Conditions: Graft vs Host Disease
Keywords: GvHD INC424 pediatric Chronic Graft versus Host Disease moderate and severe chronic graft vs. host disease allogeneic stem cell transplant ruxolitinib corticosteroids
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 46
Healthy volunteers: no

Brief summary:
This open-label, single-arm, Phase II multi-center study enrolled 46 participants and investigated the activity, pharmacokinetics and safety of ruxolitinib added to the subject's immunosuppressive regimen among infants, children, and adolescents aged ≥28 days to \<18 years old with either moderate to severe treatment-naive cGvHD or SR-cGvHD.

Although 46 participants were enrolled,1 participant (enrolled in the ≥6y to \<12y age group) received study treatment beyond protocol requirements and was excluded from analyses.

Detailed description:
Subjects were grouped according to their age as follows:

* Group 1 included subjects ≥12y to \<18y
* Group 2 included subjects ≥6y to \<12y
* Group 3 included subjects ≥2y to \<6y and
* Group 4 included subjects ≥28days to \<2y. Enrollment initiation into the youngest age group, Group 4, was subject to the availability of data in this age group from another study, as well as a review of available PK, safety, and activity data generated from Groups 1 to 3 in the current study. At least 5 evaluable participants per group were needed for the primary analysis in Groups 1, 2 and 3. No minimum number of evaluable participants were needed in Group 4. Enrollment was completed prior to the availability of the data and so no subjects were enrolled in Group 4.

After a screening period of Day -28 to Day -1: eligible subjects started study treatment on Cycle

1 Day 1 and were treated for up to a maximum of 3 years (39 cycles/156 weeks) or until early discontinuation. Subjects who discontinued study treatment for any reason earlier than 39 cycles were followed every 6 months until 3 years from their first dose of study treatment was reached.

Arms:
arm 1: All pediatric participants received ruxolitinib twice a day (BID) in either tablet or oral solution (liquid), depending on the group they were in.

Interventions: intervention 1: INC424
Intervention descriptions: intervention 1: Ruxolitinib was taken orally based on age groups as follows:

Group 1 (\>=12y to \<18y): 10mg bid as tablet Group 2 (\>=6y to \<12y): 5mg bid as tablet or liquid Group 3 (\>=2y to \<6y): 4mg/m2 bid as liquid

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................13
Amendment 2 ....................................................................................................................15
Amendment 1 ....................................................................................................................18
Protocol summary..............................................................................................................21
1
Introduction .......................................................................................................................25
1.1
Background............................................................................................................25
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment................................................................................................25
1.1.2
Introduction to investigational treatment(s)..........................................26
1.2
Purpose ..................................................................................................................33
2
Objectives and endpoints...................................................................................................34
3
Study design ......................................................................................................................36
4
Rationale............................................................................................................................37
4.1
Rationale for study design .....................................................................................38
4.2
Rationale for dose/regimen and duration of treatment ..........................................39
4.3
Rationale for exploratory biomarker assessment...................................................40
4.4
Purpose and timing of interim analyses/design adaptations..................................41
4.5
Risks and benefits..................................................................................................41
4.6
Rationale for Public Health Emergency mitigation procedures ............................44
5
Population..........................................................................................................................45
5.1
Inclusion criteria ....................................................................................................45
5.2
Exclusion criteria...................................................................................................45
6
Treatment...........................................................................................................................48
6.1
Study treatment......................................................................................................48
6.1.1
Investigational and control drugs..........................................................48
6.1.2
Additional study treatments ..................................................................50
6.1.3
Treatment arms/group ...........................................................................50
6.1.4
Guidelines for continuation of treatment ..............................................50
6.1.5
Treatment duration................................................................................50
6.2
Other treatment(s)..................................................................................................52
6.2.1
Concomitant Medications .....................................................................52
6.2.2
Prohibited medication ...........................................................................54


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6.2.3
Rescue medication ................................................................................54
6.3
Subject numbering, treatment assignment, randomization....................................55
6.3.1
Subject numbering ................................................................................55
6.3.2
Treatment assignment, randomization ..................................................55
6.4
Treatment blinding.................................................................................................55
6.5
Dose escalation and dose modification..................................................................55
6.5.1
Dose modifications................................................................................55
6.5.2
Follow-up for toxicities.........................................................................62
6.6
Additional treatment guidance...............................................................................64
6.6.1
Treatment compliance...........................................................................64
6.6.2
Emergency breaking of assigned treatment code..................................64
6.7
Preparation and dispensation.................................................................................64
6.7.1
Handling of study treatment and additional treatment..........................65
7
Informed consent procedures ............................................................................................66
8
Visit schedule and assessments .........................................................................................67
8.1
Screening ...............................................................................................................74
8.1.1
Eligibility screening ..............................................................................75
8.1.2
Information to be collected on screening failures.................................75
8.2
Subject demographics/other baseline characteristics.............................................75
8.2.1
Treatment Period...................................................................................76
8.3
Efficacy..................................................................................................................77
8.3.1
Staging and Response Assessments......................................................77
8.3.2
Graft failure monitoring........................................................................82
8.3.3
Appropriateness of efficacy assessments..............................................82
8.4
Safety.....................................................................................................................82
8.4.1
Laboratory evaluations..........................................................................83
8.4.2
Pregnancy and assessments of fertility .................................................86
8.4.3
Tanner staging.......................................................................................87
8.5
Additional assessments..........................................................................................87
8.5.1
Pharmacokinetics ..................................................................................87
8.5.2
Biomarkers............................................................................................88
8.5.3
Other Assessments ................................................................................91
9
Study discontinuation and completion ..............................................................................91
9.1
Discontinuation......................................................................................................91
9.1.1
Discontinuation of study treatment .......................................................91
9.1.2
Withdrawal of informed consent/opposition to use data/biological 
samples..................................................................................................92


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9.1.3
Lost to follow-up...................................................................................93
9.1.4
Early study termination by the sponsor.................................................93
9.2
Study completion and post-study treatment ..........................................................94
10 Safety monitoring and reporting........................................................................................95
10.1
Definition of adverse events and reporting requirements......................................95
10.1.1
Adverse events ......................................................................................95
10.1.2
Serious adverse events ..........................................................................97
10.1.3
SAE reporting........................................................................................98
10.1.4
Pregnancy reporting ..............................................................................99
10.1.5
Reporting of study treatment errors including misuse/abuse................99
10.2
Additional Safety Monitoring..............................................................................100
10.2.1
Liver safety monitoring.......................................................................100
10.2.2
Data Monitoring Committee ...............................................................100
10.2.3
Steering Committee.............................................................................100
11 Data Collection and Database management....................................................................100
11.1
Data collection.....................................................................................................100
11.2
Database management and quality control..........................................................101
11.3
Site monitoring ....................................................................................................101
12 Data analysis and statistical methods ..............................................................................102
12.1
Analysis sets ........................................................................................................102
12.1.1
Full Analysis Set .................................................................................102
12.1.2
Safety set .............................................................................................102
12.1.3
Pharmacokinetic analysis set...............................................................102
12.2
Subject demographics and other baseline characteristics....................................103
12.3
Treatments ...........................................................................................................103
12.4
Analysis of the primary endpoint(s) ....................................................................103
12.4.1
Definition of primary endpoint(s).......................................................103
12.4.2
Statistical model, hypothesis, and method of analysis........................104
12.4.3
Handling of missing values/censoring/discontinuations.....................104
12.4.4
Sensitivity and Supportive analyses....................................................104
12.5
Analysis of secondary endpoints .........................................................................105
12.5.1
Secondary efficacy objective(s)..........................................................105
12.5.2
Safety endpoints..................................................................................106
12.5.3
Pharmacokinetics ................................................................................108
12.5.4
Biomarkers..........................................................................................109
12.6
Analysis of exploratory endpoints.......................................................................111
12.6.1
Acceptability and Palatability assessment ..........................................111


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12.7
Interim analyses...................................................................................................111
12.8
Sample size calculation........................................................................................111
12.8.1
Primary endpoint(s).............................................................................111
13 Ethical considerations and administrative procedures ....................................................112
13.1
Regulatory and ethical compliance......................................................................112
13.2
Responsibilities of the investigator and IRB/IEC................................................112
13.3
Publication of study protocol and results.............................................................113
13.4
Quality Control and Quality Assurance...............................................................113
14 Protocol adherence ..........................................................................................................113
14.1
Protocol Amendments .........................................................................................113
15 References .......................................................................................................................115
16 Appendices ......................................................................................................................120
16.1
Appendix 1: Infection Severity Grading..............................................................120
16.2
Appendix 2: Staging of Chronic GvHD (NIH Criteria) ......................................124
16.3
Appendix 3: Chronic GvHD Disease Assessments (Lee 2015) ..........................128
16.4
Appendix 4: Guidelines for response assessment in cGvHD ..............................132
16.4.1
Introduction and scope ........................................................................132
16.4.2
Efficacy Assessments - Organ-specific response at one time point....132
16.4.3
Efficacy Assessments - Overall response assessment at one time 
point.....................................................................................................140
16.5
Appendix 5: HCT-Specific Comorbidity Index Score ........................................141
16.6
Appendix 6: CIBMTR Classification..................................................................143
16.7
Appendix 7: List of CYP3A4 inhibitors and inducers.........................................153


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................34
Table 6-1
Dose and treatment schedule.................................................................48
Table 6-2
Corticosteroid taper guidelines .............................................................51
Table 6-3
Criteria for dose reduction / interruption and re-initiation of 
ruxolitinib treatment for adverse drug reactions ...................................57
Table 6-4
Dose reduction steps for ruxolitinib......................................................60
Table 6-5
Dose re-escalation levels for ruxolitinib ...............................................61
Table 6-6
Assessments to determine cause of LFT abnormalities........................63
Table 6-7
Preparation and Dispensing...................................................................65
Table 6-8
Packaging and Labeling........................................................................65
Table 8-1
Assessment Schedule ............................................................................69
Table 8-2
Organs included for the post-baseline cGvHD response assessment....81
Table 8-3
Post-baseline overall response evaluation based on all organs.............81
Table 8-4
Safety Assessment.................................................................................83
Table 8-5
Local clinical laboratory parameters collection plan ............................83
Table 8-6
Pharmacokinetic blood collection log...................................................88
Table 8-7
Biomarker sample collection plan.........................................................89
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................99
Table 12-1
Probability to have a 90% CI with lower limit ≥ 50% and 90% 
confidence intervals for different number of subjects.........................111
Table 16-1
Infection severity grading table and recurrence interval definitions...120
Table 16-2
Four age groups relevant to HCT........................................................123
Table 16-3
Response determination for chronic GvHD by organ at post-
baseline assessment (comparison vs. baseline)...................................133
Table 16-4
Assessment of the skin score based on BSA and sclerotic features....139
Table 16-5
Overall response evaluation................................................................141
Table 16-6
HCT-Specific Comorbidity Index Score.............................................141
Table 16-7
CIBMTR disease risk index................................................................143
Table 16-8
List of CYP3A inhibitors and inducers...............................................153


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List of figures
Figure 3-1
Study Design .........................................................................................37
Figure 8-1
Study Treatment Period.........................................................................77
Figure 16-1
Criteria to determine liver response: general rules .............................135
Figure 16-2
Criteria to determine liver response: Example 1 (PR) ........................136
Figure 16-3
Criteria to determine liver response: Example 2 (unchanged)............137
Figure 16-4
Photographic Range of Motion (P-ROM)...........................................139


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List of abbreviations
ADL
Activities of Daily Living
ADR
adverse drug reaction
ADV
adenovirus
AE
adverse event
AESI
adverse event of special interest
aGvHD
acute graft vs. host disease
ALL
acute lymphocytic leukemia
allo-HSCT
allogeneic hematopoietic stem cell transplant
alloSCT
allogeneic stem cell transplantation
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
anti-HBc
hepatitis B core antibody
APC 
antigen presenting cells
ARDS
acute respiratory distress syndrome
AST
aspartate aminotransferase
ATC
Anatomical Therapeutical Chemical
AUC
area under the curve
B-ALL
B-cell Acute Lymphoblastic Leukemia
BALP
bone-specific alkaline phosphatase
BAT
best available therapy
BCC
basal cell carcinoma
BCR-ABL
Breakpoint Cluster Region Abelson
BCS
Biopharmaceutical Classification System
BID
twice a day
BILI
total bilirubin
BK
BK Polyomavirus
BLQ
below the limit of quantification
BM
bone marrow
BMI
Body Mass Index
BOR
best overall response
BSA
body surface area
CBC
complete blood count
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
CI
confidence interval
CIBMTR
Center for International Blood and Marrow Transplant Research
CK
creatinine kinase
CL
clearance
CL/F
plasma clearance
CLcr
creatinine clearance
Cmax
maximum concentration
CMM
cutaneous malignant melanoma
CMO
Chief Medical Office


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CMV
cytomegalovirus
CNI
calcineurin inhibitor
CNS
central nervous system
COMFORT
Controlled MyeloFibrosis Study with Oral JAK Inhibitor Treatment
CPO
Country Pharma Organization
CR
complete response
CRA
Clinical Research Associate
CRF
case report/record form (paper or electronic)
CRO
Contract Research Organization
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
minimum concentration
CTT
Clinical Trial Team
CTX
c-terminal cross-linked telopeptide of type I collagen
CV
coefficient of variation
CXCR3
chemokine receptor 3
CYP3A
cytochrome P450, family 3, subfamily A
CYPs
polymorphic cytochrome P450 enzymes
DAR
dose administration record
DHEA
dehydroepiandrosterone
DILI
drug-induced liver injury
DLCO
Diffusing capacity of the lung for carbon monoxide
DLI
donor lymphocyte infusion
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
EBV
epstein-barr virus
EC
Ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOT
end of treatment
ET
Essential Thrombocythemia
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FFS
failure free survival
G-CSF
granulocyte colony stimulating factor
GCP
Good Clinical Practice
GCS
Glasgow Coma Score
GFR
Glomerular Filtration Rate
GGT
gamma glutamyl transferase
GI
gastrointestinal


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GvHD
graft vs. host disease
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCT
hematopoietic cell transplantation
HCV
hepatitis C virus
HDPE
high-density polyethylene
HHV-6
human herpes virus
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HR
hazard ratio
HSCT
hematopoietic stem cell transplantation
HSV
herpes simplex virus
HTLV
human t-cell leukemia-lymphoma virus
HZV
herpes zoster virus
IB
Investigator Brochure
IC50
inhibition concentration
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ID 
identification
IEC
Independent Ethics Committee
IFN
Interferon
IL
Interleukin
IN
investigator notification
INR
international normalized ratio
IRB
Institutional Review Board
IRT 
interactive response technology
IUD
intra uterine device
IUS
intrauterine system
IWG
International Working Group
J&F
joints and fascia
JAK
janus kinase
JAK-STAT
janus kinase-signal transducer and activator of transcription
JMML
juvenile myelomonocytic leukemia
JUMP
JAK Inhibitor rUxolitinib in Myelofibrosis Patients
KCS
keratoconjunctivitis sicca
KPS
Karnofsky Performance Status
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LFS
leukemia-free survival
LFT
liver function test
LLN
lower limit of normal
LLOQ
lower limit of quantification
LMWH
low molecular weight heparin
LPS
Lansky Performance Status
MedDRA
Medical Dictionary for Regulatory Activities


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MF
myelofibrosis
MM
multiple myeloma
MMF
mycophenolate mofetil
mPBSC
mobilized peripheral blood stem cell
MPN
myeloproliferative neoplasms
MR
malignancy relapse/recurrence
MRT
Myeloproliferative Neoplasms Research and Treatment
NCI
National Cancer Institute
NG
nasogastric
NIH
National Institutes of Health
NMSC
non-melanoma skin cancer
NR
no response
NRM
non-relapse mortality
NSAID
nonsteroidal anti-inflammatory drug
O2
oxygen
OMRS
Oral Mucosa Rating Scale
OR 
overall response
ORR 
overall response rate
OS 
overall survival
P-ROM
photographic range of motion
PAS
pharmacokinetic analysis set
PBPK
physiologically based pharmacokinetic
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PET-MF
post-essential thrombocythemia myelofibrosis
PFT(s)
pulmonary function test(s)
PK
pharmacokinetic(s)
PLL
prolymphocytic leukemia
PLT
platelets
PMF
primary myelofibrosis
PML
progressive multifocal leukoencephalopathy
PPV-MF
post-polycythemia vera myelofibrosis
PR 
partial response
PS
patient safety
PT
prothrombin time
PV
polycythemia vera
QD
once a day
QMS
Quality Management System
QOL
Quality of Life
QTc
corrected QT interval
R value
ALT/ALP in x ULN
RA
rheumatoid arthritis
RAEB
refractory anemia with excess blasts
RAEB-T
refractory anemia with excess blasts in transformation
RBC
red blood cell(s)
REB
Research Ethics Board


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RNA
ribonucleic acid
RoW
rest of world
RP2D
recommended phase II dose
RSV
Respiratory Syncytial Virus
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Steering Committee
SCC
squamous cell carcinoma
SD
standard deviation
SDS
standard deviation scores
SIRS
systemic inflammatory response syndrome
SOC
standard of care
SOP
Standard Operating Procedure(s)
SR
steroid refractory
SR-aGvHD
steroid-refractory acute graft vs. host disease
SR-BOS
steroid refractory bronchiolitis obliterans syndrome
SR-cGvHD
steroid-refractory chronic graft vs. host disease
SUSARs
Suspected Unexpected Serious Adverse Reactions
T1/2
half-life
TB
Tuberculosis
TBIL
total bilirubin
Th
T helper cell
TNF
tumor necrosis factor
TYK2
tyrosine kinase 2
ULN
upper limit of normal
US
United States
USA
United States of America
V/F
volume of distribution
VZV
varicella zoster
WBC
white blood cell(s)
WHO
World Health Organization


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Glossary of terms
Additional Treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g., any background 
therapy).
Assessment
A procedure used to generate data required by the study.
Biological samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject.
Clinical Trial Team
A group of people responsible for the planning, execution and reporting of all 
clinical trial activities. Examples of team members include the Study Lead, 
Medical Monitor, Trial Statistician, etc.
Cycles
Number and/or timing or recommended repetitions of therapy, usually expressed 
as number of days, e.g., every 28 days.
Discontinuation from 
Study Treatment
Point/time when the subject permanently stops receiving the study treatment for 
any reason (prior to the planned completion of study drug administration, if any). 
Subject agrees to the other protocol required assessments including follow-up. 
No specific request is made to stop the use of their samples or data.
Dosage
Dose of the investigational or study treatment given to the subject in a time unit 
(e.g. 5 mg once a day, 10 mg twice a day).
Electronic Data Capture
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection symptoms, such as Web based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the use 
of Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from source data/documents used at the point of care.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol).
Healthy Volunteer
A person with no known significant health problems who volunteers to be a study 
subject.
Investigational drug
The study drug (ruxolitinib) whose properties are being tested in the study; this 
definition is consistent with US Code of Federal Regulations (CFR) 21 Section 
312.3 and is synonymous with “investigational new drug” or “investigational 
medicinal product”.
Investigational drug 
discontinuation
When the subject permanently stops taking any of the study drug(s) (ruxolitinib) 
prior to the defined study treatment completion date (if any) for any reason; may 
or may not also be the point/time of study discontinuation.
Investigational treatment
All investigational drug(s) whose properties are being tested in the study as well 
as their associated treatment controls. This includes any placebos, any active 
controls, as well as approved drugs used outside of their indication/approved 
dosage or tested in a fixed combination. Investigational treatment generally does 
not include other treatments administered as concomitant background therapy 
required or allowed by the protocol when used within approved 
indication/dosage.
Medication number
A unique identifier on the label of medication kits.
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g., any background therapy 
administered to each of the clinical trial subjects, regardless of randomization 
group, rescue medication, active drug run-ins etc.)
Oral pediatric 
formulation
The non-tablet formulation in liquid form administered orally to pediatric subjects.
Other Treatment
Treatment that may be needed/allowed during the conduct of the study (i.e., 
concomitant or rescue therapy).
Patient
An individual with the condition of interest for study.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which 
are described in the Protocol. Periods define the study phases and will be used 
in clinical trial database setup and eventually in analysis.


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Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis/Sponsor for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion 
of all study drug (ruxolitinib) administration and/or follow-up assessments; at this 
time all study drug administration is discontinued and no further assessments 
are planned.
Screen failure
A subject who is screened but not randomized/treated after the screening period.
Source Data/Document
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet, or 
even hard-coded data, such as paper or eSource.
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or when study 
drug (ruxolitinib) was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug (ruxolitinib) for any 
reason; may or may not also be the point/time of premature subject withdrawal.
Study treatment
Any single drug or combination of drugs or intervention administered to the 
subject as part of the required study procedures.
Subject
A trial participant (can be a healthy volunteer or a patient).
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be used 
to identify the subject throughout the study for all data collected, sample labels, 
etc.
Variable 
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study.
Withdrawal of consent 
(WoC)/ Opposition to 
use data/biological 
samples
Withdrawal of consent from the study occurs when the patient explicitly requests 
to stop use of their data and biological samples (opposition to use data and 
biological samples) AND no longer wishes to receive study treatment AND does 
not agree to further required assessments. This request should be in writing 
(depending on local regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal reason 
than consent.


