................................................................................................ 105 
21.13.3 
Objective ............................................................................................................. 106 
21.13.4 
Eligibility.............................................................................................................. 106 
21.13.5 
Design ................................................................................................................ 106 
21.13.6 
Introduction ......................................................................................................... 107 
21.13.7 
Eligibility assessment and enrollment ................................................................. 109 
21.13.8 
Study implementation ......................................................................................... 110 
21.13.9 
Biospecimen collection ....................................................................................... 112 
21.13.10 
Statistical section .............................................................................................. 115 
21.14 APPENDIX N: CONTRACEPTIVE AND BARRIER GUIDANCE ............................... 116 
21.14.1 
Definitions ........................................................................................................... 116 
21.14.2 
Contraception Guidance ..................................................................................... 117 
21.15 APPENDIX O: PROTOCOL AMENDMENT HISTORY ............................................. 117 
21.15.1 
Amended Protocol 01 (26 June 2019) ................................................................. 118 
21.15.2 
Amended Protocol 02 (01 June 2020) ................................................................. 124 
21.15.3 
Amended Protocol 03 (30 August 2021) ............................................................. 127 
21.15.4 
Amended Protocol 04 (11 April 2022) ................................................................. 127 
22 REFERENCES .................................................................................................................. 129 
 
LIST OF TABLES 
Table 1 - cGVHD Severity Definitions .......................................................................................42 
Table 2 - Guidelines for Management of Treatment-Emergent Toxicities ..................................45 
Table 3 - cGVHD Response Definitions ....................................................................................54 
Table 4 - Clinical Laboratory Panels ..........................................................................................56 
Table 5 - Power for Various Hypothetic ORRs ..........................................................................72 
Table 6 - Schedule of Assessments ..........................................................................................88 
Table 7 - Pharmacokinetics Sampling .......................................................................................91 
Table 8 - Pharmacokinetics Sampling Timing Allowance ..........................................................91 
Table 9 - Pharmacodynamic Sampling ......................................................................................91 
Table 10 - ECG Assessments ...................................................................................................92 
Table 11 - Examples of Clinical Inducers of CYP3A4 .............................................................. 102 
 
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LIST OF FIGURES 
Figure 1 - KD025-213 Study Schema ........................................................................................32 
Figure 2 - ORR Multiplicity Adjustment ......................................................................................73 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BA/BE 
Bioavailability/Bioequivalence 
BID 
twice daily 
BMT 
bone marrow transplant 
BUN 
blood urea nitrogen 
C1D1 
cycle 1 day 1 
C2D1 
cycle 2 day 1 
CFR 
Code of Federal Regulations 
cGVHD 
chronic graft versus host disease 
CI 
confidence interval 
Cmax 
maximum concentration observed  
CNI 
calcineurin inhibitor  
CPK 
creatinine phosphokinase 
CR 
complete response 
CRO 
contract research organization 
CTCAE 
common terminology criteria for adverse events 
DOR 
duration of response 
DLCO 
diffusing capacity of carbon monoxide 
ECG 
electrocardiogram 
ECP 
extracorporeal photopheresis  
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume (in the first second) 
FFS 
failure-free survival 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
Hb 
hemoglobin 
HBV 
hepatitis B virus 
HCT 
hematopoietic cell transplantation 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IA 
interim analysis 
IB 
investigator’s brochure 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
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IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IXRS 
Interactive voice / web response system 
KARA 
Kadmon Algorithmic Response Assessment 
LFT 
liver function tests 
LR 
lack of Response 
LR-M 
lack of Response - mixed 
LR-P 
lack of Response - progression 
LR-U 
lack of Response - unchanged 
MCV 
mean corpuscular volume 
MAD 
multiple ascending dose 
MDRD-4 
4-Variable Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMF 
mycophenolate Mofetil 
NIH 
National Institutes of Health 
ORR 
overall response rate 
OS 
overall survival 
PA 
primary analysis 
PD 
pharmacodynamic 
PE 
physical examination 
PFT 
pulmonary function test 
PK 
pharmacokinetic 
PPI 
proton pump inhibitor 
PR 
partial response 
PT 
preferred term 
QD 
once daily 
QOD 
once every other day 
QTc(F) 
corrected QT interval using Fridericia's formula 
ROCK 
rho-associated protein kinase 
RV 
residual volume 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse event 
T1/2 
half-life 
TCR 
T cell receptor 
Tmax 
observed time to reach peak plasma concentration 
TEAE 
treatment-emergent adverse event 
TLC 
total lung capacity 
TTNT 
time to next treatment 
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TTR 
time to response 
ULN 
upper limit of normal 
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1 
INTRODUCTION 
1.1 
CHRONIC GRAFT VERSUS HOST DISEASE 
Chronic graft versus host disease (cGVHD) remains a major complication of allogeneic 
hematopoietic cell transplantation (HCT) involving multiple organs and occurring in up to 70% 
of transplant recipients depending upon donor and transplant characteristics (1). Multicenter and 
registry data show a cumulative incidence of 30% to 50% (2, 3). Patients with cGVHD require 
prolonged immunosuppressive treatment for an average of 2 to 3 years from the initial diagnosis, 
with 10% of those surviving for at least 7 years still requiring immunosuppressive treatment at 
that time and beyond (4).  
Glucocorticoids, with or without calcineurin inhibitors, remain the standard initial treatment, but 
are associated with significant side effects and unsatisfactory outcomes, particularly for patients 
with high-risk features of cGVHD (5).  
Based upon data from this Study, KD025-213 (NCT03640481), the Food and Drug 
Administration (FDA) approved REZUROCK (belumosudil) for the treatment of adult and 
pediatric patients 12 years and older with cGVHD after failure of at least 2 prior lines of 
systemic therapy (6). This is the second FDA approved drug indicated specifically for patients 
with cGVHD. 
The first FDA approved cGVHD therapy is ibrutinib (IMBRUVICA) for the treatment of adult 
patients with cGVHD after failure of one or more lines of systemic therapy based upon data from 
an open-label study (Study 1129; NCT02195869) of 42 participants with cGVHD who had failed 
first line corticosteroid therapy and required additional therapy (7). Of note, participants were 
required “to have either >25% body surface area erythematous rash or a National Institutes of 
Health (NIH) mouth score >4” (8). The ORR in this selected population was 67%. Twenty-four 
percent of participants receiving IMBRUVICA in the cGVHD trial discontinued treatment due to 
adverse reactions (7).  
1.2 
RHO-ASSOCIATED PROTEIN KINASES  
Rho-associated coiled-coil kinases (ROCKs) play a central role in the control of actin 
cytoskeleton assembly and cellular functions, such as proliferation, adhesion, migration and 
phagocytosis (9, 10, 11, 12). Two isoforms of ROCK have been identified, ROCK1 and ROCK2, 
which are activated by Rho GTPases and promote actin-myosin mediated contractile force 
generation via serine-threonine phosphorylation of numerous downstream targets. During the 
immune response, ROCK signaling is critical in the coordination and balancing of T-cell-
mediated immune responses, including cellular movement, T-cell receptor (TCR) signaling and 
the acquisition of the appropriate T-cell effector program (13, 14). However, only the ROCK2 
isoform was shown to be physiologically activated in CD4+ T cells under T helper 17 (TH17) 
skewing, leading to increased secretion of IL-17 and IL-21 in both mice and humans (15, 16). 
Moreover, targeted ROCK2 inhibition effectively decreased IL-17 production in vivo and 
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ameliorated the spontaneous development of arthritis, diabetes and lupus in mice (16). 
Additionally, ROCK activity was increased in participants with RA and SLE (15, 17, 18). The 
specific inhibition of ROCK2 therefore has been examined for its potential as a therapy for 
autoimmune disorders. 
1.3 
BELUMOSUDIL BACKGROUND (NON-CLINICAL) 
Belumosudil is an orally available Rho-associated protein kinase-2 (ROCK2) selective inhibitor. 
Data from a Phase 1 clinical trial demonstrate that oral administration of belumosudil to healthy 
human participants down-regulates the ability of T cells to secrete IL-21 and IL-17, but not 
interferon (IFN)-γ in response to TCR stimulation ex vivo. Treatment with belumosudil also 
promotes the suppressive function of regulatory T cells through up-regulation of STAT5 
phosphorylation and positive regulation of Foxp3 expression (19).  
Chronic GVHD remains a major complication following allogeneic bone marrow transplantation 
(20). The underlying pathogenesis of GVHD is similar to autoimmune attack in a number of 
respects, including a contributory role of pro-inflammatory TH17 and T follicular helper (TFH) 
cells and a protective role of Tregs (21). In addition, the aberrant activation of immune cells 
leads to increased secretion of transforming growth factor (TGF)-β which promotes fibroblast 
activation, collagen production and development of tissue fibrosis (22). Belumosudil effectively 
ameliorates cGVHD in multiple models: a full MHC-mismatch model of bronchiolitis obliterans 
syndrome that involved a wide spectrum of target organs including lung and liver(23) as well as 
a minor MHC-mismatch model of sclerodermatous GVHD (24). Treatment with belumosudil 
resulted in normalization of pathogenic pulmonary function, which correlates with a marked 
reduction of antibody and collagen deposition in the lungs of treated mice to levels comparable 
to non-cGVHD controls (25). Spleens of mice treated with belumosudil had decreased frequency 
of TFH and increased frequency of T follicular regulatory cells, accompanied by a reduction in 
STAT3 and concurrent increase in STAT5 phosphorylation. Together these data highlight the 
potential of targeted ROCK2 inhibition for cGVHD therapy. 
Also refer to the belumosudil Investigator’s Brochure (IB) for more detailed information. 
1.4 
BELUMOSUDIL BACKGROUND (CLINICAL) 
Belumosudil was well tolerated in Phase 1 studies of healthy volunteers at single doses up to 
1000 mg, and with repeat doses up to 500 mg BID for 28 days. 
Administration of belumosudil 200 mg tablets in the fed state resulted in a ~2-fold increased 
exposure in terms of Cmax and AUC when compared to the fasted state. Pharmacokinetic 
analyses showed that belumosudil administered as a 200 mg tablet in the fed state was rapidly 
absorbed with a median Tmax of approximately 3 hours. Elimination half-life is approximately 
7 hours. Variability in exposure related parameters Cmax and AUC was reduced when 
belumosudil was administered in the fed state when compared to the fasted state. Belumosudil 
should be taken with food. 
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Phase 2 studies of belumosudil are ongoing or have been completed, enrolling participants with 
idiopathic pulmonary fibrosis, cGVHD and psoriasis, diffuse cutaneous systemic sclerosis 
(dcSSc). More than 750 participants have been dosed with belumosudil for inflammatory or 
fibrotic diseases or as healthy volunteers at doses ranging from 20 mg to 1000 mg QD and 
500 mg BID. 
Also refer to the belumosudil IB for more detailed information. 
1.4.1 KD025-208 
KD025-208 is a completed Phase 2a, dose-escalation, open-label study to evaluate the safety, 
tolerability, and activity of belumosudil in participants with cGVHD. Eligible participants with 
persistent, active cGVHD manifestations after at least 2 months of steroid therapy and no more 
than 3 prior lines of treatment for cGVHD are enrolled into 3 sequential cohorts: 
• Cohort 1: 200 mg belumosudil QD  
• Cohort 2: 200 mg belumosudil BID 
• Cohort 3: 400 mg belumosudil QD 
The primary endpoint is the overall response rate (ORR), as defined by the 2014 National 
Institutes of Health (NIH) Consensus Development Project on clinical trials in cGVHD. 
Secondary endpoints include Duration of Response (DOR), patient reported outcomes (Lee 
Symptom Scale Score), changes in corticosteroid dose and response by organ system. 
Refer to the belumosudil IB for more detailed information.  
1.5 
STUDY RATIONALE 
Building upon data from the KD025-208 study, this current study, KD025-213, is designed to 
further demonstrate the efficacy and safety of belumosudil in participants with cGVHD, who 
may or may not have been treated with ibrutinib. In particular, given the similar response rates 
and tolerability demonstrated in Cohorts 1 and 2 of study KD025-208, with belumosudil 
treatment at 200 mg QD and 200 mg BID respectively, this study will further evaluate the 
efficacy and safety of these 2 regimens of belumosudil. 
Eligible participants are required to have active cGVHD despite treatment with corticosteroids 
and after failure of at least 2 prior lines of systemic therapy. A target of ≥10% of the enrolled 
population will have previously received ibrutinib as a therapy for cGVHD. 
Participants will be randomized (1:1) to two treatment arms: 
• Arm A: belumosudil 200 mg QD 
• Arm B: belumosudil 200 mg BID 
This study is intended to demonstrate clinically meaningful, durable responses in this population 
of participants with significant unmet medical need, with an ORR in excess of 30%. 
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1.6 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS TO HUMAN 
PARTICIPANTS 
All the side effects related to belumosudil are not known; the belumosudil IB contains data on 
risks associated with belumosudil. Other risks to participants involve side effects from study 
procedures. There are also other risks associated with taking part in this study, such as the risks 
associated with a loss of privacy or confidentiality because of improper disclosure.  
There may be no direct benefit to participants enrolled into this study. Participants may receive a 
clinical benefit from belumosudil, and some participants may progress. The information from 
this study may help other participants with cGVHD and more may be learned about the study 
drug to further inform the prescribing information of REZUROCK.  
In July 2021 FDA granted approval of belumosudil (REZUROCK) for the treatment of adult and 
pediatric patients 12 years and older with cGVHD after failure of at least 2 prior lines of 
systemic therapy. In November 2021, belumosudil received marketing authorization approval in 
Australia. The approved indication was treatment of patients with cGVHD aged 12 years and 
older who have an inadequate response to corticosteroids. In March 2022, belumosudil received 
marketing authorization approval in Canada, and in July 2022 in the United Kingdom (UK). The 
indication is the same as in the US in both countries. 
The Sponsor will maintain clinical trial insurance to cover injury associated with clinical study 
participation. Pursuant to site-specific clinical trial agreements, the Sponsor will pay for all 
reasonable costs associated with the study. 
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2 
STUDY OBJECTIVES / PURPOSE 
2.1 
PRIMARY OBJECTIVE 
The objective of this study is to evaluate the efficacy of belumosudil, at dose levels of 
200 mg QD and 200 mg BID, in participants with cGVHD who have previously been treated 
with at least 2 prior lines of systemic therapy. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are to evaluate: 
• Duration of response (DOR). 
• Changes in the Lee Symptom Scale Score. 
• Response by organ system. 
• Time to response (TTR). 
• Time to next treatment (TTNT). 
• Percentage of participants who have a best response of PR and percentage of participants 
who have a best response of CR. 
• Change in corticosteroid dose. 
• Change in calcineurin inhibitor dose. 
• Failure-free-survival (FFS). 
• Overall survival (OS). 
• Change in cGVHD global severity rating using the Clinician-Reported Global cGVHD 
Activity Assessment. 
• Change in symptom activity using the cGVHD Activity Assessment Patient Self-Report.  
• PK of belumosudil in participants with Cgvhd. 
• Safety. 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of the study are: 
• To evaluate changes in the PROMIS Global Health subscores for physical and mental 
functioning. 
• To evaluate ORR using Kadmon Algorithmic Response Assessment (KARA) for overall 
response. 
• To evaluate changes in relevant biomarkers after belumosudil administration. 
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3 
INVESTIGATIONAL PLAN 
3.1 
STUDY DESIGN 
This is a Phase 2, randomized, multi-center, open-label, study designed to evaluate the efficacy 
and safety of belumosudil in participants with active cGVHD after at least 2 prior lines of 
systemic therapy. The study design is illustrated in Figure 1. 
Figure 1 - KD025-213 Study Schema 
 
