Conditions: Graft vs Host Disease
Keywords: cGVHD Allogeneic hematopoietic stem cell transplantation Immune System Diseases Steroid refractory chronic graft vs host disease (cGVHD) Bone Marrow Transplantation Anti-Inflammatory Agents Glucocorticoids Corticosteroids
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
This study was been conducted to evaluate the safety, tolerability, and activity of belumosudil (formerly known as KD025) in adult participants with chronic graft versus host disease (cGVHD).

Detailed description:
Fifty four (54) participants were enrolled to receive orally administered belumosudil 200 milligrams (mg) once daily (QD), belumosudil 200 mg twice daily (BID), or belumosudil 400 mg QD.

Study drug was administered in 28-day cycles until disease progression or occurrence of unacceptable toxicity. Participants received study drug in the inpatient or outpatient setting.

Arms:
arm 1: Participants received belumosudil 200 mg orally QD in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 64.2 months). arm 2: Participants received belumosudil 200 mg orally BID in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 45.9 months). arm 3: Participants received belumosudil 400 mg orally QD in each 28-day treatment cycle until disease progression, unacceptable toxicity, or death whichever occurred first (maximum duration: 49.2 months).

Interventions: intervention 1: Belumosudil (KD025)
Intervention descriptions: intervention 1: Pharmaceutical form: Capsules or Tablets Route of administration: Oral

Protocol document:
Prot_000.pdf: 


KD025 
 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
Kadmon Corporation  
Page 2 of 121 
Confidential and Proprietary 
28 October 2019 
 
PROCEDURES IN CASE OF EMERGENCY 
          
Serious and Unexpected Adverse Events  
Any serious adverse event (SAE)* or suspected unexpected serious adverse reaction (SUSAR)** 
occurring in a subject 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 AND SUSAR 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 16.3.1, 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 subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
**   A suspected unexpected serious adverse reaction (SUSAR) is any untoward and unintended responses to an investigational product 
related to any dose administered, of which the nature, or severity, is not consistent with the applicable product information (see also 
Section 16.3.2, Suspected Unexpected Serious Adverse Reactions).  All suspected adverse reactions related to an investigational 
medicinal product which occur in the concerned trial and that are both unexpected and serious are subject to expedited reporting.   
 
For SAE/SUSAR reporting: 
For any other questions or to  
contact the medical monitor: 
 
APCER Life Sciences, LLC. 
Fax: 646-430-9549 
 
In the event of an issue with the fax line, 
forward the SAE/SUSAR via email to:  
 
ClinicalSAEReporting@kadmon.com 
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KD025 
 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
Kadmon Corporation  
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SPONSOR SIGNATURE 
 
I have read and approve this protocol. My signature, in conjunction with the signature of the 
investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP), the Code of Federal Regulations (CFR), and the ethical principles that have their origins 
in the Declaration of Helsinki. 
 
 
  
 
  
 Date of Signature 
(DD MMM YYYY) 
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KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 4 of 121 
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28 October 2019 
 
INVESTIGATOR SIGNATURE 
 
I have read and approve this protocol. My signature, in conjunction with the signature of the 
sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws and regulations including, but not limited 
to, the ICH Guideline for Good Clinical Practice (GCP), the Code of Federal Regulations (CFR), 
and the ethical principles that have their origins in the Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
 
 
Investigator Signature 
 
 Date of Signature 
(DD MMM YYYY) 
Name of Investigator (please print) 
 
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Protocol Number KD025-208 
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Amendment No. 7 
 
 
 
 
 
 
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1. 
SYNOPSIS 
Study Title 
A Phase 2a, Dose-Escalation, Open-Label Study to Evaluate the Safety, 
Tolerability, and Activity of KD025 in Subjects with Chronic Graft Versus 
Host Disease 
Clinical Phase 
2a 
Number of Study 
Centers 
Approximately 10 
Study Objective(s) 
Primary Objectives 
• 
To evaluate the activity of KD025 in subjects with steroid-dependent 
chronic Graft versus Host Disease (GVHD) and active disease in 
terms of partial response (PR) and complete response (CR), as 
defined by the 2014 National Institute of Health (NIH) Consensus 
Development Project on clinical trials in cGVHD 
• 
To evaluate the safety and tolerability of KD025 in subjects with 
cGVHD 
 
Secondary Objectives  
• 
To evaluate changes in cGVHD severity using the 
Physician-reported Global cGVHD Activity Assessment form (see 
Appendix A) 
• 
To assess changes in symptom activity using the cGVHD Activity 
Assessment Patient Self-Report  
• 
To evaluate Failure-free Survival (FFS) 
• 
To evaluate changes in corticosteroid and calcineurin inhibitor (CNI) 
dose 
• 
To evaluate Duration of Response (DOR) 
• 
To evaluate response by organ system 
• 
To assess the plasma pharmacokinetics (PK) of KD025 in subjects 
with cGVHD 
• 
To evaluate Overall Survival (OS) 
• 
To evaluate Time to Next Treatment (TTNT) 
• 
To evaluate the change in symptom burden/bother using the Lee 
cGVHD Symptom Scale 
 
Exploratory Objectives  
• 
To evaluate changes in the expression of several cytokines (including 
interleukin (IL)-17A, IL-21, and IL-2) in plasma after KD025 
administration  
• 
To evaluate changes in percentage of immune-cell subtypes 
(including Th17 and regulatory T cells [Treg] cells) in whole 
blood after KD025 administration  
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Study Design 
Phase 2a, open-label, dose-escalation, safety, tolerability, and activity study  
Methodology 
Subjects who have signed an Institutional Review Board (IRB)/Independent 
Ethics Committee- (IEC)-approved informed consent form (ICF) and who 
have met all of the inclusion/exclusion criteria will be enrolled. 
Approximately 48 subjects will be enrolled to receive orally administered 
KD025 200 mg once daily (QD), KD025 200 mg twice daily (BID_, or 
KD025 400 mg QD. Study drug will be administered in 28-day cycles until 
disease progression or unacceptable toxicity occurs. Subjects may receive 
study drug in the inpatient or outpatient setting.  
Cohort 1 
16 subjects 
200 mg KD025 QD  
Cohort 2 
16 subjects 
200 mg KD025 BID  
Cohort 3 
16 subjects 
400 mg KD025 QD  
BID = twice daily; QD = once daily 
Prior to enrolling subsequent cohorts, the safety data in each previous 
cohort will be evaluated after 8 subjects have reached 2 months of treatment 
to assure there is no safety signal. If ≥ 25% of subjects in a cohort 
experience a Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 Grade 2 liver toxicity or a CTCAE v4.03 Grade 3 (or higher) adverse 
event (AE) in the same organ or body system, or if > 25% of subjects in a 
cohort are discontinued for toxicity that persists for 14 days, then dose 
escalation to the next cohort will not occur, and all subjects in that dose 
cohort will be dose reduced.      
If ≥ 25% of subjects in the 200 mg QD cohort experience a CTCAE v4.03 
Grade 2 liver toxicity or a CTCAE v4.03 Grade 3 (or higher) AE in the 
same organ or body system, or if > 25% of subjects in a cohort are 
discontinued for toxicity that persists for 14 days, then further dosing will 
not occur and the study will be terminated. 
Response criteria will be assessed on Day 1 of each cycle, starting at 
Cycle 2 Day 1, as well as the end of treatment (EOT) visit using the criteria 
of 2014 NIH Consensus Development Project on Clinical Trials in cGVHD 
(CR, PR, or lack of response (unchanged, mixed, or progression); see 
Appendix B).   
cGVHD severity (clinician-reported) and symptom (subject-reported) 
assessments will be performed on Day 1 of each cycle starting at Cycle 1 
Day 1 as well as the EOT visit using the Physician-reported Global Chronic 
GVHD Activity Assessment form (Appendix A), cGVHD Activity 
Assessment: Patient Self Report, and Lee cGVHD Symptom Scale (see 
Appendices C and D).  
At Cycle 25 Day 1 (C25D1) and all odd cycles thereafter (ie, C27D1, 
C29D1, C31D1, etc.), subjects will receive 2 cycles worth of study drug 
along with 2 diaries and will return to the clinic at the next odd cycle for 
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assessments and investigational product (IP) accountability.  Investigators 
and/or subjects have the option of coming into the clinic at one or more 
even cycles (ie, C26D1, C28D1, C30D1, etc.).  On even cycles, when 
subjects do not come to clinic, the study staff will contact the patient via 
phone and document any new adverse events and concomitant medications. 
Subjects will also undergo pre-specified safety assessments throughout the 
study.  
Follow-Up Period 
Follow-Up visits will occur 28 days (± 7 days) after the last dose of study 
drug. Subjects will undergo physical examinations (PEs); vital sign 
measurements; blood sample collection for hematology, chemistry, and 
pharmacodynamic (PD) markers; urinalysis; ECGs; AE assessments; 
concomitant medication assessments; and pregnancy testing for females of 
childbearing potential. 
Long-Term Follow-Up 
Subjects will be contacted approximately every 8 weeks and can be 
contacted via telephone, email, or postal mail to confirm survival status and 
the initiation of any anti-cancer treatment or any changes in treatment of 
cGVHD. This can also be confirmed from electronic medical records. 
Number of Subjects 
Approximately 48 subjects (adult male and female) total will be enrolled 
(16 subjects in each KD025 dose cohort).  
Approximate Duration 
of Subject Participation 
After approximately 3 weeks for screening, study drug will be administered 
in 28-day cycles until disease progression or unacceptable toxicity occurs 
followed by 4 weeks of follow-up. 
Subjects will be contacted approximately every 8 weeks and can be 
contacted via telephone, email or postal mail to confirm survival status and 
the initiation of any anti-cancer treatment or any changes in treatment of 
cGVHD. This can also be confirmed from electronic medical records 
Diagnosis and Main 
Criteria for Inclusion 
Inclusion Criteria: 
1) Adult male and female subjects at least 18 years of age who have 
had allogenic bone marrow transplant or hematopoietic stem cell 
transplantation. 
2) Receiving glucocorticoid therapy and calcineurin therapy or 
glucocorticoid therapy alone for cGVHD at study entry. Subjects 
on calcineurin therapy only, without glucocorticoid therapy, are not 
eligible. Subjects also receiving other therapies thought not to be 
immunosuppressive (such as extracorporeal photopheresis [ECP]), 
will be considered for enrollment in this study on a case-by-case 
basis. 
3) Have persistent active cGVHD manifestations, as defined by 
2014 NIH Consensus Development Project on Criteria for Clinical 
Trials in cGVHD, after at least 2 months of steroid therapy.   
4) No more than 3 prior lines of treatment for cGVHD. 
5) Karnofsky Performance Scale of >40 (see Appendix E).  
6) Adequate organ and bone marrow functions evaluated during the 
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14 days prior to enrollment as follows: 
a. Absolute neutrophil count ≥ 1.5 × 109/L (without myeloid 
growth factors within 1 week of study entry) 
b. Platelet count ≥ 50 × 109/L (without transfusion or 
thrombopoietin or thrombopoietin analogues within 
2 weeks of study entry) 
7) Adequate safety laboratory values:  
a. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
b. ALT and AST ≤ 3 × ULN 
c. Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 
using the 4-Variable Modification of Diet in Renal Disease 
(MDRD-4) variable formula (see Appendix F) 
8) Female subjects of childbearing potential have a negative 
pregnancy test at screening. Females of childbearing potential are 
defined as sexually mature women without prior hysterectomy or 
who have had any evidence of menses in the past 12 months. 
However, women who have been amenorrheic for 12 or more 
months are still considered to be of childbearing potential if the 
amenorrhea is possibly due to prior chemotherapy, anti-estrogens, 
or ovarian suppression. 
9) Women of childbearing potential (ie, menstruating women) must 
have a negative urine pregnancy test (positive urine tests are to be 
confirmed by serum test) documented within the 24-hour period 
prior to the first dose of study drug.  
10) Sexually active women of childbearing potential enrolled in the 
study must agree to use 2 forms of accepted methods of 
contraception during the course of the study and for 3 months after 
their last dose of study drug. Effective birth control includes: 
a. Intrauterine device plus 1 barrier method; 
b. Stable doses of hormonal contraception for at least 
3 months (eg, oral, injectable, implant, transdermal) plus 
one barrier method; 
c. 2 barrier methods. Effective barrier methods are male or 
female condoms, diaphragms, and spermicides (creams or 
gels that contain a chemical to kill sperm); or 
d. A vasectomized partner 
11) For male subjects who are sexually active and who are partners of 
premenopausal women: agreement to use two forms of 
contraception as in criterion 10 above during the treatment period 
and for at least 3 months after the last dose of study drug.       
12) Able to provide written informed consent prior to the performance 
of any study-specific procedures. 
 
Exclusion Criteria: 
1) Female subject who is pregnant or breastfeeding. 
2) Receiving an investigational GVHD treatment within 28 days of 
study entry. 
3) Has acute GVHD. 
4) Taking any medication known to be a moderate or strong inhibitor 
of the CYP3A4 isozyme or any drugs that are moderate or strong 
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CYP3A4 inducers (see Appendix H).  
5) History or other evidence of severe illness or any other conditions 
that would make the subject, in the opinion of the investigator, 
unsuitable for the study (such as poorly controlled psychiatric 
disease or coronary artery disease). 
6) Regular and excessive use of alcohol within the 6 months prior to 
study entry defined as alcohol intake > 14 drinks per week in a man 
or > 7 drinks per week in a woman. Approximately 10 g of alcohol 
equals one “drink” unit. One unit equals 1 ounce of distilled spirits, 
one 12-ounce beer, or one 4-ounce glass of wine. 
7) Known history of human immunodeficiency virus (HIV) or active 
hepatitis C virus (HCV) or hepatitis B virus (HBV). 
8) 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, resected in situ cervical malignancy, resected 
breast ductal carcinoma in situ, or low-risk prostate cancer after 
curative resection. 
9) Relapse of the underlying cancer or post-transplant 
lymphoproliferative disease at the time of screening.  
10) Has had previous exposure to KD025 or known allergy/sensitivity 
to KD025 or any other ROCK2 inhibitor. 
11) Taking other immunosuppressant drugs for GVHD, including 
mTOR (mammalian target of rapamycin) inhibitors (Note: Only 
steroids, CNIs, and ECP are acceptable). 
12) QTcF > 450 msec 
Investigational 
Product/Study Drug  
KD025 will be provided as 100 mg capsules or 200 mg tablets. 
Dosage and 
Administration  
Subjects will receive KD025 200 mg QD, KD025 200 mg BID, or KD025 
400 mg QD. Subjects should take study drug with a meal or within 
5 minutes of completing a meal. 
Duration of Treatment 
Study drug will be administered in 28-day cycles until disease progression 
or unacceptable toxicity occurs. 
Concomitant Treatment 
 
Subjects will be counseled to avoid non-prescribed medicines or 
complementary alternative medicines excluded by the study. Use of drugs 
that prolong QT/QTc should be used with caution in subjects who are 
receiving KD025.  
All medications a subject receives from the signing of informed consent 
through the 28-Day Follow-Up visit will be documented, including steroids 
and CNIs. 
Prohibited Medications 
The use of strong CYP3A4 inducers (see Appendix H for a listing of these 
drugs) is prohibited. 
Safety Evaluation 
Safety assessments include AEs, serious adverse events (SAEs), PEs, vital 
sign measurements, clinical laboratory evaluations (hematology, chemistry, 
and urinalysis), pulmonary function tests (PFTs), and ECGs.   
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Prior to enrolling subsequent cohorts, the safety data in each previous 
cohort will be evaluated after 8 subjects have reached 2 months of treatment 
to assure there is no safety signal. Two months was selected as the time for 
the safety review because all of the clinically significant KD025-related 
AEs to date occurred within 36 days or less of starting KD025 treatment.   
 
The AE reporting period for a subject enrolled in the study begins when the 
subject provides informed consent and is continued through 28 days after 
their last dose of study drug. All AEs that occur in enrolled subjects during 
the AE reporting period must be recorded, regardless of the relationship of 
the AE to study drug. Any known untoward event that occurs beyond the 
AE reporting period that the investigator assesses as at least possibly related 
to study drug also should be reported to Kadmon. A Follow-Up Visit will 
occur 28 days after the last dose of study drug, but prior to starting on a 
new therapy if a new therapy is started earlier. This visit may be done 
within ± 7 days of the scheduled visit. 
 
Exacerbation of any of the signs or symptoms of the disease will constitute 
a potential rationale for cessation of therapy. Both laboratory and clinical 
data may constitute a reason to pause or cease therapy. Previous studies 
have indicated that reversible and modest liver toxicity may occur 
spontaneously after a few weeks of initiation of therapy.   
• 
When treatment-related Grade 3 toxicities occur, drug administration 
will be halted until recovery to at least Grade 1, and study drug may 
be resumed at a reduced dose.   
• 
When treatment-related Grade 2 toxicities other than liver toxicities 
that cannot definitively be attributed to a cause other than the study 
drug occur, drug administration will be halted until recovery to at 
least Grade 1 at which time study drug administration may resume at 
the same dose.   
• 
When greater than Grade 2 liver toxicities occur, drug administration 
will be halted until recovery to at least Grade 1 at which time study 
drug administration may resume at a reduced dose.   
 
Pauses in therapy may not last more than 14 days; subjects requiring pauses 
of more than 14 days will be discontinued from the study. If Grade 2 or 3 
treatment-related toxicities persist for 14 days, subjects will be discontinued 
from the study.    
 
Other organ-based toxicity has not been observed in clinical studies with 
KD025, but as this is the first study in cGVHD, careful monitoring of all 
toxicities will be carried out. CTCAE v4.03 grading will be used for all 
AEs.  
Activity Evaluation 
The primary activity outcome will be the percentage of subjects who meet 
the overall response (OR) criteria (PR + CR). This will be assessed overall 
(ie, any subject meeting the PR or CR criteria at any time point).  
Response criteria and activity in terms of cGVHD severity will be evaluated 
on Day 1 of each cycle starting at Cycle 2 Day 1 using the 
Physician-reported Global Chronic GVHD Activity Assessment Form, 
while activity in terms of symptom burden will be evaluated using the 
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cGVHD Activity Assessment—Patient Self-report. Failure-free survival, 
Overall Survival, TTNT, and changes in corticosteroid and CNI dose will 
be documented. Changes in symptom burden/bother will be documented 
using the Lee cGVHD Symptom Scale. Compliance with oral dosing will 
be confirmed using patient diaries.  
Pharmacokinetics 
Blood samples (approximately 5 mL) for determination of plasma 
concentrations of KD025 and its metabolites, will be collected on Day 1 of 
Cycles 1 and 2 at the following time points: Pre-dose (Time 0), and 1, 2, 3, 
4, 5, and 6 hours after dosing (after first dose for subjects in the BID 
group). In addition, subjects will have samples collected pre-dose on Day 1 
of Cycle 4 and pre-dose at the Cycle 7, Day 1 visit. Subjects should be 
instructed to withhold taking study drug on these days as dosing will be 
performed at the clinic.  
Subjects will have a total 16 samples drawn (80 mL).  
KD025 and metabolite concentrations will be used to calculate the 
following PK parameters: Cmax, Tmax, and AUC0-6hr. 
Pharmacodynamics 
All subjects will have PD blood samples drawn 4 times over the course of 
the study: Pre-dose on Cycle 1 Day 1, Cycle 2 Day 1 (4 weeks), Cycle 4 
Day 1 (12 weeks) and Cycle 7 Day 1 (24 weeks). The samples will be 
analyzed to evaluate changes in the expression of several cytokines in 
plasma (including IL-17A, IL-21, and IL-2), and changes in percentages of 
circulating Th17 and Treg cells in blood.   
Statistical Analysis  
Four populations will be included in the analysis of study data: 
• 
The modified intent-to-treat (mITT) population will consist of all 
subjects who are enrolled in the study and receive at least 1 dose of 
study medication.   
• 
The safety population will consist of all subjects who receive at least 
one dose of KD025  
• 
The PK population will consist of all subjects who receive at least 
1 dose of study drug and have at least 1 post-dose PK sample drawn 
 
All analyses of safety will be performed on the safety population while 
activity will be performed on the mITT population. 
The primary activity outcome will be the percentage of subjects who meet 
the OR criteria (PR + CR). This will be assessed overall (ie, any subject 
meeting the PR or CR criteria at any time point).  
 
Assuming an underlying 25% rate for subjects to meet the OR, each 
treatment group of 16 subjects has an approximately 80% chance of having 
at least 3 subjects meet the overall response criteria, and approximately 
90% chance of at least 2 subjects meet the overall response criteria. 
 
The change in cGVHD severity will be evaluated using the 
Physician-reported Global cGVHD Activity Assessment form. The change 
in symptom burden will be evaluated using the cGVHD Activity 
Assessment - Patient Self-report. Changes in symptom burden/bother will 
be documented using the Lee cGVHD Symptom Scale and compared 
among KD025 treatment groups. 
 
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The FFS will be defined as the time from first dose of study drug to either 
the start of another treatment, relapse of the underlying disease, or death. 
The time to FFS will be summarized for each treatment group. 
 
The OS will be defined as the 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. 
 
The TTNT will be defined as the time from the first dose of KD025 to the 
start of additional systemic cGVHD therapy.  
 
Changes in corticosteroid and CNI dose will be evaluated and results will 
be summarized by treatment group. Corticosteroids may be tapered at the 
discretion of the investigator after 4 weeks of KD025 administration. 
 
The DOR is defined as the time of initial response until documented 
progression. Responses by organ system (PR and CR) will be assessed 
based on the 2014 NIH Consensus Development Project on Clinical Trials 
in cGVHD. 
 
The exploratory outcome variables are expression of several cytokines 
(including IL-17A, IL-21, and IL-2), and changes in percentages of 
immune-cell subtypes (including Th17 and Treg cells). Results will be 
summarized by treatment group.   
 
Demographics, subject disposition, and screening and baseline 
characteristics will be summarized overall and by treatment group. 
 
Treatment-emergent AEs will be evaluated using the CTCAE v4.03. The 
secondary safety outcome will be the number (%) of subjects experiencing 
AEs overall. The total sample size of 16 subjects per KD025 dose group 
will provide > 90% probability of one or more KD025 subjects 
experiencing an AE that has an underlying rate of ≥ 14% and > 80% 
probability of one or more subjects in the study experiencing an AE that has 
an underlying rate of ≥ 10%.  
 
Treatment-emergent AEs (TEAEs) will be summarized by treatment group 
using Medical Dictionary for Regulatory Activities (MedDRA®) System 
Organ Class (SOC) and preferred term (PT), classified from verbatim 
terms.  MedDRA® Version 20.0 or higher will be used. The incidence and 
percentage of subjects with at least 1 occurrence of a preferred term will be 
included, according to the most severe grade using a 5-point scale (mild, 
moderate, severe, life threatening, or death). The number of events per 
preferred term will also be summarized. Causality (relationship to study 
treatment) will be summarized separately. 
AEs, SAEs, treatment-related AEs, treatment-related SAEs, ≥ Grade 3 AEs, 
treatment-related ≥ Grade 3 AEs, and AEs leading to withdrawal or 
treatment discontinuation will be summarized overall and by treatment 
group according to SOC and PT. AEs will also be presented in listings. 
Duration of AEs will be determined and included in listings, along with 
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action taken and outcome. 
 