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Amendment 2
As of 17-Sept-2021, CINC424G12201 enrollment was completed with a total of 46 subjects 
enrolled, which included 22 subjects in Group 1 (age ≥12y to < 18y), 17 subjects in Group 2 
(age ≥6y to <12y) and 7 subjects in Group 3 (age ≥2y to <6y).
The main purpose of amendment 2 is to include public health emergency disruption proofing 
language, to add one exploratory objective regarding corticosteroid-free response rates, to 
provide clarification on ruxolitinib treatment management and to clarify subject withdrawal of 
consent.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. The 
following sections of the protocol have been changed:
The protocol document has been updated to implement new protocol template text, included in 
the Protocol template version 5.0, dated 14-Jan-2022. With this update, changes have been 
made throughout the document as noted.
Glossary of terms: updated with additional terminology that appear throughout the protocol and 
require further explanation.
Section 1.1.2.1: Updated to include approval of ruxolitinib for treatment of aGvHD and cGvHD.
Section 1.1.2.1.2: Updated the number of patients from approximately 385 to more than 550 
healthy adult volunteers and from more than 10,250 to more than 14,000 patients that have
received ruxolitinib treatment in Novartis- and Incyte-sponsored investigational clinical trials.
Section 1.1.2.1.2: Clinical experience data added as published by Zeiser et al 2021. Duplicate 
sentence regarding Reach 2 deleted from this section.
Section 2, Table 2-1: Exploratory objective “to evaluate systemic corticosteroid-free response 
rate” and associated endpoint added.
Section 4.5: Text added to clarify that there is no substantial risk to subject safety related to 
SARS-COV-2 and the COVID-19 pandemic and that the benefit-risk assessment remains 
unchanged.
Section 4.6: Rationale for Public Health Emergency mitigation procedures added.
Section 5.2: Exclusion criteria #19: Text added to clarify “systemic” medications that interfere 
with coagulation or platelet function.
Section 5.2: Exclusion criteria #23: Text added to clarify that investigational treatment within 
30 days prior to “ruxolitinib” treatment initiation is exclusionary.
Section 6.1: Text added to clarify that treatment for SR-cGvHD subjects with concomitant 
corticosteroids is required.
Section 6.1 and Section 6.1.2.: Text added to clarify protocol requirements regarding systemic 
immunosuppressive medications used for prophylaxis of cGvHD.
Section 6.2.2: Text edited to clarify the reference of “study treatment” to “ruxolitinib”.


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Section 6.2.2: Text added to provide guidance on the administration of rituximab for the 
treatment of EBV.
Section 6.2.2: Prohibited use of live-attenuated vaccines during study treatment added as a 
prohibited medication.
Section 6.5.1.3: Text updated to clarify that a ruxolitinib dose reduction “must” be considered 
with the use of dual CYP2C9 and CYP3A4 inhibitors.
Section 6.5.1.4: Section header name updated to clarify study “treatment” discontinuation vs. 
study discontinuation.
Section 6.5.2.1: Text updated to spell out T1D and CVD. 
Section 6.7: Text added to provide guidance on the management of IMP in the event of a public 
health emergency.
Section 7: Updates to include language on managing informed consent in the event of a public 
health emergency.
Section 8: text added to provide additional clarification regarding the end of treatment visit in 
relation to study treatment (ruxolitinib) discontinuation, and the study visits required after 
discontinuing ruxolitinib. Text updated to align with protocol template version 5.0 regarding 
managing visits in the event of a Public Health emergency.
Section 8.4: Text added to provide guidance on the management of safety monitoring in the 
event of a public health emergency.
Section 8.4.2: Text added regarding the management of serum pregnancy testing during the 
event of a public health emergency.
Section 9.1.2: Text added to clearly define withdrawal of informed consent, the opposition to 
use data and biological samples and the procedures required to document withdrawal of consent. 
Section 9.1.3: Text added to distinguish between study treatment discontinuation and study 
discontinuation.
Section 10.1.3: Text updated with safety reporting timelines.
Section 10.1.4: Text updated regarding pregnancy reporting requirements per Novartis protocol 
template version 5.0.
Section 12: The definition of analysis sets was clarified to consider subjects that have been 
treated with the full assigned dose as a result of co-administration with strong CYP3A4 or dual 
CYP3A4/CYP2C9 inhibitors.
Section 12.5.1: Clarification added regarding the use of case descriptions for subjects with graft 
failure.
Section 12.5.2: Text edited to replace “study medication” with “ruxolitinib”.
Section 12.5.2.4: Text added to describe graphical displays of percentile height and weight over 
time for signal detection of impact on growth development.
Section 12.5.3: Statistical methods for pharmacokinetic analyses were further defined to include 
“formulation” in addition to age group.


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Section 12.6; New exploratory endpoint “to estimate corticosteroid-free response rate” added 
to align with Section 2.
IRB Section 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. In addition, if the 
changes herein affect the Informed Consent, sites are required to update and submit for approval 
a revised Informed Consent that takes into account the changes described in this protocol 
amendment.


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Amendment 1
Amendment rationale
As of 20-Nov-2020, 14 subjects are enrolled into CINC424G12201, which includes 10 subjects 
in Group 1 (age ≥12y to < 18y) and 4 subjects in Group 2 (age ≥6y to <12y).
The main purpose of amendment 1 is to update the guidances regarding the management of 
ruxolitinib based on liver monitoring laboratory results, to update the inclusion criteria to allow 
for nasogastric tube administration of the oral pediatric formulation, to provide clarifications 
regarding the management of ruxolitinib tapering, to provide guidance on the assessment of 
organ involvement and response, to clarify requirements for ruxolitinib post-trial access and to 
update contraception guidelines and pregnancy reporting requirements.
An assessment of benefit, risk and trial integrity related to SARS-CoV-2 virus and the COVID-
19 pandemic was conducted and determined no substantial risk for patient safety or additional 
measures regarding study design or conduct was warranted. A copy of this amended protocol 
will be sent to the Institutional Review Board (IRBs)/Independent Ethics Committee (IECs) and 
Health Authorities. The changes described in this amended protocol require IRB/IEC approval 
prior to implementation. In addition, if the changes herein affect the Informed Consent, sites 
are required to update and submit for approval a revised Informed Consent that takes into 
account the changes described in this protocol amendment.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through for deletions and underline for insertions. The following sections 
of the protocol have been changed:
List of abbreviations: Added adenovirus (ADV), ICH update, nasogastric (NG) and severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2).
Glossary of terms: updates to clarify reference to ruxolitinib as study drug and investigational 
drug.
Protocol Summary Key Exclusion criteria, Section 5.2, Section 6.2.1.1, Section 6.2.2, Section 
6.5.1.3, and Section 16.7: the maximum fluconazole dose clarified as 6 mg/kg (maximum 
200mg) daily to better represent pediatric dosing.
Section 1.1.2.1.2: Summary of Clinical Efficacy and Safety Data: recent study results 
summarized (REACH 1 and CINC424C2301) regarding the use of ruxolitinib in the treatment 
of acute GvHD.
Section 2, Secondary endpoints: clarified text on the acceptability and palatability assessments 
exploratory endpoint as the “Responses from the acceptability and palatability questionnaire 
of ruxolitinib oral pediatric formulation.”
Section 1.1.2.1.2: updated the number of patients from more than 9,250 to 10,200 patients that 
have received ruxolitinib treatment in Novartis- and Incyte-sponsored investigational clinical 
trials.


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Section 4.5: The following clarification was added: Management of any active viral infection 
and viral prophylaxis will follow local transplant program guidelines and viral load titer data 
will be documented when results are available.
Section 5.1: Inclusion Criteria # 3 and Protocol Summary: text added to allow for physician 
decision for the diagnosis of SR-cGvHD, in case institutional criteria are not available.
Section 5.1: Inclusion Criteria #4: text added to permit the administration of ruxolitinib pediatric 
formulation by nasogastric tube.
Section 5.2: Exclusion Criteria #16; reference to local regulations regarding contraception 
methods added.
Section 5.2: Exclusion Criteria #21: a reference to Section 6.2.2. was added to refer to the 
protocol section describing prohibited medications.
Table 6-1: text added to clarify that the tablet formulation cannot be broken to achieve partial 
doses and that the crushed tablet cannot be administered by nasogastric (NG) tube.
Table 6-1: text updated to reference that calculated doses should be rounded to the nearest 
volume according to the Pharmacy manual.
Section 6.1.1: guidance added regarding the management of ruxolitinib in the event of post 
dosing vomiting or missed dosages.
Section 6.1.1: the statements “Subjects should remain on the same formulation until Cycle 7 
Day 1” and “Any change in formulation prior to Cycle 7 Day 1 requires approval from the 
Sponsor” were added to provide guidance on the management of formulations used to dose 
subjects in the study.
Section 6.1.5: text added to further describe the management of subjects upon achieving 
complete response or partial response, or subjects without complete response or partial response.
Section 6.2.1: requirement added to collect and document in the eCRF steroid usage up to 18 
months prior to the first dose of ruxolitinib.
Section 6.2.1 and Section 8.5.1.1: instructions added regarding the management of 
corticosteroid dosing on PK collection study visit days.
Section 6.2.2: clarification added regarding the prohibited use of systemic nonsteroidal anti-
inflammatory drugs (NSAIDs).
Section 6.5.1: text added to clarify the maximum dose of ruxolitinib based on the subject’s age.
Section 6.5.1.2: the word “non-hematological” added to provide clarification regarding action 
with ruxolitinib attributed to non-hematological AEs.
Table 6-3: dose modifications for ruxolitinib updated to consider the liver involvement of the 
target disease, GvHD. 
Table 6-3: dose modifications for ruxolitinib related to Grade 3 “other adverse events” updated 
to align with current guidelines.
Table 6-4: Group 2 (≥6y to <12y) a single level safety dose reduction from 5mg BID to 5mg 
QD or 2.5mg BID has been updated which allows flexibility with respect to use of tablet or 
pediatric formulation (based on availability)  This is supported by evidence from REACH-1 


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trial in SR-aGvHD where patients were allowed to reduce ruxolitinib dose to 5 mg QD for 
improvement of toxicities.
Table 6-5: dose re-escalation for group 2 has been updated to 5mg QD or 2.5mg BID on the 
reduced dose, updated to 5mg BID on the first dose escalation and N/A for the second dose 
escalation.
Section 6.5.2.1 and Table 6-6: modified to consider the liver involvement of the target disease, 
GvHD and to align with requirements of liver safety monitoring according to current best 
practices.
Section 7: additional instructional text regarding informed consent provided; list of all informed 
consents applicable to this protocol added.
Section 7, Section 10.1.4: text removed regarding contacting female partners of male 
participants. Jakavi does not induce teratogenicity, but does show in embryo and fetotoxicity as 
published in literature.
Table 8-1: chemistry panel added to collection schedule at Cycle 1 Day 8, Day 15 and Day 22 
to support the cGvHD assessment required at these study visits.
Table 8-1: graft failure assessments removed at Cycle 1 Day 8, 15 and 22. 
Section 8.3.2: graft failure monitoring assessment schedule referred to Table 8-1. 
Table 8-1, Table 8-5, Section 8.4.2: requirement added for serum pregnancy test to be conducted 
at the Safety follow-up visit as per the updated contraception guidelines.
Section 8.3.1.1: text moved from end of section to beginning of section regarding documenting 
organ-specific abnormality explained by non-GvHD causes.
Section 8.3.1.2.1 and Table 8-3: text updated to provide further guidance on assessing baseline 
organ involvement, including liver, gastrointestinal and joints/fascia involvement.
Section 8.4.1, Table 8-5, Section 8.4.1.6: Cytomegalovirus (CMV), Epstein Barr Virus (EBV), 
Human Herpes Virus (HHV-6), Herpes Simplex Virus (HSV), Varicella Zoster Virus (VZV), 
Adenovirus (ADV) and SARS-CoV-2 viral load added as tests which may be reported as 
unplanned assessment results when applicable to a patient’s condition; additional viral testing 
may be performed as per local “guidelines”, replacing “regulations”.
Section 8.4.2: Added additional language regarding highly effective contraception methods and 
use of oral contraception.
Section 8.5.2.1: clarification addressed regarding storage of biomarker samples.
Section 9.2: criteria for access to post-trial treatment revised to align with post-trial access 
eligibility criteria.
Section 10.1.4: text added to clarify pregnancy reporting requirements.
Section 10.2.1: Section added to ensure reference to Section 6.5.2.1 for liver safety monitoring.
References: three references added to align with new text within Section 1.1.2.1.2.
Section 16.4.2.1, Section 16.4.2.2 and Table 16-5: text added to provide guidance to determine 
organ response post-baseline


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Protocol summary
Protocol number
CINC424G12201
Full Title
A Phase II open-label, single-arm, multi-center study of ruxolitinib added to 
corticosteroids in pediatric subjects with moderate and severe chronic graft vs. host 
disease after allogeneic stem cell transplantation.
Brief title
Study of activity, safety and pharmacokinetics in pediatric subjects with moderate and 
severe chronic graft vs. host disease after allogeneic stem cell transplant.
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug (INC424/ruxolitinib)
Study type
Interventional
Purpose and 
rationale
The purpose of the study intends to assess the pharmacokinetics (PK), safety and 
activity of ruxolitinib treatment in pediatric subjects
(age ≥ 28 days to < 18 years) with treatment-naive chronic graft vs. host disease 
(cGvHD) or steroid-refractory chronic graft vs. host disease (SR-cGvHD).
The rationale of the study is based on current knowledge of chronic graft vs. host 
disease pathophysiology and published studies showing that ruxolitinib impairs antigen 
presenting cell (APC) function, inhibits donor T cell proliferation, suppresses adverse 
cytokine production, and improves survival and disease manifestations in graft vs. host 
disease (GvHD) mouse models. This signaling cascade in cGvHD determined in the 
mouse model and adult subjects with cGvHD, is expected to be the same in pediatric 
subjects < 12 years of age as compared to subjects ≥ 12 years of age. Further, 
published data has shown that ruxolitinib has evidence of clinical efficacy when added 
to immunosuppressive therapy in subjects with SR-cGvHD. Clinical studies using 
ruxolitinib (10 mg twice a day (BID) alone or in comparison to BAT are currently 
underway in the SR-cGvHD setting for adult patients and adolescents ≥ 12 years of 
age. Despite children being at a lower risk of developing cGvHD than adults, the 
incidence of cGvHD in the pediatric population is substantial and has increased recently 
in association with the expanded use of peripheral blood stem cells and unrelated 
donors.
Primary 
Objective(s)
The primary objective of this study is to evaluate the activity of ruxolitinib added to 
standard dose corticosteroids, ± calcineurin inhibitor (CNI), in pediatric subjects with 
moderate or severe treatment naive-cGvHD or SR-cGvHD, by measuring the overall 
response rate (ORR) at Cycle 7 Day 1. ORR is defined as the proportion of subjects 
demonstrating a complete response (CR) or partial response (PR) without the 
requirement of additional systemic therapies for an earlier progression, mixed response 
or non-response.
Secondary 
Objectives
The secondary objectives are:

To evaluate the safety of ruxolitinib

To assess the pharmacokinetics (PK) of ruxolitinib in treatment-naive cGvHD and 
SR-cGvHD pediatric subjects

To assess duration of response (DOR)

To estimate ORR at end of Cycle 3

To assess best overall response (BOR)

To estimate the failure free survival (FFS)

To assess cumulative incidence of malignancy relapse/recurrence (MR)

To assess non-relapse mortality (NRM)

To assess overall survival (OS)

To assess a reduction of at least ≥50% in daily corticosteroid use at Cycle 7 Day 1

To assess a reduction to a low dose corticosteroid dose at Cycle 7 Day 1

To assess graft failure


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Study design
This open-label, single-arm, Phase II multi-center study will enroll approximately 42 
subjects and investigate the activity, pharmacokinetics and safety of ruxolitinib added to 
the subject's immunosuppressive regimen among infants, children, and adolescents 
aged ≥ 28 days to < 18 years old with either moderate to severe treatment-naive 
cGvHD or SR-cGvHD.
Subjects will be grouped according to their age as follows: Group 1 includes subjects ≥ 
12y to < 18 yr, Group 2 includes subjects ≥ 6 yr to < 12 yr, Group 3 includes subjects ≥ 
2 yr to < 6 yr, and Group 4 includes subjects ≥ 28 days to < 2y. Enrollment initiation into 
the youngest age group, Group 4, will be subject to the availability of data in this age 
group from study [CINC424F12201], as well as a review of available PK, safety, and 
activity data generated from Groups 1 to 3 in the current study.
At least 5 evaluable subjects per Group are needed for the primary analysis in Groups 
1, 2 and 3. No minimum number of evaluable subjects are needed in Group 4.
After a screening period of Day -28 to Day -1: eligible subjects will begin study 
treatment on Cycle 1 Day 1 and will be treated for up to a maximum of 3 years (39 
cycles/156 weeks) or until early discontinuation. Subjects who discontinue study 
treatment for any reason earlier than 39 cycles will be followed every 6 months until 3 
years from their first dose of study treatment is reached.
Population
The population will include male and female subjects ≥ 28 days to < 18 years, who have 
undergone allogeneic stem cell transplant (alloSCT) with a donor-derived myeloid 
engraftment and have been diagnosed with moderate to severe cGvHD as defined by 
National Institutes of Health (NIH) Consensus Criteria and must be either treatment-
naïve cGvHD or steroid-refractory cGvHD.
Key Inclusion 
criteria
For a full list of inclusion criteria, refer to Section 5.1 key inclusion criteria include:

Male or female subjects age ≥ 28 days and < 18 years at the time of informed 
consent.

Subjects who have undergone alloSCT from any donor source (matched unrelated 
donor, sibling and haplo-identical) using bone marrow (BM), peripheral blood stem 
cells, or cord blood. Recipients of myeloablative or reduced intensity conditioning 
are eligible.

Subjects with diagnosed moderate to severe cGvHD according to NIH Consensus 
Criteria (Section 16.2) prior to Cycle 1 Day 1. Subjects must be either: 

Treatment-naive cGvHD subjects that have not received any prior systemic 
treatment for cGvHD except for a maximum 72h of prior systemic 
corticosteroid therapy of methylprednisolone or equivalent after the onset of 
chronic GvHD. Subjects are allowed to have received prior systemic therapy 
for cGvHD prophylaxis (as long as the prophylaxis was started prior to the 
diagnosis of cGvHD),
OR

Steroid refractory (SR) moderate to severe cGvHD as per institutional criteria, or 
per physician decision in case institutional criteria are not available, and still 
receiving systemic corticosteroids for the treatment of cGvHD for a duration of < 18 
months prior to Cycle 1 Day 1.
Key Exclusion 
criteria

For a full list of exclusion criteria, refer to Section 5.2 Key exclusion criteria include:

SR-cGvHD subjects with a prior cGvHD treatment with a janus kinase (JAK1) or a 
JAK2- or a JAK1/2-inhibitor are not allowed, except when the subject achieved 
complete or partial response and has been off JAK inhibitor treatment for at least 4 
weeks prior to Cycle 1 Day 1 or up to 5 times the half-life of the prior JAK inhibitor, 
whichever is longer.

Failed prior alloSCT within the past 6 months; subjects with relapsed primary 
malignancy, or who have been treated for relapse after the alloSCT was performed, 
or who require withdrawal of immune suppression as pre-emergent treatment of 
early malignancy relapse.

Subjects who initiated systemic calcineurin inhibitors (CNI; cyclosporine or 
tacrolimus) within 3 weeks prior to start of ruxolitinib on Cycle 1 Day 1. Note: 
Systemic CNI are allowed when initiated > 3 weeks from start of ruxolitinib.


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
Significant respiratory disease including subjects who are on mechanical ventilation 
or who have a resting oxygen saturation < 90% by pulse-oximetry on room-air.

Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease 
(unrelated to GvHD) that may significantly alter the absorption of oral ruxolitinib 
(e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome or small bowel resection)

Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-
occlusive disease of the liver (defined as persistent bilirubin abnormalities not 
attributable to cGvHD and ongoing organ dysfunction)

Presence of clinically active uncontrolled infection including significant bacterial, 
fungal, viral or parasitic infection requiring treatment.

Any corticosteroid therapy for indications other than cGvHD at doses > 1 mg/kg/day 
methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days 
of screening visit.

Current therapy with medications that interfere with coagulation or platelet function, 
including but not limited to aspirin and related drugs, heparin, and warfarin (to 
minimize risk of bleeding).

Subject is receiving fluconazole at daily doses higher than 6 mg/kg (maximum 200 
mg).

Presence of severely impaired renal function (confirmed within 72h prior to 
ruxolitinib start) defined by:

Glomerular Filtration Rate (GFR) < 30 mL/min/1.73 m2, using estimated creatinine 
clearance (CLcr) calculated by updated bedside Schwartz equation or Cockroft 
Gault equation
Or

renal dialysis requirement
Investigational 
therapy
Ruxolitinib (INC424)
Efficacy 
assessments
cGvHD assessment will be performed as per Table 8-2: organ assessment (skin, eyes, 
mouth, liver, upper GI, Lower GI, lungs, joints and fascia) and overall grading to assess 
ORR at Cycle 7 Day 1.
In addition, other efficacy assessments include:

Graft failure monitoring.