Participants who consented and/or provided assent documented with a signed an IRB/IEC-
approved informed consent/assent form as applicable, and meet all of the eligibility criteria will 
be enrolled. The study population will be adults and adolescents who: 
• Have undergone allogeneic hematopoietic cell transplantation (HCT). 
• Have previously received at least 2 lines of systemic therapy for cGVHD. 
• Have persistent cGVHD manifestations and systemic therapy for cGVHD is indicated. 
A target of ≥10% of the enrolled population will have previously received ibrutinib as a therapy 
for cGVHD. 
After confirmation of eligibility during a 14-day screening period, eligible participants will be 
randomized (1:1) to one of two treatment arms: 
• Arm A: belumosudil 200 mg QD 
• Arm B: belumosudil 200 mg BID 
These doses are selected based upon the data from study KD025-208 (Section 1.4.1). 
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Randomization will be stratified according to prior cGVHD treatment with ibrutinib (Yes / No) 
and severe cGVHD (Yes / No). 
With amendment 4, eligible adolescent participants were enrolled into the study at the 
belumosudil 200 mg QD dose. Since amendment 4, there are no more randomization and 
stratification factors applied for this group. The additional 20 adults in the companion study will 
be randomized (1:1) to Arm A or Arm B. The expected sample size in each Arm is therefore: 
Arm A, N = 93 with addition of 20 adolescents and 10 adults and Arm B, N = 73 with addition of 
10 adults. Any adolescent taking a PPI or a strong CYP3A4 inducer will begin C1D1 at the 
following escalated dose: belumosudil 200 mg BID. 
Concomitant treatment with standard of care systemic cGVHD therapies such as calcineurin 
inhibitors (tacrolimus, cyclosporine), sirolimus, MMF, methotrexate, rituximab or extracorporeal 
photopheresis (ECP), are permitted as long as the participant has been on a stable dose / regimen 
of these per the eligibility criteria. Initiation of new systemic cGVHD therapy while on study is 
not permitted. 
Participants will receive belumosudil treatment in 28-day cycles until clinically significant 
progression of cGVHD (defined as progression requiring addition of new systemic therapy for 
cGVHD), histologic recurrence of underlying malignancy, unacceptable toxicity, Investigator 
decision, participant preference / withdrawal of consent, lost to follow-up, sponsor decision, or 
death (whichever occurs first). 
Participants who experience cGVHD progression as defined by NIH criteria but for whom no 
new systemic therapy is planned may continue to receive belumosudil and be assessed again at 
their next cycle. If progression per NIH criteria is not confirmed or no new systemic therapy is 
planned, participants may continue on belumosudil per investigator discretion until they fulfill 
one of the criteria requiring discontinuation of study drug. 
Under Protocol Amendment 3, all participants (excluding the 20 adolescent participants) that 
have received at least 6 months of belumosudil treatment or are in long-term follow-up without 
having a failure-free survival event are expected to end participation in study KD025-213. 
Participants may continue to participate in study KD025-213 if the Investigative Site is awaiting 
IRB approval of the KD025-217 rollover study titled: “Extended Treatment and Follow-up of 
Participants Treated with Belumosudil in Study KD025-208 or Study KD025-213”. 
The primary endpoint is the overall response rate (ORR), defined as the proportion of 
participants achieving a partial response (PR) or a complete response (CR) as defined by the 
2014 NIH Consensus Development Project on Clinical Trials in cGVHD (Appendix B). 
Response criteria will be assessed after Cycles 1, 2, 3 and 4 and then after every other Cycle 
thereafter (Day 1 of Cycles 2, 3, 4, 5, 7, 9, 11, etc.) (Table 6). Following Protocol Amendment 5, 
in adolescent participants still to be enrolled, response criteria will be assessed after Cycles 1, 2, 
4, and 6 and then after every third cycle (Day 1 of cycles 2, 3, 5, 7, 10, 13, etc.). Responses are 
assessed with respect to baseline. 
Analyses of the primary endpoint will be participant to multiplicity adjustment per a Hochberg 
procedure (Section 11.2.1). 
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Secondary endpoints will include assessments to evaluate the clinical meaningfulness of 
responses. These include duration of response, changes in Lee Symptom Scale Scores, response 
by organ system and changes in corticosteroid dosage. 
This study uses the Clinician-Reported Global cGVHD Activity Assessment to evaluate cGVHD 
global severity rating along with other organ severities; the cGVHD Activity Assessment Patient 
Self Report to assess symptom activity (Appendix F) and evaluates failure-free survival (FFS). 
Full PK profiles will be collected for a subset of approximately 12 participants per arm, and 
sparse PK sampling will be conducted for the entire study population including adolescent 
participants. 
As exploratory endpoints, changes in the PROMIS Global Health score and changes in relevant 
biomarkers after belumosudil administration will be explored. 
All AEs will be followed for 28 additional days after discontinuation of belumosudil treatment. 
All SAEs and treatment-related AEs will be followed until either resolution of the event or 
determination by the Investigator that the event has become stable or irreversible. 
In addition, after discontinuation of belumosudil treatment, participants will be contacted every 
12 weeks until a failure-free survival event occurs or until study close-out (whichever occurs 
first) to allow follow up for FFS and survival status. 
3.2 
STUDY STEERING COMMITTEE 
A study Steering Committee (SC) will advise on study conduct, and study stopping rules 
(Section 10). 
The chair is
. 
The co-chair is
. 
The SC charter will serve to describe membership and responsibilities. 
3.3 
ESTIMATED STUDY DURATION 
The study enrollment period is expected to be approximately 24 months. 
Individual participant duration on study will consist of up to 2 weeks for screening, treatment 
until progression of disease (Section 4.7), and 4 weeks of post treatment follow-up. 
In addition, after discontinuation of belumosudil treatment, participants will be contacted every 
12 weeks until a failure-free survival event occurs or until study close-out (whichever occurs 
first) to allow follow up for FFS and survival status. 
Study close out is anticipated to occur within approximately 4 years after the first participant is 
enrolled. 
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4 
STUDY POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
Approximately 166 adult and adolescent participants with cGVHD treated with at least 2, but no 
more than 5, prior lines of systemic therapy will be enrolled, approximately 83 participants in 
each treatment arm. With KD025-213 Protocol Amendment 2, the sample size was increased 
from approximately 126 participants, with additional participants to be enrolled as follows: 
• 20 adolescents. 
• 20 adults into a site-specific Companion Study to be conducted at selected sites to collect 
biospecimens (Section 21.13 Appendix M). 
A target of ≥10% of the enrolled population will have previously received ibrutinib as a therapy 
for cGVHD. 
4.2 
STUDY CENTERS 
This study will be conducted at approximately 30 sites. 
4.3 
INCLUSION CRITERIA 
GVHD Criteria 
1. Male and female participants at least 12 years of age who have had allogeneic 
hematopoietic cell transplant (HCT). 
2. Previously received at least 2 and not more than 5 lines of systemic therapy for cGVHD. 
3. Participant has been on a stable dose / regimen of systemic cGVHD treatments for at 
least 2 weeks prior to screening. Note: Concomitant corticosteroids, calcineurin 
inhibitors, sirolimus, MMF, methotrexate, rituximab, and extracorporeal photopheresis 
(ECP) are acceptable. Systemic investigational GVHD treatments are not permitted.  
4. Have persistent cGVHD manifestations and systemic therapy is indicated. 
5. Karnofsky (if aged ≥16 years) / Lansky (if aged <16 years) Performance Score of ≥60.  
Laboratory Parameters 
6. Absolute neutrophil count ≥1.5 × 109/L.  
7. Platelet count ≥50 × 109/L with no transfusions within 72 hours. 
8. ALT and AST ≤3 × ULN (≤5 × ULN if due to cGVHD). 
9. Total bilirubin ≤1.5 × ULN. 
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10. Glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 using the MDRD-4 variable 
formula (if aged ≥18 years) or using the Bedside Schwartz formula (if aged <18 years).  
General Criteria 
11. I11 is no longer applicable per amended protocol 05. 
12. I12 is no longer applicable per amended protocol 05. 
13. I13 is no longer applicable per amended protocol 05. 
14. Participant (or the participant’s legally authorized representative) is able to provide 
written informed consent / assent prior to the performance of any study-specific 
procedures. 
15. Weight ≥40 kg. 
16. It is in the best interest of the participant to participate in the study. 
Sex, contraceptive/barrier method and pregnancy testing requirements/breastfeeding 
17.  All 
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.  
• Male participants 
Male participants are eligible to participate if they agree to the following during the study 
intervention period and for at least 90 days after the last administration of study 
intervention:  
- 
Refrain from donating sperm or cryopreserving sperm; 
PLUS, either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent; 
OR 
- Must agree to use contraception/barrier as detailed below: 
- 
A male condom and an additional highly effective contraceptive method as described 
in Section 21.14 (Section 21.14: Contraceptive and Barrier Guidance) when having 
sexual intercourse with a woman of childbearing potential (WOCBP) who is not 
currently pregnant. 
• Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
one of the following conditions applies: 
- 
Is a woman of nonchildbearing potential (WONCBP) as defined in Section 21.14 
Appendix N: Contraceptive and Barrier Guidance. 
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OR 
- 
Is a woman of childbearing potential (WOCBP) and agrees to use a contraceptive 
method that is highly effective (with a failure rate of <1% per year), preferably with 
low user dependency, as described in Section 21.14 (Appendix N: Contraceptive and 
Barrier Guidance) during the study intervention period (to be effective before starting 
the intervention) and for at least 90 days after the last administration of study 
intervention and agrees not to donate or cryopreserve eggs (ova, oocytes) for the 
purpose of reproduction during this period. 
- 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 28 days before the first administration of study 
intervention, see Section 6.4.5 Pregnancy testing. If a urine test cannot be confirmed 
as negative (eg, an ambiguous result), a serum pregnancy test is required. In such 
cases, the participant must be excluded from participation if the serum pregnancy 
result is positive. 
4.4 
EXCLUSION CRITERIA 
1. E01 is no longer applicable per amended protocol 05. 
2. Histological relapse of the underlying cancer or post-transplant lymphoproliferative 
disease at the time of screening. 
3. Current treatment with ibrutinib. Prior treatment with ibrutinib is allowed with a washout 
of at least 28 days prior to randomization. 
4. Female participant who is pregnant or breastfeeding. 
5. History or other evidence of severe illness or any other conditions that would make the 
participant, in the opinion of the Investigator, unsuitable for the study (such as 
malabsorption syndromes, poorly controlled psychiatric disease or coronary artery 
disease). 
6. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) or history of human 
immunodeficiency virus (HIV). 
7. Diagnosed with another malignancy (other than malignancy for which transplant was 
performed) within 3 years of enrollment, with the exception of: 
• Completely resected basal cell or squamous cell carcinoma of the skin. 
• Carcinoma in situ of the cervix. 
• Resected breast ductal carcinoma in situ. 
• Prostate cancer with Gleason score <6 and stable PSA over 12 months. 
8. Has had previous exposure to belumosudil. 
9. Known allergy/sensitivity to belumosudil or any other ROCK2 inhibitor. 
10. Participant has QTc(F) >480 ms. 
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11. Participant has FEV1 ≤39% or has lung score of 3. 
12. Participant considered unlikely to adhere to treatment and / or follow protocol in the 
opinion of the Investigator. 
13. Treatment with any non-GVHD investigational agent, or any investigational device or 
procedure, within 28 days (or 5 half- lives, whichever is greater) of enrollment. 
4.5 
PRIOR LINES OF THERAPY 
Participants must have previously received at least 2 lines of systemic therapy, and no more than 
5 lines of systemic therapy for cGVHD. When documenting prior lines of therapy for cGVHD, 
the following guidelines should be employed: 
• Initiation of one or more new systemic therapies for cGVHD is considered a new line of 
therapy: 
- 
If the intention is to initiate more than one agent at the same time, start dates may 
differ by up to 4 weeks in view of eg, scheduling delays, insurance approval, or 
obtaining drug. 
• Topical agents are not considered a line of therapy. 
4.6 
SCREENING  
The screening period commences once the informed consent form (ICF) or assent form is signed. 
Adequate time must be allowed for the participant to ask questions and make a voluntary 
decision. The ICF or assent form must be signed before any study-specific samples are taken or 
study-specific tests or evaluations are conducted. Documented standard of care assessments 
performed within 14 days of Cycle 1 Day 1 (C1D1) can be used as screening assessments even if 
done prior to signing of ICF or assent form. 
Data regarding screen-failures will be captured in the electronic data capture (EDC) system. 
Screening assessments as summarized in the Schedule of Assessments (Table 6) will be 
performed within 14 days of Cycle 1 Day 1. 
Study eligibility will be based on satisfying all of the study inclusion and exclusion criteria. 
Participant eligibility must be confirmed by the Medical Monitor or designee prior to 
randomization. 
Re-screening of participants will be allowed only upon approval of the Medical Monitor. A new 
consent/assent form must be signed to allow re-screening. 
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4.7 
WITHDRAWAL CRITERIA 
Participants will receive belumosudil treatment in 28-day cycles until clinically significant 
progression of cGVHD (defined as progression requiring addition of new systemic therapy for 
cGVHD), histologic recurrence of underlying malignancy, unacceptable toxicity, Investigator 
decision, participant preference / withdrawal of consent, loss to follow-up, sponsor decision, or 
death (whichever occurs first). Belumosudil treatment failures require discontinuation of study 
drug. 
Participants who experience cGVHD progression as defined by NIH criteria but for whom no 
new systemic therapy is planned may continue to receive belumosudil and be assessed again at 
their next cycle. If progression per NIH criteria is not confirmed or no new systemic therapy is 
planned, participants may continue on belumosudil per investigator discretion until they fulfill 
one of the criteria requiring discontinuation of study drug. 
Taper belumosudil after a sustained response for 6 months and cessation of all other 
immunosuppressants for at least 3 months, at the Investigator’s discretion. The tapering schedule 
for belumosudil is described in Section 5.2.1. 
Participants may be withdrawn from study treatment at any time by the Investigator or the 
sponsor if it is considered detrimental for the participant to continue in the study. The reason for 
withdrawal must be captured in the eCRF. 
Participants have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution. If the participant 
wishes to voluntarily withdraw from the study, the physician will consult with the participant 
regarding procedures for safe withdrawal. Every effort should be made to have such participants 
attend EOT and 28-day follow up visits. In the instances where a reason for withdrawal of 
consent/assent is given, this will be captured in the eCRF. Participant data up to withdrawal of 
consent/assent will be included in the analysis of the study, and where permitted, publicly 
available data can be included after withdrawal of consent/assent.  
If a participant becomes pregnant while on study, belumosudil will be discontinued 
(Section 6.4.5). 
Under Protocol Amendment 3, all participants (excluding the 20 adolescent participants) that 
have received at least 6 months of belumosudil treatment or are in long-term follow-up without 
having a failure-free survival event are expected to end participation in study KD025-213. 
Participants may continue to participate in study KD025-213 if the Investigative Site is awaiting 
IRB approval of the KD025-217 rollover study titled: “Extended Treatment and Follow-up of 
Participants Treated with Belumosudil in Study KD025-208 or Study KD025-213”. 
4.8 
REPLACEMENTS 
Randomized participants withdrawn from the study before receiving any study drug will be 
replaced. 
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4.8.1 Treatment Discontinuation 
Treatment discontinuation reasons include the following: 
• Clinically significant cGVHD progression requiring addition of systemic therapy for 
cGVHD. Of note, clinically significant progression does not necessarily require cGVHD 
progression as defined by NIH Consensus Criteria. For example, a participant with a 
score of 3 in a given organ may present with clinically significant progression that 
warrants urgent intervention even though the NIH score remains unchanged. 
• Progression of underlying disease as defined by established disease specific criteria. 
• An AE that requires permanent discontinuation of study drug.  
• Pregnancy. 
• Investigator decision. 
• Voluntary discontinuation/ withdrawal from the study treatment by the participant 
(participant may remain eligible for follow up). 
• In case a participant wants to permanently discontinue the treatment (ie, withdrawal of 
consent for the intervention), the participant will be asked if a final assessment is possible 
to be performed using the procedure normally planned for the last dosing day (EOT and 
at 28-day follow up visit) with the IMP prior to consent of the withdrawal. See the SoA 
(Section 6.1) for the data to be collected at the time of the study treatment 
discontinuation, for information on the follow-up, and for any further evaluations that 
would need to be completed. 
• Noncompliance to protocol. 
• Participant lost to follow-up. 
• Termination of the study by sponsor. 
• Participant death. 
• Received more than 6 months of belumosudil (this does not apply to the 20 adolescents). 
Of note, participants may continue to participate in KD025-213 if the Investigative Site is 
awaiting IRB approval of the KD025-217 rollover study titled: “Extended Treatment and 
Follow-up of Participants Treated with Belumosudil in Study KD025-208 or Study 
KD025-213”. 
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5 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCT 
Belumosudil (2-(3-(4-(1H-indazol-5-ylamino) quinazolin-2-yl) phenoxy)-N-isopropylacetamide-
methane sulfonic acid salt), formerly also known as KD025, is an orally available Rho-
associated protein kinase-2 (ROCK2) selective inhibitor. Belumosudil will be provided as 
200 mg tablets.  
In July 2021, FDA granted approval of belumosudil (REZUROCK) for the treatment of adult and 
pediatric patients 12 years and older with cGVHD after failure of at least 2 prior lines of 
systemic therapy and subsequently is commercially available for this indication.   
5.2 
DOSAGE AND ADMINISTRATION 
Eligible participants in this study will be randomized (1:1) to one of two treatment arms: 
• Arm A: belumosudil 200 mg QD 
• Arm B: belumosudil 200 mg BID 
Any adolescent taking a PPI or a strong CYP3A4 inducer will begin C1D1 at the following 
escalated dose: belumosudil 200 mg BID. On Day 1 of cycles 1, 2, 3, 5, 7 and then every 
3 cycles (C10D1, C13D1, etc.), and on scheduled PK and PD sampling days, participants must 
take their dose of belumosudil at the clinic. On Day 1 of other cycles, belumosudil may be taken 
at home or in the clinic. Other daily doses will be taken at home and the study drug will be 
dispensed for home administration (see Section 6.2.2 and Section 6.2.4). 
Participants will be instructed to start a meal within 30 minutes prior to taking their belumosudil 
treatment. 
Additional information on dosage and administration of belumosudil can be found in the 
KD025-213 Pharmacy Manual. 
5.2.1 Belumosudil Tapering Guidance 
Tapering of belumosudil is allowed after a sustained response for 6 months and cessation of all 
other immunosuppressants for at least 3 months, at the Investigator’s discretion. The tapering 
schedule for belumosudil is as follows: 
• Arm A (QD): 200 mg QD → 200 mg QOD for 2 cycles→ Discontinue 
• Arm B (BID): 200 mg BID → 200 mg QD for 2 cycles → 200 mg QOD for 2 cycles → 
Discontinue 
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Similarly, participants whose cGVHD has not progressed at the time of discontinuation of 
belumosudil treatment (Section 4.7) and who come off study for reasons other than AEs should 
be tapered off belumosudil by reducing the dose every 2 cycles as described above. 
5.3 
TREATMENT ASSIGNMENT 
Eligible participants will be randomized and assigned to a treatment arm (A or B) in this open 
label, randomized study in accordance with the randomization schedule.  
Randomization will be stratified according to: 
• Prior ibrutinib therapy (yes/no). 
• Severe cGVHD (yes/no) where severe cGVHD is defined as at least one organ with a 
score of 3, or a lung score of 2 or 3 (Table 1) (26). 
The randomization will be a block randomization with a block size of 4. 
Table 1 - cGVHD Severity Definitions 
cGVHD Severity 
Definition 
Mild cGVHD 
1 or 2 organs involved with no more than score 1 plus 
Lung score 0 
Moderate cGVHD 
3 or more organs involved with no more than score 1 OR 
At least 1 organ (not lung) with a score of 2 OR 
Lung score 1 
Severe cGVHD 
At least 1 organ with a score of 3 OR 
Lung score of 2 or 3 
Key points:  
1. 
In skin: higher of the two scores to be used for calculating global severity. 
2. 
In lung: FEV1 is used instead of clinical score for calculating global severity. 
3. 
If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD documented cause, 
that organ is not included for calculation of the global severity. 
4. 
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the scored organ 
will be used for calculation of the global severity regardless of the contributing causes (no downgrading of organ 
severity score). 
Reference: Jagasia et al. (26) 
5.4 
BLINDING 
This is an open-label study. 
5.5 
TREATMENT COMPLIANCE 
Participants will be given a study drug diary to record the details of each dose of study drug. 
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5.6 
MISSED DOSES 
Participants should make every effort to take the study drug at the same time every day with their 
morning/evening meal. Participants will be instructed to start a meal within 30 minutes prior to 
taking their belumosudil treatment. In the event that the participant misses the planned dose of 
study drug, the following protocol should be followed: 
For participants in Arm A, receiving study drug on a QD dosing schedule: 
• If less than 12 hours of time have elapsed after the scheduled dose, the drug should be 
taken. The participant should then resume the regular planned daily dosing schedule the 
following day. 
• If more than 12 hours of time have elapsed after the scheduled dose, the drug should be 
skipped for that day. The participant should then resume the regular planned dosing 
schedule the following day. 
For participants in Arm B, receiving study drug on a BID dosing schedule: 
• If less than 6 hours of time have elapsed after the scheduled dose, the drug should be 
taken. The participant should then resume the regular planned dosing schedule.  
• If more than 6 hours of time have elapsed after the scheduled dose, the dose should be 
skipped and the participant should resume dosing with the next the regular planned dose. 
If the participant skips more than 7 consecutive days of drug, the participant should be 
discontinued from the study unless approved by the Medical Monitor and Investigator. 
In the event of vomiting, the participant should report the AE and should not take additional 
doses of study drug to compensate. 
5.7 
PRODUCT ACCOUNTABILITY 
In accordance with regulatory requirements, study sites must document the amount of 
investigational product received from and returned to the sponsor, and the amounts of 
investigational product dispensed to study participants, and the amount returned by study 
participants. Product accountability records must be maintained throughout the course of the 
study.  
5.8 
CONCOMITANT MEDICATIONS AND PROCEDURES 
All concomitant medications including dietary / herbal / over the counter supplements taken 
during the study and relevant procedures will be recorded. Initiation of new systemic cGVHD 
therapy will be considered a new line of treatment and a belumosudil treatment failure; this 
necessitates discontinuing from study drug. 
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5.8.1 Corticosteroids 
Corticosteroid dose data will be collected throughout the study. Corticosteroids may be tapered at 
the discretion of the Investigator after ≥2 weeks of belumosudil administration. 
Transient increases in corticosteroid dosing (not exceeding 1mg/kg/day prednisone equivalent, 
Appendix K) are permitted for the treatment of cGVHD flare, but dose must be reduced back to 
the pre-randomization dose within 6 weeks. If the dose remains elevated for more than 6 weeks, 
this will be considered a belumosudil treatment failure. More than 2 episodes of cGVHD flare 
requiring increased corticosteroid therapy in the first 6 months of belumosudil treatment will also 
be considered a belumosudil treatment failure; this necessitates discontinuing from study drug. 
Response assessments scheduled to occur during treatment of a cGVHD flare will be conducted 
as planned but will not be included in the primary efficacy analysis. 
PD samples should be collected at time corticosteroid dose is increased. Refer to the Laboratory 
Manual for detailed instructions. 
5.8.2 Systemic cGVHD Therapies 
Per the eligibility criteria, participants receiving standard of care systemic cGVHD therapies 
such as calcineurin inhibitors (tacrolimus, cyclosporine), sirolimus, MMF, methotrexate, 
rituximab or ECP, may be enrolled if they have been on a stable dose / schedule. Changes in 
doses of drugs to maintain therapeutic levels are not considered as a change in dose/schedule. 
Doses and schedules of these therapies will be collected throughout the study and changes will 
be documented. 
Doses may be tapered at the discretion of the Investigator after ≥4 weeks of belumosudil 
administration. 
Increases in dosage to above the baseline dose are not permitted. An exception is for dose 
adjustments to maintain therapeutic drug levels. 
5.8.3 Topical / Organ Specific Therapies for cGVHD 
Use of topical / organ specific therapies for cGVHD is permitted and must be documented. 
5.8.4 CYP3A4 Inducers and Proton Pump Inhibitor  
Use of strong CYP3A4 inducers decreases belumosudil exposure (Section 21.9 Appendix I). Use 
of PPIs (eg, omeprazole [Prilosec], esomeprazole [Nexium], lansoprazole [Prevacid], 
rabeprazole [AcipHex], pantoprazole [Protonix]) decreases belumosudil exposure. Participants 
on strong CYP3A4 inducers or PPIs can dose modify to 200 mg BID if they are dosing at 
200 mg QD at the Investigator’s discretion. 
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5.8.5 Prohibited Concomitant Medications 
Treatment with investigational systemic immunosuppressant drugs for cGVHD is prohibited. 
Concomitant use of Ruxolitinib is prohibited. 
5.9 
TREATMENT OF OVERDOSE 
Any dose of belumosudil >1000 mg within a 24-hour period will be considered an overdose. In 
clinical studies of belumosudil, repeat dosing of 500 mg BID for 28 days was generally well 
tolerated in healthy volunteers. There are no known antidotes to belumosudil, and no specific 
treatment is recommended in the event of a suspected overdose. The treating Investigator should 
employ clinical judgment in managing participants with suspected overdose. Overdose should be 
reported as an AE (Section 9.2).  
5.10 
DOSE MODIFICATION GUIDELINES 
Any clinically significant toxicity will necessitate consideration of either a pause or cessation of 
therapy. Guidelines for management of treatment-emergent toxicities in participants receiving 
belumosudil are outlined in Table 2 below.  
Table 2 - Guidelines for Management of Treatment-Emergent Toxicities 
Toxicity 
Recommended Action 
ALT or AST increased (more than 20x 
ULN), blood bilirubin increased (more 
than 3x ULN) considered at least 
possibly related to belumosudil 
Discontinue belumosudil 
Other Grade 4 organ toxicities 
considered at least possibly related to 
belumosudil 
• 
Discontinue belumosudil 
AST or ALT increased (5x to 20x ULN) or 
total bilirubin increased (1.5x to 3x ULN) 
considered at least possibly related to 
belumosudil 
• 
Hold belumosudil dosing until recovery of total bilirubin (≤1.5x ULN), AST and 
ALT (≤3x ULN), then consider resuming belumosudil at the recommended dose 
• 
Complete the “Treatment Emergent LFT Elevations” eCRF 
• 
Consider resuming belumosudil. If resuming, then resume at the recommended 
dose  
• 
If toxicity recurs, discontinue belumosudil 
Other Grade ≥3 clinically significant 
toxicities considered at least possibly 
related to belumosudil  
• 
Hold belumosudil dosing until toxicity has resolved to Grade 1 or below then 
consider resuming belumosudil. If resuming, then resume at the recommended 
dose  
• 
If toxicity recurs, hold dose as above then consider resuming belumosudil at the 
recommended dose  
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; eCRF=electronic case report form; 
LFT=liver function enzymes. 
Dose interruption for up to 14 days for toxicity management is permitted. Participants requiring 
pauses of more than 14 days will be discontinued from the study unless approved by the Medical 
Monitor.
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6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
SCHEDULE OF ASSESSMENTS 
The schedule of assessments is outlined in Section 21.1 
• Table 6: Schedule of Assessments. 
• Table 7: Pharmacokinetics Sampling. 
• Table 9: Pharmacodynamic Sampling. 
Further details of pulmonary function testing are provided in Appendix J. 
In addition to the assessments detailed below, Investigators may, with appropriate consenting of 
participants, take serial photographs to further document changes in cGVHD (eg, skin, range of 
motion).  
6.2 
STUDY VISITS 
6.2.1 Screening 
During screening, participants will have the following completed: 
• Provide informed consent / assent. 
• Demographic information including gender, age (date of birth), ethnic origin and race. 
• Medical history. 
• Transplant history including indication for and type of prior transplant(s). 
• GVHD history (acute and chronic). 
• cGVHD treatment history, including prior therapies and lines of treatment for cGVHD 
(Section 4.5). 
• Physical examination. All clinically significant findings, either new of worsening 
throughout the study will be documented as AEs or SAEs. 
• Height, weight and body mass index (BMI). 
• Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature). 
• Karnofsky (if aged ≥16 years) / Lansky (if aged <16 years) Performance Scale score 
(Appendix G). 
• Hematology (Table 4). 
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• Clinical chemistry (Table 4). 
• Virology. 
• Spirometry (FEV1 and FVC) (Appendix J). 
• Supine 12 Lead ECG, single. 
• Highly sensitive urine or serum pregnancy test (for females of childbearing potential). 
Positive urine results are to be confirmed with serum testing.  
• Concomitant medications / procedures assessment 
Baseline cGVHD severity must be assessed (a stratification factor for randomization). Chronic 
GVHD severity is defined in Section 5.3 (26). 
Eligible participants may be randomized after Medical Monitor approval during the screening 
window or on C1D1 prior to dosing with belumosudil. 
6.2.2 Cycle 1, Day 1 (Baseline) 
At the Cycle 1, Day 1 visit, participants will come to the clinic to have the following procedures 
completed. (Note that if screening assessments, apart from hematology, clinical chemistry and 
urine pregnancy are done within 7 days prior to Cycle 1, Day 1, they do not need to be repeated 
on Cycle 1 Day 1). 
Pre-dose 
• Concomitant medications / procedures assessment. 
• AE assessment. 
• Symptom directed PE. 
• Highly sensitive urine or serum pregnancy test (for females of childbearing potential). 
Positive urine results are to be confirmed with serum testing. Refer to Section 6.4.5 for 
positive serum tests. 
• Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature). 
• Weight measurement.  
• Height and BMI if aged <18 years. 
• Karnofsky (if aged ≥16 years) / Lansky (if aged <16 years) Performance Scale score 
(Appendix G). 
• Hematology (Table 4). 
• Clinical chemistry (Table 4). 
• Single 12-lead ECG (Table 10). 
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• Clinician-Reported Global cGVHD Activity Assessment.  
• Full pulmonary function tests (including FEV1, FVC, diffusing capacity of lung for 
carbon monoxide [DLCO, corrected for Hb], total lung capacity [TLC], and residual 
volume [RV]) (Appendix J). Baseline PFTs may also be performed post dose on C1D1 or 
at any time in the 7 days prior to C1D1. 
• cGVHD Activity Assessment - Patient Self Report. 
• Lee cGVHD Symptom Scale (Appendix D). 
• Document dosing of corticosteroids, and other cGVHD therapies. 
• For full PK participants, PK sampling (Table 7). 
• Pharmacodynamic sampling (Table 9). 
• PROMIS Global Health score (Appendix E). 
Dosing / Post-dose 
• Study drug administration. 
• Dispense study drug. 
• Dispense study drug diary. 
• Single 12-lead ECG 3 hours post dose (Table 10).  
• For full PK participants, PK sampling 1, 2, 3, 4, 5, 6, 7 and 8 hours post dose with 
optional sample at 12 hours post dose (prior to belumosudil PM dosing for Arm B 
participants) (Table 7). 
- 
Full PK participants should also have C1D2 PK sample drawn prior to dosing with 
belumosudil. 
6.2.3 Cycles 1, Day 15 (±3 days) 
On Day 15 of Cycle 1 only, participants will come to the clinic to have the following procedures 
completed: 
• Concomitant medications / procedures assessment. 
• AE assessment. 
• Symptom directed PE. 
• Weight measurement. 
• Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature). 
• Hematology (Table 4). 
• Clinical chemistry (Table 4). 
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6.2.4 Cycle 2 and Beyond, Day 1 (±3 days) 
On Day 1 of Cycles 2, 3, 5, 7 and then every other 3 treatment cycles (C10D1, C13D1, etc.), 
participants will come to the clinic to have the following procedures completed: 
Pre-dose 
• Concomitant medications / procedures assessment. 
• AE assessment. 
• Symptom directed PE. 
• Highly sensitive urine or serum pregnancy test (for females of childbearing potential). 
Positive urine results are to be confirmed with serum testing. Refer to Section 6.4.5 for 
positive serum tests. 
• Weight measurement. 
• Height and BMI if aged <18 years. 
• Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature). 
• Karnofsky (if aged ≥16 years) / Lansky (if aged <16 years) Performance Scale score 
(Appendix G). 
• Hematology (Table 4). 
• Clinical Chemistry (Table 4). 
• Single 12-lead ECG (Table 10). 
- 
Single ECG on C2D1, C3D1, C5D1, C7D1 and Day 1 of every 3rd cycle thereafter 
through C19D1. 
- 
Starting on C19D1 only if clinically indicated. 
• Document corticosteroid dosage. 
• Document other cGVHD therapies. 
• * Pulmonary function tests (Appendix J). 
- 
Can be post-dose. 
- Full PFTs (including FEV1, FVC, DLCO (corrected for Hb), TLC, and RV) are 
required after Cycle 2, 6, 12 and every 6th Cycle thereafter (Day 1 of Cycles 3, 7, 13, 
19 etc.). At other cycles, spirometry (FEV1 and FVC) is sufficient. 
• * Clinician-Reported Global cGVHD Activity Assessment. 
• * Response assessment. 
• * cGVHD Activity Assessment - Patient Self Report. 
• * Lee cGVHD Symptom Scale (Appendix D). 
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• * PROMIS Global Health score (Appendix E). 
• Sparse PK sampling on C2D1 and C7D1 only for all participants (Table 7). 
• Pharmacodynamic sampling on C2D1 and C7D1 only (Table 9). 
Dosing / Post dose 
• Study drug administration. 
• Dispense / collect study drug. 
• Dispense / collect study drug diary. 
• Sparse PK sampling on C2D1 and C7D1 only for all participants at 3 hours post-dose 
(Table 7). 
• For full PK participants, PK sampling 1, 2, 3, 4, 5, 6, 7 and 8 hours post dose with an 
optional sample at 12 hours post dose on C2D1 only (prior to belumosudil PM dosing for 
Arm B participants) (Table 7). 
- 
Full PK participants should also have C2D2 PK sample drawn prior to dosing. 
* These items must be completed on Day 1 of Cycles 2, 3, 5, 7, then on Day 1 of every 
3 cycles thereafter, (Day 1 of Cycles 10, 13, 16, 19, etc.). These items may be completed on 
Day 1 of other cycles if deemed appropriate by the Investigator. 
Note: On Day 1 of Cycles 8 and beyond, participants will come to the clinic to have the same 
procedures as described above, except belumosudil may be administered at home or in the clinic 
(procedures can then be pre- or post-dose). 
On Cycle 2 Day 1 (C2D1) participants will receive study drug for 1 cycle along with 1 diary. On 
Cycle 3 and 5 Day 1 (C3D1 and C5D1), participants will receive the study drug for the next 2 
cycles along with 2 diaries, and from cycle 7 onwards (C7D1, C10D1, C13D1, etc.) participants 
will receive the study drug for 3 cycles along with 3 diaries and return to the clinic every 3 
cycles for assessments and investigational product accountability. On cycles when participants 
do not come to clinic, the study staff will contact the participant, eg, via phone and document any 
new AEs and concomitant medications. Also, from C19D1 onwards, ECGs will be done only if 
clinically indicated. 
6.2.5 End of Treatment (EOT) 
Participants are to return to the study site within 7 days after the participant’s last dose of study 
drug to complete all EOT assessments. This may occur at the visit at which disease progression 
is diagnosed. The following procedures will be completed: 
• Concomitant medications assessment. 
• AE assessment. 
• Symptom directed PE. 
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• Highly sensitive urine or serum pregnancy test (for females of childbearing potential). 
Positive results are to be confirmed with serum testing. 
• Weight measurement. 
• Height and BMI if aged <18 years. 
• Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature). 
• Karnofsky (if aged ≥16 years) / Lansky (if aged <16 years) Performance Scale score 
(Appendix G). 
• Hematology (Table 4). 
• Clinical Chemistry (Table 4). 
• Single 12-lead ECG (Table 10). 
• Full PFTs (including FEV1, FVC, DLCO (corrected for Hb), TLC, and RV) or spirometry 
(FEV1, FVC) if full PFTs have been taken in the previous month. 
• Clinician-Reported Global cGVHD Activity Assessment. 
• Response assessment. 
• Pharmacodynamic sampling in event of progression of cGVHD. 
• cGVHD Activity Assessment - Patient Self Report. 
• Lee cGVHD Symptom Scale. 
• PROMIS Global Health score (Appendix E). 
• Document corticosteroid dosage. 
• Document other cGVHD therapies. 
• Collect study drug. 
• Collect study drug diary. 
If the participant is discontinuing study due to enrolling in the KD025-217 study, the EOT visit is 
expected to be the same day as C1D1 of KD025-217. The EOT visit for these participants rolling 
into the extension study includes minimal assessments: collect study drug and collect study drug 
diary.  
If the participant is discontinuing and not participating in KD025-217, all the EOT visit 
assessments are to be performed. 
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6.2.6 28-Day Follow-Up Visit 
The follow-up visit should occur 28 (±7) days after the last dose of study drug. However, when 
possible, this visit should occur prior to starting on a new cGVHD therapy (if a new therapy is 
started earlier). Participants will return to the clinic and the following procedures will be 
completed: 
• Concomitant medications assessment. 
• AE assessment. 
• Symptom directed PE. 
• Highly sensitive urine or serum pregnancy test (for females of childbearing potential). 
Positive urine results are to be confirmed with serum testing. 
• Weight measurement. 
• Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature). 
• Karnofsky (if aged ≥16 years) / Lansky (if aged <16 years) Performance Scale score 
(Appendix G). 
• Hematology (Table 4). 
• Clinical chemistry (Table 4). 
• Single 12-lead ECG (Table 10). 
6.2.7 Unscheduled Visits 
For participants requiring an unscheduled visit, assessments described in Section 6 may be 
performed at the Investigator’s discretion. 
6.2.8 Long-Term Follow-Up 
After the follow-up visit is completed, participants will be contacted approximately every 
12 weeks eg, by telephone, e-mail, or postal mail until a failure-free survival event occurs or 
until the study close-out (whichever occurs first) to confirm survival status, any changes in 
treatment for cGVHD and the initiation of treatment for the underlying disease. Alternatively, 
this information may be derived from medical records. 
With Protocol Amendment 3, all participants that have not yet had a failure free survival event 
will end participation with KD025-213. Participants may continue to participate in KD025-213 if 
the Investigative Site is awaiting IRB approval of the KD025-217 rollover study titled: 
“Extended Treatment and Follow-up of Participants Treated with Belumosudil in Study 
KD025-208 or Study KD025-213”. 
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6.3 
EFFICACY 
6.3.1 Efficacy Endpoints 
6.3.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the overall response rate (ORR). Responders include 
participants that achieve a [PR+CR]. Responses are defined by the 2014 National Institutes of 
Health (NIH) Consensus Development Project on Clinical Trials in cGVHD.  
6.3.1.2 Secondary Endpoints 
• Duration of Response (DOR). 
• Change in Lee Symptom Scale Score. 
• Response rate by organ system. 
• Time to response (TTR). 
• Time to next treatment (TTNT). 
• Percentage of participants who have a best response of PR or CR. 
• Change in corticosteroid dose. 
• Change in calcineurin inhibitor dose. 
• Failure-free survival (FFS). 
• Overall Survival (OS). 
• Change in cGVHD global severity rating as based on the Clinician-Reported global 
cGVHD Activity Assessment.  
• Change in symptom activity as based on cGVHD Activity Assessment Patient 
Self-Report.  
• Pharmacokinetics. 
6.3.1.3 Exploratory Endpoints 
• PROMIS Global Health subscores for physical and mental functioning. 
• ORR per Kadmon Algorithmic Response Assessment (KARA). 
• Pharmacodynamics - Changes in relevant biomarkers after belumosudil administration.  
6.3.2 Overall Response Rate 
The overall response determination is based on the cGVHD response assessment performed by 
Investigators (see Appendix B) per the Schedule of Assessments. Where possible, the same 
assessor at the site should perform response assessments for a given participant. 
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The overall response is assessed using the global scores from ten systems (Skin, Eyes, Mouth, 
Esophagus, Upper GI, Lower GI, Liver, Lungs, Joints and Fascia and Global Severity Rating). 
The overall response at each assessment time point will be categorized as Complete Response 
(CR), Partial Response (PR), or Lack of Response (LR), where LR includes the response status 
of unchanged, mixed, or progression as defined in Table 3. For clarity, Lack of Response - Mixed 
will be considered a progression event for analysis purposes. These response categories are based 
on the 2014 NIH Consensus Development Project on Clinical Trials in cGVHD (Appendix C). 
Table 3 - cGVHD Response Definitions 
Response 
Definition 
Complete Response (CR) 
Resolution of all manifestations of cGVHD in each organ or site 
Partial Response (PR) 
Improvement in at least one organ or site without progression in any other organ or site 
Lack of Response 
Mixed (LR-M) 
Complete or partial response in at least one organ accompanied by progression in another organ* 
Unchanged (LR-U) 
Outcomes that do not meet the criteria for complete response, partial response, progression or mixed 
response 
Progression (LR-P) 
Progression in at least one organ or site without a response in any other organ or site 
* Considered progression for purposes of analysis 
Pulmonary function testing is required (FEV1) for this assessment. The same equipment and 
tester should be used during the course of the study to the extent possible. Pulmonary function 
tests should be conducted in accordance with study guidelines and the American Thoracic 
Society/European Respiratory Society standardization of lung function testing (27).  
6.3.3 Patient Reported Outcomes 
6.3.3.1 Lee Symptom Scale Score 
Changes in symptom burden/bother will be explored using the Lee cGVHD Symptom Scale 
(Appendix D). Symptom burden will be assessed on Day 1 of each cycle starting on Cycle 1 
Day 1, as well as at the EOT visit. Lee et al developed a symptom scale designed for individuals 
with chronic GVHD (28). The questionnaire asks participants to indicate the degree of bother 
that they experienced due to symptoms in seven domains potentially affected by chronic GVHD 
(skin, eyes, mouth, breathing, eating and digestion, energy, and emotional distress). 
The degree to which participants report that they are bothered by a symptom represents a global 
assessment incorporating not only the intensity of the symptom and its frequency, but also the 
degree to which it causes emotional disturbance or interferes with functioning. 
6.3.3.2 cGVHD Activity Assessment – Patient Self Report 
Changes in the cGVHD Activity Assessment – Patient Self Report will be evaluated 
(Appendix F). 
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6.3.3.3 PROMIS Global Health Score 
As an exploratory endpoint, changes in the PROMIS Global Health subscores for physical and 
mental functioning will be evaluated (Appendix E) (29).  
6.3.4 Change in Corticosteroid Dose 
The change in systemic corticosteroid dose over time will be determined. If participants are not 
using prednisone as the corticosteroid therapy, then the prednisone dose equivalent will be 
determined (Appendix K). Dose equivalency tables are provided in the Statistical Analysis Plan. 
6.3.5 Failure Free Survival 
Descriptive statistics of Failure Free Survival (FFS) will be reported. FFS is defined as the 
absence of cGVHD treatment change, non-relapse mortality and recurrent malignancy (30).  
6.4 
SAFETY 
6.4.1 Safety Endpoints 
Safety is a secondary endpoint. The primary safety outcome will be the percent of participants in 
each arm experiencing AEs. See below and Section 9 for additional details. 
• Adverse Events and SAEs. 
• Hematological and clinical chemistry parameters. 
• Vital signs. 
- 
Change from baseline in systolic blood pressure, diastolic blood pressure and heart 
rate.  
• 12-Lead ECG 
- 
Mean and maximum change from baseline in QTc(F).  
6.4.2 Vital Signs 
Seated pulse rate and blood pressure measurements will be performed as outlined in the schedule 
of assessments (Table 6). Measurements will be taken with the participant sitting, having rested 
in this position for at least 5 minutes. Vital signs should be taken before ECGs and other 
scheduled assessments. Respiratory rate and temperature will also be measured. 
6.4.3 Twelve-lead ECG 
Twelve-lead ECGs will be performed as outlined in the schedule of assessments (and Table 10). 
ECGs will be recorded after the participant has rested in the supine position for at least 
5 minutes. ECGs should be performed prior to any blood sample collections. 
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Abnormalities in the ECG that lead to a change in participant management or result in clinical 
signs and symptoms are considered clinically significant for the purposes of this study and will 
be recorded in the AE eCRF. If ECG abnormalities meet criteria defining them as serious, they 
must be reported as an SAE (Section 9.3.1). 
6.4.4 Clinical Laboratory Parameters 
Clinical laboratory tests will be performed as outlined in the schedule of assessments (Table 6). 
Samples should be taken predose and will be sent to a central laboratory for analysis. Screening 
laboratory tests will include HBsAg and hepatitis C antibodies. Full details for collection and 
shipping of samples are provided in the Laboratory Manual.  
Table 4 - Clinical Laboratory Panels 
Hematology 
Serum Chemistry 
• 
White blood cell count with differential (including at 
minimum: neutrophils, basophils, eosinophils, 
lymphocytes, monocytes) 
• 
Red blood cell count 
• 
Hemoglobin 
• 
Hematocrit 
• 
Platelet count 
• 
MCV 
• 
Albumin 
• 
Alkaline phosphatase 
• 
ALT 
• 
AST 
• 
BUN 
• 
Calcium 
• 
Chloride 
• 
CO2 
• 
Creatinine / GFR 
• 
CPK 
• 
Total and direct bilirubin 
• 
GGT 
• 
Globulin 
• 
Glucose 
• 
Lactate dehydrogenase 
• 
Magnesium 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CPK = creatine 
phosphokinase; GFR = Glomerular Filtration Rate; GGT = gamma glutamyl transferase; MCV = mean corpuscular 
volume 
Abnormalities in clinical laboratory tests that lead to a change in participant management 
(eg, dose delay, requirement for additional medication or monitoring) are considered clinically 
significant for the purposes of this study and will be recorded on the AE eCRF page. Laboratory 
results will be classified using the CTCAE v5.0. If laboratory values constitute part of an event 
that meets criteria defining it as serious, the event (and associated laboratory values) must be 
reported as an SAE (see Section 9.3.1). 
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6.4.5 Pregnancy Testing 
Pregnancy tests (highly sensitive urine or serum test) will be done at the timepoints specified in 
the SoA (Section 21) in females of childbearing potential. Positive urine results are to be 
confirmed with serum testing. If pregnancy is confirmed with serum testing, belumosudil will be 
discontinued. The Sponsor will continue to collect data on the pregnancy and the participant will 
be followed until after the birth of the baby to assess outcome of the pregnancy and the status of 
the newborn. 
In the event that a participant’s partner becomes pregnant during the study, the Sponsor will also 
collect data on the pregnancy, birth and the condition of the newborn. 
6.5 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Future research may help to further increase the understanding of the disease and the 
development of new medicines. Reuse of coded data and biological samples (leftover and 
additional) will be limited to future scientific research conducted under a research plan for the 
purpose of diagnosing, preventing or treating diseases. The future research projects will be 
conducted under the responsibility of the Sponsor’s and/or its affiliates’ and/or, if applicable, the 
partner of the Sponsor which has licensed the study drug to the Sponsor or which is 
co-developing the study drug with the Sponsor’s control, acting alone or in collaboration with 
research partners such as universities, research institutions or industrial partners with whom the 
coded data may be shared.  
Data and biological samples will be stored and used for future research only when consented to 
by participants (see Section 14.1) and, when applicable, further information on the future 
research has been provided to the study participant, unless prohibited by local laws or IRBs/IECs 
(in such case, consent for future use of sample will not be included in the local ICF). The 
conditions for reuse will be adapted locally with the appropriate language in the ICF.  
In any case, a specific consent will be collected for the performance of genetic analyses on 
leftover and/or additional samples.  
Data protection - Processing of coded clinical data  
The study participant will be provided with all mandatory details of the data processing in the 
ICF.  
The Sponsor adopts safeguards for protecting participant confidentiality and personal data (see 
Section 19). 
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Use of leftover samples and additional samples for future research 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct 
at a given timepoint (eg, at randomization visit) as defined in the study protocol. 
The study participant will be provided with all mandatory details of the use of the human 
biological samples (leftover and additional) in the ICF.  
Relating data will be stored for up to 25 years for regulatory purposes and future research. 
Biological samples for future use will be stored for up to 25 years after the end of the study. Any 
samples remaining at the end of the retention period will be destroyed. If a participant requests 
destruction of his/her samples before the end of the retention period, the Investigator must notify 
the Sponsor (or its contract organization) in writing. In such case, samples will be destroyed, and 
related coded data will be anonymized unless otherwise required by applicable laws.  
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7 
PHARMACOKINETICS 
On PK sampling days, participants will take their belumosudil morning dose in the clinic. The 
time at which the prior dose was taken will be documented. Participants should be instructed 
accordingly.  
The pre-dose and all post-dose PK collection time points are to be documented on the 
appropriate eCRF. Additionally, the time of a participant’s dose of study drug is to be 
documented. 
7.1 
SPARSE PK 
For sparse PK analyses, blood samples (approximately 6 mL) will be collected for all 
participants, as outlined in Pharmacokinetics Sampling Table 7. 
7.2 
FULL PK 
Blood samples (approximately 6 mL) for determination of plasma concentrations of belumosudil 
and its metabolites will be collected for a subset of participants, approximately 12 in each arm, at 
selected sites as outlined in Pharmacokinetics Sampling Table 7. Sites are selected based on the 
capabilities and agreement of the site to conduct Full PK sampling. Full PK profiles will be 
collected only for participants that have consented to the optional Full PK sampling. 
A total of up to 23-25 samples will be collected from full PK participants (including C7D1 sparse 
PK). Note that the 12-hour post dose PK samples are optional. 
Belumosudil and metabolite concentrations will be used to calculate the following PK 
parameters: Cmax, Tmax, T1/2 and AUC. 
Detailed instructions for sample collection and preparation will be provided in the Central 
Laboratory Manual. 
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8 
PHARMACODYNAMICS 
Pharmacodynamic samples will be collected for all participants as outlined in Pharmacodynamic 
sampling Table 9. Samples will be collected at sites with appropriate capabilities. PD samples 
will not be required from adolescents if the site has policies limiting the daily volume of blood 
allowed to be drawn as part of a clinical trial (less than the FDA guidelines). 
Detailed instructions for sample collection and preparation will be provided in the Laboratory 
Manual. 
Changes in the relevant biomarkers after belumosudil administration will be explored. 
Additional samples will be collected from participants enrolled in the site-specific Companion 
Study for PD analyses as described in Section 21.13 Appendix M. 
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9 
SAFETY 
9.1 
SAFETY PARAMETERS 
The CTCAE v5.0 will be used for grading toxicities. Laboratory results also will be classified 
using the CTCAE v5.0. Participants will be monitored throughout the treatment and follow-up 
period for occurrence of AEs (acute, delayed, and/or cumulative), as well as for changes in 
clinical status, vital sign measurements, and laboratory data. Safety parameters to be 
measured/assessed include vital sign measurements, PE findings, hematology, clinical chemistry, 
and ECG recordings. Adverse events will be recorded after the ICF/assent form is signed until 
28 days after the last dose of belumosudil. 
9.2 
ADVERSE EVENT DEFINITION 
AE definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant/participant’s parent(s)/legally authorized representative 
(LAR)(s) who has signed the informed consent. Unsolicited AEs include serious and 
nonserious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring 
a hospitalization, emergency room visit, or visit to/by a health care provider). The 
participants/ participant’s parent(s)/LAR(s) will be instructed to contact the site as soon 
as possible to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant/participant’s parent(s)/LAR(s) concern. Detailed 
information about reported unsolicited AEs will be collected by qualified site personnel 
and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant/participant’s parent(s)/LAR(s) will be collected during an interview with the 
participants/participant’s parent(s)/LAR(s) and by review of available medical records at 
the next visit. 
• Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participants in their diary. 
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Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease, or more severe than expected for the participant’s condition), eg:  
- 
Leading to belumosudil discontinuation or modification of dosing, and/or,  
- 
Fulfilling a seriousness criterion, and/or,  
- Defined as an AESI. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or severity of the condition. 
• New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• Signs, symptoms, or the clinical sequelae of any medication errors, misuse and abuse 
with belumosudil 
• Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE.  
Events NOT meeting the AE definition 
• Any abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the participant’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 participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which 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.  
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9.3 
EVALUATING ADVERSE EVENTS 
The Investigator will determine the seriousness, severity, and causality of AEs based on the 
definitions that follow. 
9.3.1 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a) Results in death 
b) Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether hospitalization occurred or was 
necessary, the AE should be considered serious. 
- 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d) Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
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- 
The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered as a medically important event. 
The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm.  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc). 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse.  
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic 
ALT increase >10 × ULN.  
- 
Suicide attempt or any event suggestive of suicidality.  
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling).  
- 
Bullous cutaneous eruptions.  
9.3.2 Recording and follow-up of AE and/or SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of severity 
The Investigator will make an assessment of severity for each AE and SAE reported during the 
study and assign it to one of the following categories as per NCI CTCAE V5.0 definitions: 
• Grade 1 Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
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• Grade 2 Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL). Instrumental ADL refers to 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
• Grade 3 Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self-care 
ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
An event is defined as serious when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The Investigator will use clinical judgment to 
determine the relationship. 
• A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• Alternative causes, such as underlying disease(s), cGVHD, concomitant therapy, and 
other risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.  
• For causality assessment, the Investigator will also consult the IB and/or product 
information, for marketed products. 
• The Investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes. There may be situations in which an SAE has 
occurred, and the Investigator has minimal information to include in the initial report to 
the Sponsor’s representative. However, it is very important that the Investigator always 
make an assessment of causality for every event before the initial transmission of the 
SAE data to the Sponsor’s representative. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
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Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
9.3.2.1 Time period and frequency for collecting AE and SAE information 
All AEs (serious or nonserious) will be collected from the signing of the informed consent form 
(ICF) and for 28 days after the last dose of belumosudil at the timepoints specified in the SoA 
(Section 21.1), and any SAEs and study drug related nonserious AEs that occur more than 
28 days after the last dose of belumosudil. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours. The Investigator will submit any updated 
SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and the Investigator considers the 
event to be reasonably related to the study intervention or study participation, the Investigator 
must promptly notify the Sponsor. 
9.3.2.2 Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
9.3.2.3 Follow-up of AEs and SAEs 
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 4.8.1). 
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9.3.3 Reporting Requirements for SAEs 
9.3.3.1 Regulatory reporting requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether 
an event meets the criteria for a SUSAR, and therefore, is expedited to regulatory 
authorities. 
9.3.3.2 Reporting of SAEs 
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
offline, then the site can report this information on a paper SAE form or to the Sponsor’s 
representative by telephone. 
• Contacts for SAE reporting can be found in Emergency Contact Information. 
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SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• Contacts for SAE reporting can be found in Emergency Contact Information. 
9.3.3.3 Pregnancy 
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until determination of the 
outcome of the pregnancy. 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy.  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate and the information will be 
forwarded to the Sponsor. Beyond the estimated delivery date follow-up should last up to 
8 weeks.  
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 9.3.3. While the Investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.  
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9.4 
OTHER SAFETY CONSIDERATIONS 
9.4.1 Laboratory Data 
All laboratory data obtained during the course of the study should be reviewed. Any abnormal 
value that leads to a change in participant management (eg, dose reduction or delay, requirement 
for additional medication or monitoring) or is considered to be of clinical significance by the 
Investigator should be reported as an AE and/or SAE as appropriate, unless this value is 
consistent with the participant’s present disease state or is consistent with values obtained before 
entry into the study. 
Laboratory results will be classified using the CTCAE v5.0. 
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10 
STUDY STOPPING RULES 
In the event of any of the following safety findings occurring in either treatment arm, after at 
least 10 participants have been enrolled into the mITT population (Section 11.2.1) in that arm, 
enrollment will be paused for assessment of safety: 
1. Secondary graft failure in >10% of participants. 
2. Histological recurrence of underlying malignancy within 6 months of randomization in 
>20% of participants. 
3. Withdrawal due to related AEs in >20% of participants. 
Note: The rates of these events observed in the ongoing KD025-208 study as of 7-Mar-2018, 
with 51 participants enrolled, were 0%, 4% and 4% respectively.  
These stopping criteria will be assessed on an on-going basis by the Medical Monitor and shared 
with the study Steering Committee (Section 3.2). 
The Sponsor has the right to terminate or to stop the study at any time (Section 16). 
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11 
STATISTICAL CONSIDERATIONS 
Three analyses are planned: 
1. An interim analysis (IA) will be conducted approximately 2 months after 126 participants 
have been enrolled into the mITT population. A nominal 1-sided alpha of 0.0025 will be 
spent, but there will be no early study termination for efficacy.  
2. The primary analysis (PA) will be conducted approximately 6 months after 
126 participants have been enrolled into the mITT population, with 1-sided alpha 0.0225 
(or 0.025 if the ORRs of both arms are significant at interim). 
3. A follow-up analysis will be conducted approximately 12 months after 126 participants 
have been enrolled into the mITT population. 
Additional analyses will be conducted to include adolescent participants and Companion Study 
participants, approximately 6 months after completion of enrollment of the respective 
participants. 
Alpha will only be allocated to the primary endpoint, ORR. 
11.1 
HYPOTHESIS 
This study is designed to show an ORR of at least 30% in participants with cGVHD, treated with 
belumosudil after at least 2 prior lines of systemic therapy. 
11.2 
SAMPLE SIZE AND POWER CALCULATION 
Sample size is based on the primary efficacy endpoint of ORR, with one planned interim analysis 
(0.0025 1-sided alpha spending) and a target ORR of 55%. With 63 participants, and a 
10% dropout rate, each treatment arm is estimated to have approximately 90% power to yield a 
95% confidence interval of ORR that excludes 30% (equivalently, 90% power to reject the null 
hypothesis of ORR ≤30% at 1-sided alpha level 0.0225). 
The Hochberg procedure will be used for multiplicity adjustment for the primary endpoint of 
ORR as described below (Section 11.2.1). 
Table 5 provides powers for interim analysis (Table 5a) under various hypothetic ORRs to 
exclude 30%, and provides study powers under various hypothetic ORRs for at least one arm to 
exclude 30% at primary analysis (Table 5b). 
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Table 5 - Power for Various Hypothetic ORRs 
Table 5a: IA Power (1-sided alpha 0.0025)* 
For both arms to be statistically significant 
 