Laboratory results will be classified using the CTCAE v4.03 and 
summarized by treatment group. 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 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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2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS ..................................................................................................................5 
2. 
TABLE OF CONTENTS ..........................................................................................14 
3. 
LIST OF ABBREVIATIONS ...................................................................................19 
4. 
BACKGROUND AND RATIONALE .....................................................................22 
4.1. 
Study Rationale ................................................................................................22 
4.2. 
Selection of Doses in this Study ......................................................................23 
4.3. 
Previous Clinical Experience with KD025 ......................................................23 
4.4. 
KD025 Nonclinical Toxicology .......................................................................29 
4.5. 
Compliance Statement .....................................................................................30 
5. 
STUDY OBJECTIVES .............................................................................................31 
5.1. 
Primary Objectives...........................................................................................31 
5.2. 
Secondary Objectives.......................................................................................31 
5.3. 
Exploratory Objective ......................................................................................31 
6. 
STUDY DESIGN......................................................................................................33 
6.1. 
Study Sites .......................................................................................................33 
6.2. 
Study Endpoints ...............................................................................................33 
6.3. 
Overview of Study Design ...............................................................................34 
6.4. 
Randomization and Blinding ...........................................................................40 
7. 
STUDY POPULATION ...........................................................................................41 
7.1. 
Target Population .............................................................................................41 
7.2. 
Inclusion Criteria .............................................................................................41 
7.3. 
Exclusion Criteria ............................................................................................43 
8. 
STUDY ASSESSMENTS ........................................................................................44 
8.1. 
Overview ..........................................................................................................44 
8.2. 
Screening Period (Day -29 to -1) .....................................................................44 
8.3. 
Enrollment........................................................................................................45 
8.4. 
Treatment Period ..............................................................................................45 
8.4.1 
Cycle 1, Day 1 (Baseline) ....................................................................45 
8.4.2 
Cycle 1, Days 8, 15, and 22 (±3 days) .................................................46 
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8.4.3 
Cycles 2 and Beyond, Day 1 (±3 days) ................................................46 
8.5. 
End of Treatment (EOT) ..................................................................................47 
8.6. 
28-Day Follow-Up Visit ..................................................................................48 
8.7. 
Unscheduled Visits ..........................................................................................48 
8.8. 
Long-Term Follow-Up.....................................................................................49 
9. 
STUDY PROCEDURES ..........................................................................................50 
9.1. 
Procedures to be Performed .............................................................................50 
9.2. 
Laboratory Assessments ..................................................................................54 
9.3. 
Electrocardiogram Assessments ......................................................................55 
9.4. 
Pulmonary Function Tests ...............................................................................55 
10. ACTIVITY ................................................................................................................56 
10.1. 2014 NIH Consensus Development Project on Clinical Trials in cGVHD .....56 
10.2. Physician-Reported Global cGVHD Activity Assessment ..............................56 
10.3. cGVHD Activity Assessment - Patient Self Report ........................................56 
10.4. Failure-Free Survival .......................................................................................56 
10.5. Overall Survival ...............................................................................................56 
10.6. Corticosteroid and Calcineurin Inhibitor Use ..................................................57 
10.7. Time to Next Treatment (TTNT) .....................................................................57 
10.8. Lee cGVHD Symptom Scale ...........................................................................57 
11. PHARMACOKINETICS ..........................................................................................58 
12. PHARMACODYNAMICS.......................................................................................59 
13. REMOVING SUBECTS FROM STUDY ................................................................60 
13.1. Subjects’ Decision to Withdraw ......................................................................60 
13.1.1 
Treatment Discontinuation...................................................................60 
13.1.2 
Study Termination ...............................................................................61 
13.2. Stopping Rules .................................................................................................61 
13.2.1 
Adverse Events Stopping Criteria ........................................................61 
13.2.2 
Liver-Related Abnormalities ...............................................................62 
13.3. Study Discontinuation ......................................................................................62 
13.4. Replacements ...................................................................................................62 
14. STUDY DRUG .........................................................................................................63 
14.1. Dose and Schedule of Study Drug ...................................................................63 
14.2. Dose Escalation ................................................................................................64 
14.3. Missed Doses ...................................................................................................64 
14.4. Dose Pause or Reduction of KD025 ................................................................65 
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14.4.1 
Dose Reduction Steps ..........................................................................65 
14.5. Identity of Investigational Products .................................................................66 
14.6. Study Drug Packaging and Labeling ...............................................................66 
14.7. Dispensing of Study Drug and Dosing Compliance ........................................67 
14.8. Study Drug Storage ..........................................................................................67 
14.9. Study Drug Accountability ..............................................................................67 
14.10. Study Drug Handling and Disposal .................................................................68 
14.10.1 Disposition of Used Supplies ...............................................................68 
14.10.2 Inventory of Unused Supplies ..............................................................68 
15. CONCOMITANT MEDICATION AND TREATMENT ........................................69 
16. SAFETY ...................................................................................................................70 
16.1. Safety Parameters.............................................................................................70 
16.2. Adverse Event Definition ................................................................................70 
16.3. Evaluating Adverse Events ..............................................................................71 
16.3.1 
Serious Adverse Events .......................................................................71 
16.3.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ..............72 
16.3.3 
Unexpected Adverse Events ................................................................72 
16.3.4 
Non-Serious Adverse Events ...............................................................72 
16.3.5 
Protocol-Related Adverse Events ........................................................72 
16.3.6 
Relationship to Study Drug ..................................................................73 
16.3.7 
Recording Adverse Events ...................................................................73 
16.3.8 
Hospitalization .....................................................................................73 
16.3.9 
Serious Adverse Event Reporting ........................................................74 
16.4. Other Safety Considerations ............................................................................76 
16.4.1 
Laboratory Data ...................................................................................76 
16.4.2 
Medication Errors ................................................................................77 
16.4.3 
Follow-Up of Adverse Events .............................................................77 
17. STATISTICAL CONSIDERATIONS......................................................................78 
17.1. General Design.................................................................................................78 
17.2. Sample Size Justification .................................................................................79 
17.3. Statistical Considerations .................................................................................79 
17.3.1 
Study Populations ................................................................................79 
17.3.2 
Subject Accountability, Demographics, and Baseline Characteristics 79 
17.3.3 
KD025 Exposure ..................................................................................79 
17.3.4 
Concomitant Medications ....................................................................80 
17.4. Activity Analysis .............................................................................................80 
17.5. Safety Data .......................................................................................................81 
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18. DATA QUALITY ASSURANCE ............................................................................83 
19. ETHICAL ASPECTS ...............................................................................................84 
19.1. Local Regulations ............................................................................................84 
19.2. Informed Consent.............................................................................................84 
19.3. Institutional Review Board ..............................................................................85 
19.4. Future Use of Subject Samples ........................................................................85 
20. CONDITIONS FOR MODIFYING THE PROTOCOL...........................................86 
21. CONDITIONS FOR TERMINATING THE STUDY .............................................87 
22. STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING .......................88 
22.1. Investigator’s Files and Retention of Documents ............................................88 
22.2. Source Documents and Background Data .......................................................89 
22.3. Audits and Inspections .....................................................................................89 
22.4. Electronic Case Report Forms .........................................................................89 
23. MONITORING THE STUDY ..................................................................................90 
24. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...91 
25. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............92 
26. REFERENCES .........................................................................................................93 
27. APPENDICES ..........................................................................................................94 
28. SUMMARY OF CHANGES TO PROTOCOL .....................................................104 
 
 
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LIST OF TABLES 
Table 1: 
Study Assessments .................................................................................... 36 
Table 2: 
Timing Allowance Windows for Pharmacokinetic and ECG 
Measurements ........................................................................................... 39 
Table 3: 
Clinical Laboratory Panels ........................................................................ 54 
Table 4: 
Grading of Liver-Related Laboratory Abnormalities (CTCAE v4.03) .... 62 
Table 5: 
Dose Reductions for Toxicity Related to Study Drug – 100 mg Capsule 66 
Table 6: 
Dose Reductions for Toxicity Related to Study Drug – 200 mg Tablet ... 66 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Mean (±SD) Concentration-Time Profiles for KD025 following QD or 
BID Oral Dosing of KD025 for 7 Days (KD025-102) ............................. 26 
Figure 2: 
Arithmetic Mean (±SD) Concentration-Time Profiles for KD025, 
KD025m1, and KD025m2 following BID Oral Dosing of KD025 (500 
mg) for 28 Days (KD025-103) ................................................................. 27 
 
LIST OF APPENDICES 
Appendix A: Physician-Reported Global cGVHD Activity Assessment Form A .... 94 
Appendix B: cGVHD Response Assessment ................................................................. 96 
Appendix C: Chronic GVHD Activity Assessment-Patient Self Report ....................... 97 
Appendix D: Lee cGVHD Symptom Scale .................................................................... 98 
Appendix E: Karnofsky Performance Scale................................................................... 99 
Appendix F: Equations to Predict Glomerular Filtration Rate (MDRD-4) ................. 100 
Appendix G: Clinical Adverse Events: Determining Relationship to Study Drug ...... 101 
Appendix H: Drugs that Induce and Inhibit CYP3A4 .................................................. 103 
 
 
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3. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0-24hr 
area under the curve from 0 to 24 hours 
BID 
twice daily 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
cGVHD 
chronic graft versus host disease 
Cmax 
maximum concentration observed  
CNI 
calcineurin inhibitor  
CPK 
creatinine phosphokinase 
CR 
complete response 
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 
GGT 
gamma-glutamyl transferase 
GFR 
glomerular filtration rate 
HBV 
hepatitis B virus 
HCT 
hematopoietic cell transplantation 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HSCT 
hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Committee on Harmonisation 
IEC 
Independent Ethics Committee 
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IL 
interleukin 
IND 
Investigational New Drug 
IP 
investigational product 
IRB 
institutional review board 
LFT 
liver function tests 
LOR 
lack of response 
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 
mTOR 
Mammalian target of rapamycin 
NIH 
National Institutes of Health 
OR 
Overall Response 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
pharmacodynamic 
PE 
physical examination 
PFT 
pulmonary function test 
PK 
pharmacokinetic 
PR 
partial response 
QD 
once daily 
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 
SD 
stable disease 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse event 
t1/2 
half-life 
Tmax 
observed time to reach peak plasma concentration 
TEAE 
treatment-emergent adverse event 
TLC 
total lung capacity 
Treg 
regulatory T cells 
TSH 
thyroid stimulating hormone 
TTNT 
Time to Next Treatment 
ULN 
upper limit of normal 
WHO 
World Health Organization 
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WHO-DD 
World Health Organization Drug Dictionary 
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4. 
BACKGROUND AND RATIONALE 
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 CNIs, remain the standard initial treatment, 
but significant side effects and unsatisfactory outcomes, particularly for patients with high-risk 
features of cGVHD, support the need for more effective and less toxic therapies.  
4.1. 
Study Rationale 
Recent studies have demonstrated that a pro-inflammatory interleukin (IL)-17-producing lineage 
of T cells termed Th17 is actively involved in the pathogenesis of cGVHD. The development and 
function of Th17 cells is dependent on activation of STAT3, and transcription factors RORγt and 
IRF4. Recent studies have demonstrated that aberrant activation of Rho-associated protein 
kinases 2 (ROCK2) leads to induction of IL-17 and IL-21 via the IRF4-dependent mechanism. 
Moreover, inhibition of ROCK effectively decreased IL-17 production in vivo and ameliorated 
the development of autoimmune models of arthritis, diabetes and lupus in mice. In addition, 
patients with cGVHD have a relative deficiency of regulatory T-cells (Treg). This deficiency 
appears to be a consequence of abnormalities in Treg homeostasis after HCT wherein increased 
proliferation of Tregs is not sufficient to compensate for reduced thymic output and increased 
susceptibility to apoptosis. Recent in vitro data indicate that KD025, a specific ROCK2 inhibitor, 
significantly reduced the production of IL-17 and IL-21 in CD4+ T cells in response to T cell 
receptor stimulation and positively regulated the suppressive function of Treg. Experiments in a 
mouse model of cGVHD show that KD025 can reverse lung pathology and improve pulmonary 
function tests (PFTs), decrease collagen deposited in the lungs, and decrease the number of 
germinal centers and frequency of T follicular helper cells in spleens. In a second rodent model, 
KD025 administration was effective in blocking the progression of chronic sclerodermatous 
GVHD. Thus, this study will evaluate the potential of KD025 to ameliorate the symptoms of 
cGVHD. 
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4.2. 
Selection of Doses in this Study  
This study will evaluate KD025 at doses of 200 mg once daily (QD), KD025 200 mg twice daily 
(BID), and KD025 400 mg QD. Preliminary data from an ongoing study of KD025 in patients 
with psoriasis suggest that the dose of 400 mg QD for 12 weeks is associated with clinical 
efficacy in psoriasis and is well tolerated.  
KD025 has a plasma elimination half-life of 5-6 hours, indicating BID dosing may be necessary 
for more consistent inhibition of ROCK2 in patients throughout a 24-hour period, but whether 
BID dosing is more effective than QD dosing is unknown. Thus, the optimal dosing frequency 
for KD025 will be examined in this study by enrolling subjects in the two cohorts 200 mg BID 
and 400 mg QD. Safety data from prior studies in healthy human volunteers evaluating doses of 
500 mg BID for 28 days support the use of 400 mg QD in this study. 
The Investigator’s Brochure (IB) includes additional nonclinical and clinical information about 
KD025.  
4.3. 
Previous Clinical Experience with KD025 
To date, there have been 6 Phase 1 trials conducted with KD025 in normal healthy subjects: a 
single-ascending dose (SAD) trial (2119-09-01), a combined single- and multiple-ascending dose 
(SAD/MAD) trial (KD025-101), a MAD trial with QD and BID dosing (KD025-102), a 
placebo-controlled safety and pharmacokinetic (PK) study (KD025-103), a food effect study 
(KD025-105), and a PK study (KD025-106) which compared a tablet formation with capsule 
formulation of KD025 (final data showed that after a single dose of KD025 200 mg, KD025 was 
rapidly absorbed with no lag time observed under both fasted and fed states and no statistically 
significant differences were observed between tablet and capsule formulation under fed 
conditions). A Phase 2a, open-label study in 8 adult subjects with moderately severe psoriasis 
vulgaris who have failed first-line therapy was recently completed (KD025-205). Additionally, a 
Phase 2 open-label, safety, and tolerability study in subjects with psoriasis vulgaris who have 
disease progression after 1 systemic therapy is currently on-going (KD025-206).  
The SAD trial (SLx-2119-09-01) assessed the safety, tolerability, and PK of KD025. The dose 
levels of KD025 tested were 20, 40, 80, and 160 mg. Thirty-two subjects were enrolled in 
4 sequential cohorts of 8 subjects, randomized with 6 receiving drug and 2 receiving placebo in 
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each cohort. No treatment-emergent adverse events (TEAEs) leading to withdrawal, deaths, or 
serious adverse events (SAEs) were reported in this trial. There were 14 TEAEs reported, 9 of 
which were determined by the investigator to be related to study drug and were mild in severity. 
One subject at the 160-mg KD025 dose level experienced joint swelling and arthralgia occurring 
after the follow-up visit. No subject had laboratory abnormalities during the dosing period or 
within 1 week after dosing. There were no changes in blood pressure or heart rate and no 
clinically significant QTcB or corrected QT interval using Fridericia's formula (QTc[F]) 
parameters.  
KD025 was readily absorbed and was measured out to 24 hours in plasma. KD025 was the main 
analyte (> 90% parent derived area under the curve [AUC]) and KD025m2 was present at about 
5%, with KD025m1 < 1%. The half-life (t1/2) of KD025 was approximately 5–6 hours, 
supporting once- or twice-daily dosing. 
A combined SAD/MAD (KD025-101) trial assessed the safety, tolerability, and PK of KD025 in 
healthy males with single doses followed by 1 week of rest and then 7 consecutive days of 
dosing. There were 8 cohorts with 8 subjects in each cohort. For each dosing cohort, 6 subjects 
received KD025 and 2 subjects received placebo. The dose levels studied were 40, 80, 120, 160, 
240, 320, 400, and 500 mg. Few TEAEs were reported and of those reported, the majority were 
determined by the investigator to be mild in severity. There were no SAEs reported during the 
study. One subject (No. 50008) was withdrawn because of a TEAE that was considered not 
related to KD025 (elevated blood creatinine phosphokinase [CPK] levels of moderate intensity). 
No clinically relevant clinical chemistry (apart from elevated [CPK] discussed above), 
hematology, coagulation, or urinalysis abnormalities were reported for any of the subjects. No 
clinically significant abnormalities were reported for any vital signs (systolic or diastolic blood 
pressure, or heart rate) or 12-lead electrocardiogram (ECG) parameters and no subject had an 
abnormal physical examination (PE) finding of concern. 
A MAD trial (KD025-102) was a single-center, placebo-controlled, double-blind, randomized 
(6:2) study to assess the safety, tolerability, and PK of KD025 administered for 7 days in up to 
32 healthy male and postmenopausal female subjects. This study enrolled 4 cohorts with 
8 subjects in each cohort (6 subjects received KD025 and 2 subjects received placebo). The dose 
regimens studied were 500, 800, and 1000 mg administered QD, and 500 mg administered BID.  
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All 32 subjects received at least 1 dose of study drug, and 31 subjects completed the study; all 
24 subjects completed all doses of study drug at 500 and 800 mg QD, and 500 mg BID. Seven of 
8 subjects completed all doses of study drug at 1000 mg QD. One subject randomized to active 
study drug 1000 mg QD received 6 days of study drug before being discontinued because of a 
positive urine drug test.  
Multiple escalating doses of KD025 ranging from 500 mg to 800 mg to 1000 mg QD and 500 mg 
BID for 7 days were generally well tolerated and no dose-limiting toxicities were reported in this 
study. Five treatment-related adverse events (AEs) were reported in 4 subjects (16.7%) receiving 
KD025, including upper abdominal pain and diarrhea in 1 subject receiving 500 mg QD, nausea 
in 2 subjects receiving 500 mg BID, and diarrhea in 1 subject receiving 1000 mg QD. There was 
1 treatment-related AE of diarrhea in 1 subject (12.5%) receiving placebo. There were no 
treatment-related AEs in subjects receiving KD025 800 mg QD. No subjects discontinued study 
participation because of AEs. There were no clinically relevant changes and no clinically 
meaningful trends in hematology, chemistry, and urinalysis laboratory results attributable to 
study drug during this study. There were no SAEs or deaths. 
The following are PK conclusions from this study: 
• KD025 was rapidly absorbed after QD oral dose administration with median observed 
time to reach peak plasma concentration (Tmax) values ranging from 1.0 to 4.0 hours 
post-dose. 
• Median Tmax values after BID dosing were more variable and ranged from 4.0 hours after 
the first dose to 12.0 hours after the second dose. 
• Mean t1/2 values were similar across dose levels for each day, with values ranging from 
4.55 to 5.76 hours for Day 1 and from 7.68 to 9.73 hours for Day 7. 
• Mean KD025 maximum concentration observed (Cmax) and area under the curve from 
0 to 24 hours (AUC0-24hr)values generally increased in a less than dose proportional 
manner with the increase in QD dose level from 500 to 1000 mg. 
• Overall exposure (AUC0-24hr) following BID dose administration of 500 mg of KD025 
was 1.9- to 2-fold higher than the AUC0-24hr after QD dose administration of 1000 mg 
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was 500 mg. There were no TEAEs, no treatment-related AEs, SAEs, or deaths reported in this 
study. 
The following are PK conclusions from this study:  
• A high fat meal given 30 minutes prior to KD025 oral administration had a significant 
effect on the PK of KD025.  
• Plasma systemic exposure (Cmax and AUCs) of KD025 was approximately 3–fold higher 
under the fed state compared with the fasted state, and the median Tmax value was delayed 
by 2 hours with food. 
• Similar food effects were observed for metabolites KD025m1 and KD025m2 as for the 
parent drug.  
• The high fat meal increased systemic exposure (mean Cmax and AUC0-t values) by 
approximately 1.7- to 2.3-fold for metabolite KD025m1 and approximately 3.1- to 
4.4-fold for metabolite KD025m2 compared with the fasted treatment. 
Recently completed, KD025-205 was a Phase 2a, open-label study in 8 adult subjects with 
moderately severe psoriasis vulgaris who had failed first-line therapy. The study evaluated the 
safety and tolerability of 200 mg KD025 daily for 28 days. Efficacy and activity measures 
included the evaluation of any decreases in Psoriasis Area and Severity Index in at least 50% of 
the subjects after 4 weeks of dosing with 200 mg of KD025 and improvement in the Physicians 
Global Assessment for psoriasis. Cytokine levels and expression associated with psoriasis were 
evaluated in pharmacodynamic (PD) whole blood samples and punch biopsies of selected 
lesions, respectively, collected at baseline and at the end of treatment. Eight subjects began 
treatment with KD025. Five SAEs were reported in this study and all 5 occurred in the same 
subject: Subject 001-008 experienced Grade 2 vomiting (2 events), Grade 2 nausea (2 events), 
Grade 3 anastomotic ulcer (related to the subject's previous gastric bypass surgery), and Grade 3 
kidney stones, none of which were assessed to be related to study drug (she was subsequently 
discontinued after 20 days of dosing). Another subject experienced reversible grade 1 elevated 
ALT and aspartate aminotransferase (AST) on Day 22 with no known etiology and permanently 
discontinued treatment with KD025. The ALT/AST returned to normal levels 13 days after the 
last dose of KD025. No other TEAEs or SAEs were reported. 
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Follow-up for efficacy and activity measures in this study has completed. The following PK 
conclusions can be made for this study: 
• KD025 was rapidly absorbed after oral dose administration with median Tmax values of 
2.0 hours and 4.0 hours post-dose on Days 1 and 28, respectively. 
• Mean t½ for KD025 was 6.08 hours and 5.27 hours on Days 1 and 28, respectively. 
• Two metabolites (KD025m1 and KD025m2) rapidly appeared in plasma and were readily 
eliminated. No accumulation of either metabolite was apparent after multiple doses.  
Exposure of daily dosing at 200 mg for 28 days was comparable to or slightly lower than that 
observed in study KD025-101 for daily dosing at similar dose levels.   
KD025-206 is an ongoing Phase 2, open-label, safety and tolerability study of KD025 in subjects 
with psoriasis vulgaris who have disease progression after at least 1 systemic therapy. The 
primary objective is to evaluate the safety and tolerability of 3 daily dosing regimens 
(200 mg BID, 400 mg QD, and 400 mg BID) of KD025 in subjects with psoriasis vulgaris who 
have progressed despite first-line therapy. To date, preliminary safety data are available on 
10 subjects who received KD025 at a dose of 200 mg BID, and 10 subjects who received KD025 
at a dose of 400 mg QD. All subjects had normal ALT and AST values during screening. Four 
subjects (3 subjects receiving 200 mg BID and 1 subject receiving 400 mg QD) had TEAEs of 
elevation of ALT or AST. Bilirubin levels remained normal, and all ALT or AST increases were 
asymptomatic and reversible. The ALT and AST elevations first occurred from study Day 16 to 
study Day 36. The ALT/AST elevations were mild or moderate in intensity, except in 1 subject 
who had severe (grade 3) ALT elevation to a maximum of 377 U/L.  KD025 administration was 
discontinued in 3 subjects, and ALT and AST levels decreased. One subject, who was receiving 
KD025 400 mg QD, had peak ALT of 121 U/L and AST of 127 U/L that then returned to the 
normal range despite continuing to receive KD025 400 mg QD. The data from these subjects 
suggest that increases in ALT and AST are modest and may be reversible despite the 
continuation of KD025.  
4.4. 
KD025 Nonclinical Toxicology  
To date, Good Laboratory Practice compliant general toxicology/toxicokinetic studies of acute, 
subchronic (1 and 3 month), and chronic (6-month rat and 9-month dog) duration have been 
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completed in rats and dogs. In addition, safety pharmacology studies have been completed 
evaluating central nervous system and respiratory (rat), and cardiovascular (dog) function. 
Furthermore, KD025 is not considered genotoxic or mutagenic based on a panel of studies. 
Developmental and reproductive toxicology studies (rat and rabbit embryo-fetal [segment 2] and 
rat fertility) have also been completed. 
Study details and potential clinically-relevant findings from these studies are summarized in the 
IB.   
4.5. 
Compliance Statement 
This study will be conducted in compliance with Good Clinical Practice (GCP), including ICH 
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 subject informed consent form (ICF) before implementation.  
Freely given written informed consent must be obtained from every subject before participation 
in this clinical trial. The rights, safety, and well-being of participating subjects 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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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objectives 
The primary objectives of the study are: 
• 
To evaluate the activity of KD025 in subjects with steroid-dependent cGVHD and active 
disease in terms of partial response (PR) and complete response (CR) as defined by the 
2014 National Institute of Health (NIH) Consensus Development Project on clinical trials 
in cGVHD  
• 
To evaluate the safety and tolerability of KD025 in subjects with cGVHD 
5.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To evaluate changes in cGVHD severity using the Physician-reported global cGVHD 
Activity Assessment form (see Appendix A) 
• 
To assess changes in symptom activity using the cGVHD Activity Assessment Patient 
Self-Report  
• 
To evaluate Failure-free Survival (FFS) 
• 
To evaluate changes in corticosteroid and CNI dose  
• 
To evaluate Duration of Response (DOR) 
• 
To evaluate response by organ system 
• 
To assess the plasma PK of KD025 in subjects with cGVHD 
• 
To evaluate Overall Survival (OS) 
• 
To evaluate Time to Next Treatment (TTNT) 
• 
To evaluate the change in symptom burden/bother using the Lee cGVHD Symptom Scale 
 