Hematologic disease relapse/ progression assessment.
Pharmacokinetic 
assessments

Collection of PK data in the first 5 subjects enrolled in Groups 1, 2 and 3 and in all 
subjects enrolled in Group 4 for PK parameters (e.g. area under the curve (AUC), 
maximum concentration (Cmax), minimum concentration (Ctrough)).
Key safety 
assessments
Key safety assessments include:

Adverse events (AEs) (including infection monitoring, viral reactivation monitoring, 
secondary primary malignancy assessment, bleeding).

Laboratory assessments.

Physical examination.

Vital signs.

Tanner staging (if applicable).
Other 
assessments
Additional assessments include:

Acceptability and palatability assessment.

Pharmacodynamic (PD) biomarkers (bone biomarkers, GvHD biomarkers, immune 
cell characterization, cytokines).


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Data analysis
The response rates for ORR at Cycle 7 Day 1 will be estimated on the Full Analysis Set 
(FAS) as the primary endpoint. Ninety percent confidence intervals (CI) will be 
calculated based on the exact method for binominal distribution. Summary statistics 
(frequencies and percentages) will be provided. ORR at Cycle 4 Day 1, FFS, MR, NRM, 
OS, BOR, DOR, reduction in daily corticosteroid use, graft failure, safety and PK will be 
analyzed as secondary objectives.
One interim analysis for the efficacy and safety results will be performed when 
all subjects have completed 1 year of treatment or discontinued earlier. The final 
analysis will be performed and the final CSR produced after all the subjects have 
discontinued from the study.
Key words
Graft vs. host disease (GvHD), chronic graft vs. host disease (cGvHD), JAK inhibitor, 
janus kinase inhibitor, stem cell transplantation, allogeneic stem cell transplantation, 
ruxolitinib.


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1
Introduction
1.1
Background
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Allogeneic stem cell transplantation (alloSCT) is a curative immunotherapy for patients with 
blood-related malignancies including leukemia, and for pediatric patients diagnosed with 
disorders such as congenital anemias or metabolic disorders. AlloSCT also provides normal 
hematopoietic function in patients with non-malignant hematologic disorders, including severe 
aplastic anemia, inherited metabolic disorders, and hemoglobinopathies (Copelan 2006). Graft 
vs. host disease (GvHD) is a major limitation to the success of alloSCT, and occurs when donor-
derived immune cells in a bone marrow or stem cell graft recognize the transplant recipient as 
foreign, thereby initiating an adverse immune reaction leading to an inflammatory cascade with 
resultant tissue damage, organ failure, or even death.
Approximately 
32,000 
alloSCT 
procedures 
are 
performed 
annually 
world-wide 
(Niederwieser et al 2016) with up to 60% of patients receiving human leukocyte antigen (HLA) 
identical marrow grafts and up to 70% of patients receiving alternative donor marrow grafts 
who survive beyond 100 days developing cGvHD (Lee et al 2003). Additionally, the 
prevalence and severity of cGvHD occurring in 30% to 70% of alloSCT adult patients 
(Lee and Flowers 2008), has increased over the past 2 decades attributable to several factors 
including: i) the increased use of mobilized peripheral blood stem cell (mPBSC) grafts 
(containing higher numbers of donor T-cells than BM), ii) advanced age of transplant recipients 
rising from 55 to 75 years due to development of better tolerated reduced intensity conditioning, 
and, iii) improvements in survival during the first months after alloSCT.
GvHD can present as two distinct conditions, namely acute graft vs. host disease (aGvHD), and 
chronic GvHD (cGvHD) with differing clinical manifestations, and separation by time of 
occurrence. aGvHD is characterized by high levels of pro-inflammatory cytokines (e.g. tumor 
necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (IFN)-γ) which enhance 
activation and proliferation of donor effector T-cells (Ferrara et al 2009). cGvHD has been 
historically characterized by autoimmune and alloimmune dysregulation occurring after the 
first 100 days of alloSCT (Baird et al 2010). While major progress has been achieved in 
understanding the pathophysiology of aGvHD; cGvHD is far less defined (Wolff et al 2010). 
Current concepts include the persistence of allo-reactive T-cells, a T helper cell (Th) Th1-Th2 
shift of the cellular immune response, defective peripheral, and central tolerance mechanisms 
(ie, failure of control by regulatory T-cells and/or impaired negative selection of T-cells in the 
thymus), replacement of antigen presenting cells (APCs) of the host by APCs of the donor 
leading to indirect antigen presentation of allo-antigens, an increasing role of B-cells producing 
auto- and allo-antibodies against the host, and unspecific mechanisms of chronic inflammation 
leading to fibrosis of involved organs (Schultz and Dixon 2009).
Chronic GvHD can involve almost any organ of the body. It is a multi-systemic disorder and 
can present as a syndrome of variable clinical features resembling autoimmune and other 
immunologic disorders with a variety of clinical signs and symptoms resembling diseases such 
as scleroderma, Sjogren’s syndrome, bronchiolitis obliterans, and chronic immunodeficiency 


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(Greinix et al 2011). It also can include primary biliary cirrhosis, wasting syndrome and 
immune cytopenias (Jagasia et al 2015). Importantly, cGvHD leads to significant morbidity, 
diminished quality of life (QOL) and decreased overall survival (Lee et al 2003). Although 
approximately 50% of newly diagnosed cGvHD patients are cured within 7 years after starting 
systemic immunosuppression, 10% require continued systemic treatment indefinitely, and the 
remaining 40% relapse or die within 7 years during ongoing prolonged immunosuppressive 
treatment (Flowers and Martin, 2015, Vigorito et al 2009). cGvHD is classified into mild, 
moderate, and severe based on degree of organ involvement according to established NIH 
Consensus Criteria for cGvHD (Jagasia et al 2015), and approximately half of affected patients 
have 3 or more involved organs.
In general, pediatric patients have a lower incidence and decreased severity of cGvHD than 
their adult counterparts (Dhir et al 2014, Elgarten et al 2018). Additionally, the long-term 
prognosis of cGvHD appears to be slightly better in children when compared to adults however, 
they suffer from similar complications and have poorer long-term outcomes (Dhir et al 2014). 
In a recent publication, a retrospective analysis was performed on 52 children who underwent 
matched sibling donor bone marrow transplant at the Children’s Hospital of Philadelphia 
between 2002 and 2014. In this review, the incidence of cGvHD (all severities) was 
approximately 10% (Elgarten et al 2018). Additionally, the proportion of patients who 
developed moderate to severe cGvHD in patients aged 0 to < 18 years was approximately 9% 
of the observed incidence in adults aged ≥ 18 years (Center for International Blood and Marrow 
Transplant Research (CIBMTR) data on file).
Although systemic corticosteroids are standard of care (SOC) in initial stages of moderate to 
severe cGvHD, only 30% to 50% of children respond to corticosteroids as initial therapy, and 
optimal initial or second-line therapies have not yet been determined (Carpenter and
Macmillan 2010). As such, more effective treatment for children and adolescents with moderate 
and severe cGvHD represents a very high unmet medical need.
1.1.2
Introduction to investigational treatment(s)
1.1.2.1
Overview of Ruxolitinib
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) is a potent, selective 
inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50% [IC50]=3.3 ± 1.2 nM) and 
JAK2 (IC50 = 2.8 ± 1.2 nM) with modest to marked selectivity against tyrosine kinase 2 
(TYK2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), respectively. Ruxolitinib 
interferes with the signaling of a number of cytokines and growth factors that are important for 
hematopoiesis and immune function.
Dysregulated janus kinase-signal transducer and activator of transcription (JAK-STAT) 
signaling, via upregulation of JAK1 and JAK2 or gain of function mutations such as 
JAK2V617F, has been implicated as a driver of Breakpoint Cluster Region Abelson (BCR-
ABL) -negative myeloproliferative neoplasms (MPNs), namely myelofibrosis (MF), 
polycythemia vera (PV) and essential thrombocythemia (ET). Ruxolitinib specifically binds to 
and inhibits JAK1, JAK2 and mutated JAK2V617F, leading to inhibition of growth factor-
mediated cell signaling and tumor cell proliferation. Given this mechanism of action of 
ruxolitinib as a JAK inhibitor and the role played by dysregulation of the JAK pathway in the 


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pathogenesis of MPNs, the primary clinical development plan for ruxolitinib initially focused 
on studies to support regulatory approval in these disorders.
Of significance to GvHD, strong pre-clinical data shows that inhibition of JAK1/2 signaling 
results in reduced proliferation of donor immune cells, suppression of adverse cytokines in 
response to recipient antigens, as well as impairment of antigen presenting cells in vitro and in 
vivo (Socié and Ritz 2014, Spoerl et al 2014). In vivo JAK1/2 inhibition by ruxolitinib has been 
shown to improve survival of mice in an established GvHD model incorporating human 
immune cells, and impairs differentiation of T-cell populations that are linked to GvHD 
(Spoerl et al 2014). The role for JAK-inhibition in GvHD was further confirmed with data from 
a retrospective study in adult subjects with SR-cGvHD, showing that the majority of these 
subjects responded to ruxolitinib treatment with improved clinical cGvHD symptoms 
(Zeiser et al 2015). In this retrospective study, subjects aGvHD subjects received 5 mg to 10 
mg BID for ≥ 1week and cGvHD subjects received 5 mg to 10 mg BID for ≥ 3 weeks.
Based on the review of the long-term safety profile for MF and PV patients, there is no evidence 
for long latency adverse drug reactions (ADRs). The mean duration of patient exposure in the 
MF clinical development program was 30.8 months (standard deviation (SD) 21.0) with a 
maximum of 68 months. The mean duration of patient exposure in the PV clinical development 
program was 19.6 months (standard deviation (SD) 15.7) with a maximum of 66.7 months. 
Therefore, potential ADRs that have a longer latency than > 30 months could have been 
observed.
Ruxolitinib is currently approved under the trade name of ‘Jakavi’ in over 100 countries for the
treatment of disease-related splenomegaly or symptoms in adult patients with primary 
myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) and post-essential 
thrombocythemia myelofibrosis (PET-MF). The use of ruxolitinib to treat polycythemia vera 
(PV) patients who are resistant to or intolerant of hydroxyurea is currently approved in more 
than 60 countries worldwide including Europe.
Ruxolitinib is also approved in the United States of America (USA) under the trade name of 
‘Jakafi’ and is indicated for the treatment of patients with intermediate or high risk 
myelofibrosis, including PMF, PPV-MF and PET-MF and for the treatment of PV patients who 
have had an inadequate response to or are intolerant of hydroxyurea. 
Ruxolitinib is currently approved for the treatment of patients aged 12 and older with acute or 
chronic graft versus host disease (GvHD) in several countries including the USA, the European 
Union, UK, Switzerland, Australia, and Brazil.
1.1.2.1.1 Non-clinical experience
Ruxolitinib has been evaluated in non-clinical investigations in pharmacology, safety 
pharmacology, repeat-dose toxicity, genotoxicity, reproductive toxicity studies, and 
carcinogenicity studies. Ruxolitinib was observed to be efficacious in mouse models of 
Philadelphia chromosome negative MPNs. Efficacy was also observed in rodent models of 
cytokine-dependent inflammation. Effects noted in multiple-dose toxicity studies in mice (up 
to 4 weeks), rats (up to 6 months), and dogs (up to 12 months) were primarily those associated 
with the mechanism of action of ruxolitinib, a potent and reversible inhibitor of JAK/STAT 
signaling. Decreases in red blood cells (RBCs), reticulocytes, eosinophils and lymphocytes 


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have been observed along with lymphoid depletion in bone marrow and lymphoid organs. In a 
cardiovascular evaluation of ruxolitinib in dogs, electrocardiogram (ECG) parameters were 
unaffected at all doses.
Ruxolitinib was not mutagenic or clastogenic, nor did it demonstrate potential for 
carcinogenicity in a 6-month study in Tg.rasH2 mice or in the 2-year rat study. In embryo-fetal 
assessments in rat and rabbit, maternal toxicity and minimal embryo-fetal toxicity were noted 
at the highest doses evaluated. Ruxolitinib was not teratogenic in either rat or rabbit. In an 
evaluation of fertility and early embryonic development, no effects were noted on reproductive 
performance or fertility in male or female rats. Increases in post-implantation loss were noted 
at the higher doses. In a pre- and post-natal development and maternal function study in rats, 
there were no adverse findings for fertility indices or for maternal and embryo-fetal survival, 
growth, and developmental parameters. Ruxolitinib passed into the milk of lactating rats with 
an exposure that was 13-fold higher than maternal plasma exposure. When administered to 7 
days old rats (corresponding to a human age at birth based on general age-equivalence) data has 
shown that ruxolitinib can cause bone effects at a dose level ≥ 15 mg/kg/day. The translatability 
of these results to humans is unknown. More detailed information on the pharmacology of 
ruxolitinib, single and multiple dose pharmacokinetic (PK) studies conducted in multiple 
species and nonclinical safety evaluations can be found in the [Ruxolitinib Investigator 
Brochure (IB)].
1.1.2.1.2 Clinical experience
Ruxolitinib has been administered in clinical trials to more than 550 healthy adult volunteers as 
single, repeat single, or multiple doses for up to 10 days duration. Ruxolitinib has also been 
administered to 32 adult subjects with various degrees of renal impairment, 24 adult subjects 
with various degrees of hepatic impairment, and 50 adult subjects with rheumatoid arthritis 
(RA). Furthermore, more than 14,000subjects have received ruxolitinib treatment in Novartis-
and Incyte-sponsored investigational clinical trials (Refer to the most recent IB for details).
Clinical Pharmacology
Clinical pharmacology of ruxolitinib has been characterized in healthy volunteers and in 
subjects with Myelofibrosis (MF), Essential Thrombocythemia (ET), Polycythemia Vera (PV), 
as well as in subjects with renal or hepatic impairment, prostate cancer, pancreatic cancer, 
Multiple Myeloma (MM), or rheumatoid arthritis (RA). Oral absorption of ruxolitinib is rapid 
and nearly complete, with ≥ 95% absorption indicating high in vivo permeability in the human 
gastrointestinal tract, consistent with a Biopharmaceutical Classification System (BCS) Class I 
compound. Mean peak plasma concentrations (Cmax) is achieved 1 to 2 h post-dose.
The effect of food on ruxolitinib exposure is minimal and is not expected to be clinically 
significant; as a result, the drug may be administered either with or without food. Dose 
proportional exposure is observed between 5 and 200 mg dose range with linear PK.
Plasma protein binding is approximately 97% in vitro. There is moderate distribution to organs 
and tissues with no long-term retention of drug-related material in preclinical species and 
limited drug penetration into the central nervous system (CNS) or across the blood-brain barrier. 
There is > 95% [14C] drug recovery in a mass balance study with 74% and 22% of the dose 
excreted in urine and feces of healthy subjects, respectively. Less than 1% of the administered 


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dose is recovered in urine and feces as unchanged parent drug. The mean terminal elimination 
half-life (T1/2) is ~3 h with no appreciable accumulation of either parent or metabolites with 
twice daily dosing. Metabolism is predominantly via the cytochrome P450 isozyme, family 3, 
subfamily A (CYP3A4) to yield oxygenated and subsequent conjugated metabolites. Oxidative 
metabolites of ruxolitinib retain pharmacological activity albeit with 0.5 to 0.2 of the activity 
of the parent compound. Ex vivo pharmacokinetic/pharmacodynamic (PD) analysis indicates 
that the total of 8 active metabolites contribute to 18% of the overall pharmacodynamic activity 
of ruxolitinib. When administering ruxolitinib with strong CYP3A4 inhibitors, the total daily 
dose should be reduced by approximately 50%. No dose adjustment is necessary when co-
administering ruxolitinib with strong CYP3A4 inducers. No dose adjustment is necessary when 
co-administering ruxolitinib with CYP3A4 substrates. Ruxolitinib did not decrease the 
exposure of a fixed dose oral contraceptive metabolized via the CYP3A4 pathway, thus 
demonstrating lack of CYP3A4 induction potential.
In subjects with severe renal impairment (creatinine clearance (CLcr) < 30 mL/min), the dose 
based on platelet count should be reduced by approximately 50% to be administered twice a 
day. Ruxolitinib doses should be titrated based on individual safety and efficacy.
In subjects with mild, moderate or severe hepatic impairment, the recommended starting dose 
based on platelet count should be reduced by approximately 50% with subsequent dose titration 
based on individual safety and efficacy.
Ruxolitinib PK in healthy volunteers was largely comparable between Japanese, Chinese and 
Western subjects and studies led to a conclusion of no meaningful ethnic differences in exposure.
A thorough QT study was conducted in 50 healthy subjects. There was no indication of a 
QT/corrected QT interval (QTc) prolonging effect of ruxolitinib in single doses up to a supra-
therapeutic dose of 200 mg indicating that ruxolitinib has no effect on cardiac repolarization.
The available pediatric clinical PK data was described by (Loh et al 2015) in subjects with 
relapsed or refractory solid tumors (ST), leukemias, or MPNs enrolled in a Phase I study. In 
general, PK of ruxolitinib was similar in pediatric cancer subjects (n=42, median age 14 years, 
range 2 to 21 years) compared to that in adult subjects with myelofibrosis. In pediatric subjects, 
peak plasma concentrations of ruxolitinib were achieved by 1 hour (range 1 to 4 hours) after 
the first oral dose and decreased in a monoexponential fashion with a mean ± standard deviation 
(SD) T1/2 of 2.3 ± 0.9 h. The mean values for ruxolitinib oral plasma clearance (CL/F) and 
volume of distribution (V/F) among all subjects were 14.8 ± 5.9 L/h and 59.4 ± 29.1 L, 
respectively, and were independent of dose level. Ruxolitinib disposition appeared linear over 
the dose range studied based on dose-proportional increases in Cmax and AUC0‑ ∞values and 
observations of trends. Children ≤12 years had higher body surface area (BSA)-corrected CL/F 
values compared with children >12 years (14.4 ± 8.5 L/h/m2 vs. 10.2 ± 3.1 L/h/m2). The 
variability in BSA-corrected CL/F values was also greater for children ≤ 12 than in children > 
12 years. No differences in CL/F were observed between males (n = 26) and females (n = 16) 
(12.1 ± 6.3 L/h/m2 vs. 12.5 ± 7.2 L/h/m2).
Please refer to the Investigational Brochure for details on pharmacokinetics and 
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Summary of Clinical Efficacy and Safety Data
The results from two phase III registration studies in myelofibrosis (COMFORT-I, COMFORT-
II) demonstrated the effectiveness of ruxolitinib in subjects with PMF, PPV-MF and PET-MF. 
The results of these two studies were consistent, demonstrating statistically significant 
differences in rates of ≥ 35% spleen volume reduction (assessed by central radiology review) 
compared with either placebo or an investigator’s selection of best available therapy (BAT). 
Although each study assessed spleen volume reduction at a different time point (Weeks 24 and 
48 for COMFORT-I and COMFORT-II, respectively), the mean reduction in spleen volume is 
similar at Week 24 (31.6% vs. 29.2%, COMFORT-I and COMFORT-II, respectively).
Additionally, COMFORT-I met two out of three key secondary endpoints: 1) 50% decrease in 
total symptom score as defined by the MF symptom assessment form (response rate of 46% in 
the ruxolitinib arm vs. 5% with placebo) (p < 0.0001), 2) Mean change from baseline in MF 
symptom assessment form (-8.6 with ruxolitinib from baseline of 18 vs. + 3.2 with placebo 
from baseline of 16.5). COMFORT-II exploratory endpoints related to symptom improvement 
and quality of life (QOL) were consistent with and supportive of the results from COMFORT-
I. Grade 3 to 4 laboratory findings of anemia and thrombocytopenia were reported with 
ruxolitinib at rates of 38.3% and 8.3%, respectively, compared with 20.6% and 6.8% on BAT 
(COMFORT-II); and with ruxolitinib at rates of 45.2% and 12.9%, respectively, compared with 
19.2% and 1.3% on placebo (COMFORT-I). Thrombocytopenia and anemia were predictable 
adverse events that are manageable with dose modifications.
Long-term outcomes such as OS, leukemia-free survival (LFS), duration of response and safety 
were reassessed at different time points, most recently in 2015 (5-year follow up report), 
comparing the subjects originally randomized to the ruxolitinib arm to those that were 
randomized to the control arm. The 5-year follow-up report for COMFORT-I suggested longer 
survival for subjects randomized to ruxolitinib versus control arm subjects, with a hazard ratio 
(HR) of 0.693 (95% confidence interval [CI]: 0.503, 0.956, p = 0.0245). In COMFORT-II, long-
term follow-up also suggested a survival advantage with ruxolitinib treatment compared with 
BAT.
There was a 33% reduction in the risk of death for subjects treated with ruxolitinib compared 
with that for subjects treated with BAT (hazard ratio [HR] = 0.67; 95% CI, 0.44-1.02). The 
estimated survival probability at 5.0 years was 56% (95%CI: 0.40, 0.62) in the ruxolitinib arm 
and 44% (95% CI: 0.31, 0.56) in the BAT arm. Safety profile in the two studies remained 
broadly unchanged. No new or unexpected safety signals occurred with the longer treatment 
exposure and follow-up period.
The JUMP trial which was a Phase IIIB Expanded Access Program (CINC424A2401), also 
demonstrated effectiveness of ruxolitinib for subjects with PMF, PPV-MF, and PET-MF. In 
JUMP, the best overall response was assessed by International Working Group (IWG) 
Myeloproliferative Neoplasms Research and Treatment (MRT) criteria. It was observed that 
421 subjects (55%) with spleen length between 5 and 10 cm below left costal margin at baseline, 
and 742 (60.6%) subjects with spleen length more than 10 cm at baseline responded to study 
treatment (either achieved non palpable spleen or ≥ 50% reduction in spleen length during the 
study. A reduction in spleen length of at least 50% was reported in 71.7% of the subjects.