Arm 1 ORR (%) 
40 
45 
50 
55 
60 
Arm 2 ORR 
(%) 
40 
<1 
<1 
<1 
<1 
<1 
45 
- 
<1 
1 
2 
3 
50 
- 
- 
2 
6 
9 
55 
- 
- 
- 
12 
22 
60 
- 
- 
- 
- 
37 
For at least one arm to be statistically significant 
 
Arm 1 ORR (%) 
40 
45 
50 
55 
60 
Arm 2 ORR 
(%) 
40 
1 
3 
10 
28 
51 
45 
- 
5 
12 
29 
53 
50 
- 
- 
20 
35 
57 
55 
- 
- 
- 
65 
65 
60 
- 
- 
- 
- 
77 
Table 5b: PA Power (1-sided alpha 0.0225)* 
 
Arm 1 ORR (%) 
40 
45 
50 
55 
60 
Arm 2 ORR 
(%) 
40 
20 
39 
64 
84 
95 
45 
- 
52 
72 
89 
97 
50 
- 
- 
83 
93 
98 
55 
- 
- 
- 
97 
99 
60 
- 
- 
- 
- 
100 
IA = Interim Analysis; PA = Primary Analysis 
* Power estimated based upon 10,000 simulations for each cell 
A 10% dropout rate (non-efficacy and non-safety related) is assumed based upon preliminary 
data from the ongoing KD025-208 study. If during the course of the current study the dropout 
rate is observed to exceed 10%, the sample size may be adjusted eg, to approximately 
85 participants per arm if the dropout rate reaches 15%. 
11.2.1 Efficacy Decision Rules with Multiplicity Adjustment 
The Hochberg procedure is the primary multiplicity adjustment method for inferential purposes 
for the primary endpoint ORR.  
The inferential decision for primary endpoint of ORR is described below and shown in Figure 2. 
1. Calculate two-sided 99.5% confidence interval of ORR by using Clopper-Pearson (exact) 
method for both arms at interim analysis. 
2. If the lower bounds of their 2-sided 99.5% confidence interval both are above 30%, then 
claim both arms are efficacious, and stop. Otherwise, go to Step 3.  
3. If the lower bounds of their 2-sided 99.5% confidence interval both are below 30%, then 
cannot determine efficacy for either arm, and go to Step 5. Otherwise, go to Step 4. 
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4. Calculate 2-sided 99.75% confidence interval of ORR by using Clopper-Pearson (exact) 
method for treatment group with higher response rate. If its lower bound is above 30%, 
then claim this arm is efficacious, and go to step 6. Otherwise, cannot decide efficacy for 
both arms, and go to Step 5. 
5. Use following Hochberg procedure for the 6-month primary efficacy analysis of ORR 
a) Calculate 2-sided 95.5% confidence interval of ORR by using Clopper-Pearson 
(exact) method for both arms. 
b) If the lower bounds of their 2-sided 95.5% confidence interval both are above 30%, 
then claim both arms are efficacious, and stop. Otherwise, go to Step 5c. 
c) If the lower bounds of their 2-sided 95.5% confidence interval both are below 30%, 
then claim both arm are non-efficacious, and stop. Otherwise, go to Step 5d. 
d) Calculate 2-sided 97.75% confidence interval of ORR by using Clopper-Pearson 
(exact) method for treatment group with higher response rate. If its lower bound is 
above 30%, then claim this arm is efficacious, and stop. Otherwise, claim both arms 
are non-efficacious, and stop. 
6. At the 6-month primary analysis, calculate 2-sided 95.5% confidence interval (CI) of 
ORR by using Clopper-Pearson (exact) method for the treatment group with lower 
response rate at interim analysis. If its lower bound is above 30%, then claim this arm is 
efficacious, and stop. Otherwise, claim this arm is non-efficacious, and stop.  
If one arm is discontinued in view of the prescribed stopping rules (Section 10), efficacy will 
only be assessed for the remaining arm without multiplicity adjustment.  
The 12-month follow up analyses is an extension of the primary analysis with more mature data 
for DOR and other endpoints. 
In addition to inferential analysis results, nominal 95% CIs will be provided for ORR and other 
efficacy endpoints without multiplicity adjustment.  
Figure 2 - ORR Multiplicity Adjustment 
 