5.3. 
Exploratory Objective 
The exploratory objectives of the study are: 
• To evaluate changes in the expression of several cytokines (including IL-17A, IL-21, and 
IL-2) in plasma after KD025 administration 
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• To evaluate changes in percentage of immune-cell subtypes (including Th17 and Treg cells) 
in whole blood after KD025 administration 
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6. 
STUDY DESIGN 
6.1. 
Study Sites 
This study will be conducted at approximately 10 sites in the United States. 
6.2. 
Study Endpoints 
Primary Endpoint 
The primary activity outcome will be the percentage of subjects who meet the Overall Response 
Rate criteria (PR + CR). This will be assessed overall (ie, any subject meeting the PR or CR 
criteria at any time point). 
Secondary Endpoints  
• 
Number and percentage of KD025 in subjects with steroid-dependent cGVHD who have a 
best response of PR or CR 
• 
Change in cGVHD severity as based on the Physician-reported global cGVHD Activity 
Assessment  
• 
Change in symptom activity as based on cGVHD Activity Assessment Patient Self-Report  
• 
Median FFS 
• 
Changes in corticosteroid and CNI dose  
• 
DOR 
• 
Response rate by organ system  
• 
Analyses of plasma PK of KD025 in subjects with cGVHD 
• 
OS 
• 
TTNT 
• 
Change in symptom burden/bother using the Lee cGVHD Symptom Scale 
Exploratory Endpoints  
• 
Changes in the expression of several cytokines (including IL-17A, IL-21, and IL-2) in 
plasma after KD025 administration to subjects with cGVHD 
• 
Changes in percentage of immune-cell subtypes (including Th17 and Treg cells) in whole 
blood after KD025 administration to subjects with cGVHD 
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Further details on the statistical and analytical plan for these endpoints are available in 
Section 17. 
6.3. 
Overview of Study Design 
This is a Phase 2a, dose-escalation, open-label study designed to evaluate the safety, tolerability, 
and activity of KD025 in subjects with steroid-dependent cGVHD and active disease in terms of 
PR and CR as defined by the 2014 NIH Consensus Development Project on clinical trials in 
cGVHD (see Appendix B). This study also is designed to use the Physician-reported global 
cGVHD Activity Assessment to evaluate cGVHD severity; use the cGVHD Activity Assessment 
Patient Self-Report to assess symptom activity (see Appendix C); evaluate FFS; evaluate OS; 
assess changes in corticosteroid and calcineurin inhibitor (CNI) dose; evaluate TTNT; and assess 
the PK of KD025 in subjects with cGVHD. Changes in symptom burden/bother will be 
documented using the Lee cGVHD Symptom Scale (see Appendix D). Changes in the expression 
of several cytokines (including IL-17A, IL-21, and IL-2) in plasma and percentages of immune-
cell subtypes (including Th17 and Treg cells) in whole blood after KD025 administration to 
subjects with cGVHD.  
Subjects who have signed an IRB/IEC-approved informed consent form, and met all of the 
inclusion/exclusion criteria (Section 7.2 and 7.3), will be enrolled. Approximately 48 subjects 
will receive orally administered KD025 200 mg QD (n = 16), KD025 200 mg BID (n = 16), or 
KD025 400 mg QD (n = 16). Study drug will be administered in 28-day cycles until disease 
progression or unacceptable toxicity occurs. For disease progression, subjects with a 
“Lack of Response (LOR) – Mixed” response assessment (Appendix B) may continue treatment 
with KD025 and remain on study if the investigator considers continued treatment to be in the 
subject’s best interest, only after approval from the medical monitor and documentation of the 
subject’s willingness to continue. Subjects may receive study drug treatment either in the 
inpatient or outpatient setting.  
Prior to enrolling subsequent cohorts, the safety data in each previous cohort will be evaluated 
after 8 subjects have reached 2 months of treatment to assure there is no safety signal. As this is 
an open-label study, safety data will be continuously monitered. If ≥ 25% of subjects in a cohort 
experience a Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade 2 liver 
toxicity or a CTCAE v4.03 Grade 3 (or higher) AE in the same organ or body system, or if 
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> 25% of subjects in a cohort are discontinued for toxicity that persists for 14 days, then dose 
escalation to the next cohort will not occur, and all subjects in that dose cohort will be dose 
reduced. 
If ≥ 25% of subjects in the 200 mg QD cohort experience a CTCAE v4.03 Grade 2 liver toxicity 
or a CTCAE v4.03 Grade 3 (or higher) AE in the same organ or body system, or if > 25% of 
subjects in a cohort are discontinued for toxicity that persists for 14 days, then further dosing will 
not occur and the study will be terminated. See Section 14.4 for additional information. 
Response criteria will be assessed on Day 1 of each cycle starting at Cycle 2 Day 1 visit as well 
as the end of treatment (EOT) visit using the criteria of 2014 NIH Consensus Development 
Project on Clinical Trials in cGVHD (CR, PR, and Lack of Response (unchanged, mixed, or 
progression); Lee et al., 2015). cGVHD severity (clinician reported) and symptom (subject 
reported) assessments will be performed on Day 1 of each cycle starting on Cycle 1 Day 1 as 
well as the EOT visit using the Physician-reported global cGVHD Activity Assessment form 
(Appendix A), cGVHD Activity Assessment: Patient Self Report, and Lee cGVHD Symptom 
Scale (see Appendices C and D).  
At Cycle 25, Day 1 (C25D1), and all odd cycles thereafter (ie, C27D1, C29D1, C31D1, etc.), 
subjects will receive 2 cycles worth of study drug along with 2 diaries and will return to the 
clinic at the next odd cycle for assessments and IP accountability.  Investigators and/or subjects 
have the option of coming into the clinic at one or more even cycles (i.e., C26D1, C28D1, 
C30D1, etc).  On even cycles, when patients do not come to clinic, the study staff will contact 
the patient via phone and document any new adverse events and concomitant medications. 
Subjects will also undergo assessments as described in Table 1. 
 
 
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n. 
If screening assessments are done within 14 days of Cycle 1, Day 1, they do not need to be repeated on Cycle 1 Day 1.  
o. 
Subjects who achieve SD, PR, or CR will continue dosing with study drug until disease progression or unacceptable toxicity occurs. For LOR –Mixed subjects please refer to 
Section 9.1 of protocol. 
p. 
At Cycle 25 Day 1 (C25D1) and all odd cycles thereafter (i.e., C27D1, C29D1, C31D1, etc.), subjects will receive 2 cycles worth of study drug along with 2 diaries and will 
return to the clinic at the next odd cycle for assessments and IP accountability.  Investigators and/or subjects have the option of coming into clinic at one or more even cycles 
(i.e., C26D1, C28D1, C30D1, etc.). On even cycles, when patients do not come to clinic, the study staff will contact the patient via phone and document any new adverse events 
and concomitant medications. 
q. 
Subjects who discontinue treatment prematurely also will be asked to come to the clinic for EOT assessments. 
r. 
The Follow-Up visit will occur 28 days after the last dose of study drug, but prior to starting on a new therapy, if a new therapy is started earlier. This visit may be done within 
± 7 days of the scheduled visit.     
s. 
These assessments are suggested for any unscheduled visits (UNS).  
t. 
Subjects are to return to the study site within 3 days after the subject’s last dose of study drug to complete all EOT assessments. This may occur at the visit at which disease 
progression is diagnosed. 
 
 
 
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As shown in the table of study assessments (Table 1), subjects will undergo PEs; vital sign 
measurements; Karnofsky Performance Scale assessments, blood sample collection for 
hematology, chemistry, PK, and PD markers; urinalysis; PFTs, ECGs; AE assessments; 
concomitant medication assessments; activity assessments, and pregnancy testing for females of 
childbearing potential.  
Follow-Up Period 
Follow-Up visits will occur 28 days (± 7 days) after the last dose of study drug. Subjects will 
undergo PEs; vital sign measurements; blood sample collection for hematology, chemistry, and 
PD markers; urinalysis; ECGs; AE assessments; and concomitant medication assessments; and 
pregnancy testing for females of childbearing potential. 
Long-Term Follow-Up 
Subjects will be contacted approximately every 8 weeks and can be contacted via telephone, 
email or postal mail to confirm survival status and the initiation of any anti-cancer treatment or 
any changes in treatment of cGVHD. This can also be confirmed from electronic medical 
records. 
6.4. 
 Randomization and Blinding  
 
This is an open-label study. 
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7. 
STUDY POPULATION 
7.1. 
Target Population 
Approximately 48 adult male and female subjects with cGVHD will be enrolled. Subjects will be 
eligible for enrollment as defined by the following inclusion and exclusion criteria.  
7.2. 
Inclusion Criteria 
The inclusion criteria are detailed below: 
1. Adult male and female subjects at least 18 years of age who have had allogenic bone 
marrow transplant or hematopoietic stem cell transplantation. 
2. Receiving glucocorticoid therapy and calcineurin therapy or glucocorticoid therapy alone 
for cGVHD at study entry. Subjects on calcineurin therapy only, without glucocorticoid 
therapy, are not eligible. Subjects also receiving other therapies thought not to be 
immunosuppressive (such as extracorporeal photopheresis [ECP]), will be considered for 
enrollment in this study on a case-by-case basis. 
3. Have persistent active cGVHD manifestations, as defined by 2014 NIH Consensus 
Development Project on Criteria for Clinical trials in cGVHD, after at least 2 months of 
steroid therapy.   
4. No more than 3 prior lines of treatment for cGVHD. 
5. Karnofsky Performance Scale of > 40 (see Appendix E).  
6. Adequate organ and bone marrow functions evaluated during the 14 days prior to 
enrollment as follows: 
a. Absolute neutrophil count ≥ 1.5 × 109/L (without myeloid growth factors within 
1 week of study entry) 
b. Platelet count ≥ 50 × 109/L (without transfusion or thrombopoietin or 
thrombopoietin analogues within 2 weeks of study entry) 
7. Adequate safety laboratory values: 
a. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) 
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b. ALT and AST ≤ 3 × ULN 
c. Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 using the 4-Variable 
Modification of Diet in Renal Disease (MDRD-4) variable formula (see 
Appendix F) 
8. Female subjects of childbearing potential have a negative pregnancy test at screening. 
Females of childbearing potential are defined as sexually mature women without prior 
hysterectomy or who have had any evidence of menses in the past 12 months. However, 
women who have been amenorrheic for 12 or more months are still considered to be of 
childbearing potential if the amenorrhea is possibly due to prior chemotherapy, 
anti-estrogens, or ovarian suppression. 
9. Women of childbearing potential (ie, menstruating women) must have a negative urine 
pregnancy test (positive urine tests are to be confirmed by serum test) documented within 
the 24-hour period prior to the first dose of study drug.  
10. Sexually active women of childbearing potential enrolled in the study must agree to use 2 
forms of accepted methods of contraception during the course of the study and for 
3 months after their last dose of study drug. Effective birth control includes: 
a. Intrauterine device plus 1 barrier method; 
b. Stable doses of hormonal contraception for at least 3 months (eg, oral, injectable, 
implant, transdermal) plus one barrier method; 
c. Two barrier methods. Effective barrier methods are male or female condoms, 
diaphragms, and spermicides (creams or gels that contain a chemical to kill 
sperm); or 
d. A vasectomized partner 
11. For male subjects who are sexually active and who are partners of premenopausal women: 
agreement to use 2 forms of contraception as in Criterion #10 above during the treatment 
period and for at least 3 months after the last dose of study drug.       
12. Able to provide written informed consent prior to the performance of any study-specific 
procedures. 
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7.3. 
Exclusion Criteria 
The exclusion criteria are detailed below: 
1. Female subject who is pregnant or breastfeeding. 
2. Receiving an investigational GVHD treatment within 28 days of study entry. 
3. Has acute GVHD. 
4. Taking any medication known to be a moderate or strong inhibitor of the CYP3A4 
isozyme or any drugs that are moderate or strong CYP3A4 inducers (see Appendix H).  
5. History or other evidence of severe illness or any other conditions that would make the 
subject, in the opinion of the investigator, unsuitable for the study (such as poorly 
controlled psychiatric disease or coronary artery disease). 
6. Regular and excessive use of alcohol within the 6 months prior to study entry defined as 
alcohol intake > 14 drinks per week in a man or > 7 drinks per week in a woman. 
Approximately 10 g of alcohol equals one “drink” unit. One unit equals 1 ounce of 
distilled spirits, one 12-ounce beer, or one 4-ounce glass of wine. 
7. Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) 
or hepatitis B virus (HBV). 
8. 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, resected in situ cervical malignancy, resected 
breast ductal carcinoma in situ, or low-risk prostate cancer after curative resection. 
9. Relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time 
of screening. 
10. Has had previous exposure to KD025 or known allergy/sensitivity to KD025 or any other 
ROCK2 inhibitor. 
11. Taking other immunosuppressant drugs for GVHD, including mammalian target of 
rapamycin (mTOR) inhibitors (Note: Only steroids, CNIs, and ECP are acceptable).  
12. QTcF > 450 msec 
 
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8. 
STUDY ASSESSMENTS  
8.1. 
Overview 
The timing for these study assessments is presented in Table 1, while a listing of clinical 
laboratory parameters to be measured in presented in Section 8.8.   
8.2. 
Screening Period (Day -29 to -1) 
Informed consent must be obtained before any study-specific samples are taken or study-specific 
tests or evaluations are conducted. The following assessments at the screening visit are to occur 
within 28 days of first dose of study drug. Study eligibility will be based on satisfying all of the 
study inclusion and exclusion criteria.   
At the screening visit, information will be collected and subjects will have clinical evaluations as 
follows: 
• 
Informed consent 
• 
Medical history and demographic data 
• 
Complete PE, including height and weight 
• 
Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
• 
Karnofsky Performance Scale score 
• 
Clinical laboratory tests (hematology and serum chemistry panel) 
• 
Thyroid stimulating hormone (TSH) 
• 
Urinalysis 
• 
Virology (HBV, HCV, and HIV) 
• 
Supine 12-Lead ECG; to be performed 3 times consecutively within 30 minutes (must 
have an interval of at least 1–2 minutes between ECGs); perform ECG immediately prior 
to blood sample collection, if possible 
• 
Urine pregnancy test (for women of childbearing potential.  Positive results are to be 
confirmed with serum testing.) 
• 
Concomitant medications assessment 
• 
AE assessment 
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8.3. 
Enrollment 
After completion of screening procedures and confirmation of subject eligibility, the subject will 
be enrolled into the study. Subjects who are enrolled into the study are to undergo all subsequent 
evaluations required by the protocol. 
8.4. 
Treatment Period 
8.4.1 
Cycle 1, Day 1 (Baseline) 
At the Cycle 1 Day 1 visit, subjects will come to the clinic to have the following procedures 
completed. (Note that if screening assessments are done within 14 days prior to Cycle 1 Day 1, 
they do not need to be repeated on Day 1). 
• 
Complete PE, including weight 
• 
Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
• 
Karnofsky Performance Scale score 
• 
Clinical laboratory tests (hematology and serum chemistry panel) 
• 
Supine 12-Lead ECG (to be obtained 4 hours post-morning dose; to be performed 3 times 
consecutively within 30 minutes [must have an interval of at least 1–2 minutes between 
ECGs]; perform ECG immediately prior to blood sample collection, if possible) 
• 
Urine pregnancy test (for women of childbearing potential.  Positive results are to be 
confirmed with serum testing.) 
• 
Pulmonary function tests (including forced expiratory volume in 1 second [FEV1], forced 
vital capacity [FVC], diffusing capacity of carbon monoxide [DLCO], total lung capacity 
[TLC], and residual volume [RV])  
• 
PK sample collection (pre-dose [Time 0], and 1, 2, 3, 4, 5, and 6 hours after dosing [after 
first dose for subjects in the BID group]) 
• 
PD blood sample collection (pre-dose) 
• 
Study drug administration 
• 
Dispense study drug 
• 
Dispense study drug diary 
• 
Physician-Reported Global cGVHD Activity Assessment  
• 
cGVHD Activity Assessment - Patient Self Report 
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• 
Lee cGVHD Symptom Scale 
• 
Concomitant medications assessment 
• 
AE assessment 
8.4.2 
Cycle 1, Days 8, 15, and 22 (±3 days) 
On Days 8, 15, and 22 of Cycle 1, subjects will come to the clinic to have the following 
procedures completed: 
• 
Complete PE, including weight 
• 
Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
• 
Karnofsky Performance Scale score 
• 
Clinical laboratory tests (hematology and serum chemistry panel) 
• 
Study drug administration 
• 
Collect study drug diary 
• 
Concomitant medications assessment 
• 
AE assessment 
8.4.3 
Cycles 2 and Beyond, Day 1 (±3 days) 
On Day 1 of Cycles 2 and beyond, subjects will come to the clinic to have the following 
procedures completed: 
• 
Complete PE, including weight 
• 
Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
• 
Karnofsky Performance Scale score 
• 
Clinical laboratory tests (hematology and serum chemistry panel) 
• 
TSH  
• 
Urinalysis 
• 
Supine 12-Lead ECG; pre-dose on Day 1 of Cycle 4 and Cycle 7 only; to be performed 
3 times consecutively within 30 minutes (must have an interval of at least 1–2 minutes 
between ECGs) 
• 
Urine pregnancy test (for women of childbearing potential.  Positive results are to be 
confirmed with serum testing.) 
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• 
Pulmonary function tests (including FEV1, FVC, DLCO, TLC, and RV; to be performed 
every other cycle, starting with Cycle 3 for subjects without lung involvement 
• 
PK sample collection (Cycle 2 only at the following time points:  pre-dose [Time 0], and 1, 
2, 3, 4, 5, and 6 hours after dosing [after first dose for subjects in the BID group]); a 
pre-dose sample is to be collected at the Cycle 4 and Cycle 7 visit 
• 
PD blood sample collection (Cycles 2, 4, and 7 only: pre-dose) 
• 
Study drug administration 
• 
Dispense/Collect study drug 
• 
Collect study drug diary 
• 
Response assessment.   
• 
Physician-Reported Global cGVHD Activity Assessment  
• 
cGVHD Activity Assessment - Patient Self Report 
• 
Lee cGVHD Symptom Scale 
• 
Concomitant medications assessment 
• 
AE assessment 
At Cycle 25, Day 1 (C25D1), and all odd cycles thereafter (i.e., C27D1, C29D1, C31D1, etc.), 
subjects will receive 2 cycles worth of study drug along with 2 diaries and will return to the 
clinic at the next odd cycle for assessments and IP accountability.  Investigators and/or subjects 
have the option of coming into clinic at one or more even cycles (i.e., C26D1, C28D1, 
C30D1, etc).  On even cycles, when patients do not come to clinic, the study staff will contact 
the patient via phone and document any new adverse events and concomitant medications. 
8.5. 
End of Treatment (EOT) 
Subjects are to return to the study site within 3 days after the subject’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: 
• 
Complete PE, including weight 
• 
Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
• 
Karnofsky Performance Scale score 
• 
Clinical laboratory tests (hematology and serum chemistry panel) 
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• 
TSH  
• 
Pulmonary function tests (including FEV1, FVC, DLCO, TLC, and RV) 
• 
Response criteria assessment  
• 
Physician-Reported Global cGVHD Activity Assessment   
• 
cGVHD Activity Assessment - Patient Self Report 
• 
Lee cGVHD Symptom Scale 
• 
Concomitant medications assessment 
• 
AE assessment  
8.6. 
28-Day Follow-Up Visit 
The Follow-Up visit will occur 28 (± 7) days after the last dose of study drug, but prior to 
starting on a new therapy (if a new therapy is started earlier). Subjects will return to the clinic 
and the following procedures will be completed: 
• 
Complete PE, including weight 
• 
Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
• 
Karnofsky Performance Scale score 
• 
Clinical laboratory tests (hematology and serum chemistry panel) 
• 
TSH  
• 
Urinalysis 
• 
Supine 12-lead ECG; to be performed 3 times consecutively within 30 minutes (must have 
an interval of at least 1–2 minutes between ECGs); perform ECG immediately prior to 
blood sample collection, if possible 
• 
Urine pregnancy test (for women of childbearing potential.  Positive results are to be 
confirmed with serum testing.) 
• 
Concomitant medications assessment 
• 
AE assessment 
8.7. 
Unscheduled Visits 
For subjects requiring an unscheduled visit, the following assessments may be performed at the 
investigator’s discretion: 
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• 
Complete PE, including weight 
• 
Seated vital sign measurements (sitting blood pressure, pulse, respiratory rate, 
temperature) 
• 
Karnofsky Performance Scale score 
• 
Clinical laboratory tests (hematology and serum chemistry panel) 
• 
TSH  
• 
Urinalysis 
• 
Supine 12-Lead ECG; to be performed 3 times consecutively within 30 minutes (must 
have an interval of at least 1–2 minutes between ECGs); perform ECG immediately prior 
to blood sample collection, if possible 
• 
Urine pregnancy test (for women of childbearing potential. Positive results are to be 
confirmed with serum testing.) 
• 
Pulmonary function tests (including FEV1, FVC, DLCO, TLC, and RV) 
• 
Collect study drug (if appropriate) 
• 
Collect study drug diary (if appropriate) 
• 
Physician-Reported Global cGVHD Activity Assessment   
• 
cGVHD Activity Assessment - Patient Self Report 
• 
Lee cGVHD Symptom Scale 
• 
Concomitant medications assessment 
• 
AE assessment 
8.8. 
Long-Term Follow-Up 
Subjects will be contacted approximately every 8 weeks and can be contacted via telephone, 
email or postal mail to confirm survival status and the initiation of any anti-cancer treatment or 
any changes in treatment of cGVHD. This can also be confirmed from electronic medical 
records. 
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9. 
STUDY PROCEDURES 
9.1. 
Procedures to be Performed 
All screening assessments are to be performed within 28 days before first study drug dose, unless 
otherwise specified. 
Study Day 1 is defined as the date the subject takes the first dose of study drug, with subsequent 
study days numbered sequentially thereafter.  
If significant changes from baseline are noted during the course of the study, additional 
unscheduled clinic visits may be undertaken by the investigator, or requested by the sponsor, in 
order to determine both the relevance of the finding(s) and the duration of the event(s). 
Informed Consent 
All subjects must take part in the informed consent process. Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision. No protocol-specific procedures, 
including screening procedures are to be performed until the subject has signed and dated an 
IRB/IEC-approved ICF.   
Demographics and Medical History 
A complete medical history will be taken. Information to be documented includes demographic 
information, prior medical illnesses and conditions, and surgical procedures. 
Physical Examination 
Complete PEs will be performed. All PEs will include assessment of cardiac (including heart 
rate, and vital sign measurements), musculoskeletal (eg, muscle aches) and neurological (eg, 
gait) body systems. A complete PE is to include documentation of height (screening only), 
weight, body temperature, and vital signs (blood pressure [sitting], pulse rate [sitting], Karnofsky 
Performance Scale, and respiratory rate) and will be performed by a physician or staff member 
who is qualified to perform such examinations (eg, physician’s assistant, nurse practitioner).   
Any abnormal or clinically significant findings from the PE must be recorded on the appropriate 
electronic case report form (eCRF) page.   
Vital Sign Measurements 
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Vital sign measurements will be collected after the subject has been sitting for 5 minutes. Vital 
sign assessments will include measurements of sitting blood pressure (mm Hg), heart rate (beats 
per minute), respiration rate (breaths per minute), and temperature (Celsius). 
Please note that blood pressure measurements are to be performed using appropriate technique 
(per guidelines of the American Heart Association). Specifically, subjects should be seated 
quietly for at least 5 minutes in a chair with their backs supported, their feet flat on floor (legs 
uncrossed), and their arms bared on a hard surface, with the arm slightly abducted and bent, with 
palm up and the midpoint of upper arm at heart level. Correct cuff and bladder size should be 
utilized. Two or more readings separated by 1 to 2 minutes should be averaged. If the first 
2 readings differ by more than 5 mm Hg, an additional 2 readings should be obtained and 
averaged. Record cuff size, arm used, and subject's position (if not seated). 
Karnofsky Performance Scale  
Subject’s performance status will be assessed using the Karnofsky Performance Scale tool (see 
Appendix E).  
Laboratory Assessments 
Laboratory samples (hematology, serum chemistry, TSH, urinalysis, and virology) are to be 
collected as outlined in Table 1and Section 8.8. Safety laboratory analyses will be performed by 
the central laboratory. Laboratory results will be graded using the CTCAE v4.03.   
12-Lead Electrocardiogram  
Electrocardiograms will be performed with the subject in a supine position having rested in this 
position for at least 5 minutes before each reading. ECGs are to be performed 3 times 
consecutively within 30 minutes (must have an interval of at least 1–2 minutes between ECGs). 
ECG is to be performed immediately prior to any blood sample collections, if possible. See 
Section 9.3 for additional ECG procedure information and Table 2 for timing allowances. 
Pregnancy Testing 
Pregnancy tests (urine) will be done in women of childbearing potential. Positive urine results 
are to be confirmed with serum testing. 
Pulmonary Function Testing 
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Pulmonary function tests (to include FEV1, FVC, DLCO, TLC, and RV) will be performed 
according to the guidelines published by the American Thoracic Society or European Respiratory 
Society for standardization of spirometry (ATC 1995; Quanjer et al., 1993). Diffusion capacity 
(DLCO) determinations will be performed at the same time as spirometric testing; FEV1, FVC, 
DLCO, TLC, and RV will also be expressed as absolute values and % predicted of normal based 
on published reference values for adults (Hankinson et al., 1999). See Section 9.4 for additional 
information. 
Pharmacokinetics (PK) Sampling 
Blood samples (approximately 5 mL) for determination of plasma concentrations of KD025 and 
its metabolites, will be collected on Day 1 of Cycles 1 and 2 at the following time points: 
Pre-dose (Time 0), and 1, 2, 3, 4, 5, and 6 hours after dosing (after first dose for subjects in the 
BID group). In addition, subjects will have samples collected pre-dose on Day 1 of Cycle 4 and 
pre-dose at the Cycle 7 Day 1 visit. See Section 11 for additional information. 
Blood Sampling for Pharmacodynamics (PD) 
All subjects will have PD blood samples drawn up to 4 times over the course of the study: Pre-
dose on Cycle 1 Day 1, Cycle 2 Day 1 (4 weeks), Cycle 4 Day 1 (12 weeks) and Cycle 7 Day 1 
(24 weeks).  Samples will be analyzed to evaluate changes in the expression of several cytokines 
in plasma (including IL-17A, IL-21, and IL-2), and changes in percentages of circulating Th17 
and Treg cells in blood. See Section 12 for additional information.     
KD025 Administration and Treatment Duration  
Subjects will receive their first dose of study drug in the clinic on Day 1 of Cycle 1, and then 
study drug will be dispensed for home administration. On scheduled visit days, subjects will take 
their dose at the clinic.  
Subjects will receive KD025 200 mg QD, KD025 200 mg BID, or KD025 400 mg QD. Subjects 
will be treated until disease progression or unacceptable toxicity.  Subjects with a “LOR -
 Mixed” response assessment may continue treatment with KD025 and remain on study if the 
investigator considers continued treatment to be in the subject’s best interest only after approval 
from the medical monitor and documentation of the subject’s willingness to continue. 
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Subjects who have SD, PR, or CR at the time of decision to discontinue treatment and who come 
off study for reasons other than AEs will be tapered off of KD025 by lowering the dose by 
50% every 2 weeks (see Section 14.1 for additional details) until they reach a dose of 100 mg 
QD or equivalent. Further instructions will be listed in the pharmacy manual.   
Study Drug Diary  
Subjects will be given a study drug diary to record the details of each dose of study drug. Diaries 
will be dispensed/collected on Day 1 of each cycle. Compliance with oral dosing will be 
confirmed using patient diaries, which will be examined at each visit. 
Response and Activity Assessments  
Response criteria will be assessed using the 2014 NIH Consensus Development Project for 
Clinical Trials in cGVHD criteria (CR, PR, or LOR [unchanged, mixed, or progression; see (Lee 
et al., 2015).     
Activity in terms of cGVHD severity will be evaluated using the Physician-reported Global 
cGVHD Activity Assessment form (see Appendix A), while activity in terms of symptom burden 
will be evaluated using the cGVHD Activity Assessment - Patient Self Report (see Appendix C). 
Failure-free survival, OS and TTNT will be evaluated at the same time points. Changes in 
corticosteroid and CNI dose will be documented as they occur on the appropriate eCRF. Changes 
in symptom burden/bother will be documented using the Lee cGVHD Symptom Scale (see 
Appendix D).  
See Section 10 for additional information on response assessment. 
Prior and Concomitant Medications 
All concomitant medications, including systemic steroids and CNIs, are to be collected from 
time the subject signs the ICF throughout the subject’s participation in the study. See Section 15 
for additional information. 
Adverse Event Assessments 
Information regarding the occurrence of AEs will be collected from the time the subject signs the 
ICF throughout their participation in the study, including a period of 28 days after last dose of 
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study drug. AE severity will be determined using the CTCAE v4.03 grading scale. Also, see 
Appendix G for criteria for determining relationship of AE to study drug. 
Note:   Adverse events resulting in a subject’s permanent discontinuation from 
the study, regardless of seriousness or relationship to study drug, 
MUST be promptly reported to the sponsor. 
See Section 13.2 for stopping rules for this study. 
9.2. 
Laboratory Assessments 
The central laboratory will perform hematology, serum chemistry, and urinalysis tests and results 
will be provided to the investigator (Table 3). Blood and urine samples for hematology, serum 
chemistry, and urinalysis will be prepared using standard procedures.   
Table 3: 
Clinical Laboratory Panels 
Hematology 
Serum Chemistry 
Urinalysis 
• 
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 
• 
carbon dioxide 
• 
chloride 
• 
cholesterol 
• 
creatinine 
• 
CPK 
• 
direct bilirubin 
• 
GGT 
• 
globulin 
• 
glucose 
• 
lactate dehydrogenase 
• 
magnesium 
• 
phosphorus 
• 
potassium 
• 
sodium 
• 
total bilirubin 
• 
total protein 
• 
uric acid 
• 
appearance 
• 
color 
• 
pH 
• 
specific gravity 
• 
ketones 
• 
protein 
• 
glucose 
• 
bilirubin 
• 
nitrite 
• 
urobilinogen 
• 
occult blood (microscopic 
examination of sediment will be 
performed only if the results of the 
urinalysis dipstick evaluation are 
positive) 
Biomarkersa 
 