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Consistent with its activity in myelofibrosis, ruxolitinib demonstrated in the Phase III 
RESPONSE study its efficacy in polycythemia vera subjects who were resistant to or intolerant 
of hydroxyurea. Significantly, more subjects randomized to ruxolitinib than subjects 
randomized to BAT met the primary endpoint (hematocrit control and at least 35% spleen 
volume reduction) at Week 32: 23% vs 0.9%, respectively (p < 0.0001). More subjects 
randomized to ruxolitinib achieved hematocrit control (defined as a hematocrit <45% without 
the need for phlebotomy) at Week 32 when compared to subjects randomized to BAT: 60.0% 
(95% CI: 50.2, 69.2) vs 18.75% (95% CI: 12.7, 28.2), respectively. More subjects randomized 
to ruxolitinib achieved at least 35% spleen volume reduction at Week 32 when compared to 
subjects randomized to BAT: 40% (95% CI: 29.1, 47.9) vs 0.9% (95% CI: 0.0, 4.9), respectively. 
The great majority of these responses in the ruxolitinib arm were also durable at Week 48. 
Furthermore, significantly more subjects randomized to ruxolitinib achieved the key secondary 
endpoint of complete hematological remission (hematocrit control, platelet count ≤ 400×109/L, 
and white blood cell (WBC) count ≤ 10×109/L) at Week 32 when compared to subjects 
randomized to BAT: 23.6% vs 8.0%, respectively (p = 0.0028, when adjusted for baseline 
platelet and white blood cell (WBC) status). In addition, the efficacy analyses at the Week 80, 
Week 208 and Week 256 data cutoff confirmed the durability of the responses in the subjects 
randomized to the ruxolitinib arm.
In graft vs. host disease (GvHD), several recently published studies provide evidence of clinical 
efficacy and safety of ruxolitinib when added to immunosuppressive therapy in subjects with 
steroid-refractory 
acute 
graft 
vs. 
host 
disease 
(SR-aGvHD) 
and 
SR-cGvHD 
(Zeiser et al 2015, Khoury et al 2018, Spoerl et al 2014, Boiko et al 2017). Spoerl included 
data from 6 SR-aGvHD subjects who received an initial ruxolitinib dose of 5 mg BID that was 
advanced to 10 mg BID after 3 days when no side effects were observed. Responses to 
ruxolitinib treatment in terms of improved GvHD grades and reduction of required 
corticosteroids were observed in all subjects; no subject experienced GvHD flare during 
corticosteroid taper requiring additional systemic therapy (Spoerl et al 2014). Further clinical 
experience with ruxolitinib among subjects with steroid-refractory SR-cGvHD was gathered in 
41 SR-cGvHD adult subjects (aged 22-74 years) from 19 stem cell transplant centers 
(Zeiser et al 2015), and 6 SR-cGvHD subjects (aged 18 months to 20 years) at the University 
of California (Boiko et al 2017). In the Zeiser study, the overall response rate (ORR) was 85.4% 
(35/41), with 78% (32/41) having a partial response (PR defined as the discontinuation or long-
lasting (4 weeks) reduction of all systemic immunosuppressive therapy by at least 50%) and 
7.3% (3/41) having a complete response (CR defined as the absence of any symptoms related 
to cGvHD). The safety profile of ruxolitinib in SR-cGvHD was generally favorable. Although 
cytopenias in the (Zeiser et al 2015) publication were observed in 17% of SR-cGvHD adult 
subjects, cytopenias preceded ruxolitinib administration in 14.6% of these subjects. 
Cytomegalovirus (CMV) reactivation was observed in 14.6% of SR-cGvHD subjects treated 
with ruxolitinib (Zeiser et al 2015). This incidence rate compares favorably with that reported 
with other second-line GvHD agents including mycophenolate mofetil (MMF), alemtuzumab, 
and others where CMV reactivation ranges from 70% to 80% (Zeiser et al 2015). Relapse of 
the underlying malignancy occurred in 2.4% (1/41) of the subjects with SR-cGvHD. This 
frequency is comparable to other studies and suggests that ruxolitinib treatment is not linked to 
a higher relapse risk when compared with other currently applied immunosuppressive drugs 
(Zeiser et al 2015). Additional 24 month follow-up was presented at the 2016 American Society 
of Hematology conference (Zeiser et al 2016) which demonstrated a 1-year overall survival 


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(OS) of 92.7% (CI: 84.7-100%), with an estimated median OS not being reached for these 
subjects. Twenty-four percent (10/41) of SR-cGvHD subjects have an ongoing response and 
are free of any immunosuppression. Any grade cytopenias (17.1%, 7/41) and CMV reactivation 
(14.6%, 6/41) were observed during ruxolitinib-treatment. GvHD relapse or progression after 
achieved partial response/complete response was observed in 13/36 (36%) subjects with SR-
cGvHD. Response to re-treatment with ruxolitinib or any immunosuppressive therapy was seen 
11/13 (86%) subjects with SR-cGvHD. These findings extend the previous report by showing 
that subjects with SR-GvHD may benefit long-term from ruxolitinib treatment 
(Zeiser et al 2016).
Of particular relevance to pediatric subjects, the retrospective chart review performed at the 
University of California, San Francisco, in six subjects (ages 18 months to 20 years at time of 
alloSCT) that were treated at their institution in the last 2-years (Boiko et al 2017). In most 
cases, ruxolitinib was added to the subject's current GvHD therapy. Median studied period of 
ruxolitinib therapy was five months (range: 3 to 7 months), and it was generally well tolerated. 
Subjects also had overall favorable therapeutic responses to ruxolitinib with median time to 
organ score improvement of 21 days.
Studies with ruxolitinib are underway in adult and adolescent subjects with SR-aGvHD 
(CINC424C2301) and SR-cGvHD (CINC424D2301). Additionally, a study with ruxolitinib is 
also ongoing in pediatric subjects with aGvHD (CINC424F2201). In addition, studies with 
ruxolitinib are underway in pediatric subjects with high risk ALL (AALL1521 18424 269). A 
non-randomized study of ruxolitinib in combination with a standard multi-agent chemotherapy 
regimen for the treatment of de novo B-cell acute lymphoblastic leukemia (B-ALL) in pediatric 
subjects who are not classified as very high or high risk (INCB18424-269) is also ongoing in 
the United States (US) with Incyte as the Sponsor (non-Novartis study).
Recently, the results of the phase II study of ruxolitinib for the treatment of steroid-refractory 
acute GvHD in 71 patients older than 12 years (REACH1) were published. A total of 39 patients 
(54.9% [95% CI, 42.7%–66.8%]) had an overall response, including 19 (26.8%) with complete 
responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were 
observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver 
(26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At Day 
28, 24/43 patients (55.8%) receiving ruxolitinib and corticosteroids had a ≥50% corticosteroid 
dose reduction from baseline. The most common treatment-emergent adverse events were 
anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and 
peripheral edema (45.1%). Overall the safety profile was consistent with expectations for 
ruxolitinib and this patient population (Jagasia et al 2020). 
The results of the study CINC424C2301 support previously reported findings with ruxolitinib 
in patients with steroid-refractory acute GvHD. This study is a phase III, multicenter, 
randomized, open-label study comparing the efficacy and safety of oral ruxolitinib (10 mg twice 
daily) with the investigator’s choice of therapy from a list of nine commonly used options in 
patients 12 years of age or older who had steroid-refractory acute GvHD after allogeneic stem-
cell transplantation. (A total of 309 patients were randomized (154 patients to the ruxolitinib 
group and 155 to the control group). Overall response at Day 28 was higher in the ruxolitinib 
group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% 
confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher 


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in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 
2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response 
at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-
free survival was considerably longer with ruxolitinib than with control (5.0 months vs.1.0 
month; hazard ratio for relapse or progression of hematologic disease, non–relapse-related 
death, or addition of new systemic therapy for acute GvHD, 0.46; 95% CI, 0.35 to 0.60). The 
median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control 
group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events 
up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 
27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and 
cytomegalovirus infection (in 39 [26%] and 31 [21%]). The safety profile of ruxolitinib in this 
trial was consistent with the known safety profile of ruxolitinib and was as expected in patients 
with steroid-refractory acute GvHD (Zeiser et al 2020).
Similarly, the results of the phase III, multicenter, randomized, open-label study comparing the 
efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator’s choice of 
therapy from a list of ten commonly used options in patients 12 years of age or older with 
moderate or severe glucocorticoid-refractory or –dependent chronic GVHD (CINC424D2301) 
support previously reported findings with ruxolitinib in patients with steroid-refractory chronic 
GVHD. A total of 329 patients were randomized (165 patients to the ruxolitinib group and 164 
to the control group). Overall response at week 24 was higher in the ruxolitinib group than in 
the control group (49.7% [82 patients] vs. 25.6% [42]; odds ratio, 2.99; 95% confidence interval 
[CI], 1.86 to 4.80; P<0.001). The median failure-free survival was considerably longer with 
ruxolitinib than with control (>18.6 months vs.5.7 month; hazard ratio for relapse or progression 
of hematologic disease, non–relapse-related death, or addition of new systemic therapy for 
chronic GVHD, 0.37; 95% CI, 0.27 to 0.51; P<0.001). The probability of failure-free survival 
at 6 months, as estimated with the use of the Kaplan-Meier method, was higher with ruxolitinib 
(74.9%; 95% CI, 67.5 to 89.9) than with control therapy (44.5%; 95% CI, 36.5 to 52.1). The 
response on the modified Lee Symptom Scale at 24 weeks was also higher with ruxolitinib than 
with control therapy (24.2% vs. 11.0%; odds ratio, 2.62 [95% CI, 1.42 to 4.82]; risk ratio, 2.19 
[95% CI, 1.31 to 3.65]; P=0.0010. The most common adverse events of grade 3 or higher up to 
week 24 were thrombocytopenia (in15.2% of patients who received ruxolitinib and 10.1% if 
patients who received control therapy), anemia (in 12.7%] and 7.6%), neutropenia (in 8.5% and 
3.8%), and pneumonia (in 8.5% and 9.5%). respectively). The safety profile of ruxolitinib was 
consistent with observations in patients with acute GvHD and expectations in patients with 
steroid-refractory chronic GvHD (Zeiser et al 2021).
1.2
Purpose
cGvHD pathophysiology begins with activation of host antigen-presenting cells (APC) 
expressed by damaged tissues and/or pathogens (Dhir et al 2014). Activated host APC then 
present host antigens to donor immune cells, leading to donor T-cell proliferation and 
inflammatory cytokine production. These inflammatory cytokines then recruit and induce 
proliferation of additional immune effector cells, thereby perpetuating an adverse cycle of allo 
reactive tissue injury and inflammation (Paczesny et al 2010). This signaling cascade in cGvHD 
determined in the mouse model and adult subjects with cGvHD, is expected to be the same in 
pediatric subjects < 12 years of age as compared to subjects ≥ 12 years of age. Ruxolitinib has 


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been shown to lower pro-inflammatory cytokines in MF patients. In addition, pre-clinical data 
support the mechanism of action of ruxolitinib in GvHD to: i.) impair APC function, ii.) inhibit 
donor T cell proliferation, iii.) suppress adverse cytokine production, and iv.) improve survival 
and disease manifestations in GvHD mouse models (Parampalli Yajnanarayana et al 2015) 
(Heine et al 2013) (Spoerl et al 2014). Published data have shown evidence of clinical efficacy 
with ruxolitinib treatment when added to immunosuppressive therapy in subjects with SR-
cGvHD (Zeiser et al 2015) (Boiko et al 2017).
Clinical studies using ruxolitinib alone or in comparison to best available therapy are currently 
underway in the SR-cGvHD setting for adult subjects and adolescents ≥ 12 years of age. Despite 
children being at a lower risk of developing cGvHD than adults (Baird et al 2010), the incidence 
of cGvHD in the pediatric population is substantial and has increased recently in association 
with the expanded use of peripheral blood stem cells and unrelated donors (Zecca et al 2002). 
The treatment of moderate to severe cGvHD in pediatrics is highly variable and mostly 
extrapolated from the experience in adults. While there is no proven “standard therapy,” 
corticosteroids and calcineurin inhibitors (CNI) are commonly employed as frontline therapy.
Similar to the adults, there are limited treatment options for moderate to severe cGvHD 
including systemic corticosteroids as initial standard of care for pediatric patients. With only 
30% to 50% of the children responding to use of corticosteroids, there is a high unmet medical 
need for optimal initial and second-line therapies in the pediatric population (Wolff et al 2011). 
Furthermore, children who respond to initial immunosuppressive treatment, most likely 
corticosteroids, require it for prolonged periods, consequently having debilitating persistent and 
irreversible impact on overall health and quality of life (Fraser et al 2006).
Given available data (presented above), in the current setting of a lack of effective first- or 
second-line treatments for pediatric cGvHD, this study aims to assess the pharmacokinetics, 
safety and activity of ruxolitinib treatment in pediatric subjects (age ≥ 28 days to < 18 years) 
with treatment-naive cGvHD or SR-cGvHD. It is expected that ruxolitinib will provide higher 
rates of disease response compared to steroids +/- Calcineurin Inhibitors (CNI) alone as upfront 
treatment of moderate to severe cGvHD. It is further expected that this response will be durable 
during steroid taper, representing a meaningful clinical benefit for pediatric subjects. Expected 
meaningful clinical benefits among those treated with ruxolitinib include it’s steroid sparing 
effect, reducing the proportion of pediatric subjects experiencing flares during steroid tapering, 
reducing proportion of subjects with infections and severity of infections, reducing 
hospitalization duration and requirement for re-admission, and maintenance of graft vs. 
malignancy effect.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To evaluate the activity of ruxolitinib added 
to standard dose corticosteroids +/- CNI in 
pediatric subjects with moderate or severe 
treatment naive-cGvHD or SR-cGvHD 
measured by overall response rate (ORR) 

Overall response rate (ORR) at Cycle 7 Day 1, defined 
as the proportion of subjects demonstrating a complete 
response (CR) or partial response (PR) without the 
requirement of additional systemic therapies for an 
earlier progression, mixed response or non-response. 


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Objective(s)
Endpoint(s)
at Cycle 7 Day 1 based on all subjects in 
the study.
The response is assessed per NIH consensus criteria 
(Lee et al 2015),and scoring of response will be relative 
to the organ stage at the start of study treatment.
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess pharmacokinetics (PK) of 
ruxolitinib in treatment-naïve cGvHD and 
SR-cGvHD pediatric subjects

Ruxolitinib concentrations by timepoint

To evaluate the safety of ruxolitinib 

Safety and tolerability will be assessed by monitoring 
the frequency, duration and severity of Adverse Events, 
including occurrence of any second primary 
malignancies or infections, and by performing physical 
exams and evaluating changes in vital signs, tanner 
stage, chemistry and hematology results from baseline.

To assess duration of response (DOR)

Duration of response (DOR) is assessed for responders 
only. DOR is defined as the time from first response until 
cGvHD progression, death, or the date of addition of 
systemic therapies for cGvHD.

To estimate ORR at end of Cycle 3

Proportion of subjects who achieve OR (CR+PR) at 
Cycle 4 Day 1

To assess best overall response (BOR)

Proportion of subjects who achieved OR (CR+PR) at 
any time point (until Cycle 7 Day 1 or the start of 
additional systemic therapy for cGvHD)

To estimate the failure free survival (FFS)

Composite time to event endpoint incorporating the 
following FFS events: i) relapse or recurrence of 
underlying disease or death due to underlying disease, 
ii) non-relapse mortality, or iii) addition or initiation of 
another systemic therapy for cGvHD.

To assess cumulative incidence of 
malignancy relapse/recurrence (MR)

Malignancy relapse/recurrence (MR) is defined as the 
time from date of treatment assignment to hematologic 
malignancy relapse/recurrence. Calculated for subjects 
with underlying hematologic malignant disease.

To assess non-relapse mortality (NRM)

Non-relapse mortality (NRM), defined as the time from 
date of treatment assignment to date of death not 
preceded by underlying disease relapse/recurrence.

To assess overall survival (OS)

Overall survival, defined as the time from the date of 
treatment assignment to the date of death due to any 
cause. 

To assess a reduction of at least ≥ 50% in 
daily corticosteroid use at Cycle 7 Day 1

Proportion of subjects with ≥ 50% reduction from 
baseline in daily corticosteroid dose at Cycle 7 Day 1

To assess a reduction to a low dose 
corticosteroid dose at Cycle 7 Day 1

Proportion of subjects with reduction from baseline in 
daily corticosteroid dose to ≤ 0.2 mg/kg/day 
methylprednisolone (or equivalent dose of ≤ 0.25 
mg/kg/day prednisone or prednisolone) at Cycle 7 Day 1

To assess graft failure

Assess using donor cell chimerism, defined as initial 
whole blood or marrow donor chimerism for those who 
had ≥ 5% donor cell chimerism at baseline. If donor cell 
chimerism declines to 
< 5% on subsequent measurements, the graft failure is 
declared.
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)

To describe the responses from the 
acceptability and palatability questionnaire 
of ruxolitinib oral pediatric formulation 

Responses from the acceptability and palatability 
questionnaire for the oral pediatric dose formulation 
after Cycle 1 (first dose), Cycle 4 and Cycle 39, as 
applicable.


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Objective(s)
Endpoint(s)

To assess pharmacokinetic (PK) / 
pharmacodynamic (PD) relationships

Pharmacokinetic parameters derived by population PK 
analysis from sparse concentration-time data, e.g., 
AUC, Cmax, Ctrough

To evaluate effect of ruxolitinib on 
cytokines, cGvHD biomarkers and immune 
cell subsets

Assess changes in immune cell subsets, inflammatory 
cytokine levels, and soluble cGvHD biomarkers. 