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11.3 
ANALYSIS POPULATIONS 
Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) population will consist of all randomized participants who 
receive at least one dose of study drug. This is the primary population for the analysis of the 
primary endpoint. 
The mITT population will be used for tables of demography, baseline characteristics, efficacy 
and safety. 
11.4 
SUBGROUP ANALYSES 
Subgroup analyses will be conducted for the following subgroups: 
• Prior ibrutinib (Yes / No). 
• Severe cGVHD (Yes / No). 
• Number of organs involved (<4 / ≥4). 
• Number of prior lines of therapy (≤3 / >3). 
• Duration of cGVHD before enrollment. 
• Lung involvement (Yes / No). 
• Concomitant treatment with a proton pump inhibitor (Yes / No). 
• Age (12-17, 18-64, ≥65). 
11.5 
DATA ANALYSIS 
All pre-specified analyses will be described in a Statistical Analysis Plan (SAP). 
11.6 
INTERIM ANALYSIS 
Interim, primary, and follow-up analyses are described above. 
Ongoing monitoring of safety data will be conducted in accordance with study stopping rules 
(Section 10). 
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11.7 
EFFICACY ANALYSES 
11.7.1 Primary Efficacy Endpoint 
The ORR is defined as the proportion of participants (from the mITT population) meeting the 
overall response criteria assessment of complete or partial responses at any post-baseline 
response assessment (Section 6.3.2). 
11.7.2 Secondary Efficacy Endpoints 
Secondary endpoints are as follows: 
• Duration of response (DOR): Assessments of DOR will include:  
- 
The time from initial response of PR or CR until documented progression from best 
response of cGVHD, new cGVHD therapy, or death. 
- 
Time from initial response to start of additional systemic cGVHD therapy or death. 
• Changes in the Lee Symptom Scale Score: Analyses will include: 
- 
Number of participants with a ≥7 point reduction. 
- 
Number of participants with a ≥7 point reduction on 2 consecutive assessments. 
- 
Duration of a ≥7 point reduction.  
• Response by organ system: The response assessment for the nine individual organs (Skin, 
Eyes, Mouth, Esophagus, Upper GI, Lower GI, Liver, Lungs, and Joints and fascia). 
• Time to response (TTR): defined as the time from the first dose of belumosudil to the 
first documented cGVHD response. 
• Time to next therapy (TTNT): defined as the time from the first dose of belumosudil to 
the start of additional systemic cGVHD therapy.  
• Number and percentage of participants who have a best response of PR and number and 
percentage of participants who have a best response of CR.  
• Change in corticosteroid dose: 
- 
The prednisone equivalent dose of corticosteroids (mg/kg/day) during the study will 
be analyzed (Appendix K). 
• Change in calcineurin inhibitor dose. 
• Failure-free-survival (FFS): FFS is defined as the absence of cGVHD treatment change, 
non-relapse mortality and recurrent malignancy (Section 6.3.5). Median FFS (from first 
dose of belumosudil) and landmark FFS at 1 year will be analyzed. 
• Overall survival (OS): Defined as time from first dose of belumosudil to the date of death 
due to any cause. 
• Changes in cGVHD global severity rating using the Clinician-Reported Global cGVHD 
Activity Assessment.  
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• Changes in symptom activity using the cGVHD Activity Assessment Patient Self-Report.  
Descriptive statistics will be provided for all secondary endpoints. 
11.8 
EXPLORATORY ANALYSES 
• Changes in the PROMIS Global Health subscores for physical and mental functioning. 
• ORR using Kadmon Algorithmic Response Assessment (KARA) for overall response. 
• Changes in the expression of relevant biomarkers after belumosudil administration 
(Section 11.11). 
11.9 
SAFETY ANALYSES 
Safety is a secondary endpoint. 
Treatment exposure will be summarized.  
Safety analyses include: 
• Adverse Events and SAEs 
- 
Treatment-emergent AEs will be summarized by treatment group using MedDRA® 
(Version 20.0 or greater) System Organ Class (SOC) and preferred term, classified 
from verbatim terms. The incidence and percentage of participants with at least 
1 occurrence of a preferred term will be included. Causality (relationship to study 
treatment) will be summarized separately. 
- 
AEs, SAEs, related AEs, related SAEs, ≥Grade 3 AEs, related ≥ Grade 3 AEs, and 
AEs leading to withdrawal, or treatment discontinuation will be summarized overall 
and by treatment arm. AEs will also be presented in listings. Duration of AEs will be 
determined and included in listings, along with action taken and outcome. 
• Hematological and clinical chemistry parameters using central laboratory 
- 
Laboratory results will be classified using CTCAE v5.0 and summarized by treatment 
arm. Incidence of laboratory abnormalities will be summarized. The worst on-study 
grade after the first dose of study drug will be summarized. The incidence of 
≥Grade 3 laboratory abnormalities under treatment and shifts in toxicity grading from 
baseline to highest grade post-baseline will be displayed. 
• Vital signs 
- 
Change from baseline in systolic blood pressure, diastolic blood pressure and heart 
rate will be presented. 
• 12-Lead ECG 
- 
Mean and maximum change from baseline in QTc(F) will be derived. 
 
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11.10 PHARMACOKINETIC ANALYSES 
The pharmacokinetic profile of belumosudil and major metabolites will be evaluated. Further 
details will be described in the Pharmacokinetic Analysis Plan. 
11.11 PHARMACODYNAMIC ANALYSES 
Further details will be described in the Pharmacodynamics Analysis Plan. 
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12 
DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be ensured by verification and cross-check of the 
eCRFs against the Investigator’s records by the study monitor (source document verification) 
and by the maintenance of a drug–dispensing log by the Investigator. Collected data will be 
entered into a computer database and participant to electronic and manual quality assurance 
procedures. 
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13 
REGULATORY OBLIGATIONS 
13.1 
COMPLIANCE STATEMENT 
This study will be conducted in compliance with Good Clinical Practice (GCP), including 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, and in general, consistent with the most recent version of the 
Declaration of Helsinki. In addition, the Investigator agrees to adhere to all applicable local laws 
and regulatory requirements relevant to the use of new therapeutic agents in the countries 
involved. 
The study is to be conducted in compliance with the protocol. The appropriate Institutional 
Review Boards/Independent Ethics Committees (IRBs/IECs) must approve the protocol and any 
amendments, and the participant informed consent form (ICF) before implementation.  
Freely given written informed consent must be obtained from every participant before 
participation in this clinical trial. The rights, safety, and well-being of participating participants 
are the most important considerations and should prevail over interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct of 
fraud (eg, loss of medical licensure, debarment). 
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14 
ETHICAL ASPECTS 
14.1 
LOCAL REGULATIONS 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6(R2) Integrated Addendum to ICH E6(R1) (March 2018), and in general, be conducted in 
a manner consistent with the most recent version of the Declaration of Helsinki. The Investigator 
will ensure that the conduct of the study complies with the basic principles of GCP as outlined in 
the current version of 21 CFR, subpart D, Part 312, “Responsibilities of Sponsors and 
Investigators”, Part 50, “Protection of Human Participants”, and Part 56, “Institutional Review 
Boards”, or applicable local equivalent. 
14.2 
INFORMED CONSENT 
Sample ICFs and assent forms will be supplied to each site. The Sponsor or its designee must 
review any ICF or assent form prior to submission for review by the IRB/IEC. The final 
IRB/IEC-approved document must be provided to the Sponsor for regulatory purposes. 
It is the responsibility of the Investigator, or a person designated by the Investigator, to obtain 
written informed consent and/ or assent from each participant (or the participant’s legally 
authorized representative) participating in this study after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study in accordance with applicable 
(eg, federal and state) regulations. In the case where the participant is unable to read, an impartial 
witness should be present during the entire informed consent/ assent discussion. After the 
participant has orally consented/ assented to participation in the trial, the witness’ signature on 
the form will attest that the information in the consent/ assent form was accurately explained and 
understood. A copy of the ICF/ assent form must be provided to the participant or to the 
participant’s legally authorized representative. If applicable, it will be provided in a certified 
translation of the local language. 
The eCRF for this study contains a section for documenting informed participant consent/ assent, 
and this must be completed appropriately. Signed ICFs/ assent forms must remain in each 
participant’s study file and must be available for verification by study monitors at any time. If 
new safety information results in changes in the risk/benefit assessment, the consent and assent 
form should be reviewed and updated as necessary. All participants (including those already 
being treated) should be informed of the new information, should be given a copy of the revised 
form, and should give their consent/ assent to continue in the study. 
14.3 
RESEARCH ETHICS COMMITTEES  
Prior to the initiation of the study, the protocol and associated documentation must be given a 
favourable opinion and/or approval by an Ethic Committee and/or an Institutional Review Board. 
A copy of this written approval and any correspondence with the EC/IRB will be provided to the 
sponsor. 
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15 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications will be reviewed, and approved by the Sponsor representatives. 
All protocol modifications must be submitted to the IRB/IEC for information and approval in 
accordance with local requirements, and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study participants, or when the change involves only logistical or 
administrative aspects of the trial (eg, change in monitor, change of telephone number). 
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16 
CONDITIONS FOR TERMINATING THE STUDY 
The Sponsor has the right to terminate the study at any time. In terminating the study, the 
Sponsor and the Investigator will ensure that adequate consideration is given to the protection of 
the participants’ interests. 
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17 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
17.1 
INVESTIGATOR’S FILES AND RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into 2 separate categories as follows: (1) Investigator’s study files; and 
(2) participant clinical source documents. 
The Investigator’s study file will contain the protocol and protocol amendments, eCRFs, query 
forms, IRB/IEC, and governmental approval with correspondence, sample informed consent, 
drug records, staff curriculum vitae and authorization forms, and other appropriate documents 
and correspondence. 
Participant clinical source documents (usually predefined by the project to record key efficacy 
and safety parameters independent of the eCRFs) may include participant hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, 
electroencephalogram, X-ray, pathology and special assessment reports, signed ICFs, consultant 
letters, and participant screening and enrollment logs. The Investigator must keep these 
2 categories of documents on file for at least 2 years following the marketing application 
approval date for the study drug and for the indication being investigated or for 2 years after the 
investigation is discontinued and the FDA is notified. After that period of time, the documents 
may be destroyed participant to local regulations with prior written permission from the Sponsor. 
If the Investigator wants to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the participant, appropriate copies should be made for storing outside of the study site. 
17.2 
SOURCE DOCUMENTS AND BACKGROUND DATA 
Upon request, the Investigator will supply the Sponsor with any required background data from 
the study documentation or clinic records. In case of special problems or governmental queries 
or requests for audit inspections, it is also necessary to have access to the complete study records, 
provided that participant confidentiality is protected. 
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17.3 
AUDITS AND INSPECTIONS 
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the the Sponsor Quality Assurance Unit (or 
designee), or to health authority inspectors after appropriate notification. The verification of the 
eCRF data must be by direct inspection of source documents. 
17.4 
ELECTRONIC CASE REPORT FORMS 
Clinical trial data for this study will be captured on electronic eCRF. The Investigator agrees to 
provide all information requested on the eCRF in an accurate manner according to instructions 
provided. Electronic CRFs are designed for computer processing and analysis. The Investigator 
should ensure the accuracy, completeness, and timeliness of the data reported to the Sponsor (or 
designee) in the eCRF and in all required reports. 
An eCRF is required to be submitted for every participant who provides informed consent/assent. 
This includes submission of retrievable data on participants who withdraw before completion of 
the study. eCRFs must be reviewed for completeness and accuracy, and electronically signed 
where indicated, by the Principal Investigator or authorized delegate from the study staff. If a 
participant stops treatment or terminates from the study, the dates and reasons must be noted on 
the eCRF. 
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18 
MONITORING OF THE STUDY 
It is understood that the responsible the Sponsor monitor (or designee) will contact and visit the 
Investigator regularly and will be allowed on request to inspect the various records of the trial 
(eCRFs and other pertinent data) provided that participant confidentiality is maintained in 
accordance with local requirements. 
It will be the monitor’s responsibility to inspect the eCRFs at regular intervals throughout the 
study, to verify the adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to laboratory test reports and 
other participant records needed to verify the entries on the eCRF. The Investigator (or designee) 
must agree to cooperate with the monitor to ensure that any problems detected in the course of 
these monitoring visits are resolved. 
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19 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PARTICIPANT 
RECORDS 
The Investigator must ensure that participants’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On eCRFs or other documents submitted to 
the Sponsor, participants should be identified by an identification code and not by their names. 
The participants’ personal information should be redacted on all source documents prior to 
submission to the Sponsor (or designee). The Investigator should keep a participant enrollment 
log showing codes, names, and addresses. The Investigator should maintain documents not for 
submission to the Sponsor (eg, participants’ written consent forms) in strict confidence. 
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20 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees to submit all manuscripts or abstracts to the Sponsor for review at least 30 days before 
submission. This allows the Sponsor to protect proprietary information and to provide comments 
based on information from other studies that may not yet be available to the Investigator. 
In the event that the Sponsor coordinates a publication or presentation of study results from all 
study sites, the participation of Investigator or other representatives of study site as a named 
author shall be determined in accordance with the Sponsor’s policy and generally accepted 
standards for authorship. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to vivli.org. 
Individual anonymized participant data and supporting clinical documents are available for 
request at vivli.org. While making information available we continue to protect the privacy of 
participants in our clinical trials. Details on data sharing criteria and process for requesting 
access can be found at this web address: vivli.org.  
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21 
APPENDICES 
21.1 
APPENDIX A: SCHEDULE OF ASSESSMENTS 
Table 6 - Schedule of Assessments 
Assessment 
Screening  
Baselinek 
Cycle 1 
Day 15 
28-Day 
Treatment 
Cyclesl  
End of 
Treatment 
(EOT) 
28-Day 
Follow-Up  
(±7 days) 
Long Term 
Follow-Up 
(LTFU) 
Cycle Day 
-14 to -1 
C1D1 
C1D15 
(±3 days) 
CxD1 
(±3 days) 
 
 
 
Written Informed Consent/Assent 
Xa 
 
 
 
 
 
 
Participant Demography 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Transplant History 
X 
 
 
 
 
 
 
GVHD History 
X 
 
 
 
 
 
 
cGVHD Prior Treatments 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
cGVHD severity assessment 
X 
 
 
 
 
 
 
Randomizationb 
X 
 
 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
Clinician-reported global cGVHD 
activity assessment 
 
X 
 
X 
X 
 
 
Response Assessment 
 
 
 
X 
X 
 
 
Pulmonary Function Testsc  
X 
X 
 
X 
X 
 
 
cGVHD Activity Assessment - Patient 
Self Report 
 
X 
 
X 
X 
 
 
Lee Symptom Scale Score 
 
X 
 
X 
X 
 
 
PROMIS Global Health Score 
 
X 
 
X 
X 
 
 
Document Corticosteroid Dosage 
Corticosteroid dosage to be collected from the date the ICF/assent form is signed until 28 days after last dose of 
study drug 
 
Document other cGVHD therapies 
Other cGVHD therapies to be collected from the date the ICF/assent form is signed until 28 days after last dose of 
study drug 
 
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Assessment 
Screening  
Baselinek 
Cycle 1 
Day 15 
28-Day 
Treatment 
Cyclesl  
End of 
Treatment 
(EOT) 
28-Day 
Follow-Up  
(±7 days) 
Long Term 
Follow-Up 
(LTFU) 
Cycle Day 
-14 to -1 
C1D1 
C1D15 
(±3 days) 
CxD1 
(±3 days) 
 
 
 
Follow-Up Contactd 
 
 
 
 
 
 
X 
New Treatment for cGVHD or 
underlying disease 
 
 
 
 
 
 
X 
Safety Assessments 
 
 
 
 
 
 
 
Complete PEe 
X 
 
 
 
 
 
 
Symptom directed PE 
 
X 
X 
X 
X 
X 
 
Vital signsf  
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
 
 
Karnofsky / Lansky Performance Scale 
score 
X 
X 
 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
 
Clinical Chemistry 
X 
X 
X 
X 
X 
X 
 
Virologyg 
X 
 
 
 
 
 
 
12-Lead ECGh (Table 10) 
Xh 
Xh 
 
Xh 
Xh 
Xh 
 
Highly sensitive urine or serum 
pregnancy testi 
X 
X 
 
X 
X 
X 
 
Concomitant medications / procedures 
Concomitant medications / procedures to be collected from the date the ICF/assent form is signed until 28 days after 
last dose of study drug. 
 
Adverse events 
AEs to be collected from the date the ICF/assent form is signed until 28 days after last dose of study drug. 
 
Investigational Product 
 
 
 
 
 
 
 
Study drug administration 
 
Xj 
Xj 
Xj 
 
 
 
Dispense/Collect Study Drug & Study 
Drug Diary 
 
X 
 
X 
X 
 
 
Pharmacokinetics 
See Table 7 Table 7and Table 8 
Pharmacodynamics 
See Table 9 
cGVHD = chronic graft versus host disease; ECG = electrocardiogram; ICF = informed consent form; ECP = Extracorporeal Photopheresis; PE = Physical Examination 
a The informed consent/assent form must be signed before any study procedures begin. Documented standard of care assessments performed within 14 days of C1D1 can be used as screening 
assessments even if done prior to signing of ICF/assent form. 
b Randomization after eligibility for the study is confirmed by the Medical Monitor or designee. Randomization may occur during screening or pre-dose on C1D1.  
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Assessment 
Screening  
Baselinek 
Cycle 1 
Day 15 
28-Day 
Treatment 
Cyclesl  
End of 
Treatment 
(EOT) 
28-Day 
Follow-Up  
(±7 days) 
Long Term 
Follow-Up 
(LTFU) 
Cycle Day 
-14 to -1 
C1D1 
C1D15 
(±3 days) 
CxD1 
(±3 days) 
 
 
 
c Lung function assessment to be conducted at time of response assessments (see item d below). Pulmonary Function Tests (PFTs), to include FEV1, FVC, DLCO (corrected for Hb), TLC, and RV, 
will be performed at baseline (within 7 days of C1D1 or on C1D1) and Day 1 of Cycles 3, 7, 13 and every 6th Cycle thereafter. During screening, and on Day 1 of other cycles with response 
assessments, spirometry (FEV1 and FVC) is sufficient (Appendix J) 
d Participants are to be contacted eg. by telephone, e-mail, or postal mail approximately every 12 weeks until a failure-free survival event occurs or until study close-out (whichever comes first) to 
confirm survival status, any changes in treatment for cGVHD, and the initiation of any anti-cancer treatment. 
e Including height. Note that for adolescents (12 – 17 years old) height is also to be assessed at Day 1 of Cycles 1 (ie, baseline), 2, 3, 5, 7, and then at every other 3 treatment cycles. 
f 
Vital sign measurements (sitting blood pressure and heart rate to be obtained after 5 minutes of rest), and respiratory rate and temperature 
g Virology to include testing for Hepatitis B and Hepatitis C 
h ECGs – see Table 10 
i 
Females of childbearing potential must have a negative urine pregnancy test. Positive results are to be confirmed with serum testing 
j 
On Day 1 of Cycles 1, 2, 3, 5, 7, and then every 3 cycles (C10D1, C13D1, etc.) and on scheduled PK and PD sampling days, participants must take their dose of belumosudil at the clinic. From 
Cycle 8 onwards, the Day 1 dose may be taken at home or in the clinic 
k If screening assessments, apart from hematology, clinical chemistry, and urine pregnancy are done within 7 days prior to C1D1, they do not need to be repeated on C1D1 
l 
Participants will come to the clinic for visit on Day 1 of Cycles 2, 3, 5, 7. Next visit after Cycle 7 Day 1 is Cycle 10 Day 1. From C10D1 onwards, participants may return to clinic after every other 3 
treatment cycles (ie, C13D1, C16D1, then every 12 weeks) ±3 days from the most recent visit. The exceptions are for 12-lead ECG, which should be performed only if clinically indicated starting 
from C19D1 and full PFT tests, which should be completed every 6 cycles starting from C13D1. 
 
 
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Table 7 - Pharmacokinetics Sampling 
PK Sample Collection 
Sample 
Blood (approximately 6 mL) 
Full PK Profile: Subset of participants at selected sites 
Cycle 1 
Day 1 
Immediately prior to belumosudil dosing, and at 1, 2, 3, 4, 5, 6, 7, 8 and 12 hours post dose. Note: 
12 hour sample is optional 
(For Arm B participants the optional 12 hour post dose sample should be drawn immediately prior to 
belumosudil PM dosing) 
Day 2 
Immediately prior to belumosudil dosing 
Cycle 2 
Day 1 
Immediately prior to belumosudil dosing, and at 1, 2, 3, 4, 5, 6, 7, 8 and 12 hours post dose. Note: 
12 hour sample is optional 
(For Arm B participants the optional 12 hour post dose sample should be drawn immediately prior to 
belumosudil PM dosing) 
Day 2 
Immediately prior to belumosudil dosing 
Sparse PK: All Participants 
Cycle 2 
Day 1 
Immediately prior to belumosudil dosing 
3 hours post dose 
Cycle 7 
Day 1 
Immediately prior to belumosudil dosing 
3 hours post dose 
Timing allowances for PK sampling are as described in Table 8. 
Table 8 - Pharmacokinetics Sampling Timing Allowance 
PK Time point 
Tolerance Window 
Full PK Profile 
Sparse PK 
Prior to belumosudil dose 
-60 mins to belumosudil dosing 
-60 mins to belumosudil dosing 
1, 2, 3 hours 
±10 minutes 
±10 minutes 
4, 5, 6, 7, 8 hours 
±15 minutes 
+60 minutes 
12 hours 
±60 minutes 
NA 
 
Table 9 - Pharmacodynamic Sampling 
PD Sample Collection 
Sample 
Blood (approximately 20 mL) 
All Participants 
Cycle 1 
Day 1 
Within 60 minutes prior to belumosudil dosing 
Cycle 2 
Day 1 
Within 60 minutes prior to belumosudil dosing 
Cycle 7 
Day 1 
Within 60 minutes prior to belumosudil dosing 
Conditional 
cGVHD Flare 
 
At time of increase of corticosteroid dosing 
EOT 
 
If progression of cGVHD 
 
 
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Table 10 - ECG Assessments 
ECG Assessments 
Screening 
Screening 
window 
Single ECG 
Cycle 1 
Day 1 
Single ECG within 60 minutes prior to belumosudil dosing and at 3 hours post 
dose (± 20 minutes) 
Cycle 2, 3, 5 
Day 1 
Single ECG  
Cycle 7 and every 3rd 
cycle thereafter through 
C19 
Day 1 
Single ECG  
From C19 onward only if 
clinically indicated 
Day 1 
Single ECG 
EOT 
Single ECG 
28-Day Follow Up 
Single ECG 
21.2 
APPENDIX B: CGVHD ACTIVITY ASSESSMENT FOR CLINICIAN  
 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
 
ESOPHAGUS 
No esophageal 
symptoms 
Occasional dysphagia or 
odynophagia with solid 
food or pills during the 
past week 
Intermittent dysphagia or 
odynophagia with solid foods or 
pills, but not for liquids or soft 
foods, during the past week 
Dysphagia or odynophagia 
for almost all oral intake, on 
almost every day of the past 
week 
 
 
□ 
□ 
□ 
□ 
 
 
□ Abnormality present but explained entirely by non-GVHD documented cause (specify): 
  
 □ Abnormality thought to represent GVHD PLUS other causes (specify):  
  
 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
 
UPPER GI 
No symptoms 
Mild, occasional 
symptoms, with little 
reduction in oral intake 
during the past week 
Moderate, intermittent 
symptoms, with some reduction 
in oral intake during the past 
week 
More severe or persistent 
symptoms throughout the 
day, with marked reduction 
in oral intake, on almost 
every day of the past week 
 
 
□ 
□ 
□ 
□ 
 
 
□ Abnormality present but explained entirely by non-GVHD documented cause (specify): 
  
 □ Abnormality thought to represent GVHD PLUS other causes (specify):  
  
 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
 
LOWER GI 
No loose or 
liquid stools 
during the past 
week 
Occasional loose or 
liquid stools, on some 
days during the past 
week 
Intermittent loose or liquid stools 
throughout the day, on almost 
every day of the past week, 
without requiring intervention to 
prevent or correct volume 
depletion 
Voluminous diarrhea 
a on almost every day of the 
past week, requiring 
intervention to prevent or 
correct volume depletion 
 
 
□ 
□ 
□ 
□ 
 
 
□ Abnormality present but explained entirely by non-GVHD documented cause (specify): 
  
 □ Abnormality thought to represent GVHD PLUS other causes (specify):  
  
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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
 
LUNGS 
No symptoms 
Mild symptoms 
(shortness of breath 
after climbing one flight 
of steps) 
Moderate symptoms (shortness 
of breath after walking on flat 
ground) 
Severe symptoms (shortness 
of breath at rest; requiring 
O2) 
 
 
□ 
□ 
□ 
□ 
 
 
 
Spirometry 
Not done □ 
 
FEV1  
(% Predicted): 
 
______ 
FEV1  
(L): 
 
______ 
FVC  
(% Predicted): 
 
______ 
FVC 
(L): 
 
______ 
 
 
□ Abnormality present but explained entirely by non-GVHD documented cause (specify): 
  
 □ Abnormality thought to represent GVHD PLUS other causes (specify):  
  
 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
 
EYES 
No symptoms 
Mild dry eye symptoms 
not affecting ADL 
(requirement of 
lubricant eye drops ≤ 3 x 
per day) 
Moderate dry eye symptoms 
partially affecting ADL (requiring 
lubricant eye drops > 3 x per day 
or punctal plugs). 
WITHOUT new vision impairment 
due to KCS 
Severe dry eye symptoms 
significantly affecting ADL 
(special eyewear to relieve 
pain) OR unable to work 
because of ocular symptoms 
OR loss of vision due to KCS 
 
 
□ 
□ 
□ 
□ 
 
 □ Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
 
 □ Abnormality thought to represent GVHD PLUS other causes (specify):  
 
 
 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
 
JOINTS 
AND 
FASCIA 
No symptoms 
Mild tightness of arms 
or legs, normal or mild 
decreased range of 
motion (ROM) AND not 
affecting ADL 
Tightness of arms or legs OR joint 
contractures, erythema thought 
due to fasciitis, moderate 
decrease ROM AND mild to 
moderate limitation of ADL 
Contractures WITH 
significant decrease of ROM 
AND significant limitation of 
ADL (unable to tie shoes, 
button shirts, dress self etc.) 
 