Thyroid Function 
• 
IL-17A 
• 
IL-21  
• 
IL-2 
• 
Th17 
• 
Treg cells 
• 
TSH 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CPK = creatinine phosphokinase; GGT = 
gamma glutamyl transferase; IL = interleukin; INR = international normalized ratio; MCV = mean corpuscular volume; TSH = thyroid 
stimulating hormone 
a:  Other markers may be added 
Abnormalities in clinical laboratory tests that lead to a change in subject management (eg, dose 
delay, requirement for additional medication or monitoring) are considered clinically significant 
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for the purposes of this study, and will be recorded on the AE eCRF page. Laboratory results will 
be classified using the CTCAE v4.03. 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 16.3.1). 
9.3. 
Electrocardiogram Assessments 
A digital 12-lead ECG will be obtained during the study (see Table 1 for timing of ECG 
assessments and Table 2 for timing allowances). 
Digital 12-lead ECG recordings are to be made with the subject in a supine position having 
rested in this position for at least 5 minutes before each reading. ECGs are to be performed 
3 times consecutively within 30 minutes (must have an interval of at least 1–2 minutes between 
ECGs). At each visit, the ECG is to be performed immediately before any blood sample 
collection, if possible. 
The following ECG parameters will be collected: PR interval, QRS interval, and QTc[F]. The 
ECG findings will be evaluated by a qualified physician for the presence of abnormalities 
(qualitative assessment). The physician will assess each ECG as normal, abnormal/not clinically 
significant, or abnormal/clinically significant.   
Abnormalities in the ECG that lead to a change in subject management (eg, dose reduction or 
delay, requirement for additional medication or monitoring) 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 (see Section 16.3.1). 
9.4. 
Pulmonary Function Tests  
Pulmonary function testing will include FEV1, FVC, DLCO, TLC, and RV. The same equipment 
and tester should be used during the course of the study to the extent possible. The person 
responsible for conducting the pulmonary function tests will be required to comply with the 
study guidelines and the American Thoracic Society/European Respiratory Society joint criteria 
on lung function testing. 
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10. 
ACTIVITY 
The primary activity endpoint of this study is subject response based on the 2014 NIH Consensus 
Development Project on Clinical Trials in cGVHD. Secondary endpoints include evaluation of 
cGVHD severity using the Physician-reported global cGVHD Activity Assessment; evaluation 
of symptom burden using the cGVHD Activity Assessment - Patient Self Report; FFS; OS; 
TTNT;  changes in corticosteroid and CNI dose; and  changes in symptom burden/bother using 
the Lee cGVHD Symptom Scale. 
10.1. 
2014 NIH Consensus Development Project on Clinical Trials in 
cGVHD  
Subject response (CR, PR, or LOR [unchanged, mixed response, progression]) based on the 2014 
NIH Consensus Development Project on Clinical Trials in cGVHD is the primary activity 
endpoint for this study (see Appendix B). Response criteria will be assessed on Day 1 of each 
cycle starting on Cycle 2 Day 1 as well as the EOT visit.   
10.2. 
Physician-Reported Global cGVHD Activity Assessment 
Activity in terms of cGVHD severity also will be evaluated using the Physician-reported Global 
cGVHD Activity Assessment (see Appendix A for form). cGVHD severity will be performed on 
Day 1 of each cycle starting on Cycle 1 Day 1 as well as the EOT visit. 
10.3. 
cGVHD Activity Assessment - Patient Self Report 
Activity in terms of symptom burden also will be evaluated using the cGVHD Activity 
Assessment - Patient Self Report (see Appendix C for report). Symptom burden will be assessed 
on Day 1 of each cycle starting on Cycle 1 Day 1 as well as the EOT visit. 
10.4. 
Failure-Free Survival 
Failure-free survival data will be collected throughout the study.     
10.5. 
Overall Survival 
Overall Survival data will be collected throughout the study. 
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10.6. 
Corticosteroid and Calcineurin Inhibitor Use 
Corticosteroid and CNI dose will be collected throughout the study and changes in requirements 
will be documented. Corticosteroids may be tapered at the discretion of the investigator after 4 
weeks of KD025 administration. In addition, data on use of non-immunosuppressive therapy, 
such as ECP, will be collected as well. 
10.7. 
 Time to Next Treatment (TTNT) 
Time to Next Treatment data will be collected throughout the study. 
10.8. 
Lee cGVHD Symptom Scale  
Changes in symptom burden/bother will be documented using the Lee cGVHD Symptom Scale 
(see 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., 2002 developed a symptom scale designed for 
individuals with chronic GVHD. The questionnaire asks subject 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 subjects 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.  
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11. 
PHARMACOKINETICS 
Blood samples (approximately 5 mL) for determination of plasma concentrations of KD025 and 
its metabolites, will be collected on Day 1 of Cycles 1 and 2 at the following time points: 
Pre-dose (Time 0), and 1, 2, 3, 4, 5, and 6 hours after dosing (after first dose for subjects in the 
BID group). In addition, subjects will have samples collected pre-dose on Day 1 of Cycle 4 and 
Day 1 of Cycle 7. Subjects should be instructed to withhold taking study drug on these days as 
dosing will be performed at the clinic.  
The pre-dose and all post-dose PK collection time points are to be documented on the 
appropriate eCRF. Additionally, the time of a subject’s dose of study drug is to be documented 
(for subjects receiving study drug BID, the time of the previous evening’s dose administration 
also is to be noted).   
A total of 16 samples will be collected (80 mL) from subjects in the dose escalation portion of 
the study. KD025 and metabolite concentrations will be used to calculate the following PK 
parameters: Cmax, Tmax, and AUC0-6hr. 
Detailed instructions for sample collection and preparation will be provided in a separate manual. 
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12. 
PHARMACODYNAMICS 
All subjects will have PD blood samples drawn 4 times over the course of the study: Pre-dose on 
Cycle 1 Day 1, Cycle 2 Day 1 (4 weeks),  Cycle 4 Day 1 (12 weeks) and Cycle 7 Day 1 (24 
weeks).  Samples will be analyzed to evaluate changes in the expression of several cytokines in 
plasma (including IL-17A, IL-21, and IL-2), and changes in percentages of circulating Th17 and 
Treg cells in blood.   
Detailed instructions for sample collection and preparation will be provided in a separate manual. 
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13. 
REMOVING SUBECTS FROM STUDY 
Every reasonable effort will be made to keep the subject in the study; however, in the event that 
a subject is withdrawn from the study, every effort will be made by the investigator to complete 
and report the reasons for withdrawal as thoroughly as possible. This evaluation should include 
final observations, as required by the protocol at the time of the subject’s withdrawal. The 
reason(s) for termination must be clearly documented on the appropriate page of the eCRF. A 
termination eCRF page must be completed for any subject who is enrolled in the study.  
13.1. 
Subjects’ Decision to Withdraw  
Subjects 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. 
Subjects can decline to continue receiving study drug and/or other protocol-required therapies or 
procedures at any time during the study. If this occurs, the investigator is to discuss with the 
subject the appropriate processes for discontinuation from study drug or other protocol-required 
therapies and must discuss with the subject the options for continuation of the Schedule of 
Assessments (Table 1) and collection of data, including endpoints and adverse events.   
Withdrawal of consent for a study means that the subject does not wish to receive further 
protocol-required therapies or procedures, and the subject does not wish to or is unable to 
continue further study participation. Subject data up to withdrawal of consent will be included in 
the analysis of the study, and where permitted, publically available data can be included after 
withdrawal of consent. The investigator is to discuss with the subject appropriate procedures for 
withdrawal from the study.   
13.1.1 
Treatment Discontinuation 
Treatment discontinuation reasons include any of the following: 
• 
Disease Progression 
• 
An AE requires permanent discontinuation of study drug (refer to Section 14.4)  
• 
Investigator decision 
• 
Voluntary withdrawal by subject 
• 
Noncompliance to protocol 
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• 
Subject lost to follow-up 
• 
Termination of the study by sponsor 
• 
Subject death 
13.1.2 
Study Termination 
Reasons for study termination include:  
• 
Completion of follow-up period 
• 
Voluntary withdrawal by subject 
• 
Subject lost to follow-up 
• 
Termination of the study by sponsor 
• 
Subject death 
In the event of premature discontinuation of treatment, subjects must return to the clinic to 
complete the EOT Visit and 28-Day Follow-Up assessments.  Refer to Section 8.5 for a complete 
list of procedures to be performed at these visits. If a subject dies, Kadmon Corporation will 
actively seek to know the date of death.  
If there is an ongoing toxicity because of KD025, subjects must be followed with appropriate 
medical management until resolution or stabilization. 
A reasonable effort should be made to contact any subject lost to follow-up during the course of 
the study in order to complete assessments and retrieve any outstanding data. If the subjects are 
unreachable by telephone after 3 attempts, a certified registered return receipt letter should be 
sent requesting that contact be made with the investigator to report survival information. 
13.2. 
Stopping Rules 
Stopping criteria will be assessed using the CTCAE scale v.4.03. 
13.2.1 
Adverse Events Stopping Criteria  
AEs that require consideration of study drug discontinuation or dose reduction (see Section 14.4) 
include the following: 
• 
AEs of clinical concern 
• 
Treatment-related Grade 3 TEAEs that cannot definitively be attributed to a cause other 
than the study drug 
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• 
Treatment-related Grade 2 (moderate) TEAEs that cannot definitively be attributed to a 
cause other than the study drug and last at least 5 days.   
13.2.2 
Liver-Related Abnormalities  
The liver-specific AE grading scale (CTCAE v4.03) shown in Table 4 will be used for 
liver-related laboratory abnormalities. Refer to Sections 14.3 and 14.4.  
Table 4: 
Grading of Liver-Related Laboratory Abnormalities (CTCAE v4.03) 
FEATURE 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT 
> ULN-3.0 × ULN 
> 3.0-5.0 × ULN 
> 5.0-20.0 × ULN 
> 20.0 × ULN 
AST 
> ULN-3.0 × ULN 
> 3.0-5.0 × ULN 
> 5.0-20.0 × ULN 
> 20.0 × ULN 
Alkaline 
Phosphatase 
> ULN - 2.5 × ULN 
> 2.5 - 5.0 × ULN 
> 5.0 - 20.0 × ULN 
> 20.0 × ULN 
GGT 
> ULN - 2.5 × ULN 
> 2.5 - 5.0 × ULN 
> 5.0 - 20.0 × ULN 
> 20.0 × ULN 
Bilirubin 
> ULN - 1.5 × ULN 
> 1.5 - 3.0 × ULN 
> 3.0 - 10.0 × ULN 
> 10.0 × ULN 
ALT = Alanine aminotransferase; AST = aspartate aminotransferase; GGT = Gamma-glutamyl transferase; ULN = upper limit 
of normal 
13.3. 
Study Discontinuation 
Kadmon Corporation has the right to terminate or to stop the study at any time. Reasons for 
study discontinuation may include, but are not limited to the following:  
• 
If ≥ 25% of subjects in the 200 mg QD cohort experience a CTCAE v4.03 Grade 2 liver 
toxicity or a CTCAE v4.03 Grade 3 (or higher) AE in the same organ or body system, or if 
> 25% of subjects in a cohort are discontinued for toxicity that persists for 14 days, then 
further dosing will not occur and the study will be terminated.   
• 
Subject enrollment is unsatisfactory 
• 
Drug supply issues 
• 
Excessive subject self-withdrawal 
• 
Significant protocol violations (eg, violation of eligibility criteria, dosing errors, missing 
data for study endpoint analysis) 
13.4. 
Replacements 
Subjects withdrawn from the study before receiving any study drug will be replaced by enrolling 
additional subjects into the study. 
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14. 
STUDY DRUG 
14.1. 
Dose and Schedule of Study Drug 
Kadmon will provide each investigator with adequate supplies of KD025.  
Eligible subjects will receive KD025 200 mg QD, KD025 200 mg BID, or KD025 400 mg QD. 
Study drug will be dispensed by the site pharmacist. After the completion and review of all 
screening and baseline procedures, qualified subjects will receive study drug.   
Cohort 
No. of 
Subjects 
Dosage 
Number of 100 mg capsules to 
be administered per dose 
Number of 200 mg 
tablets to be 
administered per dose 
Cohort 1 
16 subjects 
200 mg KD025 QD 
2 
1 
Cohort 2 
16 subjects 
200 mg KD025 BID 
2 
1 
Cohort 3 
16 subjects 
400 mg KD025 QD 
4 
2 
 
KD025 will be supplied as 100 mg capsules or 200 mg tablets.    
Product 
Strength 
Dosage Form 
Route 
KD025 
100 mg 
Yellow opaque capsule (size 00) 
Oral 
KD025 
200 mg 
Oblong yellow-coated tablet 
Oral 
 
 
 
 
Cohort 1: 
Subjects should take 2 capsules/1 tablet with their morning meal or within 
5 minutes of finishing the meal.  
Cohort 2: 
Subjects should take 2 capsules/1 tablet with their morning meal or within 
5 minutes of completing the meal and 2 capsules with their evening meal 
or within 5 minutes of finishing the meal. 
Cohort 3:  
Subjects should take 4 capsules/2 tablets with their morning meal or 
within 5 minutes of finishing the meal. 
Subjects who have SD, PR, or CR at the time of decision to discontinue treatment and who come 
off study for reasons other than AEs will be tapered off KD025 by lowering the dose by 
50% every 2 weeks until they reach a dose of 100 mg QD or equivalent.  Further instructions 
will be listed in the pharmacy manual. 
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Subjects will be dispensed study drug to self-administer while on an outpatient basis and subjects 
will be provided a study drug diary in which to record the day and time of dosing. Subjects will 
return to the clinic as outlined in the Study Assessments table (Table 1), and will receive that 
day’s dose of study drug (first dose for BID subjects) while at the clinic. 
14.2. 
Dose Escalation  
Prior to enrolling subsequent cohorts, the safety data in each prior cohort will be evaluated after 
8 subjects have reached 2 months of treatment to assure there is no safety signal. Two months 
was selected as the time for the safety review because all of the clinically significant 
KD025-related AEs to date occurred within 36 days or less of starting dosing with KD025. As 
this is an open-label study, safety results will be continuously monitered. If ≥ 25% of subjects in 
a cohort experience a CTCAE v4.03 Grade 2 liver toxicity or a CTCAE v4.03 Grade 3 (or 
higher) AE in the same organ or body system, or if > 25% of subjects in a cohort are 
discontinued for toxicity that persists for 14 days, then dose escalation to the next cohort will not 
occur, and all patients in that dose cohort will be dose reduced.  
14.3. 
Missed Doses 
Subjects should make every effort to take the study drug at the same scheduled time daily. In the 
event that the subject misses the planned dose of study drug, the following protocol should be 
followed: 
For subjects 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 subject 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 subject should then resume the regular planned dosing schedule 
the following day. 
For subjects receiving study drug on a BID dosing schedule: 
• 
If less than 6 hours of time have elapsed after the morning scheduled dose, the drug should 
be taken. The subject should then resume the regular planned dosing that evening. If less 
than 6 hours of time have elapsed after the evening scheduled dose, the drug should be 
taken. The subject should then resume the regular planned dosing the following morning.  
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• 
If more than 6 hours of time have elapsed after the morning scheduled dose, the drug 
should be skipped and the subject should resume the regular planned dosing schedule that 
evening. If more than 6 hours of time have elapsed after the evening scheduled dose, the 
drug should be skipped and the subject should resume the regular planned dosing the 
following morning. 
If the subject skips more than 7 consecutive days of drug, the subject should be discontinued 
from the study. 
14.4. 
Dose Pause or Reduction of KD025  
Exacerbation of any of the signs or symptoms of the disease will constitute a potential rationale 
for cessation of therapy. Any clinically significant toxicity will necessitate consideration of 
either a pause or cessation of therapy. Both laboratory and clinical data may constitute a reason 
to pause or cease therapy. Previous studies have indicated that reversible and modest liver 
toxicity may occur spontaneously after a few weeks of initiation of therapy.   
• 
When treatment-related Grade 3 toxicities occur, drug administration will be halted until 
recovery to at least Grade 1, at which time study drug may be resumed at a reduced dose.   
• 
When treatment-related Grade 2 toxicities, other than liver toxicities, occur, drug 
administration will be halted until recovery to at least Grade 1 at which time study drug 
administration may resume at the same dose.   
• 
When greater then Grade 2 liver toxicities occur, drug administration will be halted until 
recovery to at least Grade 1 at which time study drug administration may resume at a 
reduced dose.   
Pauses in therapy may not last more than 14 days; subjects requiring pauses of more than 
14 days will be discontinued from the study. If treatment-related Grade 2 or treatment-related 
Grade 3 toxicities persist for 14 days, subjects will be discontinued from the study.    
14.4.1 
Dose Reduction Steps 
Every effort should be made to keep the subject on the full dose of drug. When dose reduction is 
necessary (see Section 14.4), the drug should be decreased as shown in Table 5 (for subjects on 
100 mg capsules) and Table 6 (for subjects on 200 mg tablets),  until the event has resolved. 
Once a subject has the dose decreased, an increase is not allowed. 
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Table 5: 
Dose Reductions for Toxicity Related to Study Drug – 100 mg Capsule 
Study Drug 
Cohort 
Starting Dose 
Dose Reduction 
KD025 
Cohort 1 
200 mg KD025 QD 
100 mg KD025 QD 
KD025 
Cohort 2 
200 mg KD025 BID  
200 mg KD025 QD 
KD025 
Cohort 3 
400 mg KD025 QD  
200 mg KD025 QD 
BID = twice daily; QD = once daily 
No more than 1 dose reduction is permitted. Subjects who require more than 1 dose reduction will have study drug 
discontinued and enter the Follow-Up Period.   
 
Table 6: 
Dose Reductions for Toxicity Related to Study Drug – 200 mg Tablet 
Study Drug 
Cohort 
Starting Dose 
Dose Reduction 
KD025 
Cohort 1 
200 mg KD025 QD 
200 mg KD025 QOD 
KD025 
Cohort 2 
200 mg KD025 BID  
200 mg KD025 QD 
KD025 
Cohort 3 
400 mg KD025 QD  
200 mg KD025 QD 
BID = twice daily; QD = once daily; QOD = every other day 
No more than 1 dose reduction is permitted. Subjects who require more than 1 dose reduction will have study drug 
discontinued and enter the Follow-Up Period.   
14.5. 
Identity of Investigational Products 
KD025 will be supplied by Kadmon Corporation.   
14.6. 
Study Drug Packaging and Labeling 
KD025 will be packaged and labeled by the sponsor. The label attached to each bottle will 
provide the following information: 
• 
Description of contents (number and strength of capsules) and route of administration 
• 
Directions for use 
• 
Storage conditions 
• 
Product identification code 
• 
Lot Number identification  
• 
Bottle number 
• 
Name of protocol sponsor 
• 
The statement, “Caution: New Drug – Limited by Federal Law to Investigational Use”  
• 
The statement, “Keep out of the reach of children and pets.”  
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14.7. 
Dispensing of Study Drug and Dosing Compliance 
Subjects will be dispensed study drug to self-administer while on an outpatient basis. Subjects 
will return to the clinic as outlined in the Study Assessments (Table 1), and will receive that 
day’s dose of study drug while at the clinic. 
The amount of study drug dispensed to the subject at the beginning of each dosing month should 
be sufficient to allow for 1 month of dosing with KD025. 
The investigator (or designee) will be responsible for recording this information on the 
appropriate study drug inventory. This inventory will be maintained throughout the duration of 
the trial and will be periodically reviewed by a representative of the sponsor. 
The investigator (or designee) will instruct the subject that all dispensed bottles must be returned 
at each follow-up visit, at which time a capsule/tablet count will be conducted to assure subject 
dosing compliance. 
Additionally, subjects will be required to keep study drug diaries in which they will record the 
date and time of study drug administrations. These diaries will be dispensed and/or 
reviewed/collected at each visit. 
14.8. 
Study Drug Storage 
All supplies of study drug are to be stored at USP controlled room temperature of 20−25°C 
(66−77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F). At the clinic, the 
study drugs are to be stored in a securely locked area, accessible to authorized persons only, until 
needed for dosing. 
14.9. 
Study Drug Accountability 
The US Food and Drug Administration (FDA) and other regulatory agencies require accounting 
for the disposition of all investigational drugs received by each clinical site. Information on drug 
disposition required by law consists of the date received, date administered, quantity 
administered, and the subject to whom the drug was administered. The principal investigator is 
responsible for the accounting for all unused study drugs and all used study drug containers. The 
investigator must maintain a complete and current dispensing and inventory record that has been 
supplied by the sponsor. 
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14.10. 
Study Drug Handling and Disposal 
At the termination of the study, a final drug accountability review and reconciliation must be 
completed and any discrepancies must be investigated and their resolution documented. 
14.10.1 
Disposition of Used Supplies 
At the completion of a subject’s participation in the trial, all partially used and empty study drug 
containers must be returned to the investigator (or designee) so that a final subject-dosing 
inventory may be conducted. This information will be recorded on the Drug Dispensing Log.  
14.10.2 
Inventory of Unused Supplies 
Periodically throughout and at the conclusion of the study, an inventory of unused study drug 
will be conducted by a representative of the sponsor.   
 
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15. 
CONCOMITANT MEDICATION AND TREATMENT 
If the subject must use a concomitant medication during the study, it is the responsibility of the 
principal investigator to ensure that details regarding the medication are recorded on the eCRF. 
A reasonable effort is to be made to document any medications the subject received at the time 
of signing the ICF through the end of the study (follow-up visit). After discontinuation of study 
drug, any concomitant medication used during the study in response to an AE is to be recorded 
on the appropriate eCRF. 
Subjects must be receiving glucocorticoid therapy for cGVHD at study entry (subjects also may 
be receiving CNI therapy). Any changes in corticosteroid, CNI, or ECP doses will be 
documented.   
Use of drugs that prolong QT/QTc should be used with caution in subjects who are receiving 
KD025. Discuss with medical monitor the appropriate monitoring of subjects while receiving 
any of these drugs in conjunction with KD025. 
The concomitant medication names will be coded by the sponsor according to the World Health 
Organization Drug Dictionary (WHO-DD) and classified by anatomical therapeutic chemical 
categories. 
The use of medications that are strong CYP3A4 inducers is prohibited.  Other CYP3A4 
inhibitors / inducers should be used with caution. (See Appendix H for a listing of these drugs.) 
CYP1A2 inhibitors/ inducers should be used with caution.  
 