To evaluate effect of ruxolitinib on markers 
of bone development in pediatric subjects

To evaluate systemic corticosteroid-free 
response rate

Assess changes in soluble markers for bone resorption 
and formation, including but not limited to CTX, 
Osteopontin, and BALP

Proportion of subjects who achieved OR (CR or PR) at 
any time point without systemic corticosteroid therapy 
for at least one month prior to the disease assessment 
3
Study design
This open-label, single-arm, Phase II multi-center study will investigate the activity, 
pharmacokinetics and safety of ruxolitinib added to the subject's immunosuppressive regimen 
among infants, children, and adolescents aged ≥ 28 days to < 18 years old with either moderate 
to severe treatment-naive cGvHD or SR-cGvHD. Approximately 42 subjects will be enrolled 
in this study. Subjects will be grouped according to their age as follows: Group 1 includes 
subjects ≥ 12y to < 18y, Group 2 includes subjects ≥ 6y to <12 y, Group 3 includes subjects ≥ 
2y to < 6y, and Group 4 includes subjects ≥ 28days to < 2y. Subjects will remain in the age 
group throughout the study based on the age at the time of start of treatment. Enrollment 
initiation into the youngest age group, Group 4, will be subject to the availability of data in this 
age group from study [CINC424F12201], as well as a review of available PK, safety, and 
activity data generated from Groups 1 to 3 in the current study, in consultation with the data 
monitoring committee (DMC) and a final decision by the Sponsor. At least 5 evaluable subjects 
per Group are needed for the primary analysis in Groups 1, 2 and 3. No minimum number of 
evaluable subjects are needed in Group 4.
After a screening period from Day -28 to Day -1, eligible subjects will begin the investigational 
treatment (ruxolitinib) on Cycle 1 Day 1 and will be treated for up to a maximum of 3 years (39 
cycles/ 156 weeks) or until early discontinuation. Subjects who discontinue ruxolitinib for any 
reason earlier than 39 cycles will be followed every 6 months until 3 years from their first dose 
of ruxolitinib is reached. Refer to Section 8.2.1 for details of the treatment period study visits. 
All subjects continuing to receive ruxolitinib treatment benefit following 3 years of treatment 
will be given the possibility to continue ruxolitinib outside the study, from another source, 
where permitted in accordance to local laws and regulations.
The ruxolitinib dose is based on the preliminary efficacy and safety data generated with this 
dose in subjects with steroid-refractory graft vs. host disease (SR-GvHD) (Zeiser et al 2015), 
and based on PK/safety data generated from the Phase III trials CINC424C2301 and 
CINC424D2301. As subjects ≥ 12 y to < 18 y are already being treated with 10 mg BID in 
CINC424D2301, this dose is the recommended phase II dose (RP2D), and will be used to treat 
all subjects in this age group.
Pediatric subjects enrolled in the ongoing pediatric aGvHD study [CINC424F12201] will 
provide PK data that will be used to confirm the adequacy of the doses described above and 
thus patients < 12 years will only be enrolled in Groups 2 to 4 in the current study once the dose 




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(Choi et al 2012). The blockade of JAK/STAT signaling in wild-type T-cells using the 
JAK/STAT-signaling inhibitor, ruxolitinib, resulted in a similar effect to IFN-γR-/- T cells both 
in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-
HSCT). Additionally, ruxolitinib treatment in allo-hematopoietic stem cell transplantation 
(HSCT) recipients increased Forkhead box protein P3 (FoxP3+) Tregs, which are linked to 
immunologic tolerance (Wang et al 2017, Du et al 2017, Choi et al 2014).This signaling 
cascade in cGvHD determined in the mouse model and adult subjects with GvHD, is expected 
to be the same in pediatric subjects < 12 years of age as compared to subjects ≥ 12 years of age. 
As comparative data is being generated in an ongoing Phase III trial (CINC424D2301) which 
enrolls subjects ≥ 12 years of age, efficacy data from that study will be extrapolated to the 
pediatric population. Therefore, in the current setting of a lack of effective first- or second-line 
treatments for pediatric cGvHD, this study aims to assess the pharmacokinetics, safety and 
activity of ruxolitinib treatment in pediatric subjects (age ≥ 28 days to < 18 years) with 
treatment-naive cGvHD or SR-cGvHD.
4.1
Rationale for study design
This trial is designed as a single-arm phase II open label study to evaluate the activity of 
ruxolitinib among pediatric subjects with moderate to severe treatment naive- or SR-cGvHD. 
A single-arm design has been chosen based on the fact that GvHD after HSCT in children is 
rare, and therefore prioritize the generation of relevant safety, dosing, exposure and activity 
data. This approach has also been supported by investigators and treating physicians taking into 
consideration the morbidity of the disease, the fragility of the subjects and off-label access to 
ruxolitinib.
This study will include moderate to severe treatment naive-cGvHD and SR-cGvHD pediatric 
subjects aged ≥ 28 days to < 18 years. No prospective pediatric studies have been carried out to 
assess the use of newer therapeutic agents as first-line therapy for cGvHD. Inclusion of 
treatment-naive subjects ensures coverage of the entire disease entity. In addition, limited 
prospective studies have been carried out in the SR-cGvHD pediatric subjects to assess suitable 
second-line treatment options. Thus, this study will allow us to address the growing unmet 
medical need among pediatric cGvHD subjects.
The treatment phase will allow assessment of subject benefit and risk in terms of: i.) 
improvement or resolution of cGvHD manifestations, ii.) reduction or cessation of required 
systemic corticosteroids, iii.) any progression or recurrence of the underlying hematologic 
disease for which the alloSCT has been performed including malignancy progression or relapse, 
and iv.) overall survival.
The primary endpoint proposed in this trial is the proportion of patients demonstrating Overall 
Response Rate (ORR) consisting of either complete response (CR) or partial response (PR) at 
Cycle 7 Day 1 as defined by the 2014 NIH response criteria (Lee et al 2015). The primary 
endpoint of ORR is being proposed in consultation with cGvHD medical experts based on the 
fact that subject response is a clinically relevant measure of treatment efficacy. Response rates 
have been correlated to long-term outcomes in 2 independent trials. The first trial utilized the 
2005 NIH consensus response criteria and enrolled 40 subjects with cGvHD. In that trial, 
subjects were eligible if they were diagnosed with moderate to severe cGvHD and were 
refractory to at least immunosuppressive lines of therapy. Clinician assessment was performed 


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at Baseline and at 6 months. ORR at 6 months was strongly correlated with overall survival 
(OS) at 36 months (Olivieri et al 2013). The second trial used the revised 2014 NIH response 
criteria and enrolled 575 subjects with cGvHD. Clinician assessment was performed at Baseline 
and 6 months. This trial demonstrated that at 6 months, clinician-reported response predicted 
OS (Palmer et al 2016).
It is expected that ruxolitinib will provide higher rates of disease response, assessed via ORR 
at 6 months without requirement for addition of new systemic immunosuppressive treatment. It 
is further expected that this response will be durable during steroid taper, representing a 
meaningful clinical benefit for pediatric subjects.
4.2
Rationale for dose/regimen and duration of treatment
Pharmacokinetic predictions in pediatrics with GvHD were based on PK in adults with GvHD 
(clinical study CINC424C2301). Two methods were used to derive an efficacious and safe dose 
of ruxolitinib in pediatric population for the Graft vs. Host Disease indication:
1) allometric scaling method in which the exponents used for scaling were obtained as described 
by (Mahmood 2014);
and
2) Physiologically based pharmacokinetic (PBPK) modeling using the SimCYP software in 
which the already established and validated model that matched the PK profiles in healthy adults 
(5-25 mg BID) was adapted to match the PK profiles obtained in adults with GvHD (10 mg 
BID; clinical study CINC424C2301). Then changing the body physiology from adults to a 
pediatric population (available in SimCYP) enabled the prediction of ruxolitinib clearance and 
drug exposure in pediatrics. The assumption that efficacy is driven by drug exposure is 
supported by a study in children with solid and hematological malignancies (Loh et al 2015).
Overall, for an age above 2 years old the predicted doses were very similar by using either 
allometry or PBPK scaling, therefore the starting doses in pediatric patients were assessed by 
averaging the predictions from both approaches. For an age below 2 years old, the predictions 
from PBPK model that incorporate ontogeny (un-mature polymorphic cytochrome P450 
enzymes (CYPs) in pediatrics) predicted a lower CL and doses than allometry and thus a 
conservative approach will be used for this group.
The predicted efficacious doses in children that would match the drug exposure observed in 
adult with a dose of 10 mg BID (e.g. AUC0-12h: 539 ng.h/mL equivalent to 1750 h.nM 
(Shi et al 2011, Shi et al 2012) were: 1.4 to 2.7 mg/m2 BID for the youngest patients (≥ 28 days 
to < 2 years); 4 mg/m2 BID for 2-6 years; 5 mg BID for 6-12 years; and 10 mg BID for 12-18 
years.
The PBPK model predictions for the lower age-groups (≥ 28 days to < 2 years) will be 
readjusted when PK information in the higher age groups (between 2 and 18 year old) will 
become available.
Ruxolitinib will be administered either as a 5 mg tablet or as an oral pediatric formulation twice 
a day, added to standard treatment of cGvHD including methylprednisolone +/- CNI at standard 
dosing adjusted to therapeutic trough levels.


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Group 1: In the adolescent age group (≥ 12y to < 18y), the dose will be the same as adults (10 
mg BID). The dose is based on the preliminary efficacy and safety data generated with 10 mg 
BID in subjects with SR-GvHD (Zeiser et al 2015). This is further supported by published 
literature showing that adolescents have similar toxicity profiles, maximum tolerated doses, and 
pharmacokinetic parameters compared to adults, as well as safety and PK data of ruxolitinib 
from a Phase I study in pediatric subjects with various malignancies (Loh et al 2015). 
Group 2 and 3: For the younger groups (≥ 2 up to < 12 years), PBPK modeling was used to 
derive dosing schemes predicted to yield exposure equivalent to that of 10 mg BID in adults. 
The doses are thereby assigned as 5 mg BID (≥ 6y to < 12) and 4 mg/m2 BID (≥ 2y to < 6y), 
subject to dose confirmation in the pediatric aGvHD study [CINC424F12201].
Group 4: For the youngest subjects (≥ 28 days to < 2 years), the current absence of existing 
ruxolitinib PK data warrants a conservative approach. Therefore, the dose for Group 4 will be 
determined based on the Group 4 dose established by PBPK modeling in the pediatric aGvHD 
study [CINC424F12201] as well as PK data generated in Groups 1, 2 and 3 (Table 6-1) in Cycle 
1 of the current study.
Pediatric subjects enrolled in the ongoing pediatric aGvHD study [CINC424F12201] will 
provide PK data that will be used to confirm the adequacy of the doses described above and 
thus subjects < 12 years will only be enrolled in the current study once the dose is confirmed in 
the appropriate age group.
If a different dose is determined in Groups 2 and/or 3 in the pediatric aGvHD study 
[CINC424F12201], the dose will need to be adjusted accordingly in the respective group in the 
current study.
Subjects enrolled in the adult aGvHD study [CINC424C2301] and cGvHD study 
[CINC424D2301] may also provide PK data that will be used as additional information to 
confirm adequacy of the doses in Groups 2, 3 and 4.
4.3
Rationale for exploratory biomarker assessment
The goal of the exploratory biomarker assessments for this study is to understand the impact of 
ruxolitinib in pediatric cGvHD and to gain further knowledge of the disease in this population. 
Biomarker samples will be collected and explorative biomarker activities will be conducted to 
assess the effect of ruxolitinib on bone biomarkers (for formations and resorption), cells of the 
immune system, and pro-inflammatory cytokines in peripheral blood.
In order to understand any potential impact of ruxolitinib in bone development/skeletal growth 
in pediatric subjects, soluble markers for bone resorption and formation, including but not 
limited to C-terminal telopeptide (CTX) and bone-specific alkaline phosphatase (BALP), will 
be evaluated during the study.
To further explore the immuno-modulatory effects of ruxolitinib in cGvHD, immuno-
phenotyping (this may include T-cells, T-regs (including subsets), B-cells, NK cells, and 
myeloid cells) will be performed on peripheral blood samples pre- and post-treatment.
Additionally, to investigate the inflammatory state in subjects, cytokines including but not 
limited to IL-6 and TNF-α will be measured in peripheral blood prior to the start of treatment 
and during the treatment period as they relate to disease status and treatment 


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(Verstovsek et al 2010, 
Spoerl et al 2014, 
Zeiser et al 2015). 
Their 
potential 
as 
pharmacodynamic markers for ruxolitinib will be investigated.
4.4
Purpose and timing of interim analyses/design adaptations
One interim analysis for the efficacy and safety results will be performed when all subjects have 
completed 1 year of treatment or discontinued earlier. More details can be found in Section 12.7.
4.5
Risks and benefits
Appropriate eligibility criteria, as well as specific dose modification and stopping rules, are
included in this protocol. Recommended guidelines for prophylactic or supportive management 
of study-drug induced adverse events are provided in Section 6.5.1. The risk to patients in this 
trial may be minimized by compliance with the eligibility criteria and study procedures, as well 
as, close clinical monitoring, and, protocol-defined ruxolitinib dose modifications guidelines 
and treatment discontinuation criteria. There may be unforeseen risks with ruxolitinib which 
could be serious. Refer to the most recent [Investigator Brochure].
As outlined previously, the potential benefit of ruxolitinib for alloSCT patients with cGvHD is 
based on published pre-clinical and clinical data. Important risks of treatment with ruxolitinib
based on the myeloproliferative neoplasms (MPN) clinical development and post-authorization 
experience to date include myelosuppression (thrombocytopenia, anemia and leukopenia), 
infections (including tuberculosis (TB), progressive multifocal leukoencephalopathy (PML), 
hepatitis B reactivation and other opportunistic infections), bleeding and non-melanoma skin 
cancers (NMSC). Additionally, in patients with hepatic and renal impairment, Area under the 
Curve (AUC) and half-life of the metabolites of ruxolitinib increased, and hence, these subjects 
should be carefully monitored and may need to have their dose reduced to avoid dose-related 
adverse drug reactions. These risks will be monitored closely and mitigated throughout this 
study as these risks are also common in the alloSCT setting particularly patients with 
cGvHD. No substantial additional risk for subject safety due to the SARS-CoV-2 virus and the 
COVID-19 pandemic has been identified at this time and therefore the benefit-risk assessment 
remains unchanged.
Myelosuppression
Myelosuppression is a common occurrence in alloSCT patients, is commonly experienced 
effect from cGvHD. Case series in acute and chronic GvHD have identified worsening of 
myelosuppression in approximately 10% to 20% of GvHD patients treated with ruxolitinib at 
doses ranging 5-10 mg orally BID spanning several months (Zeiser et al 2015). This was 
managed with dose reduction of ruxolitinib to 5 mg orally BID and required holding ruxolitinib 
in some patients whose absolute neutrophil count (ANC) dropped below 500/mm3.
Administration of hematopoietic growth factors will be allowed per Investigator judgement.
Bleeding
Hemostatic disturbances are common in patients undergoing alloSCT and have a significant 
impact on morbidity and mortality. Ruxolitinib dose adjustment or dose holding will be based 
on platelet count (see Table 6-5), and platelet transfusions may be given as clinically indicated.


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Use in patients with hepatic impairment
As the liver could be one of the organs involved in cGvHD pathophysiology, elevated liver 
function tests (LFTs) including bilirubin and aspartate aminotransferase (AST)/alanine 
aminotransferase (ALT) cannot be used as a parameter to exclude treatment-naive cGvHD or 
SR-cGvHD patients or determine starting dose. Diagnostic evaluation and management of 
hepatic impairment in treatment-naive cGvHD or SR-cGvHD patients treated on this study will 
follow institutional guidelines. Guidelines for the required diagnostic tests for ruxolitinib 
induced liver impairment are outlined in Section 6.5.2.1.
Use in patients with renal impairment
Renal impairment is a common occurrence in patients with treatment-naive cGvHD or SR-
cGvHD due to episodes of mild dehydration attributable to GI involvement in the outpatient 
setting causing decreased oral intake as well as concurrent administration of CNI. AlloSCT 
patients with severely impaired renal function are excluded from enrollment. Diagnostic 
evaluation and management of renal impairment in treatment-naive cGvHD or SR-cGvHD 
patients will follow institutional guidelines.
Infections
Serious bacterial, mycobacterial, fungal, viral and other infections have occurred in MPN 
patients treated with ruxolitinib. Actions to minimize the risk of serious infections in treatment-
naive cGvHD or SR-cGvHD patients will follow standard alloSCT guidelines including close 
monitoring of clinical signs and symptoms of infection, their prompt recognition and treatment. 
Management of any active viral infection and viral prophylaxis will follow local transplant 
program guidelines and viral load titer data will be documented when results are available.
Tuberculosis
Subjects in this study will be monitored for any clinical signs and symptoms of active 
tuberculosis (TB) infection, and appropriate treatment provided. Skin testing for TB will not be 
performed in this study of alloSCT subjects as this assessment is non-informative due to anergy.
Progressive Multifocal Encephalopathy
Progressive multifocal leukoencephalopathy (PML) is a rare complication in alloSCT recipients. 
The median time from transplantation to symptom onset has been reported as 11 months, while 
median time to symptom onset has been notably shorter in other viral encephalitis in this 
population. These other viral entities, including human herpes virus (HHV-6), herpes simplex 
virus (HSV), epstein-barr virus (EBV), CMV, hepatitis B virus (HBV), hepatitis C virus (HCV) 
and varicella zoster (VZV), have been reported with a median time to symptom onset post-
hematopoietic cell transplantation (HCT) of between 3 and 8 months, respectively. The 
incidence of PML in the HCT population is significantly less than in patients with human 
immunodeficiency virus (HIV), with comparative incidence rates of 35.4 vs. 130 per one-
hundred thousand person years, respectively (Kaufman et al 2014). Actions to minimize the risk 
of PML in treatment-naive cGvHD or SR-cGvHD patients will follow standard alloSCT 


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guidelines including close monitoring of any clinical signs of progressive focal neurological 
symptoms, with prompt diagnostic work up and treatment.
Non-melanoma skin cancers
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell 
carcinoma have been reported in MPN patients treated with ruxolitinib. Skin cancer incidence 
is increased in alloSCT patients vs. the general population, including increased risk of basal cell 
carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma occurring late, 
generally 10-15 years after transplant (Omland et al 2016). Any occurrence of skin cancers will 
be monitored throughout this study.
Long-Term Follow-Up
Long-term side effects after alloSCT include non-malignant organ or tissue dysfunction, 
changes in quality of life, infections related to abnormal immune reconstitution and secondary 
cancers. Different categories of secondary malignancies can occur after alloSCT, including: 
post-transplant lymphoproliferative disorders, late relapse of the primary disease, donor-type 
secondary leukemia/other malignancy and de novo solid tumors (Mohty and Mohty 2011). 
Second primary malignancy rates for treatment-naive cGvHD and SR-cGvHD patients will be 
assessed during long-term follow up after transplant and will be compared with relevant 
epidemiologic data.
Safety in pediatric patients: In a Phase I study, ruxolitinib with BID continuous oral dosing 
in children aged 2.4 to 21.4 (median 14.4) years with refractory/recurrent solid tumors (ST) and 
hematologic malignancies was well tolerated and showed similar pharmacokinetics to those in 
adults. No maximum tolerated dose was reached and the recommended dose for continuous 
BID oral administration was 50 mg/m2/dose (Loh et al 2015).
Administration of ruxolitinib in juvenile rats resulted in fractures and reduced bone growth 
(diameter and/or lengths) at an exposure of 3.9 µM*h (1211 ng*h/mL) or ≥ 0.5 µM*h (150 
ng*h/mL) based on unbound AUC, respectively.
Based on the analysis of the available data bone effects have been observed in very young rats 
(human equivalent age of birth) but not in adult animals (human equivalent age of ≥ 12 years). 
Potential impact on skeletal growth is projected to be impacted by both the extent of exposure 
and the stage of skeletal development in children, with the greatest effect on those less than 2 
years of age, and proportionally greater in those children less than 1 year of age. Negative 
impacts on skeletal development are judged to be reversible, but post-treatment bone 
development may not fully compensate for the retardation occurring before the skeleton has 
matured and further growth ceases. The impact of this potential effect on subsequent growth 
should be considered relative to the therapeutic effect desired.
Besides the bone effects / growth retardation, the toxicity profile in juvenile rats was 
comparable to that observed in adult rats. Please refer to the most recent version of the 
[Investigator Brochure] for more details.
Supportive published data in pediatric patients: Although no existing clinical data is 
available among pediatric GvHD patients treated with ruxolitinib, there are several independent 
published reports suggesting no significant toxicities in this population.


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Khandelwal P et al (Khandelwal et al 2017) described a retrospective clinical experience of 13 
pediatric patients of median age 8.5 years (range, 1.6 to 16.5) who received ruxolitinib for 
steroid refractory acute GvHD, administered orally at 5 mg twice daily for children ≥ 25 kg or 
2.5 mg twice daily if < 25 kg. Adverse effects in 13 patients included grade 2 to 4 elevated 
alanine aminotransferase (n=7), grade 3 to 4 neutropenia (n=5) and grade 4 thrombocytopenia 
(n=3). No patients experienced life-threatening bleeding. All observed adverse effects resolved 
after discontinuation of ruxolitinib.
Another recent analysis in 22 SR-GvHD (acute and chronic) pediatric patients aged 5 months 
to 18 years treated with ruxolitinib dosing planned as noted in Khandelwal P et al., showed high 
overall response rate in acute GvHD (n=13) and chronic GvHD (n=9), of 77% and 89% 
respectively (Khandelwal et al 2017). There were 54%, 18% and 13% infections caused by 
virus, bacteria and fungi, respectively.
Schoettler M et al, (Schoettler et al 2019) described a single center experience of treating 
patients aged 7 to 21 years (n=5) with steroid refractory bronchiolitis obliterans syndrome (SR-
BOS), chronic GvHD of the lungs with ruxolitinib. Of 5 patients, ruxolitinib was steroid sparing 
in 4 patients with an evaluable response; 3 were able to stop steroids, and 1 weaned significantly. 
Four patients tolerated ruxolitinib with no adverse effects and one patient (treated for 4 months 
with ruxolitinib) had a grade 3 fungal infection (occurred after months of steroid treatment, not 
directly attributed to ruxolitinib) and had to discontinue ruxolitinib due to infection.
In addition, in isolated reports, ruxolitinib has been used for treating children with various 
conditions including severe juvenile dermatomyositis (Aeschlimann et al 2018), chronic 
mucocutaneous candidiasis (Bloomfield et al 2018), polycythaemia vera-associated Budd-
Chiari syndrome (Coskun et al 2017), Philadelphia like acute lymphoblastic leukemia 
(Ding et al 2018), 
vasculopathy 
associated 
with 
TMEM173-activating 
mutations 
(Frémond et al 2016) and life-threatening autoimmune cytopenias and chronic mucocutaneous 
candidiasis (Weinacht et al 2017).
Besides the bone effects / growth retardation, the toxicity profile in juvenile rats was 
comparable to that observed in adult rats. Please refer to [Investigator Brochure] for more 
details.
Adolescent female patients of child bearing potential must be informed that taking the study 
treatment may involve unknown risks to the fetus if pregnancy were to occur during the study, 
and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the subject will not 
reliably comply, they should not be entered or continue in the study.
4.6
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure subject safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.