 
□ 
□ 
□ 
□ 
 
 □ Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
 
 □ Abnormality thought to represent GVHD PLUS other causes (specify):  
 
 
 
P-ROM 
Score 
 
 
Score  _____ 
Not done  □ 
 
 
Score  _____ 
Not done  □ 
 
Score  _____ 
Not done  □ 
 
Score  _____ 
Not done  □ 
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 □ Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
 
 □ Abnormality thought to represent GVHD PLUS other causes (specify):  
 
 
 
 
 
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Additional cGVHD details per organ * 
 
LUNGS 
Pulmonary Function 
Tests (PFTs) 
DLCO (single breath, 
adjusted for 
hemoglobin) 
 
______ 
 
RV 
(L) 
 
______ 
 
TLC 
(L) 
 
______ 
 
 
OTHER SKIN GVHD FEATURES (NOT scored by BSA) 
 
 
 
Check all that apply: 
□  
Hyperpigmentation 
□  
Poikiloderma 
□  
Hair Involvement 
□ 
Hypopigmentation 
□ 
Severe or generalized pruritus 
□ 
Nail Involvement 
 
 
EYES 
Keratoconjunctivitis 
sicca (KCS) confirmed 
by ophthalmologist: 
□ Yes 
□ No 
□ Not examined 
 
 
OTHER cGVHD 
FEATURES 
Other indicators, clinical features or complications related to chronic GVHD [check all that apply and assign 
a score to severity (0-3) based on functional impact where applicable; none: 0; mild: 1; moderate: 2; 
severe: 3] 
 
□ 
Ascites (serositis) ___ 
□ 
Myasthenia Gravis ___ 
□ 
Pericardial Effusion ___ 
□ 
Peripheral Neuropathy ___ 
□ 
Pleural Effusion ___ 
□ 
Polymyositis ___ 
□ 
Nephrotic syndrome ___ 
□ 
Others (specify): _____________________ 
 
cGVHD 
STATUS 
 
Since starting belumosudil, would you say that this patient’s cGvHD is: 
Score: 
__ 
 
 
-3  
Very much 
worse 
-2 
Moderately 
worse 
-1 
A little 
worse 
0 
About the 
same 
+1 
A little 
better 
+2 
Moderately 
better 
+3 
Very much 
better 
 
 
 
* Additional cGVHD details which do not contribute to response assessments will be collected when 
available. 
Abstracted from: Lee SJ et al. (Biol Blood Marrow Transplant 2015; 21:984 – 999) and Jagasia, et al (Biol 
Blood Marrow Transplant. 2015;21:389–401)  
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21.3 
APPENDIX C: CGVHD RESPONSE ASSESSMENT  
 
Abstracted from: Lee SJ, Wolff D, Kitko C, et al. Biol Blood Marrow Transplant 2015; 21:984 – 999.  
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21.4 
APPENDIX D: LEE CGVHD SYMPTOM SCORE 
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21.5 
APPENDIX E: PROMIS GLOBAL HEALTH SCORE 
 
Please respond to each item by marking 
one box per row 
Excellent 
Very Good 
Good 
Fair 
Poor 
Global 
01 
In general, would you say your health is: 
 
5 
 
4 
 
3 
 
2 
 
1 
Global 
02 
In general, would you say your quality of life 
is: 
 
5 
 
4 
 
3 
 
2 
 
1 
Global 
03 
In general, how would you rate your physical 
health? 
 
5 
 
4 
 
3 
 
2 
 
1 
Global 
04 
In general, how would you rate your mental 
health, including your mood and your ability 
to think? 
 
5 
 
4 
 
3 
 
2 
 
1 
Global 
05 
In general, how would you rate your 
satisfaction with your social activities and 
relationships? 
 
5 
 
4 
 
3 
 
2 
 
1 
Global 
09 
In general, please rate how well you carry out 
your usual social activities and roles. (This 
includes activities at home, at work and in 
your community, and responsibilities as a 
parent, child, spouse, employee, friend, etc.) 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
 
 
Completely 
Mostly 
Moderately 
A Little 
Not At All 
Global 
06 
To what extent are you able to carry out your 
everyday physical activities such as walking, 
climbing stairs, carrying groceries, or moving 
a chair? 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
 
 
 
 
 
 
 
Never 
Rarely 
Sometimes 
Often 
Always 
Global 
10 
How often have you been bothered by 
emotional problems such as feeling anxious, 
depressed or irritable? 
 
5 
 
4 
 
3 
 
2 
 
1 
 
 
None 
Mild 
Moderate 
Severe 
Very 
Severe 
Global 
08 
How would you rate your fatigue on average? 
 
5 
 
4 
 
3 
 
2 
 
1 
Global 
07 
How would you rate your pain on average? 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
No  
Pain 
 
 
 
Worst 
Imaginable 
Pain 
 
Adapted from 
http://www.healthmeasures.net/administrator/components/com_instruments/uploads/Global%20Health%2
0Scale%20v1.2%2008.22.2016.pdf (Accessed 30-May, 2018) 
 
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21.6 
APPENDIX F: CGVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT  
 
Abstracted from: Lee SJ, Wolff D, Kitko C, et al. Measuring Therapeutic Response in Chronic Graft-versus-Host 
Disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-
versus-Host Disease: IV. The 2014 Response Criteria Working Group Report. Biol Blood Marrow Transplant 2015; 
21:984 – 999. 
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21.7 
APPENDIX G: KARNOFSKY PERFORMANCE SCALE  
Karnofsky Scale (recipient age ≥16 years) 
Lansky Scale (recipient age <16 years) 
Able to carry on normal activity; no special care is 
needed. 
Able to carry on normal activity; no special care is 
needed. 
100 
Normal, no complaints, no evidence of disease. 
100 
Fully active 
90 
Able to carry on normal activity 
90 
Minor restriction in physically strenuous play 
80 
Normal activity with effort 
80 
Restricted in strenuous play, tires more easily, 
otherwise active 
Unable to work, able to live at home and care for most 
personal needs, a varying degree of assistance is 
needed. 
Mild to moderate restriction 
70 
Cares for self, unable to carry on normal activity or to 
do active work. 
70 
Both greater restrictions of, and less time spent in 
active play 
60 
Requires occasional assistance, but is able to care for 
most needs. 
60 
Ambulatory up to 50% of time, limited active play with 
assistance / supervision 
50 
Requires considerable assistance and frequent 
medical care. 
50 
Considerable assistance required for any active play, 
fully able to engage in quiet play 
Unable to care for self, requires equivalent of 
institutional or hospice care, disease may be 
progressing rapidly. 
Moderate to severe restriction 
40 
Disabled, requires special care and assistance. 
40 
Able to initiate quiet activities 
30 
Severely disabled, hospitalization indicated. Death 
not imminent. 
30 
Needs considerable assistance for quiet activity 
20 
Very sick, hospitalization indicated. Death not 
imminent. 
20 
Limited to very passive activity initiated by others 
(eg, TV) 
10 
Moribund, fatal processes progressing rapidly. 
10 
Completely disabled, not even passive play 
Reference: Karnofsky, D.A., and Burchenal, J.H. (1949). The Clinical Evaluation of Chemotherapeutic Agents in 
Cancer. In Evaluation of Chemotherapeutic Agents: Symposium Held at the New York Academy of Medicine, C.M. 
MacLeod, ed. (New York, Columbia University Press), pp. 191-205. 
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance in childhood cancer 
patients. Cancer. 1987 Oct 1;60(7):1651-6. 
21.8 
APPENDIX H: EQUATIONS TO PREDICT GLOMERULAR FILTRATION RATE 
4-Variable Modification of Diet in Renal Disease (MDRD-4) Equation 
High Level Formula for Black or African-American Males: 
Estimated GFR = 175 × (Creatinine -1.154) × (Age -0.203) × 1.212 
High Level Formula for Males NOT Black or African-American (any other option): 
Estimated GFR = 175 × (Creatinine -1.154) × (Age -0.203) 
High Level Formula for Black or African-American Females: 
Estimated GFR = 175 × (Creatinine -1.154) × (Age -0.203) × 1.212 × 0.742 
High Level Formula for Females NOT Black or African-American (any other option): 
Estimated GFR = 175 × (Creatinine -1.154) × (Age -0.203) × 0.742 
Adapted from: Levey AS, Coresh J, Greene T et al. (August 2006). "Using standardized serum creatinine values in 
the modification of diet in renal disease study equation for estimating glomerular filtration rate". Annals of Internal 
Medicine 145 (4): 247–54. PMID 16908915. 
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Creatinine-Based Bedside Schwartz Equation 
eGFR = 0.413 x (height/Creatinine), where height is expressed in centimeters, creatinine in mg/dL 
eGFR = 41.3 x (height/Creatinine), where height is expressed in meters, creatinine in mg/dL 
Source: National Kidney Foundation https://www.kidney.org/content/creatinine-based-
%E2%80%9Cbedside-schwartz%E2%80%9D-equation-2009 
Accessed: 19 Aug 2021 
21.9 
APPENDIX I: DRUGS THAT INDUCE CYP3A4 
This is not a comprehensive list, and all concomitant medications should be evaluated for 
possible interactions with belumosudil. 
Table 11 - Examples of Clinical Inducers of CYP3A4 
Strong Inducer 
Moderate Inducer 
Weak Inducer 
Apalutamide 
Carbamazepine 
Enzalutamide 
Mitotane 
Phenytoin 
Rifampin 
St. John’s wort 
Bosentan 
Efavirenz 
Etravirine 
Phenobarbital 
Primidone 
Armodafinil 
Modafinil 
Rufinamide 
Source: FDA. Drug Development and Drug Interactions. 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/
ucm093664.htm 
Accessed 28 Jul 2021
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21.10 APPENDIX J: PFT ASSESSMENTS 
PFTs are required with each response assessment. Full PFTs (FEV1, FVC, DLCO [corrected for Hb], and TLC) are required at baseline, 
C4D1, C7D1, and every 6 cycles thereafter (C13D1, C19D1, C25D1, etc.). At other PFT timepoints, spirometry alone (FEV1 and 
FVC) is sufficient. Where possible, all PFTs should be performed consistently in the same setting. 
Schedule of PFT Assessments 
 
 
 
 
Day 1 of Cycle 
 
Screening 
Baseline 
C2 C3 
C4 
C5 C6 
C7 
C8 
C9 C10 
C11 
C12 
C13 
C14 
C15 
C16 
C17 C18 
C19 
Responsea 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Full PFTb 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Spirometryc 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
C[number] = Cycle[number]; DLCO = diffusing capacity of carbon monoxide; EOT = end of treatment; FEV1 = forced expiratory volume (in the first second); FVC = forced vital capacity; Hb = 
hemoglobin; PFT = pulmonary function test; RV = residual volume; TLC = total lung capacity 
 
a 
Response assessments are on Day 1 of Cycles 2, 3, 5, 7 then on Day 1 of every 3 cycle thereafter. 
b 
Full PFT tests include FEV1, FVC, DLCO (corrected for Hb), and TLC. Full PFTs are performed at baseline, C3D1, C7D1, and every 6 cycles thereafter (C13D1, C19D1, C25D1, etc.). At EOT, 
a Full PFT will be performed unless a Full PFT was conducted the previous month, in which case only a FEV1 and FVC is required. 
c 
Spirometry tests include FEV1 and FVC.  
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21.11 APPENDIX K: PREDNISONE DOSE EQUIVALENTS 
Change in corticosteroid doses will be analyzed by using prednisone dose equivalents. If 
participants are not using prednisone as the systemic corticosteroid, then the prednisone dose 
equivalent will be determined according to following conversion ratios:  
1 mg prednisone is equivalent to: 
• 4.0 mg Hydrocortisone 
• 0.8 mg Methylprednisolone 
• 0.15 mg Dexamethasone 
• 1.0 mg Prednisolone 
• 0.8 mg Triamcinolone 
Source: Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of 
the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 
2013;9(1):30. Published 2013 Aug 15. doi:10.1186/1710-1492-9-30 
21.12 APPENDIX L: CENTRAL LAB AND CRO CONTACT INFORMATION 
The CRO for this study is Medpace. Medpace has the following contact information: 
Medpace 
5375 Medpace Way 
Cincinnati, Ohio 45227 
Clinical laboratory testing will be performed by Medpace Reference Laboratories (MRL). 
Clinical laboratory parameters include those described in Table 4, reflexive serum pregnancy 
testing (human chorionic gonadotropin), and HBsAg and hepatitis C antibodies. MRL has the 
following contact information: 
Medpace Reference Laboratories 
5365 Medpace Way 
Cincinnati, Ohio 45227 
Pharmacokinetic testing will be performed by Labcorp. Labcorp has the following contact 
information: 
Labcorp Bioanalytical Services LLC 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704 
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Pharmacodynamic testing will be performed by Vanderbilt University Medical Center Innovative 
Translational Research Shared Resource (ITR). Vanderbilt has the following contact information:  
Vanderbilt University Medical Center 
Innovative Translational Research Shared Resource (ITR) 
c/o KD025-213  
2220 Pierce Avenue South 
722 Preston Research Building  
Nashville, Tennessee 37232 
21.13 APPENDIX M: COMPANION STUDY FOR BIOSPECIMEN COLLECTION 
Biospecimen Collection in a Phase 2, Randomized, Multicenter Study to Evaluate 
the Efficacy and Safety of KD025 in Subjects with 
 Chronic Graft Versus Host Disease (cGVHD) After 
At Least 2 Prior Lines of Systemic Therapy 
(The ROCKstar Study) 
21.13.1 Purpose 
This addendum contains a detailed description of biospecimen collection at the following sites: 
National Institutes of Health (NIH), Dana Farber Cancer Institute, the University of Texas MD 
Anderson Cancer Center, and Washington University in St. Louis. 
21.13.2 Summary 
Background: 
Preclinical and clinical data support a role of IL-17 in cGVHD pathogenesis due to increased 
activity of proinflammatory T helper (Th)17 cells and diminished regulatory T cell activity (21). 
Increased levels of IL-17 mRNA transcripts were demonstrated in skin, and oral mucosa showed 
infiltration of Th17 cells, a CD4+T cell subset that secretes IL-17 (31). IL-17 can be secreted by 
innate and adaptive (CD4+ and CD8+) immune cells, epithelial cells and may be induced by 
local inflammation (32). Elevated IL-17 supports tissue sequestration of profibrogenic 
macrophages via unclear mechanisms, leading to inflammation and fibrosis (MacDonald, Betts, 
& Couriel, 2018). Thus, understanding IL-17 secretion by various cells and its distribution in 
tissues is critical to elucidate the pathogenesis of cGVHD. 
ROCK (Rho-associated coiled-coil kinase) is an enzyme required for multiple intracellular 
processes including actin cytoskeleton assembly and cellular functions, such as proliferation, 
adhesion, migration, and phagocytosis and is critical for T cell responses (12). The ROCK2 
isoform only is physiologically activated in CD4+ T cells under Th17-skewing, leading to 
increased secretion of IL-17 and IL-21 in mice and humans (16, 15). Belumosudil is an orally 
available ROCK2 selective inhibitor which has been shown to downregulate Th17 and follicular 
Th cells and upregulate regulatory T cells.  
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This appendix details additional assays that will be included for select participants enrolled in the 
ROCKstar trial. Four (4) centers will participate in this companion biologic sample protocol: 
National Institutes of Health (NIH), Dana Farber Cancer Institute, University of Texas MD 
Anderson Cancer Center, and Washington University in St. Louis. 
Biologic samples will include oral and skin biopsies, microbiome swabs, saliva, and peripheral 
blood. These samples will be assayed to better understand the pathophysiology and 
immunopathology of cGVHD, with specific focus on differential IL-17 expression in cell types 
and tissues.  
All analyses described in this site-specific addendum are planned to take place at the NIH.  
21.13.3 Objective 
To characterize changes in the immune cellular profile before and after treatment with 
belumosudil with a focus on IL-17 production in the oral cavity. 
21.13.4 Eligibility 
Be able to complete written informed consent.  
For belumosudil treated participants:  
Must be enrolled in the KD025-213 study, and 
Must have oral mucosal cGVHD defined as lichenoid changes with or without clinical 
symptoms. Alternatively, distinctive features including mucoceles, mucosal atrophy, ulcers, or 
pseudomembranes are sufficient with or without clinical symptoms provided there is no 
suspicion for alternative causes. There is no restriction regarding oral cGVHD NIH severity.  
Must be at least 18 years of age. 
No contraindication(s) for biopsy collection. 
21.13.5 Design 
This site-specific addendum will enroll participants (approximately 20 evaluable participants) 
with cGVHD undergoing belumosudil treatment.  
Biopsies will be taken at baseline and after 6-months of belumosudil therapy (C7D1 timepoint) 
or at the time of discontinuation of belumosudil therapy (whichever comes earlier) from the oral 
buccal mucosa, labial minor salivary gland and cutaneous skin. At the same time points, 
unstimulated 5-minute whole saliva, oral microbiome swabs and a research blood sample will be 
collected. Whole biopsies will be sent to the NIH for histologic review (formalin-fixation and 
paraffin embedding [FFPE]) and fluorescent immunohistochemistry (IHC) to identify changes in 
location and distribution of IL-17-producing cells at effector sites after belumosudil treatment. 
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Plasma and saliva will be used for multiplex ELISA analysis of IL-17-pathway chemokines and 
cytokines. Flow cytometric analysis may be done on peripheral blood cells to identify phenotype, 
transcription factor expression, and cytokine production.  
All data and samples will be de-identified (ie, coded) prior to transfer to the NIH. 
21.13.6 Introduction 
21.13.6.1 Study objectives 
21.13.6.1.1 Primary Objective 
To characterize changes in the immune cellular profile before and after treatment with 
belumosudil with a focus on IL-17 production in the oral cavity 
21.13.6.1.2 Secondary Objective 
To determine feasibility of conducting a multi-center cGVHD study that includes analyses of 
tissue biopsies, saliva and peripheral blood. 
21.13.6.1.3 Exploratory Objectives 
To characterize changes in the skin immune cellular profile before and after treatment with 
belumosudil with a focus on IL-17 production. 
To analyze and compare the effector cell profile of different sites (peripheral blood, skin, oral 
mucosa, minor salivary gland) during the pathogenesis of cGVHD.  
To analyze changes in the local (saliva) and peripheral (blood) cytokine and chemokine profile 
after belumosudil treatment. 
To compare changes in the oral microbiome before and after belumosudil treatment. 
To analyze changes in the immune cell profile in peripheral blood before and after belumosudil 
treatment. 
To compare gene expression profiles in immune cells before and after treatment with 
belumosudil in GVHD-affected tissues. 
21.13.6.2 Background and rationale 
Chronic graft versus host disease (cGVHD) remains a major multi-system complication of 
allogeneic hematopoietic cell transplantation (HCT) and occurs in about 50% of transplant 
recipients depending upon donor and transplant characteristics (33). Chronic GVHD occurs 
when immune cells transplanted from a non-identical donor (the graft) recognize the transplant 
recipient (the host) as non-self, thus leading to an immune reaction that causes disease in the 
transplant recipient. 
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Participants with cGVHD require prolonged immunosuppressive treatment for an average of 2 to 
3 years from the initial diagnosis, with 10% of those surviving for at least 7 years still requiring 
immunosuppressive treatment at that time and beyond (4). There remains substantial unmet need 
for new targeted therapies with better tolerability and effectiveness.  
Manifestations of cGVHD in the oral cavity are observed in 45-85% of cGVHD participants. 
Clinically, the first line of topical therapy for oral cGVHD is oral rinses with a dexamethasone 
(0.1 mg/mL) suspension. However, this topical agent is only effective or partially effective in 
approximately 29-58% of participants (34, 35). This necessitates more specific treatment 
modalities.  
However, despite extensive research and progress over the last decade, there is still a profound 
unmet need to fully deciphering and understand cGVHD biology (36, 21, 37). The development 
of biomarkers for cGVHD has been similarly challenging (38, 39). 
Preclinical and clinical data support a role of IL-17 in cGVHD pathogenesis due to increased 
activity of proinflammatory T helper (Th)17 cells and diminished regulatory T cell activity (21). 
Increased levels of IL-17 mRNA transcripts were demonstrated in skin, and oral mucosa showed 
infiltration of Th17 cells, a CD4+T cell subset that secretes IL-17 (31). IL-17 can be secreted by 
innate and adaptive (CD4+ and CD8+) immune cells, epithelial cells and may be induced by 
local inflammation (32). Elevated IL-17 supports tissue sequestration of profibrogenic 
macrophages via unclear mechanisms, leading to inflammation and fibrosis (21). Thus, 
understanding IL-17 secretion by various cells and its distribution in tissues is critical to 
elucidate the pathogenesis of cGVHD. 
ROCK (Rho-associated coiled-coil kinase) is an enzyme required for multiple intracellular 
processes including actin cytoskeleton assembly and cellular functions, such as proliferation, 
adhesion, migration and phagocytosis and is critical for T cell responses (12). The ROCK2 
isoform only is physiologically activated in CD4+ T cells under Th17-skewing, leading to 
increased secretion of IL-17 and IL-21 in mice and humans (16, 15). Belumosudil is an orally 
available (ROCK2) selective inhibitor which has been shown to downregulate Th17 and 
follicular Th cells and upregulate regulatory T cells. 
It has been well established that the interplay between the oral microbiome and the mucosal 
immune cells is critical for the maintenance of health at the barrier sites. IL-17 plays a significant 
role in maintaining mucosal homeostasis by promoting the production of several antimicrobial 
peptides and by recruiting innate immune cells. Dysregulation in IL-17 has been associated with 
dysbiotic microbiome and exaggerated disease process.  
It is not known how inhibition of ROCK2 will affect the IL-17-secreting cellular profile or oral 
microbiome at peripheral cGVHD effector sites including skin and oral mucosa.  
There is already an ongoing Phase 2a, randomized, open-label study to evaluate the safety, 
tolerability, and activity of belumosudil in participants with cGVHD (ROCKstar trial, 
NCT03640481). In this ongoing study, participants receive belumosudil at dose levels of 200mg 
QD or 200mg BID and must have previously received at least 2 lines and more than 5 lines of 
systemic therapy for cGVHD.  
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The ROCKstar trial is multi-center, and 4 centers will participate in this companion biologic 
sample protocol: NIH, Dana Farber Cancer Institute, University of Texas MD Anderson Cancer 
Center, and Washington University in St. Louis.  
Biologic samples will include oral and skin biopsies, microbiome swabs, saliva and peripheral 
blood. These samples will be assayed to better understand the pathophysiology and 
immunopathology of cGVHD after ROCK2 inhibition, with specific focus on differential IL-17 
expression in cell types and tissues 
21.13.7 Eligibility assessment and enrollment 
This study is optional for participants. 
21.13.7.1 Eligibility criteria 
21.13.7.1.1 Inclusion Criteria 
Must be able to complete informed consent.  
Must be enrolled in ROCKstar trial (NCT03640481). 
Participants must have oral mucosal cGVHD defined as lichenoid changes with or without 
clinical symptoms. Alternatively, distinctive features including mucoceles, mucosal atrophy, 
ulcers, or pseudomembranes are sufficient with or without clinical symptoms provided there is 
no suspicion for alternative causes. There is no restriction regarding oral cGVHD severity.  
Must be at least 18 years of age. 
No contraindication(s) for biopsy collection. 
21.13.7.1.2 Exclusion Criteria 
None applicable. 
21.13.7.2 Screening evaluation 
The PI or designee will obtain written informed consent from participants for participation in the 
biologic study. 
21.13.7.2.1 Baseline evaluation [c1d1, pre-dose] 
Prior to starting therapy with belumosudil on the ROCKstar trial, eligible participants will have 
samples collected:  
• Unstimulated 5-minute whole saliva. 
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• Oral microbiome swabs from dorsal tongue and buccal mucosa. 
• Peripheral blood collection (CPT tube, 10 mL).  
• Biopsy of oral buccal mucosa (4mm punch). 
• Biopsy of labial minor salivary gland.  
• Biopsy of cutaneous skin (4mm punch). 
21.13.7.2.2 6-month or off-treatment evaluation [c7d1 or end-of-treatment] 
After 6-months of therapy with belumosudil on the ROCKstar trial or when study drug is 
stopped if this occurs prior to 6-months, eligible participants will have samples collected:  
• Unstimulated 5-minute whole saliva. 
• Oral microbiome swabs from dorsal tongue and buccal mucosa. 
• Peripheral blood collection (CPT tube, 10 mL).  
• Biopsy of oral buccal mucosa (4 mm punch). 
• Biopsy of labial minor salivary gland. 
• Biopsy of cutaneous skin (4 mm punch). 
21.13.8 Study implementation 
21.13.8.1 Study design 
Figure 8-1 - Design of Site-specific Addendum 
 