 
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16. 
SAFETY 
16.1. 
Safety Parameters 
The CTCAE v.4.03 will be used for grading toxicities. Laboratory results also will be classified 
using the CTCAE v4.03. Subjects 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, serum 
chemistries, and urinalysis results, and ECG recordings. 
16.2. 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical trial subject associated with the 
use of a drug, whether or not considered drug related. An AE can be an unfavorable and unintended 
sign (eg, an abnormal laboratory value finding), a symptom, or a disease temporally associated with 
the use of a drug, without judgment as to causality. An AE can arise from use of the drug (eg, use in 
combination with another drug) and from any route of administration, formulation or dose, including 
an overdose. An AE also includes, but is not limited to, any clinically significant worsening of a pre-
existing condition. Examples include: 
• 
Any sign, symptom, physical finding, or laboratory result that has worsened in nature, 
severity or frequency compared to baseline; 
• 
Reactions from an investigational drug, including those occurring as a result of an 
overdose, abuse of the study drug, withdrawal phenomena, sensitivity or toxicity; 
• 
Concurrent illness that was not present or worsens in nature, severity, or frequency 
compared to baseline;  
• 
Injury or accident; and/or 
• 
Exacerbation of a pre-existing condition 
For the purpose of data collection, all untoward events that occur after informed consent through 
28 days after last dose of study drug are to be recorded on eCRFs by the investigational site.   
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16.3. 
Evaluating Adverse Events 
The investigator will determine the seriousness, intensity, and causality of an AE associated with 
the use of the study drug (ie, events where there is a reasonable possibility that the event may 
have been caused by the study drug) based on the definitions that follow. 
16.3.1 
Serious Adverse Events 
(Notify sponsor or designee within 24 hours) 
The SAE definition and reporting requirements are in accordance with Title 21 Part Code of 
Federal Regulations (CFR) 312.32 and the Guidance for Industry and Investigators Safety 
Reporting Requirements for Investigational New Drug (INDs) and 
Bioavailability/Bioequivalence Studies. 
SAE: An adverse event is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death:  This includes any death that occurs while the subject is “on study” as well as any death 
that occurs within 28 days after study drug discontinuation.  
Note: Death is an outcome of an AE, and not an AE in itself. The event(s) that 
caused death (eg, illness, accident) is the SAE. Death due to any other 
cause(s) must also be reported as an outcome of the reportable SAE. 
• Life-threatening AE:  An AE or suspected adverse reaction is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an AE or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  
• Inpatient hospitalization or prolongation of existing hospitalization:  In the absence of an AE, 
the investigator should not report hospitalization or prolongation of hospitalization. This is the 
case in the following situations: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol 
• 
Hospitalization or prolongation of hospitalization is part of routine procedure followed by 
study center 
• 
Hospitalization for survey visits or annual physicals 
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In addition, a hospitalization planned before the start of the study for a pre-existing condition 
which has not worsened does not count as an SAE.  
• Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
• Congenital anomaly/birth defect 
• Important medical event:  An event that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, it 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.   
16.3.2 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
(Notify sponsor or designee within 24 hours of first awareness) 
A suspected unexpected serious adverse reaction is any adverse drug event, the specificity or 
severity of which is not consistent with those noted in the current protocol and/or IB. This refers 
to any AE that has not been previously observed (eg, included in the IB), rather than from the 
perspective of such an event not being anticipated from the pharmacological properties of the 
product.  
16.3.3 
Unexpected Adverse Events  
(Notify sponsor or designee by the next business day) 
An AE is considered “unexpected” if it is not listed in the IB or is not listed at the specificity or 
severity that has been observed; or, if an IB is not required or available, is not consistent with the 
risk information described in the General Investigational Plan or elsewhere in the current 
application. Also refers to AEs that are mentioned in the IB as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
16.3.4 
Non-Serious Adverse Events  
All other AEs, not fulfilling the previous definitions, are classified as nonserious. 
16.3.5 
Protocol-Related Adverse Events 
AEs that are not study drug related may nevertheless be considered by the investigator or the 
medical monitor to be related to the conduct of the clinical study. That is, the event may be 
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related to the fact that a subject is participating in the study. For example, a protocol-related AE 
may be an event that occurs during a washout period or that is related to a procedure required by 
the protocol. 
16.3.6 
Relationship to Study Drug 
The investigator will attempt to assess the relationship of the event to study drug using a 5-point 
scale (not related, unlikely-related, possibly related, probably related, or definitely related; (see 
Appendix G). 
16.3.7 
Recording Adverse Events 
All AEs (including SAEs) are to be accurately recorded on the Adverse Event page of the 
subject’s eCRF during the subject’s participation in the study. The severity of each AE will be 
graded using the CTCAE v 4.03 scale. The date of onset as well as the end date of the event also 
should be recorded or the event should be entered as “ongoing”. In addition, the method used to 
treat the AE and the outcome of the AE also will be noted. In the event that the grade of an AE 
worsens, an end date should be entered to the initial AE and a new AE entered with the updated 
grade and date of onset. The investigator will assess the relationship of the event to study drug. 
Note: All SAEs also are to be entered onto an SAE form and sent to sponsor or designee. 
16.3.8 
Hospitalization 
In the absence of an AE, the investigator should not report hospitalization or prolongation of 
hospitalization. This is the case in the following situations: 
• 
Hospitalization or prolongation of hospitalization is needed for a procedure required by the 
protocol. 
• 
Hospitalization or prolongation of hospitalization is part of routine procedure followed by 
study center. 
• 
Hospitalization for survey visits or annual physicals. 
In addition, a hospitalization planned before the start of the study for a pre-existing condition that 
has not worsened does not count as an SAE. 
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16.3.9 
Serious Adverse Event Reporting 
16.3.9.1. Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the sponsor is responsible 
for informing the US FDA as well as all other participating investigators of the event.  
Under FDA ruling (US Code of Federal Regulations, Title 21 CFR Part 312.32) and the 
Guidance for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE 
Studies, the sponsor is required to submit written documentation, in the form of an IND safety 
report, detailing: 
• 
Any event associated with the use of the drug, that is both serious and unexpected, or  
• 
Any findings from clinical, epidemiological, or pooled analysis of multiple studies or any 
findings from animal or in vitro testing that suggest a significant risk in humans exposed to 
the drug.  
Written submission must be made by the sponsor to the FDA and the IRB/IECs as soon as 
possible and in no event later than 15 calendar days after the sponsor’s initial notification of the 
event. Any unexpected death or life-threatening suspected adverse drug reaction must be 
reported to FDA no later than 7 calendar days after the sponsor’s initial receipt of the 
information. The sponsor shall also inform all investigators. 
16.3.9.2. Time-Frame for Reporting 
Any death, SAE, pregnancy (including pregnancy of a partner), or unexpected (and severe) AE 
experienced by a subject while receiving or within 28 days of receiving study drug, regardless of 
relationship to study drug, or any death that occurs more than 28 days after receiving study drug, 
and is believed to be study drug-related, must be promptly reported (within 24 hours of the 
investigator becoming aware of the event) by e-mail to the sponsor (or designee). 
Contact information for SAE/SUSAR reporting: 
APCER Life Sciences, Inc. 
Fax Number:  1-646-430-9549 
Email: clinicalsaereporting@kadmon.com  
Additionally, the investigator will be able to contact the medical monitor at all times: 
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16.3.9.3. Information to be Provided by the Investigator 
SAEs for all enrolled subjects must be recorded on the SAE form (during study participation). 
This requirement includes all SAEs that occur after informed consent and through 28 days after 
last dose of study drug, and in addition, any SAEs that are assessed as possibly related to study 
drug by the investigator, even if the SAE occurs more than 28 days after the last dose of study 
drug must be reported to the Kadmon Corporation Pharmacovigilance Department (or designee). 
The minimum information required for SAE reporting includes identity of investigator, site 
number, subject number, an event description, SAE term(s), onset date, the reason why the event 
is considered to be serious (ie, the seriousness criteria) and the investigator’s assessment of the 
relationship of the event to study drug. Additional SAE information including medications or 
other therapeutic measures used to treat the event, action taken with the study drug due to the 
event, and the outcome/resolution of the event will be recorded on the SAE form. Forms for 
reporting SAE will be provided to the study sites. 
In all cases, the investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. Furthermore, the investigator 
may be required to provide supplementary information as requested by the Kadmon Corporation 
Drug Safety personnel or designee. 
When reporting SAE, the following additional points should be noted: 
• 
When the diagnosis of an SAE is known or suspected, the investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs 
and symptoms may then be described in the event description. For example, dyspnea 
should not be used as an SAE term if the diagnosis which caused the dyspnea is known to 
be malignant pleural effusion.   
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• 
Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown. In the exceptional case where the events leading to 
death are unknown, then death may be used as an event term. If an autopsy was performed, 
the autopsy report should be provided.  
• 
While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
o Elective or previously scheduled surgery (eg, a previously scheduled ventral hernia 
repair) 
o Procedures for pre-existing conditions that have not worsened after initiation of 
treatment 
o Pre-specified study hospitalizations for observation 
o Events that result in hospital stays of less than 24 hours and that do not require 
admission (eg, an emergency room visit for hematuria that results in a diagnosis of 
cystitis and discharge to home on oral antibiotics) 
o SAEs must, however, be reported for any surgical or procedural complication 
resulting in prolongation of the hospitalization. 
16.3.9.4. Regulatory Reporting 
Kadmon Corporation Drug Safety (or designee) will process and evaluate all SAEs as soon as 
the reports are received. For each SAE received, Kadmon Corporation will make a determination 
as to whether the criteria for expedited reporting have been met. 
Kadmon Corporation (or designee) will submit SAEs that meet the criteria for expedited 
reporting to the Regulatory Authorities in accordance with local regulations governing safety 
reporting. Reporting of SAEs by the investigator to his or her IRB/IEC will be done in 
accordance with the standard operating procedures and policies of the IRB/IEC. Adequate 
documentation must be maintained showing that the IRB/IEC was properly notified. 
16.4. 
Other Safety Considerations 
16.4.1 
Laboratory Data 
All laboratory data obtained during the course of the study should be reviewed. Any abnormal 
value that leads to a change in subject 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 
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consistent with the subject’s present disease state or is consistent with values obtained before 
entry into the study. 
Laboratory results will be classified using the CTCAE v4.03. 
16.4.2 
Medication Errors 
Any medication error that results in an AE, even if it does not meet the definition of serious, 
requires reporting within 24 hours to the safety monitor. 
16.4.3 
Follow-Up of Adverse Events 
Any SAE or AE assessed as at least possibly related that led to treatment discontinuation 
(including clinically significant abnormal laboratory values that meet these criteria) and is 
ongoing 28 days after last dose of study drug must be followed until either resolution of the 
event or determination by the investigator that the event has become stable or irreversible. This 
follow-up guidance also applies to possibly related SAEs that occur more than 28 days after last 
dose of study drug. The status of all other continuing AEs will be documented as of 28 days after 
last dose of study drug.   
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17. 
STATISTICAL CONSIDERATIONS  
All descriptive and inferential statistical analyses will be performed using SAS® (SAS Institute, 
Cary, North Carolina) statistical software, unless otherwise noted. For categorical variables, the 
number and percent of each category within a parameter will be calculated for non-missing data. 
For continuous variables, the mean, median and standard deviation, as well as the minimum and 
maximum values, will be presented.  
Statistical significance will be declared when the P value is found to be ≤ 0.05, unless otherwise 
noted. All clinical data captured will be provided in data listings. 
17.1. 
General Design  
All data for enrolled subjects will be presented in data listings by subject number. For those 
summary tables in which baseline and change from baseline measurements will be presented, the 
last observed measurement prior to the initial dose of KD025 will be considered the baseline 
measurement.   
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 discrete (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. Two-sided 95% confidence interval employing the exact binomial 
method will be provided for activity outcomes. 
Hypothesis testing, if appropriate, will be carried out at the 5% (2-sided) significance level. 
Because of the exploratory nature of the study, no adjustments will be made for the multiplicity 
of endpoints. Nonparametric tests may be used in preference to parametric tests if parametric 
assumptions are notably violated. Missing values will not be imputed. If a subject does not have 
sufficient data for a particular analysis, they will be excluded from that analysis. Endpoints 
defined as an average of multiple measurements will be used those data points that are 
non-missing, and the denominator was adjusted accordingly. 
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17.2. 
Sample Size Justification  
The total sample size of 16 subjects per KD025 dose group will provide > 90% probability of 
one or more KD025 subjects experiencing an AE that has an underlying rate of ≥ 14% and 
> 80% probability of one or more subjects in the study experiencing an AE that has an 
underlying rate of ≥ 10%. 
Assuming an underlying 25% rate for subjects to meet the ORR, each treatment group of 
16 subjects has an approximately 80% chance of having at least 3 subjects meet the overall 
response criteria, and approximately 90% chance of at least 2 subjects meet the overall response 
criteria. 
17.3. 
Statistical Considerations  
The statistical methodology will be further described in a Statistical Analysis Plan, which will be 
finalized prior to database lock. 
17.3.1 
Study Populations  
Four populations will be employed in the analysis of study data: 
• 
The modified intent-to-treat (mITT) population will consist of all subjects who are enrolled 
in the study and receive at least 1 dose of study medication.  
• 
The safety population will consist of all subjects who receive at least one dose of KD025  
• 
The PK population which will consist of all subjects who receive at least one dose of study 
drug and have at least 1 post-dose PK sample drawn 
17.3.2 
Subject Accountability, Demographics, and Baseline Characteristics  
Demographics, subject disposition, and screening and baseline characteristics will be 
summarized for the mITT population.  
17.3.3 
KD025 Exposure  
The amount of KD025 administered by visit and overall will be tabulated and presented by 
subject in data listings. In addition, delays and all other alterations in KD025 administration will 
be presented.  
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17.3.4 
Concomitant Medications  
Concomitant medications will be coded using WHO-DD and the data will be summarized by 
treatment group and presented in tables and listings.  
17.4. 
Activity Analysis 
The primary activity outcome will be the percentage of subjects who meet the OR criteria (PR + 
CR). This will be assessed overall (ie, any subject meeting the PR or CR criteria at any time 
point).  For clarity, addition of new systemic therapy for cGVHD will be considered a KD025 
treatment failure and will be considered progression of cGVHD for analysis purposes. 
Secondary Endpoints  
• Number and percentage of KD025 in subjects with steroid-dependent cGVHD who have a 
best response of PR or CR 
• Change in cGVHD severity as based on the Physician-reported Global cGVHD Activity 
Assessment  
• Change in symptom activity as based on cGVHD Activity Assessment Patient Self-Report  
• Median FFS will be defined as the time from first dose of study drug to either the start of 
another treatment, relapse of the underlying disease, or death.   
• Changes in corticosteroid and calcineurin inhibitor dose  
• To evaluate DOR, which will be defined as the time of initial response until documented 
progression.  
• To evaluate response by organ system. The response by organ system (PR and CR) will be 
assessed based on the 2014 NIH Consensus Development Project on Clinical Trials in 
cGVHD. 
• Analyses of plasma PK of KD025 in subjects with cGVHD 
• OS will be defined as the 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. 
• TTNT will be defined as the defined as the time from the first dose of KD025 to the start of 
additional systemic cGVHD therapy Change in symptom burden/bother using the Lee 
cGVHD Symptom Scale. 
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Exploratory Endpoints  
• Changes in the expression of several cytokines (including IL-17A, IL-21, and IL-2) in 
plasma after KD025 administration to subjects with cGVHD 
• Changes in percentage of immune-cell subtypes (including Th17 and Treg cells) in whole 
blood after KD025 administration to subjects with cGVHD 
17.5. 
Safety Data  
The primary safety endpoint is the percent of subjects experiencing AEs in Cohort 1 
(200 mg QD), Cohort 2, (200 mg BID), and Cohort 3 (400 mg QD).  
Safety assessments include AEs, SAEs, PEs, vital sign measurements, clinical laboratory 
evaluations (including TSH measurements), ECGs, PFTs, and reasons for treatment 
discontinuation due to toxicity.  
Treatment-emergent AEs will be evaluated using the CTCAE v4.03. The secondary safety 
outcome will be the number and percent of subjects experiencing AEs overall. The total sample 
size of 16 subjects per KD025 dose group will provide > 90% probability of one or more KD025 
subjects experiencing an AE that has an underlying rate of ≥ 14% and > 80% probability of one 
or more subjects in the study experiencing an AE that has an underlying rate of ≥ 10%.  
Treatment-emergent AEs will be summarized by treatment group using Medical Dictionary for 
Regulatory Activities (MedDRA®) System Organ Class (SOC) and preferred term, classified 
from verbatim terms.  MedDRA® Version 20.0 or higher will be used.  The incidence and 
percentage of subjects with at least 1 occurrence of a preferred term will be included. The 
number of events per preferred term will also be summarized. Causality (relationship to study 
treatment) will be summarized separately. 
All AEs, SAEs, treatment-related AEs, treatment-related SAEs, ≥ Grade 3 AEs, treatment-related 
≥ Grade 3 AEs, and AEs leading to withdrawal, or treatment discontinuation will be summarized 
overall and by treatment group according to SOC and preferred terms. AEs will also be presented 
in listings. Duration of AEs will be determined and included in listings, along with action taken 
and outcome. 
Laboratory results will be classified using the CTCAE v4.03 and summarized by treatment 
group. Incidence of laboratory abnormalities will be summarized. The worst on-study grade after 
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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 sign measurements will be summarized by treatment group at each scheduled time point 
using descriptive statistics. 
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18. 
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 subject to electronic and manual quality assurance procedures. 
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19. 
ETHICAL ASPECTS 
19.1. 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
ICH E6 Tripartite Guideline (January 1997), 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 Subjects”, and Part 56, “Institutional Review Boards”. 
19.2. 
Informed Consent 
Sample ICFs will be supplied to each site. Kadmon Corporation or its designee must review any 
ICF prior to submission for review by the IRB/IEC. The final IRB/IEC-approved document must 
be provided to Kadmon Corporation for regulatory purposes. 
It is the responsibility of the investigator, or a person designated by the investigator, to obtain 
written informed consent from each subject (or the subject’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 federal and state regulations. In the case 
where the subject is unable to read, an impartial witness should be present during the entire 
informed consent discussion. After the subject has orally consented to participation in the trial, 
the witness’ signature on the form will attest that the information in the consent form was 
accurately explained and understood. A copy of the ICF must be provided to the subject or to the 
subject’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 subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’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 form should be reviewed and updated as 
necessary. All subjects (including those already being treated) should be informed of the new 
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information, should be given a copy of the revised form, and should give their consent to 
continue in the study. 
19.3. 
Institutional Review Board 
This study is being conducted under a United States IND application. This protocol (and any 
modifications) and appropriate consent procedures must be reviewed and approved by an 
IRB/IEC. This board must operate in accordance with the current federal or local regulations. 
The investigator will send a letter or certificate of IRB/IEC approval to Kadmon Corporation (or 
designee) before subject enrollment and whenever subsequent modifications to the protocol are 
made. 
19.4. 
Future Use of Subject Samples 
Not all of the tissue and blood components obtained during this study may be required for the 
tests that are part of the clinical trial. Following the conclusion of the study, the samples may be 
used for additional research. This research will help to understand disease subtypes, drug 
response and toxicity, and possibly identify new drug targets or biomarkers that predict subject 
response to treatment. The use of the samples for internal research will be done according to the 
guidelines defined by the FDA guidance for In Vitro Diagnostic Device Studies Using Leftover 
Human Specimens that are Not Individual Identifiable (issued 25 April 25 2006) and the 
European Medicines Agency Reflection Paper on Pharmacogenetic Samples, Testing and Data 
Handling (EMEA/CHMP/PGxWP/201914/2006). If a subject requests destruction of their tissue 
and blood samples and the samples have not yet been de-identified, Kadmon Corporation will 
destroy the samples as described in this FDA guidance. Kadmon Corporation will notify the 
investigator in writing that the samples have been destroyed. 
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20. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications will be reviewed, and approved by Kadmon Corporation 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 subjects, 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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21. 
CONDITIONS FOR TERMINATING THE STUDY 
Kadmon Corporation has the right to terminate the study at any time. In terminating the study, 
Kadmon Corporation and the investigator will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
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22. 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
22.1. 
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) subject 
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. 
Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the eCRFs) may include subject 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 subject 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 notified. After that period of time, the documents may be destroyed 
subject to local regulations with prior written permission from Kadmon Corporation. If the 
investigator wants to assign the study records to another party or move them to another location, 
Kadmon Corporation 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 Kadmon 
Corporation 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 subject, appropriate copies should be made for storing 
outside of the study site. 
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22.2. 
Source Documents and Background Data 
Upon request, the investigator will supply Kadmon Corporation 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 subject confidentiality is protected. 
22.3. 
Audits and Inspections 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Kadmon Corporation 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. 
22.4. 
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 Kadmon 
Corporation (or designee) in the eCRF and in all required reports. 
An eCRF is required to be submitted for every subject who receives any amount of study drug. 
This includes submission of retrievable data on subjects 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 subject 
stops treatment or terminates from the study, the dates and reasons must be noted on the eCRF. 
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23. 
MONITORING THE STUDY 
It is understood that the responsible Kadmon Corporation 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 subject 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 subject 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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24. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS 
The investigator must ensure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On eCRFs or other documents submitted to Kadmon 
Corporation, subjects should be identified by an identification code and not by their names. The 
subjects’ personal information should be redacted on all source documents prior to submission to 
Kadmon Corporation (or designee). The investigator should keep a Subject Enrollment Log 
showing codes, names, and addresses. The investigator should maintain documents not for 
submission to Kadmon Corporation (eg, subjects’ written consent forms) in strict confidence. 
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25. 
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 Kadmon Corporation for review at least 30 days 
before submission. This allows Kadmon Corporation 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 Kadmon Corporation 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 Kadmon Corporation policy and generally 
accepted standards for authorship. 
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26. 
REFERENCES 
 
American Thoracic Society.  Standardization of Spirometry.  Am J Respir Crit Care Med.  1995; 
152:  1107-1136. 
Cobert, B. Cobert’s Manual of Drug Safety and Pharmacovigilance (2nd ed) 2012.  
Massachusetts:  Jones & Bartlett Learning, LLC. 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Published: May 28, 
2009 (v4.03: June 14, 2010). U.S. Department of Health and Human Services. National 
Institutes of Health. National Cancer Institute. 
Hankinson, JL, Odencrantz, JR, Fedan, KB. Spirometric Reference Values from a Sample of the 
General U.S. Population. Am J Respir Crit Care Med. 1999; 159:  179-187. 
Karnofsky, DA, and Burchenal, JH. 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), 
1940; pp. 191-205. 
Lee S, Cook EF, Soiffer R, et al. Development and validation of a scale to measure symptoms of 
chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002; 8:444-452. 
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. 
Levey AS, Coresh J, Greene T et al. Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration 
rate. Ann Intern Med. 2006; 145 (4): 247–54. PMID 16908915. 
Quanjer PH, Tammeling GJ, Cotes JE, Pederson OF, et al.  Lung Volumes and Forced 
Ventilatory Flows.  Report Working Party Standardization of Lung Function Tests, 
European Community for Steel and Coal.  Official Position of the European Respiratory 
Society.  Eur Respir J. 1993; 16(Suppl):  5-40.
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27. 
APPENDICES 
Appendix A: Physician-Reported Global cGVHD Activity Assessment Form A 
 
 
 
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Appendix A: Physician-Reported Global cGVHD Activity Assessment Form A (cont.) 
 
Abstracted from:  Lee SJ, et al. Biol Blood Marrow Transplant. 2015; 21:984-999. 
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Appendix B: cGVHD Response Assessment  
Abstracted from:  Lee SJ, Wolff D, Kitko C, et al. Biol Blood Marrow Transplant 2015; 21:984 – 999.  
 
Definition of Response 
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 (LOR-M) 
Complete or partial response in at least one organ accompanied by 
progression in another organ* 
 
Unchanged (LOR-U) 
Outcomes that do not meet the criteria for complete response, 
partial response, progression or mixed response 
 
Progression (LOR-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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Appendix C: Chronic GVHD 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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Appendix D: Lee cGVHD Symptom Scale   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abstracted from:  
Lee S, Cook EF, Soiffer R, et al. Development and validation of a scale to measure symptoms of 
chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002; 8:444-452. 
 
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Appendix E: Karnofsky Performance Scale  
Condition 
Percent 
Description 
Able to carry on 
normal activity and to 
work. No special care 
needed. 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
Unable to work.  Able 
to live at home and 
care for most personal 
needs.  A varying 
degree of assistance is 
needed. 
70 
Cares for self, unable to carry on normal activity or to do active 
work. 
60 
Requires occasional assistance, but is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and frequent medical care. 
Unable to care for 
self. Requires 
equivalent of 
institutional or 
hospice care. Disease 
may be progressing 
rapidly. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
 
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. 
 