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5
Population
The subject population will include male and female subjects aged ≥ 28 days to < 18 years, who 
have undergone alloSCT with a successful donor-derived myeloid engraftment and have been 
diagnosed with either treatment-naïve moderate to severe cGvHD or steroid-refractory 
moderate to severe cGvHD as defined by NIH 2014 Consensus Criteria (Jagasia et al 2015, 
Martin et al 2015). It is important that the NIH criteria are strictly applied and it is 
recommended that the diagnosis of cGvHD requires at least one pathognomonic manifestation 
of cGvHD or, if a pathognomonic feature is not present, at least one distinctive manifestation 
of cGvHD supported by histologic evidence of GvHD from any site (Socié and Ritz 2014, 
Jagasia et al 2015). These data must be documented in the source documentation and results 
should be made available upon request.
The investigator or designee must ensure that only subjects who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Male or female subjects age ≥ 28 days and < 18 years at the time of informed consent.
2. Subjects who have undergone a successful alloSCT from any donor source (matched 
unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, 
or cord blood. Recipients of myeloablative or reduced intensity conditioning are eligible.
3. Subjects with diagnosed moderate to severe cGvHD according to NIH 2014 Consensus 
Criteria (Section 16.2) prior to Cycle 1 Day 1. Other possible diagnoses for clinical
symptoms supporting the cGvHD diagnosis must be excluded (e.g. infection, drug side 
effects, malignancy). Subjects must be either:

Treatment-naive cGvHD subjects that have not received any prior systemic treatment 
for cGvHD except for a maximum 72h of prior systemic corticosteroid therapy of 
methylprednisolone or equivalent after the onset of chronic GvHD. Subjects are 
allowed to have received prior systemic treatment for cGvHD prophylaxis (as long as 
the prophylaxis was started prior to the diagnosis of cGvHD).
OR

Steroid-refractory moderate to severe cGvHD as per institutional criteria, or per 
physician decision in case institutional criteria are not available, and still receiving 
systemic corticosteroids for the treatment of cGvHD for a duration of <18 months prior 
to Cycle 1 Day 1; in case the corticosteroids were previously interrupted due to response, 
the duration of < 18 months applies to the last period of corticosteroids use. 
4. Able to swallow study medication or administer the ruxolitinib pediatric formulation by 
nasogastric (NG) tube, as applicable.
5. Written study informed consent (and assent if appropriate) from the subject and/or 
parent/legal guardian
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.


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1. SR-cGvHD subjects with a prior cGvHD treatment with a JAK1- or a JAK2- or a JAK1/2-
inhibitor are not allowed, except when the subject achieved complete or partial response 
and has been off JAK inhibitor treatment for at least 4 weeks prior to Cycle 1 Day 1, or up 
to 5 times the half-life of the prior JAK inhibitor, whichever is longer.
2. Subjects who initiated systemic calcineurin inhibitors (CNI; cyclosporine or tacrolimus) 
within 3 weeks prior to the start of ruxolitinib on Cycle 1 Day 1. Note: Systemic CNI are 
allowed when initiated > 3 weeks from start of ruxolitinib.
3. Failed prior alloSCT within the past 6 months; subjects with relapsed primary malignancy, 
or who have been treated for relapse after the alloSCT was performed, or who require 
withdrawal of immune suppression as pre-emergent treatment of early malignancy relapse.
4. Significant respiratory disease including subjects who are on mechanical ventilation or who 
have a resting oxygen saturation < 90% by pulse-oximetry on room-air.
5. Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease (unrelated 
to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative 
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel 
resection).
6. Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive 
disease of the liver (defined as persistent bilirubin abnormalities not attributable to cGvHD 
and ongoing organ dysfunction).
7. Presence of clinically active uncontrolled infection including significant bacterial, fungal, 
viral or parasitic infection requiring treatment. Infections are considered controlled if 
appropriate therapy has been instituted and, at the time of screening, no signs of progression 
are present. Progression of infection is defined as hemodynamic instability attributable to 
sepsis, new symptoms, worsening physical signs or radiographic findings attributable to 
infection. Persisting fever without other signs or symptoms will not be interpreted as 
progressing infection. 
8. Known human immunodeficiency virus (HIV) infection.
9. Evidence of uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV) based on 
assessment done by Investigator or delegate.
10. cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered for 
pre-emptive treatment of malignancy recurrence. Subjects who have received a scheduled 
DLI as part of their transplant procedure and not for management of malignancy relapse are 
eligible.
11. Any condition that would, in the investigator's judgment, interfere with full participation in 
the study, including administration of study drug and attending required study visits; pose 
a significant risk to the subject; or interfere with interpretation of study data.
12. Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, 
or similar compounds.
13. History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, 
osteomyelitis, osteopenia, fibrous dysplasia, osteomalacia etc. prior to the underlying 
diagnosis which resulted in the alloSCT.
14. History of endocrine or kidney related growth retardation prior to the underlying diagnosis 
which resulted in the alloSCT.
15. Female adolescent subjects who are pregnant or breast feeding.


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16. Female subjects of childbearing potential (e.g., are menstruating) who do not agree to 
abstinence, or, if sexually active, do not agree to use highly effective contraception as 
defined in Section 8.4.2. If local regulations are more vigorous than that from the 
contraception methods listed in Section 8.4.2. to prevent pregnancy, local regulations apply 
and will be described in the ICF.
17. Evidence of clinically active tuberculosis (clinical diagnosis per local practice)
18. Any corticosteroid therapy for indications other than cGvHD at doses > 1 
mg/kg/daymethylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 
days of the screening visit.
19. Current therapy with systemic medications that interfere with coagulation or platelet 
function including but not limited to aspirin and related drugs, heparin, and warfarin (to 
minimize risk of bleeding). Note: Heparin or Low Molecular Weight Heparin (LMWH) is 
allowed if used at sub-therapeutic dose for e.g., prophylaxis of sinusoidal obstructive 
syndrome/veno-occlusive disease of the liver.
20. Subject is receiving fluconazole at daily doses higher than 6 mg/kg (maximum 200mg).
21. Subject is receiving and does not agree to stop herbal preparations/medications. These 
herbal medications include, but are not limited to, St. John’s Wort, Kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and 
ginseng. Subjects must stop using herbal medications at least 7 days prior to first dose of 
study treatment. Refer to Section 6.2.2
22. History of progressive multifocal leuko-encephalopathy (PML).
23. Investigational treatment within 30 days prior to ruxolitinib treatment initiation or within 5 
half-lives of the investigational product, whichever is greater.
24. Presence of severely impaired renal function (confirmed within 72h prior to ruxolitinib start) 
defined by:

Glomerular Filtration Rate (GFR) < 30 mL/min/1.73 m2, using estimated creatinine 
clearance calculated by updated bedside Schwartz equation or Cockroft Gault equation,
or

renal dialysis requirement
25. Serious comorbid diseases as per investigator judgement
26. Life expectancy of less than 1 month as per investigator judgement.
27. Clinically significant or uncontrolled cardiac disease, including any of the following:

Acute myocardial infarction within 6 months from Cycle 1 Day 1 ruxolitinib 
administration

Uncontrolled hypertension

New York Heart Association Class III or IV congestive heart failure

Unstable angina within last 6 months from screening

Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker, circulatory collapse requiring vasopressor or inotropic support, or 
arrhythmia requiring therapy).


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6
Treatment
6.1
Study treatment
Study treatment includes:

Investigational treatment:

Refers to ruxolitinib (investigational drug)

Other study treatment:

Refers to the concomitant use of corticosteroids to treat treatment-naive cGvHD or SR-
cGvHD
Ruxolitinib will be administered as a 5 mg ruxolitinib tablet or as ruxolitinib oral pediatric 
formulation twice a day.

Treatment-naive cGvHD: In addition to ruxolitinib, treatment must include 
methylprednisolone (or equivalent prednisone)

SR-cGvHD: In addition to ruxolitinib, concomitant use of corticosteroids is required
In addition to study treatment, subjects may receive standard alloSCT supportive care including 
anti-infective medications and transfusion support.Systemic immunosuppressive medications 
used for the prophylaxis of cGvHD may be continued after Cycle 1 Day 1 if initiated prior to 
diagnosis of cGvHD, i.e., not used as therapy but as continuation of prophylaxis. Dose 
adjustments of immunosuppressive prophylactic drugs with therapeutic intent or addition of 
systemic immunosuppressive medications for treatment of cGvHD are not allowed.Systemic 
CNIs may be continued after Cycle 1 Day 1 if initiated at least 3 weeks prior to the start of 
ruxolitinib, i.e. at Cycle 1 Day 1. CNI should be used at standard dosing and adjusted to 
therapeutic trough levels. Continued use of topical corticosteroid therapy for cGvHD per 
institutional guidelines are permitted. For SR-cGvHD subjects, cessation of other systemic 
treatment for cGvHD other than corticosteroids +/- CNI will be required prior to ruxolitinib 
initiation. Permitted concomitant medications are described in Section 6.2.1.1.
6.1.1
Investigational and control drugs
Table 6-1
Dose and treatment schedule
Investigational 
treatment
Age groups
Pharmaceutical 
form and Route of 
Administration
Dose
Frequency and/or 
Regimen
Ruxolitinib 
(INC424)
Group 1
≥ 12 years old to < 
18 years old
5 mg tablet* for oral 
use OR
oral pediatric 
formulation
10 mg BID
(2 tablets orally 
BID) OR
10 mg BID oral 
pediatric 
formulation**
Twice per day
Ruxolitinib 
(INC424)
Group 2
≥ 6 years old to < 
12 years old
5 mg tablet* for oral 
use OR
oral pediatric 
formulation*
5 mg BID
(1 tablet orally BID) 
OR
5 mg BID oral 
pediatric 
formulation**
Twice per day


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Investigational 
treatment
Age groups
Pharmaceutical 
form and Route of 
Administration
Dose
Frequency and/or 
Regimen
Ruxolitinib 
(INC424)
Group 3
≥ 2 years old to < 6 
years old
5 mg tablet* for oral 
use OR oral 
pediatric 
formulation
4 mg/m2 BID
(either tablet orally 
OR
oral pediatric 
formulation)**
Twice per day
Ruxolitinib 
(INC424)
Group 4
≥ 28 days to < 2 
years old
oral pediatric 
formulation
X mg/m2 BID
(oral pediatric 
formulation)**
To be defined from 
study 
CINC424F12201
Twice per day
*A whole tablet for oral use may be crushed as per instructions in the pharmacy manual (if calculated dose 
based on BSA is not 5 mg or 10 mg, then crushing is not permitted. Tablet cannot be broken to achieve partial 
doses. In this case, oral pediatric formulation should be administered). Oral pediatric formulation should be 
dispensed according to instructions in the pharmacy manual. 
Note: Crushed tablet(s) can only be administered orally and cannot be administered by nasogastric (NG) tube.
**Calculated doses should be rounded to the nearest available volume as per instructions in the pharmacy 
manual
The Investigator will instruct the subject to take the investigational treatment as per protocol.
All dosages prescribed and dispensed to the subject and all dose changes during the study must 
be recorded on the Dosage Administration Record electronic case report form (CRF).
Ruxolitinib will be administered orally twice per day at the assigned dose based on age group, 
given as 5 mg tablets or equivalent dose as oral pediatric formulation. 
Ruxolitinib (tablet or oral pediatric formulation) should be taken approximately 12 hours apart 
(morning and night) without regards to food. Ruxolitinib will be administered by Investigator 
or delegate, or self-administered by the subject or parent/legal guardian in an outpatient setting.
Subjects should be instructed not to take ruxolitinib at home on the days of the scheduled pre-
dose blood collection for PK and biomarker samples. Refer to Section 8.5.1 and Section 8.5.2
Dosing will be administered after pre-dose blood collection at these visits.
If a dose is vomited within any timeframe after dosing, re-dosing should not occur.
If a dose is missed, the subject should not take an additional dose, but should take the prescribed 
dose at the next scheduled dosing time.
The ruxolitinib dose as assigned on Cycle 1 Day 1 (based on age) must not be changed until 
the subject completes the Cycle 7 Day 1 visit assessments, unless dose adjustments are needed 
to manage safety events. After Cycle 7 Day 1, the Investigator must re-evaluate the assigned 
ruxolitinib dose based on the subject's age and/or growth. Dosing based on growth should be 
adjusted if the newly calculated dose is a > 10% change from the previously calculated dose. 
Subjects should remain on the same formulation until Cycle 7 Day 1. Any change in formulation 
prior to Cycle 7 Day 1 requires approval from the Sponsor. All dose changes must be recorded 
on the Dosage Administration Record electronic case report form (eCRF).


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6.1.2
Additional study treatments
The following non-investigational treatment will be taken during the treatment period by the 
subject as per standard of care:

Systemic corticosteroids
Dose adjustments of immunosuppressive prophylactic drugs with therapeutic intent or addition 
of systemic immunosuppressive medications for treatment of cGvHD are not allowed.
6.1.3
Treatment arms/group
This is an open-label, single treatment arm study. There will be up to 4 age groups included in 
the study: Group 1 (Age ≥ 12 years to < 18 years), Group 2 (Age ≥ 6 years to < 12 years), Group 
3 (Age ≥ 2 years to < 6 years) and Group 4 (Age ≥ 28 days to < 2 years).
6.1.4
Guidelines for continuation of treatment
Subjects may continue investigational treatment until one of the discontinuation criteria is met. 
Refer to Section 6.5 for dose modifications and guidelines for continuation of treatment.
6.1.5
Treatment duration
The planned duration of study treatment is approximately 36 months (39 cycles).
The Treatment Period for each subject will begin on Cycle 1, Day 1 and continue until the end 
of Cycle 39 (Week 156), unless treatment change for any reason including treatment failure, 
e.g. cGvHD progression, mixed response or no response, or a GvHD flare as defined in 
Section 6.1.5.2.1, intolerable toxicity, death, or withdrawal from the study for other reasons 
occurs.
During the Treatment period, the subjects' treatment will be managed according to their 
response as follows: 
Subjects that achieve CR or PR: On Cycle 7 Day 1, subjects still receiving benefit from 
ruxolitinib may continue on ruxolitinib until the end of Cycle 39 (Week 156) and will follow 
the Visit Evaluation Schedule per Table 8-1:
Subjects that achieve a CR or PR may taper corticosteroids at any time from two weeks of 
documented CR or PR. See Section 6.1.5.2 for details 
In subjects that achieve a CR or PR: A taper of ruxolitinib is allowed only on or after Cycle 7 
Day 1.

A taper of CNI is allowed after Cycle 7 Day 1.
Subjects who taper off ruxolitinib and all immunosuppressive therapy due to achieving a CR or 
PR will continue to follow the currently assigned Visit Evaluation Schedule (Table 8-1),
including all safety and efficacy assessments, and will be monitored for cGvHD recurrence 
which must be reported in the database. Subjects experiencing cGvHD recurrence after tapering 
off ruxolitinib will be treated per Investigator discretion, which may include re-initiation of 
ruxolitinib and will follow the assigned Visit Evaluation Schedule (Table 8-1).


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Subjects without CR or PR: If the subject is not receiving benefit from ruxolitinib therapy per 
investigator decision, the subject should discontinue ruxolitinib and be treated per institutional 
practice. 
These subjects will enter the early discontinuation follow-up until completion of 39 cycles from 
their first dose of ruxolitinib.
Subjects who permanently discontinue ruxolitinib for reasons other than achieving a CR or PR 
prior to completion of 39 cycles on study will complete the safety follow-up visit and then 
follow the early discontinuation follow-up visit schedule (as described in Table 8-1). These 
subjects may be treated per Institutional practice.
6.1.5.1
Treatment beyond disease progression
Not applicable.
6.1.5.2
Tapering Guidelines
Tapering of corticosteroids, CNI, and ruxolitinib will follow 2 steps: first taper systemic 
corticosteroids following documented CR or PR, and follow with taper of CNI/ruxolitinib.
The taper of corticosteroids, in responding subjects (CR or PR) as outlined in Table 6-2, must 
not be attempted earlier than approximately 2 weeks from the time of documented CR or PR. 
In responding subjects, the taper of ruxolitinib must not be attempted until the subject is off 
corticosteroids and CNIs AND the subject has completed the assessments for Cycle 7 Day 1.
During the Treatment Period, immunosuppression taper guidelines are:

Corticosteroids: Every effort should be made to use the minimum dose of corticosteroid 
that is sufficient to control cGvHD manifestation. It is recommended that a taper of 
corticosteroids should be attempted approximately two weeks after achieving a 
documented CR or PR. Guidelines are included in Table 6-2. If a flare should occur during 
the taper, the treatment should continue for at least 3 months prior to attempting to resume 
the taper.
Table 6-2
Corticosteroid taper guidelines
Week (time from achieving a CR or PR)
Dose, mg/kg body weight
0
Current dose of corticosteroid every (Q) day (example 1 mg)
2
Current dose of corticosteroid (1 mg)/ decrease alternate day 
dose by 50%* (0.5 mg)
4
Current dose of corticosteroid (1 mg)/decrease alternate day 
dose by 50%* (0.25 mg)
6
Current dose of corticosteroid every other day (QOD): 1 mg 
every other day
8
Decrease current dose of corticosteroid by 10% every 2 
weeks until off
*Alternate-day administration
(Flowers and Martin, 2015)

CNI (cyclosporine or tacrolimus): Once off systemic corticosteroids, and documented CR 
or PR, starting at Cycle 7 Day 1 at 25% dose reduction per month is allowed, or to be tapered 
per institutional practice.


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
Ruxolitinib: Once off systemic corticosteroids, ruxolitinib taper is allowed in subjects 
demonstrating a CR or PR, starting no earlier than Cycle 7 Day 1. The following guidance 
may be followed based on evaluation of patient condition, current dosing regimen and the 
clinical judgement of Investigator: a 50% dose reduction every 2 months (approximately 56 
days) can be initiated. If sustained cGvHD response is observed (i.e. no worsening of 
cGvHD signs and symptoms), subject can be further tapered by a second 50% dosage 
reduction based on investigator assessment and judgement.
6.1.5.2.1 cGvHD Flare
If a cGvHD flare occurs during the taper of any immunosuppressive medications, the dose of 
corticosteroids may be re-escalated at the Investigator's discretion and will not be considered 
treatment failure. If cGvHD flare requires initiation of a new systemic therapy due to inability 
to taper corticosteroids below methylprednisolone 1 mg/kg/day (or equivalent <1.25 mg/kg/day 
of prednisone) for a minimum 7 days, OR due to re-escalation of corticosteroids to 
methylprednisolone >2 mg/kg/day (or equivalent >2.5 mg/kg/day of prednisone), the subject
will be considered to have experienced treatment failure.
If cGvHD flare occurs during ruxolitinib taper after Cycle 7 Day 1, subjects may have their 
ruxolitinib dose increased to the prior dose level, their response monitored, and ruxolitinib taper 
attempted again if subjects have a response within 28 days. If the flare is unresponsive to 
increased ruxolitinib dose within 28 days, or more than one flare is observed, the subject will 
be considered to have experienced cGvHD flare-failure, and further treatment with ruxolitinib 
is allowed per Investigator’s judgement.
For any subject who develops severe worsening cytopenias necessitating abrupt interruption of 
ruxolitinib, flare of cGvHD may occur. To avoid significant cGvHD flare during abrupt 
ruxolitinib interruption, the subject’s corticosteroid dose should be maintained or increased to 
≥ 0.4 mg/kg/day methylprednisolone (or equivalent prednisone to ≥ 0.5 mg/kg/day) for a 
minimum 7 days after abrupt cessation of ruxolitinib. See Section 6.5.1.1 for more details.
6.2
Other treatment(s)
6.2.1
Concomitant Medications
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
enrolling a subject or allowing a new medication to be started. If the subject is already enrolled, 
contact Novartis to determine if the subject should continue participation in the study.
Supportive treatments per institutional guidelines for management of alloSCT subjects with 
cGvHD or SR-cGvHD are allowed. The subject must be told to notify the investigational site 
about any new medications he/she takes after the start of treatment.
All medications (other than ruxolitinib and systemic corticosteroids) including over-the-counter 
medications and vitamins must be listed on the Concomitant Medications electronic case report 


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form (eCRF). Refer to Section 6.2.2 for a list of prohibited concomitant medications during 
study treatment. Significant non-drug therapies (including physical therapy and blood 
transfusions) administered during the study must be listed on the significant non-drug therapies 
eCRF. Steroid usage in the 18 months prior to the first dose of ruxolitinib and any other prior 
medication received up to 30 days prior to the first dose of ruxolitinib must be recorded on the 
appropriate eCRF. Subjects will be instructed not to take any additional medications (including 
over-the-counter products) during the course of the study without consultation with the 
Investigator.
In addition to assigned ruxolitinib, subjects may receive standard alloSCT supportive care 
including anti-infective medications and transfusion support.
Use of CNIs (cyclosporine or tacrolimus) if initiated at least 3 weeks prior to the start of 
ruxolitinib (Cycle 1 Day 1), and topical corticosteroid therapy per institutional guidelines is 
permitted and must be listed on the corresponding concomitant medications eCRF.
Permitted concomitant medications are described in Section 6.2.1.1.
On the days of the PK blood collection, subjects should be instructed to refrain from taking 
corticosteroids until after the last PK samples are collected (i.e., approximately 6 hours post-
dose on Cycle 1 Day 1 and after the pre-dose sample collection on all other PK collection days). 
See Section 8 for additional information.
Doses of methylprednisolone will be converted to prednisone equivalents by multiplying the 
methylprednisolone dose by 1.25. Prednisone doses for each subject are converted to mg/kg/day. 
For subjects that weigh over 100 kg, maximal starting dose of prednisone will be 200 mg (or 2 
mg/kg/day based on a modified starting weight of 100 kg). For calculation of subsequent 
prednisone doses/kg on subsequent measures, the modified starting weight of 100kg will be 
used.
6.2.1.1
Permitted concomitant medications requiring caution and/or action
Subjects receiving ruxolitinib with concomitant medications provided per standard institutional 
guidelines for management after alloSCT including: anti-emetics, CNIs, azole fungal 
prophylaxis, broad spectrum antibiotics in the event of fever (either semi-synthetic penicillin or 
third generation cephalosporin with vancomycin, gentamicin or equivalent), acyclovir 
prophylaxis, ganciclovir, foscarnate, granulocyte colony stimulating factor (G-CSF), steroid 
pre-medications prior to RBC/platelet transfusions, narcotics, and sedatives warrant close 
monitoring of potential drug-drug interaction effects of these concurrent drugs.
Ruxolitinib dose adjustments may be required, particularly in subjects treated with CYP450 
modulators (See Section 6.5.1.3).
Upon initiation of a strong CYP3A4 inhibitor or a dual CYP3A4/CYP2C9 inhibitor, including 
fluconazole up to a dose of 6 mg/kg (maximum 200mg) daily, the dose of ruxolitinib should be 
considered to be reduced (e.g. by 50%), and more frequent monitoring of hematology 
parameters and clinical signs and symptoms of ruxolitinib related adverse events is 
recommended. The subject and the Investigator should be aware of potential signs of overdose 
of the concomitant medications and in the event of suspected study drug related toxicity, 
administration of ruxolitinib should be dose reduced or held according to guidelines (See 


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Table 6-4) and Investigator judgment, with appropriate corticosteroid immunosuppression 
provided to avoid cGvHD flare.
6.2.2
Prohibited medication
The following therapies are prohibited during the study until ruxolitinib treatment 
discontinuation:

Due to the high risk of bleeding in alloSCT subjects with cGvHD or SR-cGvHD, systemic 
Nonsteroidal anti-inflammatory drugs (NSAIDs) and related medications that would 
expectedly reduce platelet function, and/or heparin, Vitamin K antagonists (e.g., warfarin), 
aspirin and other oral anticoagulants or related medications that would adversely affect 
blood coagulation are prohibited. Note: Heparin or Low Molecular Weight Heparin 
(LMWH) is allowed if used at sub-therapeutic dose for e.g., prophylaxis of sinusoidal 
obstructive syndrome/veno-occlusive disease of the liver. 