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Participants with cGVHD undergoing belumosudil treatment. Samples will be collected at 
4 selected study centers sites (n = 20 evaluable participants). 
Biopsies from the oral buccal mucosa, labial minor salivary gland and cutaneous skin will be 
taken at baseline and after 6-months of belumosudil therapy or at the time going off treatment 
(whichever comes earlier) for belumosudil treated participants. At the same time points, 
unstimulated 5-minute whole saliva, oral microbiome swabs and a research blood sample (in a 
CPT tube to allow for separation of cells for flow and plasma for ELISA) will be collected.  
The whole biopsy will be deposited into formalin and shipped to the NIH for processing and 
histologic review (formalin-fixation and paraffin embedding [FFPE]) prior to planned analyses. 
FFPE blocks will be used for fluorescent immunohistochemistry (IHC) to identify change in 
location and distribution of IL-17-producing cells at effector sites after belumosudil treatment. 
Plasma and saliva will be used for multiplex ELISA analysis of IL-17-pathway chemokines and 
cytokines. Flow cytometric analysis may be done on fresh blood cells to identify phenotype, 
transcription factor expression and cytokine production. All samples will be de-identified prior to 
transfer to the NIH. 
21.13.8.2 Study calendar 
The study calendar of assessments is presented in Table 8-1. 
Table 8-1 - Calendar of Assessments 
  
Assessments 
ROCKstar Participants  
Laboratory/ Sample Details 
  
2Baseline 
  
3Post-
Belumosudil 
(6 months or 
off-treatment) 
Processing 
Shipping 
1Biologic sample collection  
Saliva collection (5-
minute unstimulated 
whole saliva, collect in 
tared-tube on ice )  
X 
X 
Keep cold and process ASAP. Weight 
tube and record. Pipette into cryovials. 
Centrifuge at 2800g for 5 minutes. 
Transfer supernatant into storage set of 
cryovials, discard pellet, and freeze saliva 
at -80°C.  
Batch ship when 
collections are complete. 
Ship overnight on dry ice.  
Microbiome swab 
collection (30-second 
swab on tongue and 
buccal mucosa, separate 
swab for each site)  
X 
X 
Clip head of polysterene swab off into 
cryovial with RNAlater using sterile 
scissors. Close vial.  
Ship overnight at room 
temperature with swabs, 
blood and biopsies. 
Blood collection (10 mL 
in CPT tube) 
X 
X 
Store upright and process within 2 hrs of 
collection. Centrifuge at room temperature 
(18-25° C) in a horizontal rotor (swing-out 
head) for a minimum of 20 minutes (max 
30 minutes) at 1500 to 1800 RCF.  
Pack carefully around 
tubes with absorbent 
material. Ship overnight at 
room temperature with 
swabs, blood and biopsies. 
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Assessments 
ROCKstar Participants  
Laboratory/ Sample Details 
  
2Baseline 
  
3Post-
Belumosudil 
(6 months or 
off-treatment) 
Processing 
Shipping 
1Biologic sample collection  
Oral buccal mucosa 
biopsy (4mm)  
X 
X 
Deposit biopsy tissue into labelled cryovial 
filled with formalin.  
Ship overnight at room 
temperature with swabs, 
blood and biopsies 
Labial minor salivary 
gland biopsy 
X 
X 
Deposit biopsy tissue into labelled cryovial 
filled with formalin.  
Ship overnight at room 
temperature with swabs, 
blood and biopsies. 
Skin biopsy (4mm)  
X 
X 
Deposit biopsy tissue into labelled cryovial 
filled with formalin.  
Ship overnight at room 
temperature with swabs, 
blood and biopsies. 
1 PI or designee will clear participant for sampling per site’s policies. 
2.The baseline assessments can be collected from time of consent through pre-dose on C1D1. 
3 The C7D1 assessments have a ± 7-day window. If participant discontinues prior to the C7D1 time point, every effort should be made to 
collect the samples as close to the treatment discontinuation date as possible. 
21.13.9 Biospecimen collection 
21.13.9.1 Collection and shipping 
21.13.9.1.1 Collection 
All samples will be collected and processed as outlined below (also see lab manual) 
Unstimulated 5-minute whole saliva collection: Each participant will split into a previously tared 
50 mL conical tube, held on ice, every 30 seconds for 5 minutes; total saliva tube weight will be 
measured, and the sample will be processed immediately (centrifuged at 2800g for 5 mins at 
4°C). Supernatant only will be aliquoted in 500-800 µl increments and frozen at -80oC prior to 
shipping.  
Oral microbiome swabs from dorsal tongue and buccal mucosa: a polyester swab will be rubbed 
on either the oral buccal mucosa (bilateral) or dorsal tongue for 30 seconds. The head of the 
swab will be cut off into a cryovial containing RNA later and will be held at room temperature 
until storage at -20oC prior to DNA extraction for analysis.  
10 mL peripheral blood collection (CPT tube): Peripheral blood will be drawn into 2 CPT tubes. 
After collection, store tube upright at room temperature until centrifugation. Centrifuge at room 
temperature (18-25° C) in a horizontal rotor (swing-out head) for a minimum of 20 minutes (max 
30 minutes) at 1500 to 1800 RCF (Relative Centrifugal Force) then prepare tubes for shipping. 
Blood samples should be centrifuged within 2 hours of blood collection for best results. 
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Biopsy of oral buccal mucosa, 4 mm punch: A 4 mm punch biopsy should be taken from affected 
area of oral buccal mucosal lining of cheek, ideally from an area with erythema and lichenoid 
lesion. Do not biopsy an ulcer, but tissue adjacent to an ulcer is fine. Deposit biopsy tissue into 
formalin and prepare for shipping.  
Biopsy of labial minor salivary gland: An approximate 0.5 cm incision should be made in the 
labial mucosa, and 4-6 salivary glands lobules should be clipped out, deposited into formalin or 
saline, and then the site should be sutured closed. Deposit biopsy tissue into formalin if not 
already completed and prepare for shipping. 
Biopsy of cutaneous skin, 4 mm punch: A 4 mm punch biopsy should be taken from affected area 
of cutaneous skin—generally from the most active area that will heal reasonably well. If skin is 
unaffected, biopsy should generally be taken from medial upper arm or torso. Face, hands, feet, 
and lower extremities should be avoided. If possible, the post-treatment biopsy should be done 
adjacent to the site of the pre-treatment biopsy. Deposit biopsy tissue into formalin and prepare 
for shipping. 
21.13.9.2 Sample Shipping 
Biospecimens will be shipped to the NIH for further processing, storage and analysis. Samples 
should be shipped overnight via FedEx on Monday through Wednesday. Please notify lab below 
at time of shipping. Please make arrangements with lab if sample needs to be shipped Thursday 
or Friday and may arrive on the weekend. 
Saliva aliquots may be stored at -80oC and shipped as a batch on dry ice.  
All other samples: biopsies, blood and microbiome samples should be shipped at room 
temperature (not frozen) to the address below as soon as possible after collection 
NIH, NIDCR, Oral Immunobiology Unit 
ATTN:
 
 
Office: 
 
Cell: 
Email:
Note: CPT tubes containing separated blood cells must be placed in a red biohazard bag 
containing an absorbent material, such as a clinical pad. All glass has the potential for breakage; 
therefore, precautionary measures should be taken during handling. Please follow the 
instructions listed under “General Packaging Requirements” in the associated SOP document. 
Tubes for sample processing including cryovials with formalin for biopsies will be sent by the 
NIH lab to the collecting sites.  
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21.13.9.3 Correlative research studies 
The following biospecimens will be collected and analyzed: 
Saliva: Saliva will be processed and stored at -80oC until batched analyses are done using 
ELISA technology. Specific protein biomarkers of interest include IL-17A, IL-22, IL-21, IL-23, 
CCL20, IL-6, IL-17F, IL-1b, TNF, IL-26, CXCL10 and Zymogen Granule Protein 16B. 
Microbiome swabs: Compositional and functional shifts in the oral microbiome will be assessed 
using targeted 16s sequencing or open-ended shotgun metagenomic sequencing approaches of 
non-human material only. Correlative laboratory assays may be done to corroborate initial 
findings. 
Oral and skin biopsies: The oral tissue sections will be examined by a pathologist to assess oral 
cGVHD status. Fluorescent immunohistochemistry (IHC, 5+color) will be used to identify 
change in location and distribution of IL-17-producing cells at effector sites after belumosudil 
treatment. Correlative analysis of gene expression may be done using NanoString analysis on 
paraffin sections for interferon- and IL-17-related molecules. 
Blood: Plasma will be used for multiplex ELISA analysis of IL-17-pathway chemokines and 
cytokines. Flow cytometric analysis may be done on fresh blood cells to identify phenotype, 
transcription factor expression and cytokine production. 
21.13.9.3.1 Sample storage, tracking and disposition 
The saliva, tissue and blood samples, collected for research will be stored by the Oral 
Immunobiology Unit (OIU), National Institute of Dental and Craniofacial Research (NIDCR), 
NIH. All data associated with archived clinical research samples is entered into a secure 
database. Access to this system is limited to OIU clinical staff, requiring individual login and 
password. All staff in the OIU laboratory complete training and maintain standards of computer 
security, as required locally.  
The data recorded for each sample includes the deidentified (i.e., coded) participant ID number 
(as assigned by the ROCKstar study), trial name/protocol number, and date collected, as well as 
box and freezer location. All samples currently receive a unique bar code number, which is 
included in the OIU Stored Sample database. Only this bar code will be recorded on the sample 
vial and the vials will not be traceable back to the participants without authorized access to the 
Kadmon database.  
Samples are stored in locked, monitored freezers at -80°C (saliva and blood) or -20oC (oral 
swabs) according to stability requirements. These freezers are located on site at the OIU Unit in 
Bethesda, MD.  
Samples will not be sent outside NIH for analysis without appropriate Institutional Review 
Board (IRB) notification and an executed Material Transfer Agreement (MTA) if required.  
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All specimens obtained in the protocol will be used as defined in the protocol. Any specimens 
that are remaining at the completion of the protocol will be stored in the conditions described 
below. The study will remain open so long as sample or data analysis continues. Samples from 
consenting participants will be stored until they are no longer of scientific value or if a 
participant withdraws consent for their continued use, at which time they will be destroyed. The 
responsible site PI will report any loss or destruction of samples to the sponsor as soon as made 
aware of such loss.  
If a participant withdraws consent, the associated data will be excluded from future sample 
distributions and analyses, but data already distributed for approved research use are not 
retrievable. 
21.13.9.3.2 Data sharing plans 
Participant’s data will be deidentified and will be kept confidential. Participants will be identified 
by participant ID numbers in the clinical database. The link between the participants and their ID 
numbers will be securely maintained by the enrolling sites per local practices. 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  
The microbiome genomic data will be shared according to the NIH Genomic Data Sharing 
Policy: https://osp.od.nih.gov/wp-content/uploads/NIH_GDS_Policy.pdf. 
This non-human data will be shared no later than the time of initial publication, per NIH policy: 
https://osp.od.nih.gov/wp-content/uploads/Supplemental_Info_GDS_Policy.pdf. 
21.13.10 
Statistical section 
To facilitate evaluation of the primary and other objectives, a control group will be included in 
the sample analyses. These control samples will be acquired only at the NIH from existing open 
protocols. The primary analysis group (i.e., Group 1, as described herein) will be the pre- and 
post-treatment samples from 20 evaluable participants treated with belumosudil on the 
ROCKstar study. Group 2 will be post-transplant (post-HSCT) control participants without 
cGVHD (PT cohort, n=10, single timepoint, must be 1-4 years out of transplant, with matched 
samples will be taken at a single visit). Group 3 will be healthy volunteers (HV Cohort, n = 5, 
age 30-65 years, collected only at the NIH under protocol NCT03602599 with matched samples, 
will be taken at a single visit). 
The primary objective of this Companion Study is to characterize changes in the immune cellular 
profile before and after treatment with belumosudil with a focus on IL-17 production in the oral 
cavity. A total of 20 evaluable participants will have oral samples obtained both at pre-treatment 
and post-treatment; with 20 complete paired samples, a paired t-test will have 88.9% power to 
detect a difference in values between the two time points equal to 0.75 standard deviation of the 
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change (effect size = 0.75), based on a 0.05 two-sided significance level test. In practice, if the 
paired differences are not normally distributed (p<0.05 by a Shapiro-Wilks test), a Wilcoxon 
signed rank test will be used.  
The secondary objective of this study, to determine feasibility of conducting a multi-center 
cGVHD study that includes analyses of tissue biopsies, saliva and peripheral blood, will be 
assessed by the estimate of the percentage of usable specimens which are obtained from the 
procedure. There is no fixed target, but the percentage of specimens which are usable will be 
reported along with a 95% confidence interval (CI). In addition, the fraction of participants in 
which both pre- and post-treatment oral samples are usable will be reported along with a 95% CI. 
Although they are considered exploratory objectives, the sample sizes for the comparisons with 
controls will be assessed as follows: 
The baseline IL-17-producing cells from the oral cavity identified at pre-treatment for 
participants who are to receive belumosudil will be compared to the number of cells 
obtained at a single time point from participants who do not have cGVHD. 
20 participants and 10 non-GVHD controls would have 87.6% power to detect an effect 
size of 1.25 (difference between the two groups equal to 1.25 SD of the values within 
each group) using a two-sample t-test with a 0.05 two-sided significance level. In 
practice, if the values within both groups are not normally distributed (p<0.05 by a 
Shapiro-Wilks test), a Wilcoxon rank sum test will be used. 
The baseline IL-17-producing cells from the oral cavity identified at pre-treatment for 
participants who are to receive belumosudil will be compared to the number of cells 
obtained at a single time point from healthy volunteers; 20 participants with cGVHD and 
5 healthy controls would have 81.9% power to detect an effect size of 1.5 (difference 
between the two groups equal to 1.5 SD of the values within each group) using a two-
sample t-test with a 0.05 two-sided significance level. In practice, if the values within 
both groups are not normally distributed (p<0.05 by a Shapiro-Wilks test), a Wilcoxon 
rank sum test will be used. 
All other evaluations will be considered completely exploratory and will be based on the 
available participants and usable data. 
To allow for a small number of participants and controls which may not yield usable results for 
the primary analysis (or the main exploratory analyses involving the control participants), up to 
24 participants with cGVHD, and 6 healthy volunteers may be enrolled. 
21.14 APPENDIX N: CONTRACEPTIVE AND BARRIER GUIDANCE 
21.14.1 Definitions  
• A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
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• A postmenopausal state is defined as the period of time after a woman has experienced 
no menses for 12 consecutive months without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range should be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel's review of the participant's medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
21.14.2 Contraception Guidance  
Participants should be given advice about donation and cryopreservation of germ cells prior to 
the start of the study intervention, in line with the fact that study intervention may affect ova and 
sperm up to 90 days (see Section 4.3). 
If locally required, acceptable contraceptive methods are limited to those which inhibit ovulation 
as the primary mode of action. 
21.15 APPENDIX O: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located after 
the title page. 
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21.15.1 Amended Protocol 01 (26 June 2019)  
 
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21.15.2 Amended Protocol 02 (01 June 2020)  
 
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21.15.3 Amended Protocol 03 (30 August 2021)  
 
21.15.4 Amended Protocol 04 (11 April 2022)  
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22 
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MacDonald  KP, Blazar BR, Hill GR. Cytokine mediators of chronic graft-versus-host 
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Flynn R,  Paz K, Du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A, et al. 
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26. 
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al, National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic 
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Blood Marrow Transplant. 2015;21:389–401 
27. 
ATS/ERS Task Force: Standardisation of Lung Function Testing; Standardization of 
Spirometry.  Eur Respir J 2005;26:319–38. 
28. 
Lee S, Cook EF, Soiffer R. Development and validation of a scale to measure symptoms 
of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8:444-52. 
29. 
Broderick JE, DeWitt EM, Rothrock N, Crane PK, Forrest CB. Advances in Patient 
Reported Outcomes: The NIH PROMIS Measures. eGEMs. 2013;2(1):1015. 
30. 
Inamoto Y, Flowers MED, Sandmaier BM, Aki SZ, Carpenter PA, Lee SJ, et al. Failure-
free survival after initial systemic treatment of chronic graft-versus-host disease  
Blood.2014;124(8):1363-71. 
31. 
Brüggen MC, Klein I, Greinix H, Bauer W, Kuzmina Z, Rabitsch W, et al. Diverse T-cell 
responses characterize the different manifestations of cutaneous graft-versus-host disease. 
Blood. 2014;123(2):290–9. 
32. 
Zenobia C, Hajishengallis G. Basic biology and role of interleukin-17 in immunity and 
inflammation. Periodontol 2000. 2015;69(1):142-59. 
33. 
Lee SJ, Nguyen TD, Onstad L, Bar M, Krakow EF, Salit RB, et al. Success of 
Immunosuppressive Treatments in Patients with Chronic Graft-versus-Host Disease. Biol Blood 
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34. 
Park AR, La HO, Cho BS, Kim SJ, Lee BK, Rhie JY, et al. Comparison of budesonide 
and dexamethasone for local treatment of oral chronic graft-versus-host disease. Am J Health 
Syst Pharm. 2013;70(16):1383–91.  
35. 
Treister N, Li S, Kim H, Lerman M, Sultan A, Alyea EP, et al. An Open-Label Phase II 
Randomized Trial of Topical Dexamethasone and Tacrolimus Solutions for the Treatment of 
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36. 
Cooke KR, Luznik L, Sarantopoulos S, Hakim FT, Jagasia M, Fowler DH, et al. The 
Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes 
of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-
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37. 
Zeiser R, Blazar BR. Pathophysiology of Chronic Graft-versus-Host Disease and 
Therapeutic Targets. N Engl J Med. 2017;377(26):2565-79. 
38. 
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Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic 
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Graft-versus-Host Disease: III. The 2014 Biomarker Working Group Report. Biol Blood Marrow 
Transplant. 2015;21(5):780–92.  
39. 
Wolff D, Greinix H, Lee SJ, Gooley T, Paczesny S, Pavletic S, et al. Biomarkers in 
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SAP_001.pdf: 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Kadmon 
Corporation and any unauthorized use or disclosure of such information without the prior written 
authorization of Kadmon Corporation is expressly prohibited. 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Randomized, Multicenter Study to Evaluate the Efficacy and Safety of KD025 in 
Subjects with Chronic Graft Versus Host Disease (cGVHD) After At Least 2 Prior Lines of 
Systemic Therapy 
(The ROCKstar Study) 
Protocol Number: 
KD025-213 
Study Drug: 
KD025 
IND Number: 
IND 125890 
Phase: 
2 
Sponsor: 
Kadmon Corporation, LLC 
450 East 29th Street 
New York, NY 10016 
Version 2.1: 
26 June 2020 
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NCT Number:
 NCT03640481


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KD025-213 
Statistical Analysis Plan 
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Kadmon Corporation 
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DOCUMENT HISTORY 
Version 
Author 
Description 
1.0 
 
Original Document 
2.0 
 
Revision according to “KD025-213_Protocol Amendment 
1_26Jun19_FINAL” 
The primary reasons for this new version include: 

Change of study design: add a formal interim analysis
with alpha spending .0025

Change definitions of duration of response in accordance
with FDA type B meeting held on 01 May 2019

Rearrange and add some secondary efficacy endpoints

Add subgroup analysis for proton pump inhibitor
2.1 
 
The primary reasons for this new version include: 

Add censoring rule of new systemic cGVHD treatment for
organ and overall response, corticosteroids usage and
Lee symptom score

Change term of “Sponsor Assessments” into “Kadmon
Algorithmic Response Assessments (KARA)”

Add some additional analyses (section 3.8.2.12)

Add analyses of PROMIS for responder and
nonresponder populations

In subgroup analyses: add baseline GFR, change age
into <65 / ≥65 from by 50 percentile

Clarify response assessment in appendix B

Minor typo and wording changes
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TABLE OF CONTENTS 
Statistical analysis plan ...............................................................................................................1 
SIGNATURE PAGE ....................................................................................................................2 
Document History .......................................................................................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
List of Tables ..............................................................................................................................5 
List of Figures .............................................................................................................................5 
LIST OF ABBREVIATIONS .........................................................................................................6 
1 
INTRODUCTION ...................................................................................................................8 
2 
STUDY SUMMARY ...............................................................................................................8 
2.1 
Study Objectives...........................................................................................................8 
2.2 
Study Design ................................................................................................................9 
2.3 
Number of Subjects ....................................................................................................10 
2.4 
Randomization ...........................................................................................................10 
2.5 
Replacements ............................................................................................................10 
3 
STATISTICAL METHODS ...................................................................................................11 
Three analyses are planned: .....................................................................................................11 
3.1 
Sample Size Justification ............................................................................................11 
3.2 
Multiplicity Adjustment ................................................................................................12 
3.3 
Sample Size Adjustment .............................................................................................12 
3.4 
Analysis Populations ..................................................................................................12 
3.5 
Protocol Deviations .....................................................................................................14 
3.6 
Subject Disposition .....................................................................................................14 
3.7 
Demographics and Baseline Characteristics ...............................................................15 
3.7.1 Demographics ............................................................................................................15 
3.7.2 Medical History ...........................................................................................................15 
3.7.3 GVHD and Transplant History ....................................................................................15 
3.7.4 Other Baseline Characteristics ...................................................................................16 
3.8 
Efficacy Endpoints and Analyses ................................................................................16 
3.8.1 Primary Efficacy Endpoint: ORR .................................................................................16 
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3.8.2 Secondary Efficacy Endpoints ....................................................................................18 
3.8.3 Exploratory Endpoints.................................................................................................23 
3.8.4 Subgroup Analyses ....................................................................................................24 
3.8.5 Multivariate Modeling ..................................................................................................24 
3.9 
Concomitant Medications ...........................................................................................25 
3.10 Treatment Compliance and Exposure .........................................................................25 
3.11 Safety Analysis ...........................................................................................................26 
3.11.1 Adverse Events ..........................................................................................................26 
3.11.2 Adverse events of Note ..............................................................................................27 
3.11.3 Clinical Laboratory Evaluation ....................................................................................27 
3.11.4 Vital Signs and Other Physical Findings .....................................................................28 
3.11.5 ECG ...........................................................................................................................28 
3.11.6 Physical Examination .................................................................................................28 
3.12 Pharmacokinetic Analysis ...........................................................................................28 
3.13 Pharmacodynamics Analysis ......................................................................................29 
3.14 General Methods ........................................................................................................29 
4 
REFERENCES ....................................................................................................................32 
5 
APPENDIX A: Tables, Listings and Figures (TLFs) .............................................................33 
6 
APPENDIX B: Kadmon Algorithmic Response Assessments ..............................................39 
 
List of Tables 
Table 1:  Power for various hypothetic ORRs .......................................................................13 
Table 2:  cGVHD Response Definitions .................................................................................17 
Table 3: Demographics and Baseline Characteristics TLFs ......................................................33 
Table 4: Efficacy TLFs ..............................................................................................................33 
Table 5: Safety TLFs .................................................................................................................36 
 
List of Figures 
Figure 1 KD025-213 Study Schema 
10 
Figure 2 ORR Multiplicity Adjustment 
12 
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LIST OF ABBREVIATIONS 
7-PtR 
≥7 point reduction 
ADI 
Actual dose intensity 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
BMI 
body mass index 
CI 
confidence interval 
CNI 
Calcineurin inhibitor 
CR 
Complete response 
CRF  
case report form 
CSR 
clinical study report 
DLCO 
diffusing capacity of carbon monoxide 
DO7-PtR 
Duration of a ≥7-PtR 
DOR 
duration of response 
FFS 
Failure free survival 
FVC 
forced vital capacity 
GFR 
Glomerular filtration rate 
GSR 
Global Severity Rating 
Hb 
Hemoglobin 
HLGT 
high level group term 
IA 
interim analysis 
ICH 
International Conference on Harmonisation  
ITT 
Intent-to-treat 
KARA 
Kadmon Algorithmic Response Assessments 
KPS 
Karnofsky Performance Scale 
LR 
Lack of Response 
LR-M 
Lack of Response: Mixed 
LP-U 
Lack of Response: Unchanged 
LP-P 
Lack of Response: Progression   
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
mL 
Milliliter 
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Ms 
Millisecond 
OS 
Overall survival 
ORR 
Overall response rate 
PA 
primary analysis 
PDI 
Planned dose intensity 
PE 
physical exam 
PFTs 
pulmonary function tests 
PPI 
proton pump inhibitor 
PR 
Partial response 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
preferred term 
RDI 
Relative dose intensity 
QD 
once-daily 
OMRS 
oral mucosa rating scale 
QTcF 
corrected QT interval using Fridericia's formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC  
system organ class 
TEAE 
treatment emergent adverse event 
TTNT 
Time to next treatment 
TTR 
Time to response 
WHO 
World Health Organization 
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1 
INTRODUCTION 
The objective of the KD025-213 study is to evaluate the efficacy and safety of KD025, at dose 
levels of 200mg QD and 200mg BID, in subjects with cGVHD who have previously been treated 
with two to five prior lines of systemic therapy. 
This Statistical Analysis Plan (SAP) describes data-handling and statistical procedures to be 
used for the analysis and reporting of efficacy and safety data collected under Study KD025-213 
and presented in the clinical study report (CSR). This SAP has been developed and finalized 
prior to locking the clinical database.  Pharmacokinetic (PK) and Pharmacodynamic (PD) 
analyses will be described in separate documents. 
The SAP was written in accordance with the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the most recent ICH-E3 Guideline, entitled “Guidance for 
Industry: Structure and Content of Clinical Study Reports.”  
 