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Appendix F: Equations to Predict Glomerular Filtration Rate (MDRD-4)  
 
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. . Using standardized serum creatinine values in the modification 
of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006; 
145 (4): 247–54. PMID 16908915. 
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Appendix G: Clinical Adverse Events: Determining Relationship to Study Drug 
 
1 
NOT RELATED 
This category applies to those AEs, which after careful medical consideration, are clearly 
felt to be due to extraneous causes (eg, disease, environment, etc.) that are unrelated to 
the administration of study drug. 
 
2 
UNLIKELY RELATED (must have first 2) 
This category applies to those AEs, which, after careful medical consideration, are felt 
unlikely to be related to the administration of the study drug.  The relationship of an AE 
to the study drug can be considered unlikely if: 
 
• It does not follow a reasonable temporal sequence from administration of the drug. 
• It could readily have been a result of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
• It does not follow a known response pattern to the suspected drug. 
• It does not reappear or worsen when the drug is re-administered. 
 
3 
POSSIBLY RELATED (must have first 2) 
 
This category applies to those AEs, which, after careful medical consideration, are felt 
unlikely to be related to the administration of the study drug, but the possibility cannot be 
ruled out with certainty.  The relationship of an AE to the study drug can be considered 
possible if: 
 
• It follows a reasonable temporal sequence from administration of the drug. 
• It could readily have been a result of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
• It follows a known response pattern to the suspected drug. 
 
4 
PROBABLY RELATED (must have first 3) 
 
This category applies to those AEs, which, after careful medical consideration, are felt 
with a high degree of certainty to be related to the administration of the study drug.  The 
relationship of an AE to the study drug can be considered probable if: 
 
• It follows a reasonable temporal sequence from administration of the drug.  
• It could not be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors or other modes of therapy administered to 
the subject. 
• It disappears or decreases upon cessation of drug or reduction in dose.* 
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• It follows a known response pattern to the suspected drug. 
 
5 
DEFINITELY RELATED (must have first 3) 
 
This category applies to those AEs, which after careful medical consideration, are felt to 
be related to the administration of the study drug.  The relationship of an AE to the study 
drug can be considered related if: 
• It follows a reasonable temporal sequence from administration of the drug or drug 
levels have been established in body fluids or tissues. 
• It could not be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors or other modes of therapy administered to 
the subject. 
• It disappears or decreases upon cessation of drug or reduction on dose and appears 
upon rechallenge.* 
• It follows a known response pattern to the suspected drug. 
 
 
 
*There are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug relatedness clearly exists. 
 
 
Adapted from:  Cobert, B..  Cobert’s Manual of Drug Safety and Pharmacovigilance 2012 (2nd ed).  Massachusetts:  Jones 
& Bartlett Learning, LLC. 
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Appendix H: Drugs that Induce and Inhibit CYP3A4 
Use of drugs that are strong inducers of the CYP3A4 family of enzymes is prohibited in subjects 
who are receiving KD025.  Other CYP3A4 inhibitors/ inducers should be used with caution. 
This is not a comprehensive list, and all concomitant medications should be evaluated for 
possible interactions with KD025. 
Drug Type 
Drug Name 
Moderate or 
Strong Inhibitors 
Human immunodeficiency virus 
antivirals 
amprenavir 
atazanavir 
atazanavir 
fosamprenavir 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
Antifungals 
itraconazole 
fluconazole  
ketoconazole  
Antibiotics 
clarithromycin 
erythromycin 
telithromycin 
Antidepressants 
nefazodone 
Calcium-channel blockers 
diltiazem  
verapamil  
Others 
aprepitant 
grapefruit juice 
Source: http://medicine.iupui.edu/flockhart/table htm, 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664 htm 
Use of drugs that are strong inducers of the CYP3A4 family of enzymes (refer to source below) 
is prohibited in subjects who are receiving KD025. 
Source: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm09366
4.htm 
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28. 
SUMMARY OF CHANGES TO PROTOCOL 
DOCUMENT HISTORY 
Document 
Date 
Amendment 7 
23 Oct 2019 
Amendment 6 
15 Oct 2018 
Amendment 5 
24 May 2018 
Amendment 4.1 
26 Oct 2017 
Amendment 4 
19 Oct 2017 
Amendment 3 
06 Jun 2017 
Amendment 2 
14 July 2016 
Amendment 1 
22 Feb 2016 
Original Protocol 
22 Dec 2015 
Amendment 7, 23 October 2019 
This protocol was amended to include the following secondary endpoints:  
• Overall Survival (OS) 
• Time to Next Treatment (TTNT) 
• Change in symptom burden/bother using the Lee cGVHD Symptom Scale 
Also, clarification regarding Long Term Follow Up of subjects and mode of contact was made.  
Pharmacokinetic samples and Pharmacodynamic samples are not required to be collected at the 
End of Treatment visit.  Also, CYP3A4 strong inducers are prohibited and other CYP3A4 
inducers/ inhibitors are to be used with caution. 
 
Minor grammatical and typographical corrections were also made.  
Note that the changes made within the text of the protocol were also made within the synopsis of 
the protocol. 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Synopsis-Study Objectives 
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Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Secondary objectives 
• To evaluate changes in cGVHD 
severity using the Physician-reported 
global cGVHD Activity Assessment 
form (see Appendix A) 
• To assess changes in symptom 
activity using the cGVHD Activity 
Assessment Patient Self-Report  
• To evaluate failure-free survival 
(FFS) 
• To evaluate changes in corticosteroid 
and calcineurin inhibitor (CNI) dose 
• To evaluate duration of response 
(DOR) 
• To evaluate response by organ 
system 
• To assess the plasma 
pharmacokinetics (PK) of KD025 in 
subjects with cGVHD 
• To evaluate Overall Survival (OS) 
• To evaluate Time to Next 
Treatment (TTNT) 
• To evaluate the change in symptom 
burden/bother using the Lee 
cGVHD Symptom Scale 
 
Exploratory objectives 
• To evaluate changes in the expression 
of several cytokines (including IL-
17A, IL-21, and IL-2) in plasma after 
KD025 administration  
• To evaluate changes in percentage of 
immune-cell subtypes (including Th17 
and Treg cells) in whole blood after 
KD025 administration 
• To evaluate the change in symptom 
burden/bother using the Lee cGVHD 
Symptom Scale 
 
Secondary objectives 
• To evaluate Overall Survival  (OS) 
• To evaluate Time to Next Treatment 
(TTNT) 
• To evaluate the change in symptom 
burden/bother using the Lee cGVHD 
Symptom Scale 
 
Exploratory objectives 
• To evaluate changes in the expression 
of several cytokines (including IL-
17A, IL-21, and IL-2) in plasma after 
KD025 administration  
• To evaluate changes in percentage of 
immune-cell subtypes (including Th17 
and Treg cells) in whole blood after 
KD025 administration 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
Synopsis- Methodology 
Subjects will be contacted 
Subjects will be contacted 
Long-Term Follow-Up 
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Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
approximately every 8 weeks and 
can be contacted via telephone, 
email or postal mail to confirm 
survival status and the initiation 
of any anti-cancer treatment or 
any changes in treatment of 
cGVHD. This can also be 
confirmed from electronic 
medical records.   
After the follow up visit is 
completed, subjects will be 
contacted by telephone every 8 
weeks until study closeout to 
confirm survival status and the 
initiation of any anti cancer 
treatment or any changes in 
treatment for cGVHD 
approximately every 8 weeks and 
can be contacted via telephone, 
email or postal mail to confirm 
survival status and the initiation of 
any anti-cancer treatment or any 
changes in treatment of cGVHD. 
This can also be confirmed from 
electronic medical records.   
clarification provided. 
Synopsis—Approximate Duration of Subject  Participation 
Subjects will be contacted 
approximately every 8 weeks and 
can be contacted via telephone, 
email or postal mail to confirm 
survival status and the initiation of 
any anti-cancer treatment or any 
changes in treatment of cGVHD. 
This can also be confirmed from 
electronic medical records. 
In addition, subjects will be contacted 
by telephone every 8 weeks until study 
closeout to confirm survival status and 
the initiation of any anti cancer 
treatment or any changes in treatment 
for cGVHD 
Subjects will be contacted 
approximately every 8 weeks and can 
be contacted via telephone, email or 
postal mail to confirm survival status 
and the initiation of any anti-cancer 
treatment or any changes in treatment 
of cGVHD. This can also be confirmed 
from electronic medical records 
Long-Term Follow-Up 
clarification provided. 
Synopsis—Concomitant Treatment 
The use of strong CYP3A4 
inhibitor/inducers (see Appendix H for 
a listing of these drugs) is prohibited. 
The use of strong CYP3A4 inducers 
(see Appendix H for a listing of these 
drugs) is prohibited. 
Based upon data from 
KD025-107 (KD025 
Drug-Drug-Interaction 
study). 
Synopsis- Activity Evaluation 
Failure-free survival, Overall 
Failure-free survival, Overall Survival, 
Statistical Analysis Plan 
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Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 107 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Survival, Time to Next Treatment 
and changes in corticosteroid and 
calcineurin inhibitor dose will be 
documented. Changes in symptom 
burden/bother will be documetned 
explored using the Lee cGVHD 
Symptom Scale. 
 
Time to Next Treatment and changes 
in corticosteroid and calcineurin 
inhibitor dose will be documented. 
Changes in symptom burden/bother 
will be documented using the Lee 
cGVHD Symptom Scale. 
is being updated to reflect 
these endpoints that will 
be analyzed.   
Synopsis- Pharmacokinetics 
Blood samples (approximately 5 mL) 
for determination of plasma 
concentrations of KD025 and its 
metabolites, will be collected on Day 1 
of Cycles 1 and 2 at the following time 
points: Pre-dose (Time 0), and 1, 2, 3, 
4, 5, and 6 hours after dosing (after 
first dose for subjects in the BID 
group). In addition, subjects will have 
samples collected pre-dose on Day 1 of 
Cycle 4, and pre-dose at the Cycle 7, 
Day 1 visit., and at the EOT visit. 
Also, if appropriate, a sample will be 
requested if a subject discontinues 
treatment prematurely. Subjects should 
be instructed to withhold taking study 
drug on these days as dosing will be 
performed at the clinic.  
Subjects will have a total 17 16 
samples drawn (85 80 mL).  
Blood samples (approximately 5 mL) 
for determination of plasma 
concentrations of KD025 and its 
metabolites, will be collected on Day 1 
of Cycles 1 and 2 at the following time 
points: Pre-dose (Time 0), and 1, 2, 3, 
4, 5, and 6 hours after dosing (after 
first dose for subjects in the BID 
group). In addition, subjects will have 
samples collected pre-dose on Day 1 of 
Cycle 4, and pre-dose at the Cycle 7, 
Day 1 visit. Subjects should be 
instructed to withhold taking study 
drug on these days as dosing will be 
performed at the clinic.  
Subjects will have a total 16 samples 
drawn (80 mL).  
 
Last subjects enrolled into 
study more than one year 
ago and no more 
Pharmacokinetics samples 
will be analyzed. 
Synopsis- Pharmacodynamics 
All subjects will have PD blood 
samples drawn 4 6 times over the 
course of the study: Pre-dose on Cycle 
1 Day 1, Cycle 2 Day 1 (4 weeks), and 
Cycle 4 Day 1 (12 weeks) and at the 
Cycle 7 Day 1 (24 weeks)visit; at the 
EOT visit, and at the 28 Day Follow
Up visit. Samples will be analyzed to 
evaluate changes in the expression of 
several cytokines in plasma (including 
IL-17A, IL-21, and IL-2), and changes 
All subjects will have PD blood 
samples drawn 4 times over the course 
of the study: Pre-dose on Cycle 1 Day 
1, Cycle 2 Day 1 (4 weeks), Cycle 4 
Day 1 (12 weeks) and Cycle 7 Day 1 
(24 weeks) will be analyzed to 
evaluate changes in the expression of 
several cytokines in plasma (including 
IL-17A, IL-21, and IL-2), and changes 
in percentages of circulating Th17 and 
Treg cells in blood.   
Pharmacodynamic 
samples do not have to be 
collected at the End of 
Treatment visit. Since it 
is not possible to predict 
the End of Treatment 
visits for the remaining 
subjects in the study, 
EOT samples for each 
subject would have to be 
analyzed on an as-
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 108 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
in percentages of circulating Th17 and 
Treg cells in blood.   
PD blood samples also will be 
requested for any subject who 
discontinues treatment prematurely 
 
collected basis. 
 
Synopsis- Statistical Analysis 
Four populations will be included in 
the analysis of study data: 
• 
The modified intent-to-treat 
(mITT) population will consist 
of all subjects who are enrolled 
in the study and receive at least 
1 dose of study medication 
who are not screen failures.   
• 
The safety population will 
consist of all subjects who 
receive at least one dose of 
KD025  
• 
The per protocol population will 
consist of subjects who have 
received at least 50% of study 
drug and have at least one 
evaluable response assessment 
• 
The PK population will consist 
of all subjects who receive at 
least one dose of study drug and 
have at least 1 post-dose PK 
sample drawn 
All analyses of safety will be 
performed on the safety population 
while activity will be performed on the 
mITT and Per Protocol populations. 
 
Overall survival (OS) will be defined 
as the 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 
Four populations will be included in 
the analysis of study data: 
• 
The modified intent-to-treat 
(mITT) population will consist 
of all subjects who are enrolled 
in the study and receive at least 
1 dose of study medication.   
• 
The safety population will 
consist of all subjects who 
receive at least one dose of 
KD025  
• 
The PK population will consist 
of all subjects who receive at 
least one dose of study drug and 
have at least 1 post-dose PK 
sample drawn 
 
All analyses of safety will be 
performed on the safety population 
while activity will be performed on the 
mITT population. 
 
 
 
 
 
Overall survival (OS) will be defined 
as the 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, 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
 
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 109 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
6, 12, 18 and 24 months will be 
provided. 
Time to Next Treatment (TTNT) 
will be defined as the time from the 
first dose of KD025 to the start of 
additional systemic cGVHD therapy.  
 
12, 18 and 24 months will be provided. 
Time to Next Treatment (TTNT) will 
be defined as the time from the first 
dose of KD025 to the start of 
additional systemic cGVHD therapy.  
 
Section 5.2 Secondary Objectives 
The secondary objectives of the study 
are: 
• To evaluate changes in cGVHD 
severity using the Physician-reported 
global cGVHD Activity Assessment 
form (see Appendix A) 
• To assess changes in symptom 
activity using the cGVHD Activity 
Assessment Patient Self-Report 
• To evaluate failure-free survival 
(FFS) 
• To evaluate changes in corticosteroid 
and calcineurin inhibitor (CNI) dose 
• To evaluate duration of response 
(DOR) 
• To evaluate response by organ 
system 
• To assess the plasma PK of KD025 
in subjects with cGVHD 
• To evaluate Overall Survival (OS) 
• To evaluate Time to Next 
Treatment (TTNT) 
• To evaluate the change in symptom 
burden/bother using the Lee 
cGVHD Symptom Scale 
The secondary objectives of the study 
are: 
• To evaluate changes in cGVHD 
severity using the Physician-reported 
global cGVHD Activity Assessment 
form (see Appendix A) 
• To assess changes in symptom 
activity using the cGVHD Activity 
Assessment Patient Self-Report  
• To evaluate failure-free survival 
(FFS) 
• To evaluate changes in corticosteroid 
and calcineurin inhibitor (CNI) dose  
• To evaluate duration of response 
(DOR) 
• To evaluate response by organ system 
• To assess the plasma PK of KD025 in 
subjects with cGVHD 
• To evaluate Overall Survival (OS) 
• To evaluate Time to Next Treatment 
(TTNT) 
• To evaluate the change in symptom 
burden/bother using the Lee cGVHD 
Symptom Scale 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
Section 5.3 Exploratory Objective 
To evaluate changes in the expression 
of several cytokines (including IL-
17A, IL-21, and IL-2) in plasma after 
KD025 administration 
To evaluate changes in percentage of 
immune-cell subtypes (including Th17 
and Treg cells) in whole blood after 
To evaluate changes in the expression 
of several cytokines (including IL-
17A, IL-21, and IL-2) in plasma after 
KD025 administration 
To evaluate changes in percentage of 
immune-cell subtypes (including Th17 
and Treg cells) in whole blood after 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 110 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
KD025 administration 
To evaluate the change in symptom 
burden/bother using the Lee cGVHD 
Symptom Scale 
 
KD025 administration 
 
Section  6.2 Study Endpoints 
Secondary Endpoints 
• Number and percentage of KD025 in 
subjects with steroid-dependent 
cGVHD who have a best response of 
PR or CR 
• Change in cGVHD severity as based 
on the Physician-reported global 
cGVHD Activity Assessment 
• Change in symptom activity as based 
on cGVHD Activity Assessment 
Patient Self-Report 
• Median failure-free survival (FFS) 
• Changes in corticosteroid and 
calcineurin inhibitor dose 
• DOR 
• Response rate by organ system 
• Analyses of plasma PK of KD025 in 
subjects with cGVHD 
• Overall Survival 
• Time to Next Treatment 
• Change in symptom burden/bother 
using the Lee cGVHD Symptom 
Scale 
 
Exploratory Endpoints  
• Changes in the expression of several 
cytokines (including IL-17A, IL-21, 
and IL-2) in plasma after KD025 
administration to subjects with 
cGVHD 
• Changes in percentage of immune-
cell subtypes (including Th17 and Treg 
cells) in whole blood after KD025 
administration to subjects with 
Secondary Endpoints 
• Number and percentage of KD025 in 
subjects with steroid-dependent 
cGVHD who have a best response of 
PR or CR 
• Change in cGVHD severity as based 
on the Physician-reported global 
cGVHD Activity Assessment  
• Change in symptom activity as based 
on cGVHD Activity Assessment 
Patient Self Report  
• Median failure-free survival (FFS) 
• Changes in corticosteroid and 
calcineurin inhibitor dose  
• DOR 
• Response rate by organ system  
•Analyses of plasma PK of KD025 in 
subjects with cGVHD 
• Overall Survival 
• Time to Next Treatment 
• Change in symptom burden/bother 
using the Lee cGVHD Symptom Scale 
 
Exploratory Endpoints  
•Changes in the expression of several 
cytokines (including IL-17A, IL-21, 
and IL-2) in plasma after KD025 
administration to subjects with 
cGVHD 
• Changes in percentage of immune-
cell subtypes (including Th17 and Treg 
cells) in whole blood after KD025 
administration to subjects with 
cGVHD 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 111 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
cGVHD 
• Change in symptom burden/bother 
using the Lee cGVHD Symptom Scale 
 
 
 
Section 6.3  Overview of Study Design 
 
This is a Phase 2a, dose-escalation, 
open-label study designed to evaluate 
the safety, tolerability, and activity of 
KD025 in subjects with steroid-
dependent cGVHD and active disease 
in terms of partial response (PR) and 
complete response (CR) as defined by 
the 2014 NIH Consensus Development 
Project on clinical trials in cGVHD 
(see Appendix B). This study also is 
designed to use the Physician-reported 
global cGVHD Activity Assessment to 
evaluate cGVHD severity; use the 
cGVHD Activity Assessment Patient 
Self-Report to assess symptom activity 
(see Appendix C); evaluate failure-free 
survival (FFS); evaluate Overall 
Survival (OS); assess changes in 
corticosteroid and calcineurin inhibitor 
dose; evaluate Time to Next 
Treatment (TTNT); and assess the 
PK of KD025 in subjects with 
cGVHD. Changes in symptom 
burden/bother will be documented 
using the Lee cGVHD Symptom 
Scale (see Appendix D). Changes in 
the expression of several cytokines 
(including IL-17A, IL-21, and IL-2) in 
plasma and percentages of immune-
cell subtypes (including Th17 and Treg 
cells) in whole blood after KD025 
administration to subjects with 
cGVHD, as well as changes in 
symptom burden/bother using the Lee 
cGVHD Symptom Scale, will be 
explored (see Appendix D). 
 
Long-Term Follow-Up 
This is a Phase 2a, dose-escalation, 
open-label study designed to evaluate 
the safety, tolerability, and activity of 
KD025 in subjects with steroid-
dependent cGVHD and active disease 
in terms of partial response (PR) and 
complete response (CR) as defined by 
the 2014 NIH Consensus Development 
Project on clinical trials in cGVHD 
(see Appendix B). This study also is 
designed to use the Physician-reported 
global cGVHD Activity Assessment to 
evaluate cGVHD severity; use the 
cGVHD Activity Assessment Patient 
Self-Report to assess symptom activity 
(see Appendix C); evaluate failure-free 
survival (FFS); evaluate Overall 
Survival (OS); assess changes in 
corticosteroid and calcineurin inhibitor 
dose; evaluate Time to Next Treatment 
(TTNT); and assess the PK of KD025 
in subjects with cGVHD. Changes in 
symptom burden/bother will be 
documented using the Lee cGVHD 
Symptom Scale (see Appendix D). 
Changes in the expression of several 
cytokines (including IL-17A, IL-21, 
and IL-2) in plasma and percentages of 
immune-cell subtypes (including Th17 
and Treg cells) in whole blood after 
KD025 administration to subjects with 
cGVHD. 
 
 
 
Long-Term Follow-Up 
Subjects will be contacted 
approximately every 8 weeks and can 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
 
Long-Term Follow-Up is 
clarified. 
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 112 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Subjects will be contacted 
approximately every 8 weeks and 
can be contacted via telephone, 
email or postal mail to confirm 
survival status and the initiation of 
any anti-cancer treatment or any 
changes in treatment of cGVHD. 
This can also be confirmed from 
electronic medical records.  Once 
subjects complete the 28 Day Follow
Up visit, subjects will be contacted by 
telephone every 8 weeks until study 
closeout to confirm survival status and 
the initiation of any anti cancer 
treatment or any changes in treatment 
for cGVHD. 
be contacted via telephone, email or 
postal mail to confirm survival status 
and the initiation of any anti-cancer 
treatment or any changes in treatment 
of cGVHD. This can also be confirmed 
from electronic medical records. 
Table 1 
g. All Blood samples (approximately 5 
mL) for determination of plasma 
concentrations of KD025 and its 
metabolites will be collected on Day 1 of
Cycles 1 and 2 at the following 
timepoints: Pre-dose (Time 0), and 1, 2, 
3, 4, 5, 6 hours after dosing (after first 
dose for subjects in the BID group). In 
addition, subjects will have samples 
collected pre-dose on Day 1 of Cycle 4, 
pre-dose at the Cycle 7 Day 1 visit, and 
at the EOT visit. Also, if appropriate, a 
sample will be requested if a subject 
discontinues treatment prematurely. 
  
h. All subjects will have pre-dose PD 
blood samples drawn up to 6 4 times 
over the course of the study.  Also, if 
appropriate, a sample will be requested 
if a subject discontinues treatment 
prematurely. 
 
m. Subjects will be contacted 
approximately every 8 weeks and 
can be contacted via telephone, 
email or postal mail to confirm 
g. All Blood samples (approximately 5 
mL) for determination of plasma 
concentrations of KD025 and its 
metabolites will be collected on Day 1 
of Cycles 1 and 2 at the following 
timepoints: Pre-dose (Time 0), and 1, 
2, 3, 4, 5, 6 hours after dosing (after 
first dose for subjects in the BID 
group). In addition, subjects will have 
samples collected pre-dose on Day 1 of 
Cycle 4, pre-dose at the Cycle 7 Day 1 
visit 
 
 
 
h. All subjects will have pre-dose PD 
blood samples drawn up to 4 times 
over the course of the study. 
 
 
 
 
 
m. Subjects will be contacted 
approximately every 8 weeks and can 
be contacted via telephone, email or 
postal mail to confirm survival status 
and the initiation of any anti-cancer 
Last subjects enrolled 
into study more than one 
year ago and no more 
Pharmacokinetics 
samples will be analyzed. 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamics 
samples are not required 
to be collected. 
 
 
 
 
 
Long-Term Follow-Up 
clarification provided. 
 
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 113 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
survival status and the initiation of 
any anti-cancer treatment or any 
changes in treatment of cGVHD. 
This can also be confirmed from 
electronic medical records Subjects 
are to be contacted by telephone 
every 8 weeks until study close out to 
confirm survival status and the 
initiation of any anti cancer 
treatment or any changes in 
treatment for cGVHD.  
treatment or any changes in treatment 
of cGVHD. This can also be confirmed 
from electronic medical records  
Section 8.5 End of Treatment 
• PK sample collection 
• PD sample collection  
 
Last subjects enrolled 
into study more than one 
year ago and no more 
Pharmacokinetics 
samples will be analyzed. 
 
Pharmacodynamics 
samples are not required 
to be collected. 
Section 8.6 28 Day Follow Up 
• PD sample collection  
 
Pharmacodynamics 
samples are not required 
to be collected. 
Section 8.7 Unscheduled Visits 
• 
PK sample collection (if 
appropriate) 
• 
PD sample collection 
 
 
Last subjects enrolled 
into study more than one 
year ago and no more 
Pharmacokinetics 
samples will be analyzed. 
 