Concomitant use of another JAK inhibitor besides ruxolitinib.

Any investigational medication (other than ruxolitinib) that is not approved for any 
indication. Use of such medications is prohibited within 30 days or 5 half-lives, whichever 
is longer, prior to the first dose of ruxolitinib and until treatment discontinuation.

Use 
of 
chemotherapeutic agents and/or 
non-scheduled 
DLI 
for 
malignancy 
recurrence/relapse is not permitted. If required for subject management, the subject is 
discontinued from study treatment.

Any pre-emergent intervention related to graft failure or underlying disease 
relapse/recurrence including but not limited to: stem cell graft boost, additional conditioning 
chemotherapy or anti-T-cell therapy, non-scheduled DLI, and/or abrupt cessation/taper 
immunosuppression is not permitted. If required for subject management, the subject is 
discontinued from study treatment

Administration of fluconazole at daily doses higher than 6 mg/kg (maximum 200 mg) 
(Section 6.2.1.1)

Addition of any new systemic immunosuppressive therapy after start of ruxolitinib may be 
decided by the Investigator. In this case, the subject must discontinue ruxolitinib 
(Section 9.1.1). Rituximab can be administered for the treatment of EBV. EBV infection 
must be captured either in the Medical History or Adverse Event eCRF. 

Herbal preparations/medications are not allowed, as a potential drug-drug interaction is 
possible. These herbal medications include, but are not limited to, St. John’s Wort, Kava, 
ephedra (ma huang), gingko biloba, dehydroepiandrsterone (DHEA), yohimbe, saw 
palmetto, and ginseng. Subjects must stop using herbal medications at least 7 days prior to 
first dose of study treatment.

Considering the underlying population with immunocompromised state and ruxolitinib 
therapy, use of live-attenuated vaccines (i.e., against SARS-CoV-2) are prohibited. The 
restriction of vaccines is applicable during study treatment. [Note: the use of mRNA SARS-
CoV-2 vaccines are permitted.]
6.2.3
Rescue medication
Not applicable.


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6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form (ICF) and assent form, if appropriate, the subject is 
assigned to the next sequential Subject No. available.
The investigator or designated staff will contact the Interactive Response Technology (IRT) and 
provide the requested identifying information for the subject to register them into the IRT. Once 
assigned, the Subject No. must not be reused for any other subject. If the subject fails to start 
treatment for any reason, the reason will be entered into the appropriate Disposition page.
IRT must be notified within 2 days that the subject will not be entering the treatment phase of 
the study.
6.3.2
Treatment assignment, randomization
This is a non-randomized study. The assignment of a subject to the appropriate dosing group 
will be based on age using the IRT system and coordinated by Novartis.
6.4
Treatment blinding
Treatment will be open to subjects, parent/legal guardians, caregivers, investigator staff, 
persons performing the assessments, and the Novartis Clinical Trial Team (CTT).
6.5
Dose escalation and dose modification
A standardized dosing paradigm will be used to determine dose adjustments for safety and 
efficacy so that each subject is titrated to their most appropriate dose. These changes must be 
recorded on the Dosage Administration Record eCRF.
6.5.1
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow subjects to continue 
ruxolitinib.
These dose modifications are summarized in Table 6-3. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-3.
Based on the subject’s age, the ruxolitinib dose will not exceed the starting dose level defined 
for that age Group. The dose for CNI and/or corticosteroids can be modified as per Investigator 
discretion, institutional guidelines, or as per product label.


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A standardized dosing paradigm in Table 6-4 and Table 6-5 will be used to determine dose 
adjustments for safety and efficacy so that each subject is titrated to their most appropriate dose. 
These dose changes must be recorded on the Dosage Administration Record eCRF.
A more frequent schedule of safety assessments is recommended (i.e. every 2 weeks) after 
restarting ruxolitinib due to a dose hold.
If a subject requires a dose interruption of > 21 days from ruxolitinib, then the subject must be 
permanently discontinued from ruxolitinib, and will be entered into early discontinuation 
follow-up with assessments as described in Table 8-1.
6.5.1.1
Dose adjustments for ruxolitinib hematologic safety
Dose reductions or interruptions for worsening cytopenias attributed to ruxolitinib are permitted 
in order to allow the subject to continue on the study treatment. Doses adjustments for different 
ranges of cytopenias are described in Table 6-3. The objective of the dose adjustment rules is 
to optimize treatment response for each individual subject while avoiding significant cytopenias. 
Dose adjustment steps for ruxolitinib are listed in Table 6-4 and Table 6-5.
For any subject who develops severe worsening cytopenias necessitating abrupt interruption of 
ruxolitinib, flare of cGvHD is expected to occur. To avoid significant cGvHD flare during 
abrupt ruxolitinib interruption, the subject’s corticosteroid dose should be maintained or 
increased to ≥ 0.4 mg/kg/day methylprednisolone (or equivalent prednisone to ≥ 0.5 mg/kg/day) 
for a minimum 7 days after abrupt cessation of ruxolitinib.
Ruxolitinib dosing may be restarted or increased following recovery of the hematologic 
parameter(s) to acceptable levels. The objective for restarting or escalating after a reduction for 
hematologic safety is to find the highest safe dosing regimen of ruxolitinib for each subject that 
is necessary to obtain a clinical response, with increases in dose not more than in increments of 
5 mg BID and not more often than every 2 weeks. See Table 6-5.
Treatment with ruxolitinib may be delayed up to 21 days to allow for resolution of toxicity. 
Subjects may resume treatment if no medical condition or other circumstance exists that, in the 
opinion of the Investigator, would make the subject unsuitable for further participation in the 
study. The Investigator should contact the Novartis medical monitor to discuss cases where 
treatment has been delayed for more than 14 days before restarting treatment.
Transfusions are allowed during study treatment, if needed.
6.5.1.2
Dose adjustments for ruxolitinib non-hematologic safety
Dose reductions or interruptions for non-hematologic toxicity attributed to ruxolitinib are 
permitted in order to allow the subject to continue on ruxolitinib. Dose adjustments for different 
ranges of non-hematologic toxicity are described in Table 6-3. The objective of the dose 
adjustment rules is to optimize treatment response for each individual subject while avoiding 
significant non-hematologic toxicities.
As organ toxicities are relatively common in alloSCT subjects, any adverse event must be 
assessed to determine whether it is suspected to be related to ruxolitinib treatment. Ruxolitinib 
dose adjustments are only required for adverse events that are suspected to be related to the 
study drug. This has particular relevance in evaluation of elevated serum creatinine, as 


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elevations related to CNI administration are often seen. Dose adjustment of CNI will follow 
institutional guidelines and investigator judgement, with CNI dose reductions anticipated if 
rising creatinine occurs, to potentially alleviate the need for ruxolitinib dose reductions.
Treatment with ruxolitinib may be delayed up to 21 days to allow for resolution of toxicity. 
Subjects may resume treatment if no medical condition or other circumstance exists that, in the 
opinion of the Investigator, would make the subject unsuitable for further participation in the 
study.
Ruxolitinib must be permanently discontinued upon any one of the following non-
hematological adverse events attributed to study drug that fails to resolve to Grade 2 or better 
within 14 days or if a lower re-start dose or administration schedule subsequent to any of the 
following non-hematologic toxicities is either not available or likely to be clinically ineffective:

occurrence of a Grade 4 laboratory or non-laboratory abnormality attributable to ruxolitinib

occurrence of a Grade 3 laboratory or non-laboratory abnormality attributable to ruxolitinib 
that remains at Grade 3 or worse for greater than 14 days
If any one or more of the treatment discontinuation criteria are met prior to Cycle 7 Day 1, the 
subject will be considered to be a non-responder in terms of the primary endpoint.
Subjects who permanently discontinue ruxolitinib for reasons other than achieving a CR or PR 
prior to completion of 39 cycles on study, will complete the safety follow-up visit and enter the 
early discontinuation follow-up (as described in Table 8-1) and may be treated per Institutional 
practice. 
The date the subject discontinued ruxolitinib and the specific reason for permanent study 
treatment discontinuation will be recorded in the eCRF.
Table 6-3
Criteria for dose reduction / interruption and re-initiation of ruxolitinib 
treatment for adverse drug reactions
Dose modifications for ruxolitinib for adverse eventsa suspected to be drug-related
Worst toxicity
Investigations (Hematologic)
Neutropenia (ANC)
Grade 1 (ANC < LLN - 1500/mm3)
Recommendation: Maintain dose level.
Grade 2 (ANC < 1500 - 1000/mm3)
Recommendation: Maintain dose level.
Grade 3 (ANC < 1000 - 750/mm3)
Recommendation: Maintain dose level.
Grade 3 (ANC < 750 - 500/mm3)
Mandatory: Reduce 1 dose level (see Table 6-4), monitor 
ANC daily until resolved to ≤ Grade 2, then resume initial 
dose level.
Grade 4 (ANC < 500/mm3)
Mandatory: Hold dose, monitor ANC daily until resolved to 
≤ Grade 3, then resume at reduced 1 dose level. If 
resolves to ≤ Grade 2, can resume initial dose level. 
Ruxolitinib must be permanently discontinued if fails to 
resolve to Grade 2 or better within 14 days. If not resolved 
in ≤ 21 days the subject must be discontinued.
Febrile neutropenia (ANC < 750/mm3, fever ≥ 
38.5°C)
Mandatory: Hold dose until resolved, then restart at 
reduced 1 dose level
Thrombocytopenia 
Grade 1 (PLT < LLN-75,000/mm3)
Recommendation: Maintain dose level.


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Dose modifications for ruxolitinib for adverse eventsa suspected to be drug-related
Worst toxicity
Grade 2 (PLT< 75,000 - 50,000/mm3)
Recommendation: Maintain dose level.
Grade 3 (PLT< 50,000 - 25,000/mm3)
Recommendation: Maintain dose level.
Grade 4 (PLT< 25,000 - 20,000/mm3)
Recommendation: Maintain dose level.
Grade 4 (PLT< 20,000 - 15,000/mm3)
Mandatory: Reduce 1 dose level until resolved to 
≥20,000/mm3. If resolved in ≤ 7 days, then resume initial 
dose level. If resolved in > 7 days, then maintain at 
reduced 1 dose level.
Grade 4 (PLT < 15,000/mm3)
Mandatory: Hold dose until resolved to ≥20,000/mm3, 
then resume at reduced 1 dose level. If resolves to ≤ 
Grade 3, can resume initial dose level. If not resolved in 
≤14 days, the subject must be discontinued.
Investigations (Renal)
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN)
Recommendation: Maintain dose level.
Grade 2 (> 1.5 - 3.0 x ULN)
Mandatory: Reduce 1 dose level until resolved to ≤ Grade 
1 or baseline, then resume initial dose level.
Grade 3 (> 3.0 - 6.0 x ULN)
Mandatory: Hold dose until resolved to ≤ Grade 2, then 
restart at reduced 1 dose level. If resolves to ≤ Grade 1, 
can resume initial dose level.
Grade 4 (> 6.0 x ULN)
Mandatory: Discontinue subject from study treatment.
Investigations (Hepatic)
Total Bilirubin elevation
> ULN – 1.5 x ULN
Recommendation: Maintain dose level.
> 1.5 - 3.0 x ULN
Recommendation: Maintain dose level.
> 3.0 - 10.0 x ULN*
Mandatory: Interrupt treatment. Monitor LFTsb weekly or 
more frequently if clinically indicated, until resolved to ≤ 3.0 
x ULN: If resolved in ≤ 14 days, then resume same dose 
level. If resolved in > 14 days, then resume at reduced one 
dose level.
> 10.0 x ULN*
Mandatory: Interrupt treatment. Monitor LFTsb weekly, or 
more frequently if clinically indicated, until resolved to ≤ 3.0 
x ULN: If resolved in ≤ 14 days, then resume at reduced 1 
dose level. If resolved in > 14 days, then discontinue 
subject from study treatment. The subject should be 
monitored weekly (including LFTsb), or more frequently if 
clinically indicated, until total bilirubin has resolved to 
baseline or stabilization over 4 weeks.
AST or ALT elevation
> ULN - 3.0 x ULN
Recommendation: Maintain treatment and dose level.
If normal at baseline:
> 5.0 x ULN for more than 2 weeks, OR > 10 x 
ULN 
If elevated at baseline:
>3 x baseline and > 10 x ULN 
Mandatory: Interrupt treatment. Repeat LFTsb as soon as 
possible, preferably within 48-72 hours from awareness of 
the abnormal results; Monitor LFTsb weekly, or more 
frequently if clinically indicated, until resolved to ULN or to 
baseline. : If resolved, then resume at reduced one dose 
level. 


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Dose modifications for ruxolitinib for adverse eventsa suspected to be drug-related
Worst toxicity
> 20.0 x ULN: 
Mandatory: Permanently discontinue patient from study 
treatment.. Repeat LFTsb as soon as possible, preferably 
within 48-72 hours from awareness of the abnormal 
results; monitor LFTsb weekly, or more frequently if 
clinically indicated, until resolved to baseline or stabilization 
over 4 weeks. 
Combined celevations of AST or ALT and total bilirubin
For participants with normal baseline ALT and 
AST and total bilirubin value:
AST or ALT > 3.0 x ULN combined with total 
bilirubin > 2.0 x ULN without evidence of 
cholestasisd
OR
For participants with elevated baseline AST or 
ALT or total bilirubin value:
[AST or ALT > 3 x baseline OR [> 8.0 x ULN], 
whichever is lower combined with Total bilirubin 
> 2 x baseline AND >2.0 x ULN
Note: For participants with Gilbert’s syndrome, at 
least 2-fold increase in direct bilirubin
Mandatory: Interrupt treatment and adjudicate for DILI:
Repeat as soon as possible, preferably within 48 hours 
from awareness of the abnormal results, then with weekly 
monitoring of LFTsb, or as clinically indicated, until AST, 
ALT, or total bilirubin have resolved ≤ ULN or to baseline.
Refer to Section 6.5.2.1 (for additional follow-up 
evaluations as applicable.)
If causality assessment indicates that DILI is probable: 
Permanently discontinue participant from treatment.
If not DILI: Treat the identified cause according to 
institutional guidelines. Once resolved, resume at reduced 
one dose level.
Investigation (metabolic)
Asymptomatic amylase and/or lipase elevation**
Grade 1 (> ULN - 1.5 x ULN)
Recommendation: Maintain dose level.
Grade 2 (> 1.5 - 2.0 x ULN)
Recommendation: Maintain dose level.
Grade 3 (> 2.0 - 5.0 x ULN)
Recommendation: Hold dose of until resolved to Grade ≤ 
2, then: 
If resolved in ≤ 7 days, then resume same dose level. If 
resolved in > 7 days, then resume at reduced 1 dose level.
Grade 4 (> 5.0 x ULN)
Recommendation: Discontinue subject from study 
treatment.
Vascular disorders
Hypertension
CTCAE Grade 3
Recommendation: Reduce 1 dose level until resolved to ≤ 
Grade 2, then increase by one dose level.
CTCAE Grade 4
Mandatory: Discontinue subject from study treatment.
Gastro intestinal
Pancreatitis
Grade 2
Recommendation: Maintain dose level.
Grade ≥ 3
Mandatory: Discontinue subject from study treatment.
Diarrhea***
Grade 1
Recommendation: Maintain dose level. May initiate anti-
diarrhea treatment.
Grade 2
Recommendation: Maintain dose level. May initiate anti-
diarrhea treatment.
Grade 3
Recommendation: Reduce 1 dose level until resolved to ≤ 
Grade 2, then increase by one dose level.
Grade 4
Mandatory: Discontinue subject from study treatment.
Skin and subcutaneous tissue disorders
Rash/photosensitivity


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Dose modifications for ruxolitinib for adverse eventsa suspected to be drug-related
Worst toxicity
Grade 1
Recommendation: Maintain dose level.
Grade 2
Recommendation: Maintain dose level.
Grade 3
Recommendation: Reduce 1 dose level until resolved to ≤ 
Grade 2, then: If resolved in ≤ 7 days, increase by one 
dose level. If resolved in > 7 days, then maintain the 
reduced dose level.
Grade 4
Mandatory: Discontinue subject from study treatment.
Other adverse events
Grade 1 or 2
Recommendation: Maintain dose level.
Grade 3
Recommendation: 
Hold dose until ≤grade 2, then decrease 1 dose level
Grade 4
Recommendation: Discontinue subject from study 
treatment.
All dose modifications should be based on the worst preceding toxicity.
For dose level refer to Table 6-3 and Table 6-4
a Common Terminology Criteria for Adverse Events (CTCAE Version 4.03)
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated (direct and indirect), if total bilirubin > 2.0 x 
ULN), and alkaline phosphatase (AP) (fractionated (quantification of isoforms), if alkaline phosphatase > 2.0 x 
ULN.)
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold.
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose 
or at one dose lower if meeting a criterion for dose reduction.
d “Cholestasis” defined as ALP elevation (> 2.0 x ULN and R value <2 ) in patients without bone metastasis or 
elevation of ALP liver fraction in patients with bone metastasis 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It 
denotes whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular 
( R ≥ 5), or mixed (R >2 and < 5) liver injury
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and 
haptoglobin determination), then reduce 1 dose level and continue treatment at the discretion of the 
Investigator.
** Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within 1 week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. If asymptomatic Grade 2 
elevations of lipase and/or amylase occur again at the reduced dose, subjects will be discontinued permanently 
from study treatment.
*** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea
Table 6-4
Dose reduction steps for ruxolitinib
Dose Reduction steps of ruxolitinib *
Groups
Starting dose level – 0
Dose level – 1
Dose level – 2
Group 1
10 mg BID
5 mg BID
5 mg QD**
Group 2
5mg BID
5 mg QD or 2.5mg BID
Not applicable


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Dose Reduction steps of ruxolitinib *
Group 3
4 mg/m2 BID
50% of starting dose BID
Not applicable
Group 4
Starting dose BID***
50% of starting dose BID
Not applicable
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
**Dose reduction below 5 mg total daily dose is not allowed.
***Based on prior data collected from [CINC424F12201] and [CINC424C2301],
[CINC424D2301].
Subjects who have had a dose reduction of ruxolitinib in order to manage toxicity may resume 
treatment at the previous dose if hematologic/non-hematologic parameters meet the required 
threshold(s).
Table 6-5
Dose re-escalation levels for ruxolitinib
Dose Re-escalation*
Current dose
First dose escalation
Second dose escalation
Group 1
5 mg QD
5 mg BID
10 mg BID
5 mg BID
10 mg BID
*
Group 2
5mg QD or 2.5 mg BID
5mg BID
Not applicable
Group 3
50% of starting dose BID
Starting dose BID
Not applicable
Group 4
50% of starting dose BID
Starting dose BID
Not applicable
Except for Group 1, all other dose escalations are examples and may not reflect the actual starting dose.
*Dose increases may not exceed 10 mg BID, in increments of 5 mg and not more often than every 2 weeks.
6.5.1.3
Dose modification for ruxolitinib when combined with CYP450 
modulators
In all cases when ruxolitinib is co-administered with CYP450 modulators, subjects should be 
closely monitored and dose titrated based on safety (see Section 6.5.1.2).
See Section 16.7 for a list of CYP3A4 inhibitors and inducers.
Strong CYP3A4 inhibitors
A dose reduction of ruxolitinib (e.g. by 50%) should be considered when using strong CYP3A4 
inhibitors. No dose adjustment of ruxolitinib is needed for use with topical ketoconazole. See 
Section 6.5.1.2
Mild or moderate CYP3A4 inhibitors
No dose adjustment is recommended when ruxolitinib is co-administered with mild or moderate 
CYP3A4 inhibitors.
Dual CYP2C9 and CYP3A4 inhibitors
A dose reduction of ruxolitinib (e.g. by 50%) must be considered when using medicinal 
products which are dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid 
the concomitant use of ruxolitinib with fluconazole doses greater than 6 mg/kg (maximum 200 
mg) daily.