2 
STUDY SUMMARY 
2.1 
Study Objectives 
Primary objective:  
 
To evaluate the efficacy (overall response rate (ORR) as assessed by investigator) and 
safety of KD025, at dose levels of 200mg QD and 200mg BID, in subjects with cGVHD 
who have previously been treated with two to five prior lines of systemic therapy. 
Secondary objectives:  
 
Duration of response (DOR) 
 
Changes in the Lee Symptom Scale Score 
 
Response by organ system 
 
Time to response 
 
Time to next treatment (TTNT) 
 
Percentage of subjects who have a best response of partial response (PR) and 
percentage of subjects who have a best response of complete response (CR) 
 
Change in corticosteroid dose 
 
Change in calcineurin inhibitor dose 
 
Failure-free-survival (FFS) 
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
Overall survival (OS)

Change in cGVHD severity using the Clinician-Reported Global cGVHD Activity
Assessment

Change in symptom activity using the cGVHD Activity Assessment Patient Self-Report

PK of KD025 in subjects with cGVHD
Exploratory Objectives: 

To evaluate changes in the PROMIS Global Health sub-scores for physical and mental
functioning

To evaluate ORR using sponsor assessments of overall response

To evaluate changes in relevant biomarkers after KD025 administration
2.2 
Study Design 
KD025-213 is a Phase 2, open label, randomized, multicenter study in subjects with cGVHD 
who have previously been treated with two to five prior lines of systemic therapy.  The study 
schematic is shown below in Figure 1.  Approximately 126 subjects with active cGVHD will 
be randomized (1:1) to receive treatment with one of two KD025 regimens: 

Arm A: KD025 200mg QD

Arm B: KD025 200mg BID
Subjects may receive treatment in 28-day treatment cycles until clinically significant progression 
of cGVHD (defined as progression requiring addition of new systemic therapy for cGVHD), 
histologic recurrence of underlying malignancy, unacceptable toxicity, Investigator decision, 
subject preference / withdrawal of consent, loss to follow-up, sponsor decision, or death 
(whichever occurs first)  Subjects who have not achieved a response after 12 cycles of KD025 
should be withdrawn if in the Investigator’s judgment there is no evidence of clinical benefit. 
Subjects will undergo evaluations as outlined in the Schedule of Assessments (see Table 12 in 
KD025-213 Study Protocol). 
The primary endpoint is the ORR with responses as defined by the 2014 National Institute of 
Health (NIH) Consensus Development Project on clinical trials in cGVHD. 
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Figure 1 
KD025-213 Study Schema 
 
2.3 
Number of Subjects 
Approximately 126 subjects will be enrolled. 
2.4 
Randomization  
Subjects will be randomized to either Arm A (200mg QD) or Arm B (200mg BID) with 1:1 ratio 
and block size 4.  Randomization will be stratified according to: 
 Prior ibrutinib therapy (Yes / No) 
 Severe cGVHD (yes/no) where severe cGVHD is defined as at least one organ with a 
score of 3, or a lung score of 2 or 3  
2.5 
Replacements  
Randomized subjects withdrawn from the study before receiving any study drug will be 
replaced. 
 
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3 
STATISTICAL METHODS 
Three analyses are planned: 
 
An interim analysis (IA) will be conducted approximately 2 months after 126 subjects 
have been enrolled into the mITT population. A nominal 1-sided alpha of 0.0025 will be 
spent, but there will be no early study termination for efficacy. 
 
The primary analysis (PA) will be conducted approximately 6 months after 126 subjects 
have been enrolled into the mITT population, with 1-sided alpha 0.0225 (or 0.025 if the 
ORRs of both arms are significant at interim). 
 
A follow-up analysis will be conducted approximately 12 months after 126 subjects have 
been enrolled into the mITT population. 
Alpha will only be allocated to the primary endpoint, ORR. 
 
3.1 
Sample Size Justification 
The sample size for KD025-213 is based upon the following considerations: 
 
The primary efficacy objective is to demonstrate an ORR > 30%, i.e. that the lower 
bound of the CI of ORR is greater than 30% 
 
There is an interim analysis with .0025 1-sided alpha spending  
 
A true ORR of 55% is assumed based upon data from an ongoing study of KD025 
(KD025-208) in patients with cGVHD after 1-3 prior lines of systemic therapy.  In the 
KD025-208 study, the ORR was 65% in Cohort 1 (200mg QD), 63% in Cohort 2 (200mg 
BID) and 52% in Cohort 3 (400mg QD) as of 13-September, 2018.   
 
A 10% dropout rate is assumed based upon data from the ongoing KD025-208 study 
(estimated ~6% dropout rate in KD025 208).  Dropouts are defined as a subjects 
discontinuing KD025 treatment prior to any response assessment, due to reasons other 
than an AE related to study drug or cGVHD progression 
For a single arm, assuming a true ORR of 55%, dropout rate of 10%, power 90%, and 2-side 
alpha of .045 to demonstrate ORR > 30%, the sample size is calculated to be 63. 
 
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3.2 
Multiplicity Adjustment 
Since the study has two KD025 treatment arms, the Hochberg procedure will be used 
for multiplicity adjustment for the primary endpoint as shown in Figure 2. 
Figure 2 
ORR Multiplicity Adjustment 
Simulations were conducted with various hypothetic ORR scenarios for two arms of 63 subjects, 
by using the Hochberg procedure for multiplicity adjustment; results (10000 runs per setting) 
are presented in Table 1. 
Only descriptive statistics will be provided for all secondary and exploratory endpoints, without 
multiplicity adjustment. 
3.3 
Sample Size Adjustment 
If during the course of the current study the dropout rate is observed to exceed 10%, the sample 
size may be adjusted to maintain overall power e.g., to approximately 85 subjects per arm if the 
dropout rate reaches 15%. 
3.4 
Analysis Populations 
mITT: The primary population for efficacy analyses will be a modified Intent to treat (mITT) 
population defined as all randomized subjects who receive at least one dose of study 
medication.  
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Table 1:  Power for various hypothetic ORRs 
Table 1a: IA Power (1-sided alpha 0.0025)* 
For both arms to be statistically significant 
 
Arm 1 ORR (%) 
40 
45 
50 
55 
60 
Arm 2 
ORR (%) 
40 
< 1 
< 1 
< 1 
< 1 
< 1 
45 
- 
< 1 
1 
2 
3 
50 
- 
- 
2 
6 
9 
55 
- 
- 
- 
12 
22 
60 
- 
- 
- 
- 
37 
For at least one arm to be statistically significant 
 
Arm 1 ORR (%) 
40 
45 
50 
55 
60 
Arm 2 
ORR (%) 
40 
1 
3 
10 
28 
51 
45 
- 
5 
12 
29 
53 
50 
- 
- 
20 
35 
57 
55 
- 
- 
- 
65 
65 
60 
- 
- 
- 
- 
77 
Table 1b: PA Power (1-sided alpha 0.0225)* 
 
Arm 1 ORR (%) 
40 
45 
50 
55 
60 
Arm 2 
ORR (%) 
40 
20 
39 
64 
84 
95 
45 
- 
52 
72 
89 
97 
50 
- 
- 
83 
93 
98 
55 
- 
- 
- 
97 
99 
60 
- 
- 
- 
- 
100 
IA = Interim Analysis; PA = Primary Analysis 
* Power estimated based upon 10,000 simulations for each cell 
 
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The mITT population will be used for tables of demography, baseline characteristics and 
efficacy. 
Responder: The responder population is defined as subjects in the mITT population that 
achieved a partial or complete response at any post-baseline response assessment.  
Nonresponder: The nonresponder population is defined as anyone in mITT population that is 
not a responder. 
The responder and nonresponder populations will be used for some subgroup analyses. 
Safety: The safety population is defined as all randomized subjects who receive at least one 
dose of study medication.  In this study, safety population is equivalent to mITT population.  
3.5 
Protocol Deviations 
All protocol deviations will be identified and classified as major or minor (as defined below) 
before the clinical database lock, and will be presented in a listing.  
Major Deviation: Protocol deviation that may impact the accuracy, and/or reliability of the study 
data or that may impact subject rights, safety or well-being. 
Minor Deviation: Protocol deviation that does not impact the accuracy, and/or reliability of the 
study data or subject rights, safety or well-being. 
Serious non-compliance: Serious noncompliance presents a significant risk to the safety of 
study patients or significantly affects the scientific value of the reported results of the study.  
This classification may include fraud, scientific misconduct and serious breaches of ethical 
conduct. Persistent clinical investigator site noncompliance, even if not serious, is also 
considered within this definition.   
3.6 
Subject Disposition  
A disposition of all enrolled subjects will be summarized. The number of subjects discontinuing 
from the study and the primary reason for discontinuation will be summarized.  
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3.7 
Demographics and Baseline Characteristics 
3.7.1 
Demographics 
Subject demographics and baseline characteristics will be summarized for the mITT population. 
Descriptive statistics will be provided for age, height, weight, and body mass index (BMI). 
Frequencies and percentages will be tabulated for sex, race, and ethnicity.  
3.7.2 
Medical History 
Medical history will be summarized by primary system organ class (SOC) and preferred term 
(PT). Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 20.1 or higher) terminology. 
3.7.3 
GVHD and Transplant History 
The GVHD history will be summarized including transplant history and prior therapies.   
Transplant history will be summarized for: 
 
Indication for transplant 
 
Stem cell type (bone marrow, peripheral blood, cord blood) 
 
Donor source (related, unrelated) 
 
Conditioning regimen (myeloablative, nonmyeloablative) 
 
Donor age 
 
Donor gender 
 
Donor-recipient gender mismatch 
 
Donor-recipient CMV serostatus 
The baseline characteristics of GVHD will be summarized for:  
 
GVHD prophylaxis 
 
Prior aGVHD 
 
Time from transplant to cGVHD diagnosis 
 
Time from cGVHD diagnosis to enrollment 
 
Time from transplant to enrollment 
 
cGVHD severity: mild / moderate / severe 
Prior Therapies 
 
Number of prior lines of systemic cGVHD therapy 
 
Ongoing systemic cGVHD therapies at baseline 
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
Listing of all non-systemic cGVHD therapies
Organ Involvement 

Number of organs involved at baseline

Organ involvement at baseline, Including
o
baseline skin NIH score and skin feature score
o
eye NIH score
o
NIH modified oral mucosa rating scale (OMRS) score
o
esophagus NIH score
o
upper GI NIH score
o
lower GI NIH score
o
alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin
o
lung NIH score and FEV1 (% predicted)
o
joint/fascia NIH score and P-ROM score
o
global severity rating
3.7.4 
Other Baseline Characteristics 
Other baseline values including Karnofsky Performance Scale (KPS), child bearing potential, 
will also be summarized.  
3.8 
Efficacy Endpoints and Analyses 
3.8.1 
Primary Efficacy Endpoint: ORR 
The primary efficacy endpoint is the overall response rate, with response status as assessed by 
investigators based upon the 2014 NIH Consensus Development Project on Clinical Trials in 
cGVHD (see Protocol Appendix F: cGVHD Response Assessment). 
Response is assessed using individual scores from ten systems (Skin, Eyes, Mouth, 
Esophagus, Upper GI, Lower GI, Liver, Lungs, Joints and Fascia and Global Severity Rating 
(GSR)). Response is assessed with respect to the baseline (Cycle 1, Day 1 (C1D1)) cGVHD 
assessment.  The overall response at each assessment time point will be categorized as 
Complete Response (CR), Partial Response (PR), or Lack of Response (LR), where LR 
includes the response status of unchanged, mixed, or progression as defined in Table 2.  
The ORR is defined as the proportion of subjects with a best response meeting the overall 
response criteria assessment of CR or PR at any post-baseline response assessment. 
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If a treated subject is lost to follow up without response assessment, this subject will be counted 
as a non-responder. Any response on and after new systemic cGVHD treatment will be 
censored as non-response.   
Point estimates, various confidence intervals (Clopper-Pearson (exact)  method) listed in 
Figure 2, and raw and Hochberg adjusted p-values corresponding to the null hypothesis 
of ORR ≤ 30% vs alternative hypothesis of ORR > 30% by treatment arms will be 
reported. 
 
The number and percentage of subjects who have a best response of PR and number and 
percentage of subjects who have a best response of CR will also be reported. 
Table 2:  cGVHD Response Definitions 
Response 
Definition 
Complete Response (CR) 
Resolution of all manifestations of cGVHD in each 
organ or site 
Partial Response (PR) 
Improvement in at least one organ or site without 
progression in any other organ or site 
Lack of Response (LR) 
 
   Mixed (LR-M) * 
Complete or partial response in at least one organ 
accompanied by progression in another organ 
   Unchanged (LR-U) 
Outcomes that do not meet the criteria for 
complete response, partial response, progression 
or mixed response 
   Progression (LR-P) 
Progression in at least one organ or site without a 
response in any other organ or site 
* Considered progression for purposes of analysis 
 
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3.8.2 
Secondary Efficacy Endpoints 
3.8.2.1 
Duration of Response (DOR) 
The primary definition of DOR is the time from first documentation of response to the time of first 
documentation of deterioration from best response (e.g., CR to PR, or PR to LR). 
The secondary definition of DOR is the time from first documentation of response to the time of 
first documentation of lack of response. 
The tertiary definition of DOR is the time from first documentation of response to the time of 
initiation of new systemic cGVHD therapy. 
The quaternary definition of DOR is the time from first documentation of response to the time of 
first documentation of lack of response (as the secondary definition) but with durations summed 
for multiple response/lack of response episodes. 
The DOR will be reported only for responders and statistics will include: 
 Kaplan-Meier plots and descriptive statistics of DOR. The censoring rules in Table 3 will be 
applied 
 Landmark analyses: Number and percentage of subjects with response sustained for ≥ 12, ≥ 
20, ≥ 24, ≥ 32, ≥ 36, and ≥ 48 weeks 
 
Table 3.  Censoring Rules for Duration of Response 
DOR 
Events 
Censoring 
Primary 
 Deterioration from best response 
 Initiation of new systemic therapy for cGVHD 
 Death 
 Last documented response 
assessment 
 If LR or initiation of new systemic 
therapy happens immediately 
after two or more missed 
response assessments, the 
event date should be set as four 
weeks (one cycle) after last 
documented response 
assessment prior this event 
Secondary 
 Documented LR 
 Initiation of new systemic therapy for cGVHD 
 Death 
Tertiary 
 Initiation of new systemic therapy for cGVHD 
 Death 
Last response assessment or long 
term follow up assessment, 
whichever is the latest and available  
Quaternary 
 Documented LR 
 Initiation of new systemic therapy for cGVHD 
 Death 
With summation of DOR from multiple episodes  
Same with censoring rule for 
primary and secondary 
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cGVHD = chronic graft versus host disease; DOR = duration of response; LR = lack of response 
 
3.8.2.2 
Lee Symptom Scale Score (LSS) 
Lee cGVHD Symptom Scale1  (see questionnaire in Protocol Appendix D) will be assessed on 
Day 1 of Cycles 2-5, then on Day 1 of every other Cycle thereafter and EOT. The questionnaire 
consists 30 items of 7 domains: skin, eyes and mouth, breathing, eating and digestion, muscles 
and joints, energy, and mental and emotional. Each question is scored 0, 1, 2, 3 or 4.  
A domain score will be calculated for each domain by taking the mean of all items completed if 
more than 50% were answered and normalizing to a 0 to 100 scale. A summary score will be 
calculated as average of all nonmissing domain scores if more than 50% of them are 
nonmissing. A higher score indicated more bothersome symptoms. 7 points difference on the 
summary score of cGVHD symptom scale was found to be clinically meaningful.   
100
*
)
4
/
(
,
1
Score
Raw
Score
Domain
m
I
I
Score
Raw
m





 
n
Score
Domain
Score
Domain
Score
Summary
n




1
 
In the above formulas, m is the number of items have nonmissing value in a domain, and n is 
the number of domains have nonmissing domain scores.  
Analyses will include: 
 
Both score and change-from-baseline values (summary score and domain scores) will 
be summarized as continuous variables by visit  
 
Number and percent of subjects with a ≥7-point reduction (7-PtR) from baseline (C1D1) 
 
Number and percent of subjects with a 7-PtR from baseline on 2 consecutive 
assessments 
 
Duration of a 7-PtR (DO7-PtR) (defined as time from documentation of the first ≥7-point 
reduction to the first documentation of less than 7-point reduction). If there are multiple 
episodes, then DO7-PtR will be measured as the sum of DO7-PtR from all episodes.   
These analyses will be performed on mITT, responder and nonresponder populations. 7-PtR 
and DO7-PtR will be censored after new systemic cGVHD treatment. 
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3.8.2.3 
Response by organ system 
The best response (CR, PR) for the nine individual organs (Skin, Eyes, Mouth, Esophagus, 
Upper GI, Lower GI, Liver, Lungs, and Joints and fascia) plus global severity rating will be 
summarized. 
Time to response at the organ level will also be evaluated.  Descriptive statistics and plots of 
cumulative number and % of responders over time (4, 8, 12, 16, 24, 32, 40, >=48 weeks) will be 
provided.  Two series of percentages will be presented: 
1. with total number of subjects in mITT with involvement of the given organ at baseline as 
denominator 
2. with number of subjects in the responder population with involvement of the given organ 
at baseline as denominator.  
3.8.2.4 
Time to Response (TTR) 
TTR will be measured as the time from first treatment to the time of first documentation of 
response. Descriptive statistics and plots of cumulative number and percent of responders over 
time (4, 8, 12, 16, 24, 32, 40, ≥48 weeks) will be provided. TTR analyses will only be conducted 
for the responder population.  
3.8.2.5 
Time to Next Therapy (TTNT) 
The TTNT will be measured as the time from first treatment to the time of new systemic cGVHD 
treatment, censored by last response assessment or long term follow up assessment, 
whichever is the latest and available. TTNT will be analyzed by the Kaplan-Meier survival 
method as well as the landmark analysis at 6, 12, 18, and 24 months. 
3.8.2.6 
Corticosteroid dose 
Corticosteroid doses will be presented as mg/kg/day prednisone equivalent dose.  Descriptive 
statistics for the mITT population, responder /nonresponder populations and subgroups defined 
by baseline corticosteroid dose level (upper and lower 50 percentiles) will be provided for: 
 
Systemic corticosteroid dose over time 
 
Change and % change from baseline (C1D1) to the greatest corticosteroid dose 
reduction during KD025 treatment period 
 
Number and % of subjects who reduced systemic corticosteroid dose during KD025 
treatment period 
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
Number and % of subjects who ever discontinued systemic corticosteroid usage for over
28 days during KD025 treatment period
The above analyses will be censored on or after new systemic cGVHD treatment. 
If subjects are not using prednisone as the systemic corticosteroid, then the prednisone 
dose equivalent will be determined according to following conversion ratios2: 
1 mg prednisone is equivalent to: 

4mg Hydrocortisone

0.8mg Methylprednisolone

0.15mg Dexamethasone

1mg Prednisolone

0.8mg Triamcinolone
Transient increases in corticosteroid dosing (not exceeding 1mg/kg/day prednisone equivalent, 
are permitted for the treatment of cGVHD flare, but dose must be reduced back to the pre-
randomization dose within 6 weeks. If the dose remains elevated for more than 6 weeks, this 
will be considered a KD025 treatment failure. More than 2 episodes of cGVHD flare requiring 
increased corticosteroid therapy in the first 6 months of KD025 treatment will also be considered 
a KD025 treatment failure. 
3.8.2.7 
Calcineurin inhibitor (CNI) doses  
CNI includes systemic tacrolimus and cyclosporine. Descriptive statistics will be provided for: 

Number and % of subjects who reduced CNI dose during KD025 treatment period

Number and % of subjects who ever discontinued CNI during KD025 treatment period
3.8.2.8 
Failure-free-survival (FFS) 
FFS is defined as the absence of new cGVHD systemic therapy, non-relapse mortality and 
recurrent malignancy (i.e. underlying disease) and is censored by by last response assessment 
or long term follow up assessment, whichever is the latest and available. Kaplan-Meier plots, 
descriptive statistics of FFS and landmark FFS at 6, 12, 18 and 24 months will be provided. In 
addition, analyses for the three components of FFS will also be provided.  
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3.8.2.9 
Overall survival (OS) 
OS is defined as time from first dose of KD025 to the date of death due to any cause. Kaplan-
Meier plots, descriptive statistics of OS and landmark OS at 6, 12, 18 and 24 months will be 
provided. 
3.8.2.10 
Change in cGVHD severity using the Clinician-Reported Global cGVHD 
Activity Assessment 
The Clinician-reported global cGVHD Activity Assessment is a 0-10 point numeric rating scale 
with a score of 0 indicating “cGVHD symptoms not at all severe” and a score of 10 being “Most 
severe cGVHD symptoms possible”. The activities are assessed on Day 1 of each cycle from 
Cycle 1 Day 1 to EOT.  
Change from baseline in cGVHD severity based on the Clinician-reported global cGVHD Activity 
Assessment will be summarized as a categorical endpoint at all scheduled assessment visits. 
3.8.2.11 
Change in symptom activity using the cGVHD Activity Assessment Patient 
Self-Report  
The cGVHD Activity Assessment-Patient Self Report is in Protocol Appendix F. Activities are 
assessed on Day 1 of each cycle from C1D1 to end of treatment (EOT). The symptom activity 
item is a 0-10-point numeric rating scale with a score of 0 indicating “cGVHD symptoms not at 
all severe” and a score of 10 being “most severe cGVHD symptoms possible”. The status 
reported by subjects are categorized as none, mild, moderate, and severe. The comparison of 
cGVHD symptoms to a month ago will also be reported by subjects, ranging from -3 (very much 
worse) to +3 (very much better).   
Changes in cGVHD symptoms based on global cGVHD Activity Assessment by the Patient Self 
Report will be summarized as a continuous endpoint at all scheduled assessment visits. Both 
scores as well as the change-from-baseline values will be presented.   
The summary of the change-from-baseline of Global Severity Rating on categorical status and 
the summary of comparison of cGVHD to a month ago will also be presented.  
The number and percentage of subjects reporting none, mild, moderate, and severe cGVHD will 
be summarized by visit.  
 
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In addition to the specific analyses described above, descriptive statistics by visit and arm will 
be provided for all applicable secondary endpoints. 
3.8.2.12 
Additional Analyses 
Additional analyses will be presented including: 

ORR and DOR for responses occurring within the first 6 and 12 months of treatment with
KD025

Organ responses according to baseline NIH / severity score

Landmark FFS with CR/PR at 6 months and at 12 months

Time to corticosteroid discontinuation
3.8.3 
Exploratory Endpoints 
3.8.3.1 
Changes in the PROMIS Global Health subscores for physical and mental 
functioning (see definition in Protocol Appendix E) 
Patient-Reported Outcomes Measurement Information System (PROMIS)3, a state-of-the-
science PRO measurement system, was developed using mixed qualitative and quantitative 
methods and uses item response theory–calibrated item banks for numerous patient-reported 
symptoms and functional domains. These PRO measures can be used across chronic diseases 
and in the general population. A feature of PROMIS measures is that an individual's or group's 
score is represented as a T score, normalized and calibrated against the US population (United 
States population average score, 50; 10 points = 1 standard deviation [SD]). The PROMIS 
Global Health 10 measure comprises ten items with two summary scores for physical and 
mental functioning with higher scores indicating better functioning. Those two summary scores 
were calculated using the Assessment Center Scoring Service 
(https://www.assessmentcenter.net/ac_scoringservice)from raw data. 
Analyses will include: 

Both raw scores and change-from-baseline values (physical and mental domains) will be
summarized as continuous variables by visit.

Number of subjects with a ≥4.7-point reduction from baseline (C1D1)
These analyses will be performed on mITT, responder and nonresponder populations. 
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3.8.3.2 
ORR using Kadmon Algorithmic Response Assessment (KARA)  
In addition to ORR assessed by investigators, the sponsor will conduct response assessments 
according to criteria listed in Appendix B for each individual organ, then assign overall response 
according to Table 2 (cGVHD response definitions). Analyses of ORR and DOR will be repeated 
with this sponsor assessment of overall response. 
Concordance with investigator determined responses will be analyzed. 
3.8.4 
Subgroup Analyses 
Subgroup analyses for the endpoints of ORR and DOR will be conducted for the following 
subgroups: 
 
Prior ibrutinib (Yes / No) 
 
Severe cGVHD at screening (Yes / No) 
 
Number of organs involved at baseline (<4 / ≥4) 
 
Number of prior lines of therapy (≤3 / >3) 
 
Duration of cGVHD before enrollment (by 50th percentile)  
 
Baseline corticosteroid dose level (by 50th percentile) 
 
Lung involvement at baseline (Yes / No) 
 
Take concomitant medication proton pump inhibitor (PPI) on C1D1 (Yes/No) 
 
Gender 
 
Age (<65, ≥65 years)) 
 
Race 
 
Prior ruxolitinib (Yes / No) 
 
Best response to the last prior treatment (SD/PD) 
 
Take concomitant medication proton pump inhibitor (PPI) on C1D1 (Yes/No) 
 
Baseline GFR (<60, 60-90 and ≥90 mL/min) 
All subgroup analyses will be exploratory and with no multiplicity adjustment.   
3.8.5 
Multivariate Modeling 
Logistic regression will be carried out as exploratory/supportive analyses. This will provide a 
means to assess the effects of those potential prognostic indicators listed in subgroup analyses 
section. The following modeling procedure will be used: 
 
Univariate modeling 
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A logistic regression model (response ~ an individual factor) will be used for a factor of arm, 
potential prognostic factors listed in subgroup analyses section and other potential 
prognostic indicators. The resulting odds ratio, its confidence interval (CI) and p value will be 
summarized in a univariate analysis table. 
 
Multivariate modeling 
Based on the univariate modeling results and clinical judgement, a multivariate logistic 
regression model might be chosen as a predictive model.  
 