Pharmacodynamics 
samples are not required 
to be collected. 
Section 8.8 Long-Term Follow-Up 
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 114 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
After the follow up visit is completed, 
subjects will be contacted by telephone 
every 8 weeks until study closeout to 
confirm survival status and the 
initiation of any anti cancer treatment 
or any changes in treatment for 
cGVHD. 
Subjects will be contacted 
approximately every 8 weeks and 
can be contacted via telephone, 
email or postal mail to confirm 
survival status and the initiation of 
any anti-cancer treatment or any 
changes in treatment of cGVHD. 
This can also be confirmed from 
electronic medical records 
Subjects will be contacted 
approximately every 8 weeks and can 
be contacted via telephone, email or 
postal mail to confirm survival status 
and the initiation of any anti-cancer 
treatment or any changes in treatment 
of cGVHD. This can also be confirmed 
from electronic medical records 
 
Long-Term Follow-Up 
clarification provided. 
 
Section 9.1 Procedures to be Performed 
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 115 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Pharmacokinetics (PK) Sampling 
Blood samples (approximately 5 mL) 
for determination of plasma 
concentrations of KD025 and its 
metabolites, will be collected on Day 1 
of Cycles 1 and 2 at the following time 
points: Pre-dose (Time 0), and 1, 2, 3, 
4, 5, and 6 hours after dosing (after 
first dose for subjects in the BID 
group). In addition, subjects will have 
samples collected pre-dose on Day 1 of 
Cycle 4 and pre-dose at the Cycle 7 
Day 1 visit as well as the EOT visit.  
Also, if appropriate, a sample will be 
requested if a subject discontinues 
treatment prematurely.. See Section 11 
for additional information. 
Blood Sampling for 
Pharmacodynamics (PD) 
All subjects will have samples drawn 
to evaluate changes in the expression 
of several cytokines (including IL
17A, IL 21and IL 21) in plasma, and 
changes in percentages of immune cell 
subtypes (including Th17 and Treg 
cells) in blood.   
All subjects will have PD blood 
samples drawn up to 6 times over the 
course of the study: Pre dose on Cycle 
1 Day 1, Cycle 2 Day 1 (4 weeks), and 
Cycle 4 Day 1 (12 weeks); at the Cycle 
7 Day 1 visit; and at the EOT visit and 
28 Day Follow Up visit. Also, if 
appropriate, a sample will be requested 
if a subject discontinues treatment 
prematurely. See Section 12 for 
additional information.   
All subjects will have PD blood 
samples drawn up to 4 times over 
the course of the study: Pre-dose on 
Cycle 1 Day 1, Cycle 2 Day 1 (4 
weeks), Cycle 4 Day 1 (12 weeks) 
and Cycle 7 Day 1 (24 weeks).  
Pharmacokinetics (PK) Sampling 
Blood samples (approximately 5 mL) 
for determination of plasma 
concentrations of KD025 and its 
metabolites, will be collected on Day 1 
of Cycles 1 and 2 at the following time 
points: Pre-dose (Time 0), and 1, 2, 3, 
4, 5, and 6 hours after dosing (after 
first dose for subjects in the BID 
group). In addition, subjects will have 
samples collected pre-dose on Day 1 of 
Cycle 4 and pre-dose at the Cycle 7 
Day 1 visit. See Section 11 for 
additional information. 
 
 
 
Blood Sampling for 
Pharmacodynamics (PD) 
All subjects will have PD blood 
samples drawn 4 times over the course 
of the study: Pre-dose on Cycle 1 Day 
1, Cycle 2 Day 1 (4 weeks), and 
Cycle 4 Day 1 (12 weeks) and Cycle 7 
Day 1 (24 weeks) will be analyzed to 
evaluate changes in the expression of 
several cytokines in plasma (including 
IL-17A, IL-21, and IL-2), and changes 
in percentages of circulating Th17 and 
Treg cells in blood. See Section 12 for 
additional information.     
 
 
 
 
 
 
 
 
 
 
 
Last subjects enrolled 
into study more than one 
year ago and no more 
Pharmacokinetics 
samples will be analyzed. 
 
 
Pharmacodynamics 
samples are not required 
to be collected  
 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
 
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 116 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Samples will be analyzed to evaluate 
changes in the expression of several 
cytokines in plasma (including IL-
17A, IL-21, and IL-2), and changes 
in percentages of circulating Th17 
and Treg cells in blood. See Section 
12 for additional information     
 
Response Activity and Assessments 
Activity in terms of cGVHD severity 
will be evaluated using the Physician-
reported global cGVHD Activity 
Assessment form (see Appendix A), 
while activity in terms of symptom 
burden will be evaluated using the 
cGVHD Activity Assessment - Patient 
Self Report (see Appendix C). Failure-
free survival (FFS), Overall Survival 
(OS) and Time to Next Treatment 
(TTNT), will be evaluated at the same 
time points. Changes in corticosteroid 
and calcineurin inhibitor dose will be 
documented as they occur on the 
appropriate eCRF. Changes in 
symptom burden/bother will be 
explored documented using the Lee 
cGVHD Symptom Scale (see 
Appendix D).  
 
 
 
 
 
 
 
Response Activity and Assessments 
Activity in terms of cGVHD severity 
will be evaluated using the Physician-
reported global cGVHD Activity 
Assessment form (see Appendix A), 
while activity in terms of symptom 
burden will be evaluated using the 
cGVHD Activity Assessment - Patient 
Self Report (see Appendix C). Failure-
free survival (FFS), Overall Survival 
(OS) and Time to Next Treatment 
(TTNT) will be evaluated at the same 
time points. Changes in corticosteroid 
and calcineurin inhibitor dose will be 
documented as they occur on the 
appropriate eCRF. Changes in 
symptom burden/bother will be 
documented using the Lee cGVHD 
Symptom Scale (see Appendix D).  
  
Section 10 Activity 
Secondary endpoints include 
evaluation of cGVHD severity using 
the Physician-reported global cGVHD 
Activity Assessment; evaluation of 
symptom burden using the cGVHD 
Activity Assessment - Patient Self 
Report; failure-free survival (FFS); 
Overall Survival (OS); Time to Next 
Treatment (TTNT); and changes in 
corticosteroid and calcineurin inhibitor 
dose; and Cchanges in symptom 
burden/bother using the Lee cGVHD 
Symptom Scale. will be an exploratory 
endpoint. 
Secondary endpoints include 
evaluation of cGVHD severity using 
the Physician-reported global cGVHD 
Activity Assessment; evaluation of 
symptom burden using the cGVHD 
Activity Assessment - Patient Self 
Report; failure-free survival (FFS); 
Overall Survival (OS); Time to Next 
Treatment (TTNT); changes in 
corticosteroid and calcineurin inhibitor 
dose; and  changes in symptom 
burden/bother using the Lee cGVHD 
Symptom Scale. 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
 
VV-CLIN-0638576 7.0


KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 117 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Section 10.5 Overall Survival 
 
Overall Survival (OS) data will be 
collected throughout the study 
 
Overall Survival has been 
included as a secondary 
endpoint in this protocol 
amendment 
Section 10.7 Time to Next Treatment 
 
Time to Next Treatment (TTNT) data 
will be collected throughout the study 
 
Time to Next Treatment 
has been included as a 
secondary endpoint in 
this protocol amendment 
Section 10.8 Lee cGVHD Symptom Scale 
Changes in symptom burden/bother 
will be documented explored using 
the Lee cGVHD Symptom Scale (see 
Appendix D). 
Changes in symptom burden/bother 
will be documented using the Lee 
cGVHD Symptom Scale (see 
Appendix D). 
Change in symptom 
burden/bother using the 
Lee cGVHD Symptom 
Scale has been included 
as a secondary endpoint 
in this protocol 
amendment 
Section 11 Pharmacokinetics 
In addition, subjects will have samples 
collected pre-dose on Day 1 of Cycle 
4, and Cycle 7 Day 1 visit, and at the 
EOT visit. Subjects should be 
instructed to withhold taking study 
drug on these days as dosing will be 
performed at the clinic. 
A total of 16 17 samples will be 
collected (80 85 mL) from subjects in 
the dose escalation portion of the 
study. 
In addition, subjects will have samples 
collected pre-dose on Day 1 of Cycle 
4, and Cycle 7 Day 1 visit. 
 
A total of 16 samples will be collected 
(80 mL) from subjects in the dose 
escalation portion of the study. 
Last subjects enrolled 
into study more than one 
year ago and no more 
Pharmacokinetics 
samples will be analyzed. 
 
Section 12 Pharmacodynamics 
All subjects will have PD blood 
samples drawn 6 times over the course 
of the study: Pre dose on Cycle 1 Day 
1, Cycle 2 Day 1 (4 weeks), and Cycle 
4 Day 1 (12 weeks); at the Cycle 7 
Day 1 (24 weeks); at the EOT visit, 
and at the 28 Day Follow Up visit. 
Samples will be analyzed to evaluate 
changes in the expression of several 
cytokines (including IL 17A, IL 21, 
All subjects will have PD blood 
samples drawn 4 times over the course 
of the study: Pre-dose on Cycle 1 Day 
1, Cycle 2 Day 1 (4 weeks), and Cycle 
4 Day 1 (12 weeks) and Cycle 7 Day 1 
(24 weeks) will be analyzed to 
evaluate changes in the expression of 
several cytokines in plasma (including 
IL-17A, IL-21, and IL-2), and changes 
in percentages of circulating Th17 and 
Pharmacodynamics 
samples are not required 
to be collected  
 
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Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
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Confidential and Proprietary 
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Original Text with Changes Shown 
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New wording 
Brief Rationale/ 
Justification for Change 
and IL 2) in plasma, and changes in 
percentages of immune cell subtypes 
(including Th17 and Treg cells) in 
blood.   
PD blood samples also will be 
requested for any subject who 
discontinues treatment prematurely. 
 
All subjects will have PD blood 
samples drawn 4 times over the 
course of the study: Pre-dose on 
Cycle 1 Day 1, Cycle 2 Day 1 (4 
weeks), and Cycle 4 Day 1 (12 
weeks) and Cycle 7 Day 1 (24 weeks) 
will be analyzed to evaluate changes 
in the expression of several cytokines 
in plasma (including IL-17A, IL-21, 
and IL-2), and changes in 
percentages of circulating Th17 and 
Treg cells in blood.      
Treg cells in blood.      
Section 14.4 Dose Pause or Reduction of KD025 
If treatment-related Grade 2 or 
treatment-related Grade 3 toxicities 
persist for 14 days, subjects will be 
discontinued from the study.    
If treatment-related Grade 2 or 
treatment-related Grade 3 toxicities 
persist for 14 days, subjects will be 
discontinued from the study.    
Guidance for this 
discontinuation reason 
was always intended for 
G2 and G3 treatment-
related toxicities; now 
clarified with revised 
wording. 
Section 15 Concomitant Medication and Treatment 
The use of medications that are strong 
CYP3A4 inhibitor/inducers (see 
Appendix H for a listing of these 
drugs) is prohibited. Other CYP3A4 
inhibitors / inducers should be used 
with caution. (See Appendix H for a 
listing of these drugs) 
 
The use of medications that are strong 
CYP3A4 inducers is prohibited.  Other 
CYP3A4 inhibitors / inducers should 
be used with caution. (See Appendix H 
for a listing of these drugs.) 
Based upon data from 
KD025-107 (KD025 
Drug-Drug-Interaction 
study). 
Section 17.3 Statistical Considerations 
Four populations will be employed in 
the analysis of study data: 
• 
The modified intent-to-treat 
Four populations will be employed in 
the analysis of study data: 
• 
The modified intent-to-treat 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
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Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
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Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
(mITT) population will consist of 
all subjects who are enrolled in the 
study and receive at least 1 dose 
of study medication. who are not 
screen failures.  The safety 
population which will consist of all 
subjects who receive at least one 
dose of KD025.   
• 
The safety population will consist 
of all subjects who receive at least 
one dose of KD025. The per 
protocol population will consist of 
subjects who have received at least 
50% of study drug and have at 
least one evaluable response 
assessment. 
• 
The PK population which will 
consist of all subjects who receive 
at least one dose of study drug and 
have at least 1 post-dose PK 
sample drawn 
 
Demographics, subject disposition, and 
screening and baseline characteristics 
will be summarized for the mITT 
population and Per Protocol 
popualtions, where appropriate.  
(mITT) population will consist of 
all subjects who are enrolled in the 
study and receive at least 1 dose of 
study medication.   
• 
The safety population will consist 
of all subjects who receive at least 
one dose of KD025.  
• 
The PK population which will 
consist of all subjects who receive 
at least one dose of study drug and 
have at least 1 post-dose PK 
sample drawn 
 
Demographics, subject disposition, and 
screening and baseline characteristics 
will be summarized for the mITT 
population.  
 
 
Section 17.4 Activity Analysis  
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Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
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Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Secondary Endpoints  
• Number and percentage of KD025 in 
subjects with steroid-dependent 
cGVHD who have a best response of 
PR or CR 
• Change in cGVHD severity as based 
on the Physician-reported global 
cGVHD Activity Assessment  
• Change in symptom activity as based 
on cGVHD Activity Assessment 
Patient Self Report  
• Median FFS will be defined as the 
time from first dose of study drug to 
either the start of another treatment, 
relapse of the underlying disease, or 
death 
• Changes in corticosteroid and 
calcineurin inhibitor dose  
• To evaluate DOR. The DOR is 
defined as the time of initial response 
until documented progression.  
• To evaluate response by organ 
system. The response by organ system 
(PR and CR) will be assessed based on 
the 2014 NIH Consensus Development 
Project on Clinical Trials in cGVHD. 
• Overall Survival (OS) will be 
defined as the 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 
• Time to Next Treatment  (TTNT) 
will be defined as the defined as the 
time from the first dose of KD025 to 
the start of additional systemic 
cGVHD therapy  
• Change in symptom burden/bother 
using the Lee cGVHD Symptom 
Scale 
 
Secondary Endpoints  
• Number and percentage of KD025 in 
subjects with steroid-dependent 
cGVHD who have a best response of 
PR or CR 
• Change in cGVHD severity as based 
on the Physician-reported global 
cGVHD Activity Assessment  
• Change in symptom activity as based 
on cGVHD Activity Assessment 
Patient Self Report  
• Median FFS will be defined as the 
time from first dose of study drug to 
either the start of another treatment, 
relapse of the underlying disease, or 
death 
• Changes in corticosteroid and 
calcineurin inhibitor dose  
• To evaluate DOR. The DOR is 
defined as the time of initial response 
until documented progression.  
• To evaluate response by organ 
system. The response by organ system 
(PR and CR) will be assessed based on 
the 2014 NIH Consensus Development 
Project on Clinical Trials in cGVHD. 
• Overall Survival (OS) will be defined 
as the 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 
• Time to Next Treatment  (TTNT) 
will be defined as the defined as the 
time from the first dose of KD025 to 
the start of additional systemic 
cGVHD therapy  
• Change in symptom burden/bother 
using the Lee cGVHD Symptom Scale 
 
 
Statistical Analysis Plan 
is being updated to reflect 
these endpoints that will 
be analyzed.   
 
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KD025 
Protocol Number KD025-208 
IND 125890 
Amendment No. 7 
 
 
 
 
 
 
Kadmon Corporation 
Page 121 of 121 
Confidential and Proprietary 
28 October 2019 
 
Original Text with Changes Shown 
(deleted text in strikethrough and 
added text in bold) 
New wording 
Brief Rationale/ 
Justification for Change 
Exploratory Endpoints  
• Changes in the expression of several 
cytokines (including IL-17A, IL-21, 
and IL-2) in plasma after KD025 
administration to subjects with 
cGVHD 
• Changes in percentage of immune-
cell subtypes (including Th17 and Treg 
cells) in whole blood after KD025 
administration to subjects with 
cGVHD 
• Change in symptom burden/bother 
using the Lee cGVHD Symptom Scale 
 
Exploratory Endpoints  
• Changes in the expression of several 
cytokines (including IL-17A, IL-21, 
and IL-2) in plasma after KD025 
administration to subjects with 
cGVHD 
• Changes in percentage of immune-
cell subtypes (including Th17 and Treg 
cells) in whole blood after KD025 
administration to subjects with 
cGVHD 
 
 
Appendix H: Drugs that Induce and Inhibit CYP3A4 
Use of drugs that are moderate or 
strong inhibitors inducers of the 
CYP3A4 family of enzymes is 
prohibited in subjects who are 
receiving KD025. Other CYP3A4 
inhibitors/ inducers should be used 
with caution. 
Use of drugs that are moderate or 
strong inducers of the CYP3A4 family 
of enzymes (refer to source below) is 
prohibited in subjects who are 
receiving KD025. 
Use of drugs that are strong inducers 
of the CYP3A4 family of enzymes is 
prohibited in subjects who are 
receiving KD025.  Other CYP3A4 
inhibitors/ inducers should be used 
with caution. 
 
Use of drugs that are strong inducers 
of the CYP3A4 family of enzymes 
(refer to source below) is prohibited in 
subjects who are receiving KD025. 
Based upon data from 
KD025-107 (KD025 
Drug-Drug-Interaction 
study). 
 
 
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SAP_001.pdf: 
Kadmon Corporation 
KD025-208
Statistical Analysis Plan 
SAP Version 2.3: 17-October-2019 
       Page 1 of 43 
STATISTICAL ANALYSIS PLAN 
A Phase 2a, Dose-Escalation, Open-Label Study to Evaluate the 
Safety, Tolerability, and Activity of KD025 in Subjects with 
Chronic Graft Versus Host Disease
Protocol Number: KD025-208 
Statistical Analysis Plan Version: 
Date of Statistical Analysis Plan: 
Version 1 
30-Nov-2017
Version 2 
06-Jun-2019
Version 2.1 
12-Aug-2019
Version 2.2 
23-Sep-2019
Version 2.3 
29-Oct-2019
NCT02841995  






 
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Table of Contents 
1 
INTRODUCTION .............................................................................................. 9 
2 
STUDY SUMMARY ........................................................................................... 9 
2.1 
Study Objectives ............................................................................................ 9 
2.1.1 
Primary Objectives.................................................................................. 9 
2.1.2 
Secondary Objectives............................................................................ 10 
2.1.3 
Exploratory Objectives ......................................................................... 10 
2.2 
Study Design ................................................................................................ 10 
2.3 
Visit Schedule and Study Assessment ......................................................... 11 
3 
STATISTICAL METHODS ............................................................................ 11 
3.1 
General Methods .......................................................................................... 11 
3.1.1 
Computing Environment ....................................................................... 11 
3.1.2 
General Considerations ......................................................................... 12 
3.1.3 
Study Day.............................................................................................. 12 
3.1.4 
Baseline ................................................................................................. 13 
3.1.5 
Handling of Incomplete or Missing Data .............................................. 13 
3.2 
Analysis Populations .................................................................................... 14 
3.3 
Subject Disposition and Evaluability ........................................................... 15 
3.4 
Protocol Deviations ...................................................................................... 15 
3.5 
Demographics and Baseline Characteristics ................................................ 16 
3.5.1 
Demographics ....................................................................................... 16 
3.5.2 
Medical History .................................................................................... 16 


 
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3.5.3 
cGVHD History .................................................................................... 16 
3.5.4 
Other Baseline Characteristics .............................................................. 17 
3.6 
Prior and Concomitant Medications ............................................................. 17 
3.7 
Treatment Compliance and Exposure .......................................................... 18 
3.8 
Endpoints for Activity Analysis ................................................................... 19 
3.8.1 
Primary Endpoint .................................................................................. 19 
3.8.2 
Secondary Endpoints ............................................................................ 19 
3.8.3 
Exploratory Endpoint ............................................................................ 25 
3.8.4 
Subgroup Analyses ............................................................................... 25 
3.9 
Safety Analysis ............................................................................................. 26 
3.9.1 
Adverse Events ..................................................................................... 26 
3.9.2 
Clinical Laboratory Evaluation ............................................................. 27 
3.9.3 
Vital Signs ............................................................................................. 27 
3.9.4 
ECG....................................................................................................... 27 
3.10 
Pharmacokinetic Analysis ........................................................................ 28 
3.11 
Pharmacodynamic Analysis ..................................................................... 28 
3.12 
Sample Size Justification .......................................................................... 28 
3.13 
Interim Analysis ....................................................................................... 28 
3.14 
Primary CSR Analysis .............................................................................. 28 
4 
LIST OF TABLES, FIGURES, AND LISTINGS .......................................... 29 
5 
REFERENCES .................................................................................................. 36 
6 
APPENDICES ................................................................................................... 37 


 
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List of Tables 
Table 1.  Cohorts in the Study .................................................................................... 11 
Table 2.  Censoring Rules for Duration of Response ................................................. 20 
Table 3.  Demographics and Baseline Characteristics TLFs ...................................... 29 
Table 4.  Treatment Exposure and Concomitant Medication TLFs............................ 30 
Table 5.  Efficacy TLFs .............................................................................................. 31 
Table 6.  Safety TLFs.................................................................................................. 34 
 
 


 
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LIST OF ABBREVIATIONS  
Abbreviation 
Full Term 
7-PtR 
7-point reduction 
ADI 
Actual dose intensity 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ATC 
American Therapeutic Chemical (Classification) 
BID 
Twice daily 
BMI 
Body mass index 
C1D1 
Cycle 1 Day 1 
CI 
Confidence interval 
cGVHD 
Chronic graft versus host disease 
CM 
Concomitant medication 
CNI 
Calcineurin inhibitor 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
Diffusing capacity of carbon monoxide 
DO7-PtR 
Duration of ≥ 7-PtR 
DOR 
Duration of response 
ECG  
Electrocardiogram 
EOT 
End of treatment 
FEV1 
Forced Expiratory Volume in One Second 
FFS 
Failure-free survival 
HCT 
Hematopoietic cell transplantation 
FVC 
Forced vital capacity 
ICH 
International Conference on Harmonisation  
IL 
Interleukin 
LR 
Lack of response 
LSS 
Lee cGVHD Symptom Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-treat 
KPS 
Karnofsky Performance Scale 
NE 
Not evaluable 
ORR 
Overall response rate 
OS 
Overall survival 
PFT  
Pulmonary function test 


 
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Abbreviation 
Full Term 
PD 
Pharmacodynamics 
PDI 
Planned dose intensity 
PK 
Pharmacokinetics 
PO 
Oral(ly) 
PPI 
Proton pump inhibitor 
PR 
Partial response 
PT 
Preferred Term 
RDI 
Relative dose intensity 
RV 
Residual volume 
QD 
Once daily 
ORR 
Overall response rate 
QTcF 
Corrected QT interval using Fridericia's formula 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC  
System Organ Class 
STB 
Stable 
TEAE 
Treatment-emergent adverse event 
TLC 
Total lung capacity 
TTNT 
Time to next therapy 
TTR 
Time to response 
 
 
 


 
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1 INTRODUCTION 
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. Subjects with cGVHD 
require prolonged immunosuppressive treatment for an average of 2 to 3 years from 
the initial diagnosis. Ten percent of those surviving for at least 7 years still require 
immunosuppressive treatment. Glucocorticoids, with or without calcineurin inhibitors 
(CNI), remain the standard initial treatment, but significant side effects and 
unsatisfactory outcomes, particularly for subjects with high-risk features of cGVHD, 
support the need for more effective and less toxic therapies.  
This Statistical Analysis Plan (SAP) describes detailed statistical procedures to be 
used for study KD025-208 as specified in the protocol (Amendment No. 6, 
15-Oct-2018): A Phase 2a, Dose-Escalation, Open-Label Study to Evaluate the 
Safety, Tolerability, and Activity of KD025 in Subjects with Chronic Graft Versus 
Host Disease. A primary clinical study report (CSR) analysis will be conducted 1 year 
after the last patient is enrolled. The pharmacokinetic (PK) and pharmacodynamic 
(PD) data will be analyzed and reported separately.  
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  
2.1.1 Primary Objectives 
The primary objectives of this study are to evaluate: 
 The activity of KD025 in subjects with steroid-dependent cGVHD and active 
disease in terms of partial response (PR) and complete response (CR), as defined 


 
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by the 2014 National Institute of Health (NIH) Consensus Development Project 
on clinical trials in cGVHD (see Appendix A) 
 The safety and tolerability of KD025 in subjects with cGVHD 
2.1.2 Secondary Objectives  
The secondary objectives of this study are to evaluate: 
 Duration of response (DOR) 
 Time to response (TTR) 
 Response by organ system 
 Time to next therapy (TTNT) 
 Changes in corticosteroid and CNI doses 
 Failure-free survival (FFS) 
 Overall survival (OS) 
 Change in cGVHD severity as based on the Clinician-reported Global cGVHD 
Activity Assessment 
 Changes in symptom activity using the cGVHD Activity Assessment Patient 
Self-Report (Appendix C) 
 Plasma PK of KD025 in subjects with cGVHD 
2.1.3 Exploratory Objectives 
The exploratory objectives of this study are to evaluate: 
 Changes in the expression of several cytokines (including interleukin [IL]-17A, 
IL-21, and IL-2) in plasma after KD025 administration  
 Changes in percentage of immune-cell subtypes (including Th17 and Treg cells) 
in whole blood after KD025 administration  
 Changes in symptom burden/bother using the Lee cGVHD Symptom Scale (LSS, 
Appendix D) 
2.2 Study Design 
This is a Phase 2a, open-label, dose-escalation, safety, tolerability, and activity study.  


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Subjects who have signed an Institutional Review Board/Independent Ethics 
Committee-approved informed consent form and who have met all of the 
inclusion/exclusion criteria will be enrolled. After approximately 4 weeks for 
screening, subjects will receive KD025 orally (PO) in 28-day cycles until disease 
progression or unacceptable toxicity occurs followed by 4 weeks of follow-up. In 
addition, subjects will be contacted every 8 weeks until study close-out to confirm 
survival status and the initiation of any anticancer treatment or any changes in 
treatment for cGVHD.  
Sequential cohorts of approximately 16 subjects will be dosed at KD025 200 mg 
once daily (QD) PO, KD025 200 mg twice daily (BID) PO, and KD025 400 mg QD 
(Table 1). Prior to enrolling subsequent cohorts, the safety data in each previous 
cohort will be evaluated after 8 subjects have reached 2 months of treatment.  
Table 1.  Cohorts in the Study 
Cohort 
Number of Subjects 
Treatment 
Cohort 1 
~16 
200 mg KD025 QD 
Cohort 2 
~16 
200 mg KD025 BID 
Cohort 3 
~16 
400 mg KD025 QD   
BID = twice daily; QD = once daily 
2.3 Visit Schedule and Study Assessment 
The flow chart of visit schedule and study assessments is given in the KD025-208 
Protocol. 
3 STATISTICAL METHODS 
3.1 General Methods 
3.1.1 Computing Environment 
All statistical programming and data analyses will be performed using SAS 
Version 9.4 on Windows platform. 


 
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3.1.2 General Considerations  
General considerations for descriptive statistics and presentation for continuous and 
categorical data are given below.  
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 discrete (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 cohort or in the 
specified analysis population.  
Means, medians, standard deviations, and confidence intervals (CIs) will be reported 
to one decimal place more than the data reported on the case report form (CRF) or by 
the vendor. Minimum and maximum will be reported to the same number of decimal 
places displayed on the CRF or by the vendor. P-values will be reported to 4 decimal 
places. 
Unless otherwise indicated, all summary tables will be presented by the following 
groups: Cohort 1 (KD025 200 mg QD PO), Cohort 2 (KD025 200 mg BID PO), 
Cohort 3 (KD025 400 mg QD PO), and Overall.  
Because of the exploratory nature of the study, no adjustments will be made for the 
multiplicity of endpoints.  
3.1.3 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., 
adverse event [AE] onset date, assessment date, sample collection date) 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 


 
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onset date, assessment date, sample collection date) and the start date of study 
treatment plus one day. The first day of study treatment is Study Day 1. 
3.1.4 Baseline 
Baseline value is defined as the valid and last non-missing value obtained within 
28 days prior to subject receiving the first study medication, unless otherwise stated 
under the related 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.  
3.1.5 Handling of Incomplete or Missing Data 
Missing data will not be imputed in general and 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: 


 
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 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 the 
listings. 
If the assessment of the relationship of the AE to KD025 is missing, then it will be 
assumed that the AE is related to KD025 and the AE considered as such in the 
frequency tables of possibly related AEs. 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. 
3.2 Analysis Populations 
The following populations will be analyzed: 
Modified Intent-to-treat (mITT) Population: The primary population for efficacy 
analyses will be a Modified Intent-to-treat (mITT) Population defined as all subjects 
who receive at least 1 dose of study medication. The mITT Population will be used 
for tables of demography, baseline characteristics, and efficacy. 


 
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Responder Population: The Responder Population is defined as subjects in the 
mITT population that achieved a PR or CR response at any post-baseline response 
assessment. 
Non-responder Population: The Non-responder Population is defined as any subject 
in the mITT Population who is not a responder. 
The responder and non-responder populations will be used for some subgroup 
analyses. 
Safety Population: The Safety Population is defined as all subjects who receive at 
least 1 dose of study medication. In this study, the Safety Population is equivalent to 
the mITT Population. 
3.3 Subject Disposition and Evaluability 
Subjects who failed screening (i.e., subjects who signed the informed consent were 
screened but never started the study treatment, and their basic demographics and any 
AE after signing the informed consent may have been collected in the CRF) will be 
excluded from any populations defined in Section 3.2. Therefore, these subjects will 
be excluded from any summary tables or listings.  
The number of subjects discontinuing from the study and the primary reason for 
discontinuation will be summarized.  
3.4 Protocol Deviations 
All protocol deviations will be identified and classified as major or minor before 
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. 


 
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Serious Non-compliance: Serious non-compliance 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. 
3.5 Demographics and Baseline Characteristics 
3.5.1 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.  
BMI will be calculated as follows:  
BMI (kg/m2) = weight (kg)/height2 (m2), 
where the weight and height are obtained at baseline.  
3.5.2 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.   
3.5.3 cGVHD History 
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 


 
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 Donor-recipient cytomegalovirus (CMV) serostatus 
The baseline characteristics of cGVHD will be summarized for: 
 Time from most recent transplant to cGVHD diagnosis 
 Time from cGVHD diagnosis to study enrollment 
 Time from most recent transplant to enrollment 
 Prior therapies for cGVHD will be summarized for:  
o Number of lines of prior systemic therapies 
o Prior systemic therapies 
 Organ involvement will be summarized for 
o Number of organs involved at baseline 
o Organ involvement at baseline including: 
 NIH Skin Score and Skin Features Score 
 NIH Eye Score 
 NIH-modified Oral Mucosa Rating Scale (OMRS) 
 NIH Esophagus Score 
 NIH Upper Gastrointestinal (GI) Score 
 NIH Lower GI Score 
 Alanine transaminase (ALT), Alkaline phosphatase (ALP), 
Total Bilirubin 
 NIH Lung Symptom Score and Forced Expiratory Volume in 
One Second (FEV1) (% predicted) 
 NIH Joint and Fascia Score and P-ROM score 
 Global Severity Rating 
3.5.4 Other Baseline Characteristics  
Other baseline values including Karnofsky Performance Scale (Appendix E; 
Karnofsky et al., 1949) and childbearing potential will also be summarized.  
3.6 Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Prior medications are defined as those medications that began and 


 
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stopped before the start of study treatment. Concomitant medications are defined as 
medications taken after the start of study treatment and during the study period, 
including those began before but ongoing at the start of study treatment. If a 
medication start date is partially or fully missing and it is unclear as to whether the 
medication is prior or concomitant, it will be assumed that the medication is 
concomitant. 
Number and percentage of incidence of prior and CM will be summarized according 
to Anatomical Therapeutic Class (ATC) and preferred drug name. 
3.7 Treatment Compliance and Exposure 
The relative dose intensity (RDI) will be used to assess the treatment compliance. 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: 
 
PDI (mg/day) = planned cumulative dose (mg) / duration of exposure (days), 
 
ADI (mg/day) = actual cumulative dose (mg)/ duration of exposure (days). 
The planned cumulative dose is the planned daily dose amount multiplied by the 
duration of exposure, while the actual cumulative dose is the sum of actual total daily 
dose amount over the duration of exposure. The actual total daily dose will need the 
information of dose change and dose held (interruption) captured in CRF (Missed 
Dose and Dose Modification). If a subject did not take any study drug, the actual RDI 
by definition is zero. 
The duration of exposure is defined as: 
 
Duration of exposure (days) = (Date of last dose – Date of Study Day 1) + 1. 
The descriptive summary statistics of the treatment duration, actual cumulative dose, 
ADI, and RDI will be presented.  


 
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3.8 Endpoints for Activity Analysis 
3.8.1 Primary Endpoint 
The overall response rate (ORR) is the primary endpoint of the study. 
The ORR is defined as the proportion of subjects meeting the overall response criteria 
assessment of CR or PR at any post-baseline response assessment. 
The overall response determination of cGVHD is based on the cGVHD response 
assessment performed by clinicians as per the 2014 NIH Consensus Development 
Project for Clinical Trials in cGVHD criteria. The overall response is defined using 
the scores from 9 organs (skin, eyes, mouth, esophagus, upper GI, lower GI, liver, 
lungs, and joints and fascia; see Appendix B) plus global severity rating. The results 
of overall response at each assessment time point are evaluated by investigator and 
categorized as CR, PR, or Lack of Response (LR), where LR includes the response 
status of unchanged, mixed, or progression.  
If a treated subject does not have any response assessment, this subject will be 
counted as a non-responder. 
The ORR and its two-sided 95% CI using Clopper-Pearson method will be presented.  
3.8.2 Secondary 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 (which will be defined by clinical 
team review). 


 
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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 2 will be applied 
 Landmark analyses: Number and percentage of subjects with response sustained 
for ≥ 12, ≥ 20, ≥ 24, ≥ 32, ≥ 36, and ≥ 48 weeks 
 
Table 2.  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 
cGVHD = chronic graft versus host disease; DOR = duration of response; LR = lack of response 
 
3.8.2.2 Time-to-Response (TTR) 
Time-to-response 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 (at 4, 8, 12, 16, 24, 32, 40, and ≥ 48 weeks) will be 
provided. The TTR analyses will only be conducted for the Responder Population. 


 
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3.8.2.3 Response by Organ System 
The database did not specifically capture baseline organ involvement. Organ 
involvement was determined as follows: 
 All organs, except lungs: 
o If the baseline score is > 0, the organ will be defined as Involved, unless all 
response assessments are Not Evaluable (NE) 
o If the baseline score is 0, the organ will be defined as Not Involved, unless 
any response assessment of CR or PR which triggers clinical review to 
confirm baseline involvement.  
 For the lungs: 
o If FEV1 ≥ 75%, the organ will be defined as Not Involved 
o If FEV1 < 75%, the organ will be defined as Involved, unless all responses 
are NE 
The response assessment for the 9 individual organs (skin, eyes, mouth, esophagus, 
upper GI, lower GI, liver, lungs, and joints and fascia) and global severity rating is 
categorized into 5 response status: CR, PR, Progression (P), NE, Stable (STB).  
Number and percentage of subjects with best response of CR or PR and total 
(CR+PR) by individual organ system and global severity rating will be summarized 
and 2 series of percentages presented: 
1. 
With the total number of subjects in the mITT Population with involvement of 
the given organ at baseline as denominator 
2. 
With the number of subjects in the Responder Population with involvement of 
the given organ at baseline as denominator 
3.8.2.4 Time to Next Therapy (TTNT) 
The TTNT will be measured as the time from first treatment to the time of new 
systemic cGVHD treatment (which will be defined by clinical team review), 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. 


 
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3.8.2.5 Corticosteroid Dose 
Corticosteroid doses on Day 1 of each treatment cycle will be presented as mg/kg/day 
prednisone equivalent dose. Descriptive statistics for the mITT Population, 
Responder and Non-responder Populations and subgroups defined by baseline 
corticosteroid dose level (upper and lower 50th percentiles) will be provided for: 
 Systemic corticosteroid dose over time 
 Change and percent change from baseline (Cycle 1 Day 1 [C1D1]) to the greatest 
corticosteroid dose reduction during KD025 treatment period 
 Number and percentage of subjects who reduced systemic corticosteroid dose 
during KD025 treatment period 
 Number and percentage of subjects who ever discontinued systemic corticosteroid 
usage during KD025 treatment period  
If subjects are not using prednisone as the systemic corticosteroid, then the equivalent 
dose of 1 mg of prednisone will be determined according to following conversion 
ratios: 
 4 mg Hydrocortisone 
 0.8 mg Methylprednisolone 
 0.15 mg Dexamethasone 
 1 mg Prednisolone 
 0.8 mg Triamcinolone 
3.8.2.6 Calcineurin Inhibitor (CNI) Doses 
Calcineurin inhibitors include systemic tacrolimus and cyclosporine. Descriptive 
statistics will be provided for: 
 Number and percentage of subjects who reduced CNI dose 
 Number and percentage of subjects who ever discontinued CNI during KD025 
treatment period 
3.8.2.7 Failure-free Survival (FFS) 
Failure-free survival will be defined as the time from first dose of study drug to either 
the start of another new systemic treatment for cGVHD, relapse of the underlying 


 
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disease (both will be defined by clinical team review), or death. If no such events 
happen, FFS will be censored by last response assessment or long term follow up 
assessment, whichever is the latest and available. Failure-free survival will be 
analyzed by the Kaplan-Meier survival method as well as the landmark analyses at 6, 
12, 18, and 24 months. In addition, analyses for the three components of FFS will 
also be provided. 
3.8.2.8 Overall Survival (OS) 
Overall survival will be defined as the time from first dose of study drug to death due 
to any reason. If there is no death, OS will be censored by last visit, last long term 
follow up, or study cutoff date, whichever is the latest. OS will be analyzed by the 
Kaplan-Meier survival method as well as the landmark analyses at 6, 12, 18, and 24 
months.  
3.8.2.9 Change in cGVHD Severity as Based on 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.    
3.8.2.10 Change in Symptom Activity Based on cGVHD Activity Assessment 
Patient Self Report  
The cGVHD Activity Assessment-Patient Self Report is in Appendix C. 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).   


 
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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. 
3.8.2.11 Lee Symptom Scale Score (LSS) 
The Lee cGVHD Symptom Scale Score (LSS) is the exploratory endpoint in this 
study. 
The LSS (see 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 of 30 items over 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 non-missing domain scores if 
more than 50% of them are non-missing. A higher score indicates more bothersome 
symptoms. A 7-point difference on the summary score of cGVHD symptom scale has 
been found to be clinically meaningful (Lee et al., 2002). 
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 formulae, ‘m’ is the number of items that have non-missing values in a 
domain, and ‘n’ is the number of domains have non-missing domain scores. 


 
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The 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 percentage of subjects with a ≥ 7-point reduction (7-PtR) from 
baseline (C1D1) 
 Number and percentage 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 Non-responder 
Populations. 
Descriptive statistics of domain, overall scores, and their change from baseline will be 
provided by cohort and visit.  
3.8.2.12 Pulmonary Function Tests (PFT) 
Five test variables of PFTs, Forced Vital Capacity (FVC), Residual Volume (RV), 
Diffusing Capacity of Carbon Monoxide (DLco), FEV1, and Total Lung Capacity 
(TLC) are collected from the CRF. Change from baseline values of FVC, RV, DLco, 
FEV1, and TLC will be summarized at each scheduled time point.  
3.8.3 Exploratory Endpoint 
Not applicable. 
3.8.4 Subgroup Analyses 
Subgroup analyses for the endpoints of ORR and DOR will be conducted for the 
following subgroups: 
 Number of prior line therapies (1 vs. ≥ 2) 
 Number of organs involved at baseline (< 4 vs. ≥ 4)  
 Baseline severity  (severe vs. not severe, baseline activity assessment used as 
surrogate) 


 
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 Take concomitant medication proton pump inhibitor (PPI) on C1D1 (Yes/No)  
 Refractory to  most recent line of therapy prior to enrollment (Yes / No) 
3.9 Safety Analysis 
Safety assessments will include AEs, serious adverse events (SAEs), vital sign 
measurements, clinical laboratory evaluations (hematology and chemistry), and 
electrocardiograms (ECGs). Unscheduled visits for safety assessments will not be 
presented in summary tables but will be in listings. All safety analyses will be 
performed using the safety population.  
3.9.1 Adverse Events 
AEs will be coded using the MedDRA dictionary (Version 20.1 or higher). 
Treatment-emergent AEs (TEAEs) are any AE occurring or worsening in severity 
after the first administration of study medication. All AEs (including SAEs) will be 
graded using the 5-point Common Terminology Criteria for Adverse Events 
(CTCAE) V5.0 scale (mild, moderate, severe, life-threatening, or death). Causality 
with KD025 will be classified as: definitely related; probably related; possibly 
related; unlikely related; or not related. 
 The investigator will further assess the relationship of AEs 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 AEs of each specific SOC 
and PT will be presented. For the presentation of AE incidences, the SOCs and the 
PTs within each SOC will be presented by decreasing total frequency. Tabulation by 
maximum severity and relationship to KD025 will also be included by treatment 
group. 
The TEAEs, Grade ≥ 3 TEAEs, SAEs, and TEAEs leading to dose 
modification/discontinuation will be summarized by treatment arm, SOC, and PT. 
These analyses will be repeated for events considered related (definitely 
related/probably related/possibly related) to KD025.  


 
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Subject listings will be provided for SAEs, AEs resulting in study drug 
discontinuation and deaths. 
Adverse events will also be presented in listings. Time to onset and duration of AEs 
will be included in listings, along with action taken and outcome. 
3.9.2 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 
white blood cell counts, neutrophils (absolute count), lymphocytes (absolute count), 
monocytes (absolute count), hemoglobin, platelets, ALP, ALT, aspartate 
aminotransaminase, gamma glutamyl transferase, total bilirubin, glomerular filtration 
rate, 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 Version 5.0. 
All graded laboratory parameters will be summarized separately for hematology and 
biochemistry. Corresponding shift tables comparing baseline to the worst 
post-baseline grade within the treatment period will be provided. 
3.9.3 Vital Signs 
Descriptive statistics for vital signs (weight, temperature, blood pressure, pulse rate, 
and respiratory rate) values and the change from baseline will be presented for each 
scheduled assessment time point.  
3.9.4 ECG 
Descriptive statistics for ECG parameters (i.e., PR interval, QRS interval, and QTcF 
interval) at each time point with triplicate ECGs will be presented for the values and 
change from baseline scores. (QTcF is the QT interval using Fridericia’s correction 
which is calculated by QTcF = QT/RR1/3.)  


 
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The number and percentage of subjects with observed QTcF values that satisfy the 
following conditions will be presented by treatment group and study visit and 
categorized as: ≤ 450 ms; > 450 to 480 ms; > 480 to 500 ms; and > 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 and categorized as: ≤ 0 ms; > 0 to ≤ 30 ms; > 30 to ≤ 60 ms; and > 60 ms. 
3.10 Pharmacokinetic Analysis  
Further details will be described in the Pharmacokinetic Analysis Plan. 
3.11 Pharmacodynamic Analysis  
Further details will be described in the Pharmacodynamics Analysis Plan. 
3.12 Sample Size Justification  
The total sample size of 16 subjects per KD025 dose group will provide 
> 90% probability of ≥ 1 subject experiencing an AE that has an underlying rate of 
≥ 14% and > 80% probability of ≥ 1 subject in the study experiencing an AE that has 
an underlying rate of ≥ 10%.  
3.13 Interim Analysis 
This is a dose-escalation, open-label study. Interim analyses may occur periodically 
during the course of this trial. There is no early stopping for efficacy.   
3.14 Primary CSR Analysis 
A primary CSR analysis will be conducted 1 year after the last subject is enrolled. 
 
 


 
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4 LIST OF TABLES, FIGURES, AND LISTINGS 
In all tables, figures and listing, results will be presented by treatment cohorts and 
overall, unless be otherwise specified. 
Table 3 lists demographic and baseline characteristics TLFs; Table 4 lists treatment 
exposure and concomitant medication TLFs; Table 5 lists efficacy TLFs; and Table 6 
lists safety TLFs. 
Table 3.  Demographics and Baseline Characteristics TLFs 
T/F/L 
Title 
Population 
T 
Analysis populations by cohort (mITT Population) 
mITT 
T 
Subject disposition 
mITT 
L 
Subject disposition  
mITT 
T 
Summary of follow-up duration 
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 
T 
Summary of prior systemic cGVHD therapy by ATC class 
 
L 
Prior systemic cGVHD therapy 
mITT 
 
 
 


 
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Table 4.  Treatment Exposure and Concomitant Medication TLFs 
T/F/L Title 
Population 
T 
Concomitant corticosteroid medications for cGVHD by ATC class, 
preferred term and cohort 
mITT 
L 
Concomitant corticosteroid medications for cGVHD by cohort and 
subject 
mITT 
T 
Concomitant calcineurin inhibitors for cGVHD by ATC class, 
preferred term and cohort 
mITT 
L 
Concomitant calcineurin inhibitors for cGVHD by cohort and 
subject 
mITT 
T 
Concomitant medications prior to the start of study drug by ATC 
class, preferred term and cohort 
mITT 
L 
Concomitant medications prior to the start of study drug by cohort 
and subject 
mITT 
T 
Concomitant medications after the start of study drug by ATC 
class, preferred term and cohort 
mITT 
L 
Concomitant medications after the start of study drug by cohort 
and subject 
mITT 
T 
KD025 treatment exposure and compliance 
mITT 
T 
KD025 dose reductions and interruptions 
mITT 
L 
KD025 dose reductions and interruptions 
mITT 
 
 
 








 
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Table 6.  Safety TLFs 
T/F/L 
Title 
Population 
T 
Overview of subjects for safety analysis by cohort  
Safety 
T 
Treatment emergent adverse events regardless of the relationship 
of study drug by primary system organ class, preferred term, 
maximum grade  
Safety 
T 
Treatment-emergent adverse events related to the study drug by 
primary system organ class, preferred term, maximum grade 
Safety 
T 
Treatment emergent serious adverse events regardless of the 
relationship of study drug, by primary system organ class, 
preferred term, maximum grade  
Safety 
T 
Treatment emergent serious adverse events related to the study 
drug, by primary system organ class, preferred term, maximum 
grade 
Safety 
T 
Treatment emergent adverse events leading to treatment 
discontinuation, regardless of the relationship of study drug, by 
primary system organ class and preferred term  
Safety 
T 
Serious adverse events leading to treatment discontinuation, 
regardless of the relationship of study drug, by primary system 
organ class and preferred term 
Safety 
T 
Adverse events with grade ≥ 3, regardless of the relationship of 
study drug, by primary system organ class and preferred term  
Safety 
T 
Treatment emergent adverse events leading to treatment 
discontinuation, regardless of the relationship of study drug, by 
preferred term 
Safety 
T 
Serious adverse events leading to treatment discontinuation, 
regardless of the relationship of study drug, by preferred term 
Safety 
T 
Adverse events with grade ≥ 3, regardless of the relationship of 
study drug, by preferred term 
Safety 
T 
Adverse events with any grade, regardless of the relationship of 
study drug, by preferred term 
Safety 
L 
Listings of deaths, other serious and significant AEs 
Safety 
T 
Summary of the worst on-treatment grade for hematology by 
cohort  
Safety 
T 
Summary of the worst on-treatment grade for biochemistry by 
cohort  
Safety 
T 
Hematology shift table based on CTC grade by cohort 
Safety 
T 
Biochemistry shift table based on CTC grade by cohort 
Safety 
T 
Change from baseline of PFT by visit and cohort 
Safety 
T 
Change from baseline of hematology by visit and cohort 
Safety 
T 
Change from baseline of biochemistry by visit and cohort 
Safety 
T 
Change from baseline of urinalysis by visit and cohort 
Safety 


 
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T/F/L 
Title 
Population 
F 
Liver function test: Mean ALT over time by cohort 
Safety 
F 
Liver function test: Mean change from baseline of ALT over time 
by cohort 
Safety 
F 
Liver function test: Distribution of ALT over time by cohort  
Safety 
F 
Liver function test: Mean AST over time by cohort 
Safety 
F 
Liver function test: Mean change from baseline of AST over time 
by cohort 
Safety 
F 
Liver function test: Distribution of AST over time by cohort 
Safety 
F 
Liver function test: Mean alkaline phosphatase over time by 
cohort 
Safety 
F 
Liver function test: Mean change from baseline of alkaline 
phosphatase over time by cohort 
Safety 
F 
Liver function test: Distribution of alkaline phosphatase over 
time by cohort 
Safety 
F 
Liver function test: Mean total bilirubin over time by cohort 
Safety 
F 
Liver function test: Mean change from baseline of total bilirubin 
over time by cohort 
Safety 
F 
Liver function test: Distribution of total bilirubin over time by 
cohort 
Safety 
T 
Vital signs shift table of vital signs by visit and cohort 
Safety 
T 
Change from baseline of in ECG by visit and cohort 
Safety 
T 
Number and percentage of subjects with QTcF by visit and 
cohort 
Safety 
T 
Number and percentage of subjects with QTcF change from 
baseline by visit and cohort 
Safety 
L 
Deaths during on-treatment period by cohort 
Safety 
L 
Adverse events by cohort  
Safety 
 
 


 
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5 REFERENCES 
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. 
Lee S, Cook EF, Soiffer R, et al. Development and validation of a scale to measure 
symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002; 
8:444-452. 
 
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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KD025-208                                                                                      Statistical Analysis Plan 
 
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6 APPENDICES 


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Appendix A: Clinician-Reported Global cGVHD Activity Assessment Form A 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 


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KD025-208                                                                                           Statistical Analysis Plan 
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Appendix A: Clinician-Reported Global cGVHD Activity Assessment Form A (cont.) 
 
Abstracted from:  Lee SJ, et al. Biol Blood Marrow Transplant. 2015; 21:984-999. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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KD025-208                                                                                           Statistical Analysis Plan 
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Appendix B: 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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KD025-208                                                                                           Statistical Analysis Plan 
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Appendix C: 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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KD025-208                                                                                           Statistical Analysis Plan 
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Appendix D: Lee cGVHD Symptom Scale   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abstracted from:  
Lee S, Cook EF, Soiffer R, et al. Development and validation of a scale to measure 
symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002; 
8:444-452.  
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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KD025-208                                                                                           Statistical Analysis Plan 
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Appendix E: Karnofsky Performance Scale  
Condition 
Percent 
Description 
Able to carry on normal 
activity and to work. 
No special care needed. 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
Unable to work.  Able 
to live at home and care 
for most personal 
needs.  A varying 
degree of assistance is 
needed. 
70 
Cares for self, unable to carry on normal activity or to do active 
work. 
60 
Requires occasional assistance but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
Unable to care for self. 
Requires equivalent of 
institutional or hospice 
care. Disease may be 
progressing rapidly. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not 
imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
 
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.