3.9 
Concomitant Medications 
Concomitant medications will be coded using WHO Drug Dictionary Enhanced.  Concomitant 
medications are all medications taken after the start of study consent, during the treatment 
period (day 1 until 28 days after last dose), including those started before but ongoing at the 
start of study treatment.  
Concomitant medications will be summarized according to ATC class and preferred drug name. 
 
3.10 
Treatment Compliance and Exposure 
The extent of KD025 exposure will be assessed using the duration of KD025 treatment.  Pill 
dispensation and return counts will be the primary source of data. 
Duration of KD025 treatment is defined as last dose date – first dose date + 1 day regardless of 
unplanned intermittent discontinuations.  Duration of treatment will be summarized as a 
continuous variable and also categorically by numbers and percentages for each of the 
following categories and cumulatively according to these categories: 0 to 6, 6 to 12, and ≥12 
months.  
The cumulative duration of treatment will be provided, defined as the sum of the duration of 
treatment for all patients, and will be expressed in patient years. 
The relative dose intensity (RDI) will be presented. The RDI is defined as: 
 
RDI (%) = 100*ADI (mg/day)/PDI (mg/day) 
where ADI and PDI are the actual dose intensity and planned dose intensity, respectively: 
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PDI (mg/day) = planned cumulative dose (mg) / duration of treatment (days), 
 
ADI (mg/day) = actual cumulative dose (mg) / duration of treatment (days). 
The planned cumulative dose is the planned daily dose amount * duration of treatment, while 
the actual cumulative dose is the sum of actual doses received over the duration of treatment.  
The actual total dose will incorporate information of dose reductions and dose interruptions 
captured in the CRF. 
Descriptive summary statistics of the treatment duration, actual cumulative dose, ADI, RDI, 
dose reduction and dose interruption will be presented. 
 
3.11 
Safety Analysis 
Safety assessments include AEs, serious adverse events (SAEs), vital sign measurements, 
clinical laboratory evaluations (hematology, chemistry) and ECGs.  Clinically significant PE 
findings will be captured as AEs. 
Safety analyses will further include assessments of the defined stopping rules (protocol section 
10), namely rates of: 
1. Secondary graft failure  
2. Histological recurrence of underlying malignancy within 6 months of randomization 
3. Withdrawal due to related AEs within 3 months of randomization 
3.11.1 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
(Version 20.0 or higher). TEAEs are any AEs occurring or worsening in severity after the first 
administration of study medication.  All AEs (including SAEs) will be graded using the 5-point 
CTCAE V5.0 scale (mild, moderate, severe, life threatening, or death); their causality with 
KD025 will be classified into following 5 classes: definitely related, probably related, possibly 
related, unlikely related, not related.  The Investigator will further assess the relationship of 
adverse events to cGVHD or the underlying disease. 
The number and percentage of patients who experienced at least one TEAE as well as the 
number and percentage of patients who experienced adverse events of each specific system 
organ class (SOC) and preferred term (PT) will be presented.  For the presentation of AE 
incidences, the SOCs and the PTs within each SOC will be presented by decreasing total 
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frequency. Tabulation by maximum severity and relationship to KD025 will also be included by 
treatment group.  
TEAEs, Grade ≥3 TEAEs, SAEs and TEAEs leading to dose modification / discontinuation will 
be summarized according to treatment arm, system-organ-class, and preferred terms.  These 
analyses will be repeated for events considered related (definitely related / probably related / 
possibly related) to KD025  
Subject listings will be provided for SAEs, AEs resulting in study drug discontinuation and 
deaths. 
AEs will also be presented in listings.  Time to onset and duration of AEs will be included in 
listings, along with action taken and outcome. 
3.11.2 Adverse events of Note 
AEs of note include: 
 
Hepatic AEs by CTCAE V5.0 criteria; grouped terms will also be presented. 
 
Bacterial infection, Viral infection and Fungal infection 
 
Cytopenias 
Those AEs of note will be summarized according to treatment group and preferred terms.  Also 
see Section 3.11.3 for LFT analyses. 
3.11.3 Clinical Laboratory Evaluation 
The summary statistics (including number, mean, standard deviation, median, minimum and 
maximum) of all laboratory variables and changes from baseline will be calculated for each visit 
or study assessment by treatment group.  For parameters of WCC, neutrophils (absolute count), 
lymphocytes (absolute count), monocytes (absolute count), Hb, platelets, ALP, ALT, AST, GGT, 
total bilirubin, GFR, plots of mean / mean changes from baseline with the corresponding 
standard error will be displayed.  
For shift tables, laboratory results will be classified using the CTCAE V5.0. All graded laboratory 
parameters will be summarized separately for hematology and biochemistry. Corresponding 
shift tables to compare baseline to the worst post-baseline grade within the treatment period will 
be provided.   
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3.11.4 Vital Signs and Other Physical Findings 
Descriptive statistics for vital signs (weight, heart rate, body temperature, systolic and diastolic 
blood pressure, pulse rate, and respiratory rate) values and the change from baseline will be 
presented by treatment group for each scheduled assessment time point. 
3.11.5 ECG 
Descriptive statistics for ECG parameters (i.e., heart rate (HR), PR interval, RR interval, QRS 
interval, QT interval, and QTcF interval) at each time point with triplicate ECGs will be presented 
for the values and change from baseline scores (note: Fridericia’s correction:  QTcF = 
QT/RR1/3).  
The number and percentage of subjects with observed QTcF values that satisfy the following 
conditions will be presented by treatment group and study visit: 
 
≤ 450 ms  
 
>450 to ≤ 480 ms 
 
>480 to ≤ 500 ms 
 
> 500 ms 
The number and percentage of subjects having change from baseline QTcF values that satisfy 
the following conditions will be presented by treatment group and study visit: 
 
≤ 0 ms 
 
>0 to ≤ 30 ms 
 
>30 to ≤ 60 ms 
 
> 60 ms 
3.11.6 Physical Examination 
Clinically significant physical examination findings will be captured as AEs. 
 
3.12 
Pharmacokinetic Analysis  
Further details will be described in the Pharmacokinetic Analysis Plan. 
 
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3.13 
Pharmacodynamics Analysis  
Further details will be described in the Pharmacodynamics Analysis Plan. 
 
3.14 
General Methods 
Computing Environment  
All statistical analyses will be performed using SAS® Version 9.3 or higher for Windows. 
Reporting of Numerical Values 
Continuous data will be described using descriptive statistics: number of observations (n), 
mean, standard deviation, median, minimum and maximum. Frequencies and percentages will 
be used for summarizing categorical data. When categorical data are presented, the percent will 
be suppressed when the count is zero in order to draw attention to the nonzero counts. The 
denominator for all percentages, unless otherwise specified, will be the number of subjects in 
the specified analysis population or group. 
Means, medians, standard deviations, and confidence intervals will be reported to one decimal 
place more than the data reported on the case report form (CRF) or by the laboratory/vendor. 
Minimum and maximum will be reported to the same number of decimal places displayed on the 
CRF or by the laboratory/vendor. P-values will be reported to 4 decimal places. 
Study Day 
The study day for all assessments prior to the first study drug administration is calculated as the 
difference between the date of the event or measurement (e.g., AE onset date, assessment 
date, sample collection date, etc.) and the start date of study treatment. The day before the start 
of study treatment is Study Day -1. 
The study day for all post assessments after the first study drug administration is calculated as 
the difference between the date of the event or measurement (e.g., AE onset date, assessment 
date, sample collection date, etc.) and the start date of study treatment, plus one day. The first 
day of study treatment is Study Day 1. 
Baseline 
Baseline value is defined as the valid and last non-missing value obtained within 14 days prior 
to subject receiving the first study medication, unless otherwise stated under the related 
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assessment section. Baseline can be the day before the first study medication or on the same 
day as the first study medication if a pre-dose assessment is available. Subjects without data on 
a parameter before the first study medication will have a missing baseline for this parameter.  
Handling of Incomplete or Missing Data 
Missing data will not be imputed in general and it will be reported as missing in all listings. For 
categorical variables, patients with missing data are not included in calculations of percentages 
unless otherwise specified.  
Missing start and end dates for AE and concomitant medication (CM)  
The assumption will be the worst or most conservative judgment when imputing AE and CM 
start and end dates. The purpose of imputing a start date is to help define whether the AE/CM 
started while taking study drug. 
For a partial or missing start date: 
 If the day is missing, the first day of the month will be imputed. If the missing day is the 
same as the month of first dose of study drug, then the first dose date will be imputed. 
 If the day and month are missing, the first day of January will be imputed. If the year is the 
same as the first dose date, then the first dose date will be imputed. 
 If the day is completely missing, the first dose date will be imputed. If the end date suggests 
it could have started prior to this, the first day of January of the same year as the end date 
will be imputed. 
 When imputing a start date, the start date will ensure that the new imputed date is sensible, 
i.e., is prior to the end date of the AE or CM. 
For a partial or missing end date: 
 If the day is missing, the last day of the month or the last assessment date, whichever is 
earlier, will be imputed. 
 If the day and month are missing, the 31st of December or the last assessment date, whichever 
is earlier, will be imputed 
 If the date is completely missing, there will be a need to look at whether the AE/CM is still 
ongoing before imputing a date. If the ongoing flag is missing, then it will be assumed that 
AE is still present, or CM is still being taken (i.e., do not impute a date). If the AE/CM has 
stopped, then the last assessment date will be imputed. 
These data imputations are for categorization purpose only and will not be used in listings. 
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If the assessment of the relationship of the AE to KD025 is missing, then the relationship to 
KD025 has to be assumed and the AE considered as such in the frequency tables of possibly 
related AEs, but no imputation should be done at the data level. 
Missing event dates  
Event date will be imputed only when day is missing, and the purpose of imputing an event date 
is to most conservatively calculate time to event.  
If the day is missing, the first (mid, last) day of the month will be imputed for undesired (neutral, 
desired) event. If the missing day is the same as the month of first dose of study drug, then the 
first dose date will be imputed for undesired event. 
These data imputations are for time to event calculation only and will not be used in the listings. 
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4 
REFERENCES 
1. Lee SJ, Cook EF, Soiffer R, et al. Development and validation of a scale to measure 
symptoms of chronic graft-versus-host disease. Biology of Blood and Marrow 
Transplantation 2002; 8:444-452 
2. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the 
complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 
2013;9(1):30. Published 2013 Aug 15. doi:10.1186/1710-1492-9-30 
3. Lee SJ, Onstad L, Chow EJ, et al. Patient-reported outcomes and health status associated 
with chronic graft-versus-host disease. Haematologica. 2018; 103(9), 1535-1541 
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5 
APPENDIX A: Tables, Listings and Figures (TLFs)1 
Table 3: Demographics and Baseline Characteristics TLFs 
T/F/L 
Title 
Population 
T 
Patient disposition 
mITT 
L 
Patient disposition  
mITT 
L 
Protocol deviations 
mITT 
T 
Demographics and baseline characteristics 
mITT 
L 
Demographics and baseline characteristics  
mITT 
T 
Medical histories by primary system organ class and preferred 
terms  
mITT 
L 
Medical history 
mITT 
T 
cGVHD and transplant history 
mITT 
L 
cGVHD and transplant history 
mITT 
T 
Summary of organ involvement at baseline and baseline score 
mITT 
T 
Summary of prior systemic cGVHD therapy 
mITT 
L 
Prior systemic cGVHD therapy 
mITT 
 
Table 4: Efficacy TLFs 
T/L/F 
Title 
Population 
Primary Endpoint: ORR 
T 
Overall Response Rate* 
mITT 
T 
Overall response rate (ORR) for responses occurring within 6 months 
of treatment  
mITT 
T 
Overall response rate (ORR) for responses occurring within 12 months 
of treatment 
mITT 
T 
Landmark ORR at 6 months 
mITT 
T 
Landmark ORR at 12 months 
mITT 
F 
Forest plot of ORRs (1. all subjects in an arm, subgroups within 
arm; 2. Two arm combined if ORRs of those two arms are 
similar) 
mITT 
                                               
1 In all tables, figures and listing, results will be presented by two treatment arms and overall, unless be 
otherwise specified. 
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T/L/F 
Title 
Population 
L 
Listing of overall response by subject by visit  
mITT 
Secondary Endpoint: DOR 
T 
Descriptive Kaplan-Meier and landmark (12, 20, 24, 32, 36, 48  
weeks) statistics for DOR* 
Responder 
F 
Kaplan-Meier plot of DOR* 
 
Responder 
L 
Listing of all DOR episodes for each subject 
Responder 
Secondary Endpoint: TTR 
T 
Descriptive statistics for cumulative response rate over time 
(TTR) 
Responder 
F 
Cumulative response rate over time (TTR) 
Responder 
L 
Listing of TTR for each subject 
Responder 
Secondary Endpoint: LSS score 
T 
Descriptive statistics for LSS score for: a) number of subjects 
with a 7-PtR from baseline; b) number of subjects with 7-PtR on 
2 consecutive assessments; c) DO7-PtR (<8, 8-16, 16-24, 24-
32, 32-40, 40-48, >48 weeks) 
mITT, Responder, 
Nonresponder 
T 
Summary of LSS Score (overall and each of seven domains) 
raw and change from baseline by visit 
mITT, Responder, 
Nonresponder 
F 
Summary of Lee Symptom Scale Score (overall and each of 
seven domains) raw and change from baseline by visit 
mITT, Responder, 
Nonresponder 
L 
Listing of Lee Symptom Scale Score by subject, domain and  
visit  
mITT 
Secondary Endpoint: Response by Organ System 
T 
Best response by individual organ 
mITT 
T 
Organ responses according to baseline NIH / severity score  
mITT 
L 
Listing of organ score and response assessment by subject and 
visit  
mITT 
T 
Descriptive statistics for cumulative response rate over time 
(TTR) by organ 
mITT, Responder 
F 
Cumulative response rate over time (TTR) by organ 
mITT, Responder 
Secondary Endpoint: Corticosteroid Dose 
T 
Descriptive statistics for prednisone equivalent dose of 
corticosteroids for a) change and % change from baseline to 
greatest reduction; b) the number and % subjects who reduced 
dose; c) number and % subjects who discontinued 
corticosteroid usage 
mITT, Responder, 
Nonresponder, BL 
corticosteroid dose 
level (upper and 
lower 50th 
percentiles) 
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T/L/F 
Title 
Population 
T 
Descriptive Kaplan-Meier statistics for time to corticosteroid 
discontinuation 
mITT 
T 
Summary of raw and change from baseline on prednisone 
equivalent dose of corticosteroids by visit 
mITT, Responder, 
Nonresponder, BL 
corticosteroid dose 
level (upper and 
lower 50th 
percentiles) 
F 
Box plot of prednisone equivalent dose of corticosteroids over 
time 
mITT, Responder, 
Nonresponder, BL 
corticosteroid dose 
level (upper and 
lower 50th 
percentiles) 
L 
Listing of all the steroid raw and standardized dosing by subject 
and visit   
mITT 
Secondary Endpoint: CNI Dose 
T 
Summary of descriptive statistics for CNI for a) the number and 
% subjects who reduced dose from baseline; b) number and % 
subjects who discontinued CNI 
mITT 
L 
Listing of all the CNI dosing by subject and visit 
mITT 
Secondary Endpoint: FFS 
T 
Descriptive Kaplan-Meier and landmark (6, 12, 18 and 24 
months) statistics for FFS (with cumulative failure rates for each 
of the 3 components FFS) 
mITT 
F 
Kaplan-Meier plot for FFS (with cumulative failure rates for 3 
components of failures) 
mITT 
L 
Listing of failure events 
mITT 
Secondary Endpoint: OS 
T 
Descriptive Kaplan-Meier and landmark (6, 12, 18 and 24 
months) statistics for OS 
mITT 
F 
Kaplan-Meier plot of OS 
mITT 
Secondary Endpoint: Symptom activity using the cGVHD Activity Assessment Patient Self-
Report 
T 
Descriptive statistics of change from baseline in symptom 
activity based on cGVHD Activity Assessment Patient Self 
Report (global rating) by visit 
mITT 
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T/L/F 
Title 
Population 
T 
Descriptive statistics of symptom activity based on cGVHD 
Activity Assessment Patient Self Report (change of cGVHD 
symptom to a month ago) by visit 
mITT 
L 
Listing of symptom activity based on cGVHD Activity 
Assessment Patient Self Report 
mITT 
Exploratory Endpoints 
T 
Overall Response Rate (KARA) 
mITT 
T 
Concordance of overall response between investigator 
determined responses and KARA 
mITT 
T 
Descriptive Kaplan-Meier and landmark (12, 20, 24, 32, 36, 48  
weeks) statistics for DOR (KARA) 
Responder 
F 
Kaplan-Meier plot of DOR (KARA) 
Responder 
T 
Best response by individual organ (KARA) 
mITT 
T 
Descriptive statistics of change from baseline in PROMIS scale 
by visit 
mITT, Responder, 
Nonresponder 
T 
Summary table of univariate modeling 
mITT 
* Repeat TLF for subgroups of:  
 
Prior ibrutinib (Yes / No) 
 
Severe cGVHD at baseline (Yes / No) 
 
Number of organs involved at baseline (<4 / ≥4) 
 
Number of prior lines of therapy (≤3 / >3) 
 
Duration of cGVHD before enrollment (by 50th percentile) 
 
Baseline corticosteroid dose level (by 50th percentile) 
 
Lung involvement at baseline (Yes / No) 
 
Proton pump inhibitor (PPI) on C1D1 (Yes/No) 
 
Gender 
 
Age (<65 / ≥65 years ) 
 
Race 
 
Prior ruxolitinib (Yes / No) 
 
Best response to the last prior treatment (SD/PD) 
 
Take concomitant medication proton pump inhibitor (PPI) on C1D1 (Yes/No) 
 
Baseline GFR (<60, 60-90 and ≥90 mL/min) 
 
Table 5: Safety TLFs 
T/F/L 
Title 
Population 
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T 
Concomitant medications 
mITT 
L 
Concomitant medications 
mITT 
T 
Treatment exposure and compliance 
mITT 
L 
Treatment exposure and compliance  
mITT 
T 
Dose modifications and interruption 
mITT 
L 
Dose modifications and interruption 
mITT 
T 
Overall summary of TEAEs 
Safety 
T 
TEAEs by Soc/PT  
Safety 
T 
TEAEs by PT  
Safety 
T 
TEAEs by severity and PT  
Safety 
T 
Treatment related AEs by PT 
Safety 
T 
Serious TEAEs by Soc/PT 
Safety 
T 
Serious TEAEs by PT 
Safety 
T 
Treatment related SAEs by PT 
Safety 
T 
Grade 3-5 TEAEs by Soc/PT 
Safety 
T 
Grade 3-5 TEAEs by PT 
Safety 
T 
Treatment related grade 3-5 AEs by Soc/PT 
Safety 
T 
TEAEs leading to Study treatment discontinuation by Preferred 
Term 
Safety 
T 
Related TEAEs leading to Study treatment discontinuation by 
Preferred Term 
Safety 
T 
TEAEs leading to dose interruption by Preferred Term 
Safety 
T 
Related TEAEs leading  to dose interruption by Preferred Term 
Safety 
T 
TEAEs leading to dose modification by Preferred Term 
Safety 
T 
Related TEAEs leading  to dose modification by Preferred Term 
Safety 
T 
TEAEs leading to dose reduction by Preferred Term 
Safety 
T 
Related TEAEs leading  to dose reduction by Preferred Term 
Safety 
L 
AEs 
Safety 
L 
AE Leading to treatment discontinuation 
Safety 
L 
Death 
Safety 
T 
Lab values and their change from baseline 
Safety 
F 
Lab values by visit 
Safety 
T 
Shifts in CTC grade from baseline to highest grade post-
baseline of laboratory 
Safety 
L 
Lab values with CTC grade ≥ 3 
Safety 
T 
Vital signs and their change from baseline 
Safety 
L 
Vital signs 
Safety 
T 
ECG parameters and their change from baseline 
Safety 
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F 
ECG parameters by visit 
Safety 
T 
Number and percentage of subjects with QTcF by visit a) 
absolute ranges and b) change from baseline 
Safety 
T 
QTcF abnormalities 
Safety 
L 
ECG values 
Safety 
 
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6 
APPENDIX B: Kadmon Algorithmic Response Assessments  
For determination of responses and DOR per sponsor assessment, criteria for baseline organ 
involvement and response assessments are described below. 
Baseline Organ Involvement 
Organ 
Organ Involvement 
Esophagus 
NIH Esophagus Score ≥ 1, not entirely explained by non-cGVHD cause 
Upper GI 
NIH Upper GI Score ≥ 1, not entirely explained by non-cGVHD cause 
Lower GI 
NIH Lower GI Score ≥ 1, not entirely explained by non-cGVHD cause 
Lungs 
FEV1 <75% predicted, not entirely explained by non-cGVHD cause  
If no PFTs available, use NIH lung score ≥ 1, not entirely explained by non-cGVHD cause 
Eyes 
NIH Eye Score ≥ 1, not entirely explained by non-cGVHD cause 
Joints and 
Fascia 
P-ROM Score <25 (< maximal score) or NIH Joints/Fascia Score ≥ 1, not entirely explained by 
non-cGVHD cause 
Skin 
NIH Skin Score ≥ 1, not entirely explained by non-cGVHD cause 
Mouth 
NIH Modified Oral Mucosal Rating Score ≥ 1, not entirely explained by non-cGVHD cause 
Liver 
Elevation  > 2x ULN of one or more (ALT, ALP, Total Bilirubin), not entirely explained by non-
cGVHD cause 
 
 
 
 
 
 
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Response Assessments 
Organ 
Complete 
Response 
Partial 
Response 
Unchanged 
Progression 
Non Evaluable 
Esophagus 
NIH Esophagus 
Score 0 after 
previous 
involvement 
Decrease in NIH 
Esophagus 
Score by 1 or 
more points 
No change or 
increase from 0 
to 1 in NIH 
Esophagus 
Score  
Increase in NIH 
Esophagus 
Score by 1 or 
more points, 
except 0 to 1 
NIH esophagus 
score is Non 
evaluable 
Upper GI 
NIH Upper GI 
Score 0 after 
previous 
involvement 
Decrease in NIH 
Upper GI Score 
by 1 or more 
points 
No change or 
increase from 0 
to 1 in NIH 
Upper GI Score 
Increase in 
Upper GI Score 
by 1 or more 
points, except 0 
to 1 
NIH upper GI 
score is Non 
evaluable 
Lower GI 
NIH Lower GI 
Score 0 after 
previous 
involvement 
Decrease in NIH 
Lower GI Score 
by 1 or more 
points 
No change or 
increase from 0 
to 1 in NIH 
Lower GI Score 
Increase in 
Lower GI Score 
by 1 or more 
points, except 0 
to 1 
If NIH Lower GI 
score is Non 
evaluable 
Lungs 
%FEV1 ≥ 80% 
after previous 
involvement; or 
NIH Lung 
Symptom Score 
0 after previous 
involvement if 
PFTs not 
available 
Increase by 10% 
absolute value 
of %FEV1; or 
decrease in NIH 
Lung Symptom 
Score by 1 or 
more points if 
PTSs not 
available 
Not in the other 
categories 
Decrease by 
10% absolute 
value of %FEV1 
and %FEV1 < 
75%; or 
increase in NIH 
Lung Symptom 
Score by 1 or 
more points, 
except 0 to 1 if 
PFTs not 
available 
NIH Lung score 
is Non evaluable 
and %FEV1 is 
missing   
Eyes 
NIH Eye Score 0 
after previous 
involvement 
Decrease in NIH 
Eye Score by 1 
or more points 
No change or 
increase from 0 
to 1 in NIH Eye 
Score 
Increase in NIH 
Eye Score by 1 
or more points, 
except 0 to 1 
NIH eye score is 
Non evaluable 
Joints and 
Fascia 
NIH Joint and 
Fascia Score 0 
and P-ROM 
score 25 after 
previous 
Decrease in NIH 
Joint and Fascia 
Score by 1 or 
more points or 
increase in P-
Not in the other 
categories 
Increase in NIH 
Joint and Fascia 
Score by 1 or 
more points or 
decrease in P-
Both in NIH 
Joint and Fascia 
and P-ROM 
scores are Non 
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Organ 
Complete 
Response 
Partial 
Response 
Unchanged 
Progression 
Non Evaluable 
involvement in 
at least one 
measure 
ROM score by 1 
or more points 
for any site  
ROM score by 1 
or more points 
for any site  
evaluable 
Skin 
NIH Skin Score 
0 after previous 
involvement 
Decrease in NIH 
Skin Score from 
baseline by 1 or 
more points 
No change or 
increase from 0 
to 1 in NIH Skin 
Score 
Increase in NIH 
Skin Score from 
baseline by 1 or 
more points, 
except 0 to 1 
NIH skin score 
is Non evaluable 
 
Mouth 
NIH Modified 
OMRS 0 after 
previous 
involvement 
Decrease in NIH 
Modified Oral 
Mucosa Rating 
Score of 2 or 
more points 
No change in 
NIH Modified 
Oral Mucosa 
Rating Score 
Increase in NIH 
Modified Oral 
Mucosa Rating 
Score of 2 or 
more points 
NIH mouth 
score is Non 
evaluable 
Liver 
Normal ALT, 
ALP and total 
bilirubin after 
elevation of one 
or more at 
baseline 
50% 
improvement in 
ALT, ALP, or 
total bilirubin 
without increase 
by 2x ULN for 
any other 
parameters of 
ALT, ALP or 
total bilirubin 
Not in the other 
categories 
Increase by 2x 
ULN for any one 
of ALT, ALP or 
total bilirubin 
If ALT, ALP and 
total bilirubin are 
missing 
Global 
GSR 0 
GSR decreases 
by 2 or more 
points 
Not in the other 
categories 
GSR increases 
by 2 or more 
points 
Not applicable 
 
Organs not involved at baseline can progress according to the definitions in this Response 
Assessments table, but cannot achieve a response (PR or CR).  
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