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CYP3A4 inducers
No dose adjustment is recommended when ruxolitinib is co-administered with CYP3A4 
inducers.
6.5.1.4
Optional dose tapering strategy for study treatment discontinuation
When a decision is made to permanently discontinue ruxolitinib therapy for reasons other than 
for hematologic/non-hematologic safety (e.g. when cGvHD complete response is observed), a 
dose tapering strategy should be followed, based on evaluation of the condition of the subject, 
current dosing regimen, and the clinical judgment of the Investigator.
Following any abrupt interruption or discontinuation of ruxolitinib, symptoms of cGvHD flare 
are expected. If considered to be medically necessary, the Investigator may use any treatment 
to manage withdrawal from ruxolitinib including a gradual tapering of the study drug dosage or 
use of other medications including corticosteroid as minimum dosage ≥ 0.4 mg/kg/day 
methylprednisolone (or equivalent prednisone ≥ 0.5 mg/kg/day) to manage cGvHD flare 
anticipated after abrupt ruxolitinib discontinuation.
When a decision has been made to discontinue the subject with utilization of a tapering strategy, 
regardless of the use of concomitant medications, safety data will continue to be assessed in 
accordance with the protocol for a period of time at least through the continued administration 
of ruxolitinib and until the safety follow-up visit is completed (30 days from last ruxolitinib 
dose intake) for adverse event monitoring.
6.5.2
Follow-up for toxicities
6.5.2.1
Follow up on potential drug-induced liver injury cases
Subjects with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential drug-induced liver injury (DILI) and should be considered as clinically 
important events and assessed appropriately to establish the diagnosis. The required clinical 
information, as detailed below, should be sought to obtain the medical diagnosis of the most 
likely cause of the observed laboratory abnormalities.
The threshold for potential direct bilirubin increase may depend on the subject's baseline 
AST/ALT and TBIL value; subjects meeting any of the following criteria will require further 
follow-up as outlined below:

For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
upper limit of normal (ULN) combined with TBIL > 2.0 x ULN

For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 3.0 x 
baseline] OR [AST or ALT > 8.0 x ULN], whichever occurs first, combined with [TBIL > 
2.0 x baseline AND > 2.0 x ULN]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests (including 
liver GvHD) should be considered and their role clarified before DILI is assumed as the cause 
of liver injury.


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A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
GLDH, prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase.
Obtain PK sample, as close as possible to last dose, if possible.
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using CT, 
MRI, or duplex sonography.
Perform relevant examinations (Ultrasound or MRI, ERCP) as appropriate, to rule out an 
extrahepatic cause of cholestasis. (Cholestasis is defined as an ALP elevation > 2.0 x ULN with 
R value < 2 in patients without bone metastasis, or elevation of the liver-specific ALP 
isoenzyme in patients with bone metastasis).
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. For children, 
there are caveats to calculating the R-ratio as normal levels of ALP are higher than in adults 
with standard ranges varying by developmental age. In clinical situations where it is suspected 
that ALP elevations are from an extrahepatic source, the GGT can be used if available. GGT 
may be less specific than ALP as a marker of cholestatic injury, since GGT can also be elevated 
by enzyme induction or by ethanol consumption. It is more sensitive than ALP for detecting 
bile duct injury (livertox.nih.gov/rucam.html).
Table 6-6 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities.
Table 6-6
Assessments to determine cause of LFT abnormalities
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, 
HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, EBV, HSV, ADV, VZV 
infection

CMV PCR (viral load) , EBV PCR (viral load), HSV PCR (viral load), 
ADV PCR (viral load), VZV (viral load)
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin
Other causes should also be considered based upon the patients’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; Cardiovascular Disease (CVD) / 
ischemic hepatitis – ECG, prior hypotensive episodes; Type 1 Diabetes (T1D) / glycogenic 


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hepatitis). Liver biopsy may be considered as clinically indicated, or after consultation with a 
specialist/hepatologist.
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of serious adverse event (SAE) (Section 10.1.2) and 
reported as SAE using the term “potential drug-induced liver injury”. All events should be 
followed up with the outcome clearly documented.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the subject to take ruxolitinib exactly 
as prescribed and stating that compliance is necessary for the subject’s safety and the validity 
of the study. The subject must also be instructed to contact the investigator if he/she is unable 
for any reason to take the study treatment as prescribed. Compliance will be assessed by the 
investigator and/or study personnel at each visit using pill count, remaining oral pediatric 
formulation volume measurements and information provided by the subject and/or caregiver. 
This information should be captured in the source document at each subject visit. All study 
treatment dispensed and returned must be recorded in the Drug Accountability Log.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
as detailed in pharmacokinetics section.
6.6.2
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
The investigator or responsible site personnel must instruct the subject or caregiver to take the 
study drugs as per protocol. Ruxolitinib will be dispensed to the subject or caregiver by 
authorized site personnel only. All dosages prescribed to the subject and all dose changes during 
the study must be recorded on the Dosage Administration Record eCRF.


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Table 6-7
Preparation and Dispensing
Investigational Treatment
Dispensing
Preparation
INC424/ruxolitinib
Tablets or oral pediatric 
formulation including instructions 
for administration are dispensed by 
study personnel on an outpatient 
basis. Subjects will be provided 
with adequate supply of ruxolitinib 
for self-administration at home until 
at least their next scheduled study 
visit
Not applicable
Ruxolitinib should be administered to subjects as per instructions in the pharmacy manual.
Ruxolitinib will be provided as global, clinical open-label supply and will be packed and labeled 
under the responsibility of Novartis Global Clinical Supply.
Ruxolitinib labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to ruxolitinib and strength). 
Responsible site personnel will identify the investigational treatment package(s) to dispense by 
the medication number(s) assigned by IRT to the subject. Site personnel will add the subject 
number on the label. If the label has 2-parts (base plus tear-off label), immediately before 
dispensing the package to the subject, site personnel will detach the outer part of the label from 
the package and affix it to the subject’s source document.
As per Section 4.6, during a Public Health emergency, as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of IMP directly to a subject's home may be permitted (if allowed by Local or Regional 
Health Authorities and Ethics Committees as appropriate) in the event the Investigator has 
decided that an on-site visit by the subject is not possible, and that it is in the interest of the 
subject's health to administer the study treatment even without performing an on-site visit. The 
dispatch of IMP from the site to the subject’s home remains under the accountability of the 
Investigator. Each shipment/provisioning will be for a maximum of 1-month supply. In this 
case, regular phone calls or virtual contacts (every week or more frequently if needed) will 
occur between the site and the subject for instructional purposes, safety monitoring, 
investigation of any adverse events, ensuring subjects continue to benefit from treatment, and 
discussion of the subject's health status until the subject can resume visits at the study site.
Table 6-8
Packaging and Labeling
Investigational Treatment
Packaging
Labeling (and dosing frequency)
INC424/ruxolitinib
Tablets in HDPE bottles OR oral 
pediatric formulation
Tablet: INC424 5 mg or
Oral pediatric formulation: INC424, 
dose strength
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Investigational treatment must be received by a designated person at the study site, handled and 
stored safely and properly and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, all investigational treatment must be stored 
according to the instructions specified on the labels and in the Investigator’s Brochure. Clinical 


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supplies are to be dispensed only in accordance with the protocol. Technical complaints are to 
be reported to the respective Novartis/ Country Pharma Organization (CPO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the investigational treatment but no 
information about the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
6.7.1.2
Handling of additional treatment
In the context of this protocol, the following non-investigational treatment will be taken by the 
subject as per standard of care, but will be monitored specifically because dose adjustments of 
these non-investigational treatments may contribute to the efficacy assessment:

Systemic corticosteroids
All dosages prescribed to the subject and all dose changes during the study must be recorded 
on the Dosage Administration Record eCRF.
Details are described in the Monitoring Plan.
7
Informed consent procedures
Eligible subjects may only be included in the study after parents or caregivers provide written 
(witnessed, where required by law or regulation), Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)/Research Ethics Board (REB)-approved informed 
consent.
In cases where the subject's representative(s) gives consent (if allowed according to local 
requirements), the subject must be informed about the study to the extent possible given his/her 
understanding. If the subject is capable of doing so, he/she must indicate assent by personally 
signing and dating the written informed consent form (ICF) or a separate assent form.
Informed consent, and assent if appropriate, must be obtained before conducting any study-
specific procedures (e.g. all of the procedures described in the protocol). The process of 
obtaining informed consent/assent must be documented in the subject source documents. The 
date when a subject's informed consent/assent was obtained will be captured in their eCRF.
Novartis will provide to investigators in a separate document a proposed ICF and assent form 
that complies with the International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines and regulatory requirements and is considered appropriate for this study. Any 


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changes to the proposed ICF or assent form suggested by the investigator must be agreed by 
Novartis before submission to the IRB/IEC/REB.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent/assent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification (IN) or an aggregate safety finding. New information might require an update to 
the informed consent/assent and then must be discussed with the subject.
The following informed consents are included in the study:

Main study patient, parent/guardian consent

Adolescent assent

Child assent

As applicable, Pregnancy Outcomes Reporting Consent for female subjects
Females of child-bearing potential must be informed that taking the investigational treatment 
may involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study they must adhere to the contraception requirements for 
the duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
A copy of the approved version of all informed consent/assent forms must be provided to 
Novartis after IRB/IEC/REB approval.As per Section 4.6, during a Public Health emergency as 
declared by Local or Regional authorities i.e. pandemic, epidemic or natural disaster, that may 
challenge the ability to obtain a standard written informed consent due to limits that prevent an 
on-site visit, Investigator may conduct the informed consent discussion remotely (e.g. telephone, 
videoconference) if allowable by a local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate ICFs 
by trial subject and person obtaining informed consent, etc.).
8
Visit schedule and assessments
Assessment schedule lists all of the assessments and indicates with an “X”, the visits when they 
are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue study treatment (ruxolitinib) 
for any reason should be scheduled for an end of treatment (EOT) visit within the time required 
per Table 8-1, at which time all of the assessments listed for the EOT visit should be performed. 
At this End of treatment visit, all dispensed investigational product should be reconciled, and 
the adverse event and concomitant medications recorded on the eCRF. Subjects should then 
follow the early discontinuation follow-up visit schedule as described in Section 8.2.1.


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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates.


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Table 8-1
Assessment Schedule
Period
Screeni
ng
Treatment Period Cycles 1-39, q28 day cycles
Safety Follow-
up
Early Discontinuation 
Follow-up
Visit Name
Screeni
ng
Cycle 1
Cycle 2 -
Cycle 6
Cycle 7
Cycle 9 - Cycle 
39 (q 12 weeks)
End of treatment 
visit (EOT)
Safety Follow-
up
Every 6 months until 3 
years from first dose
Days
-28 to -
1
1
8 (+/-
3d)
15 (+/-
3d)
22 (+/-
3d)
D1 each 
cycle (+/-7d)
Day 1 (+/-
7d)
D1 each cycle 
(+/-14d) 
(+7d from last 
dose)
Last dose +30 
days,(+3d)
Q 6 months (+/- 14d)
Obtain 
Informed 
Consent/Asse
nt
X
Inclusion / 
Exclusion 
criteria
X
Disease 
history 
(alloSCT 
history, 
aGvHD 
history, cGvHD 
history, 
CIBMTR 
classification, 
donor history)
X
HCT-Specific 
Comorbidity 
Index Score
X
Demography
X
Relevant 
medical 
history/current 
medical 
conditions
X


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Period
Screeni
ng
Treatment Period Cycles 1-39, q28 day cycles
Safety Follow-
up
Early Discontinuation 
Follow-up
Visit Name
Screeni
ng
Cycle 1
Cycle 2 -
Cycle 6
Cycle 7
Cycle 9 - Cycle 
39 (q 12 weeks)
End of treatment 
visit (EOT)
Safety Follow-
up
Every 6 months until 3 
years from first dose
Days
-28 to -
1
1
8 (+/-
3d)
15 (+/-
3d)
22 (+/-
3d)
D1 each 
cycle (+/-7d)
Day 1 (+/-
7d)
D1 each cycle 
(+/-14d) 
(+7d from last 
dose)
Last dose +30 
days,(+3d)
Q 6 months (+/- 14d)
Prior/Concomit
ant 
Medications
X
X
X
X
X
X
X
X
X
X
Non-drug 
therapy and 
procedures
X
X
X
X
X
X
X
X
X
X
Physical 
Examination
S
S
S
S
S
S
S
S
S
Height
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Tanner staging 
(if not Tanner 
Stage 5 at 
Screening)
X
X (Annually)
X
X (Annually)
Laboratory 
Assessments
-
Hematology
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X 
X 
X
X
X
X
Hepatitis 
serology 
markers (HBV, 
HCV)
X
Hepatitis viral 
load (HBV, 
HCV)
X
X
X (drawn 
every 6 
months 
while on 
ruxolitinib)
X (drawn every 6 
months while on 
ruxolitinib)
X


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Period
Screeni
ng
Treatment Period Cycles 1-39, q28 day cycles
Safety Follow-
up
Early Discontinuation 
Follow-up
Visit Name
Screeni
ng
Cycle 1
Cycle 2 -
Cycle 6
Cycle 7
Cycle 9 - Cycle 
39 (q 12 weeks)
End of treatment 
visit (EOT)
Safety Follow-
up
Every 6 months until 3 
years from first dose
Days
-28 to -
1
1
8 (+/-
3d)
15 (+/-
3d)
22 (+/-
3d)
D1 each 
cycle (+/-7d)
Day 1 (+/-
7d)
D1 each cycle 
(+/-14d) 
(+7d from last 
dose)
Last dose +30 
days,(+3d)
Q 6 months (+/- 14d)
Urinalysis
X
X
Pregnancy test 
(serum)
S
S
S
Pregnancy 
Test (urine)
S
S
S
S
cGvHD staging X
Chronic GvHD 
assessment
X
X
X
X
X
X
X
X
Graft Failure 
Assessment
X
X
X
X
X
X
X
X
Hematologic 
underlying 
disease 
relapse/progre
ssion 
assessment
X
X
X
X
X
X
X
X
X
Safety
-
Adverse 
Events
X
X
X
X
X
X
X
X
X
X
Infection 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
Second 
primary 
malignancy 
assessment
X
X
X
X
X
X
X
Biomarkers 
(refer to table 
8-7)
-


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Period
Screeni
ng
Treatment Period Cycles 1-39, q28 day cycles
Safety Follow-
up
Early Discontinuation 
Follow-up
Visit Name
Screeni
ng
Cycle 1
Cycle 2 -
Cycle 6
Cycle 7
Cycle 9 - Cycle 
39 (q 12 weeks)
End of treatment 
visit (EOT)
Safety Follow-
up
Every 6 months until 3 
years from first dose
Days
-28 to -
1
1
8 (+/-
3d)
15 (+/-
3d)
22 (+/-
3d)
D1 each 
cycle (+/-7d)
Day 1 (+/-
7d)
D1 each cycle 
(+/-14d) 
(+7d from last 
dose)
Last dose +30 
days,(+3d)
Q 6 months (+/- 14d)
Immune cell 
characterizatio
n
X
X
X
X
X
X
Cytokines
X
X
X
X
X
X
cGvHD 
biomarkers 
assessment
X
X
X
X
X
X
Bone 
biomarkers
X
X
X
X
X
Study 
Procedures
-
IRT entry / 
dispense 
ruxolitinib
IRT 
entry 
only
X
X
X
X
IRT entry only
Investigational 
Drug 
(ruxolitinib) 
administration 
(Refer to 
Section 6.1.1)
X
X
X
X
X
X
X
Acceptability 
and 
Palatability 
questionnaire
X
X (Cycle 4)
X (C39D1)
X (only if ruxolitinib 
ended prior to 
C39D1 or not done 
at C39D1)
PK sampling 
(refer to 
Table 8-6)
X
X
X
X
Cycle 3 and 
Cycle 5
X
End of Phase 
Disposition
X
X


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Period
Screeni
ng
Treatment Period Cycles 1-39, q28 day cycles
Safety Follow-
up
Early Discontinuation 
Follow-up
Visit Name
Screeni
ng
Cycle 1
Cycle 2 -
Cycle 6
Cycle 7
Cycle 9 - Cycle 
39 (q 12 weeks)
End of treatment 
visit (EOT)
Safety Follow-
up
Every 6 months until 3 
years from first dose
Days
-28 to -
1
1
8 (+/-
3d)
15 (+/-
3d)
22 (+/-
3d)
D1 each 
cycle (+/-7d)
Day 1 (+/-
7d)
D1 each cycle 
(+/-14d) 
(+7d from last 
dose)
Last dose +30 
days,(+3d)
Q 6 months (+/- 14d)
Survival follow-
up
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only


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8.1
Screening
Screening
Subjects diagnosed with either treatment naive-cGvHD (moderate to severe) or SR-cGvHD 
(moderate to severe) after alloSCT will be consented to the study prior to any study procedures 
being performed.
Screening period will begin once the subject and/or parent/legal guardian has signed the Study 
Informed Consent and assent, if appropriate. The Screening Period will be a maximum of 28 
days (Day -28 to Day -1).
Screening procedures are outlined in the visit evaluation schedule Table 8-1 including blood 
samples tested as needed, and assessment of inclusion and exclusion criteria.
All study procedures should be performed within 28 days before ruxolitinib initiation on Cycle 
1 Day 1. Continued use of systemic corticosteroids, CNI (cyclosporine or tacrolimus), and 
topical corticosteroid therapy per institutional guidelines is permitted if they have been started 
prior to initiation of study treatment on Cycle 1 Day 1. Other systemic medications for cGvHD 
may be continued after Cycle 1 Day 1 only if used for cGvHD prophylaxis and started prior to 
diagnosis of cGvHD. For SR-cGvHD subjects, cessation of other systemic treatment for 
cGvHD other than corticosteroids +/- CNI will be required prior to ruxolitinib initiation. 
Permitted concomitant medications are described in Section 6.2.1.1.
A subject who has a laboratory test result(s) that does not satisfy the entrance criteria may have 
the test(s) repeated. These tests may be repeated as soon as the investigator believes the retest 
result is likely to be within the acceptable range to satisfy the entrance criteria, and can be 
completed within the 28 day screening period. In this case, the subject will not be required to 
sign another ICF/assent, and the original subject identification (ID) number assigned by the 
investigator will be used.
All baseline assessments should be performed on Day 1 as per Table 8-1.
In the event that a laboratory test(s) cannot be performed within the 28 day screening period, or 
the retest(s) do not meet the entrance criteria or the subject’s medical condition has changed 
significantly during the screening period so that the inclusion/exclusion criteria are no longer 
met, the subject is considered a Screen Failure and must be discontinued from the study. 
Eligibility details are outlined in Section 5.
A new study ICF will need to be signed if the investigator chooses to re-screen a subject after 
a subject has screen failed. A new subject number will be assigned, the subject will be entered 
in the IRT as a re-screen and a new re-screen eCRF will be entered. All required screening 
activities must be performed when the subject is re-screened for participation in the study. An 
individual subject may only be re-screened once for the study.
Subjects meeting all inclusion and exclusion criteria will be assigned to one of 4 dose groups 
according to their age.


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8.1.1
Eligibility screening
Subjects must meet all eligibility criteria at screening in order to proceed with the dose 
assignment and enter the Treatment Period of the study.
Subject eligibility will be confirmed by the investigator or deputy and captured within the 
source documents maintained at the site. Only when eligibility has been confirmed should the 
site then follow instructions to enter the subject into the IRT system and be assigned a 
ruxolitinib dose based on the subject's age. This information will be made available during 
planned interim monitoring visits and compared against the clinical database for accuracy.
Additionally, investigator's site staff will enter subject information into the eCRF.
8.1.2
Information to be collected on screening failures
Subjects who sign the study informed consent form/assent, but fail to start investigational 
treatment for any reason, will be considered a screen failure.
The reason for not starting investigational treatment will be entered on the appropriate 
Disposition eCRF pages.
The demographic information, informed consent/assent, and Inclusion/Exclusion eCRF pages 
must also be completed for all screen failure subjects. In addition, the cGvHD assessment at 
screening will also be recorded in the eCRF with overall grade and staging to better characterize 
the cGvHD population screened for this trial.
No other data will be entered into the clinical database for subjects who are screen failures, 
unless the subject experienced a Serious Adverse Event during the screening period (see 
Section 10.1.3 for SAE reporting details). The IRT must be notified within 2 days of the screen 
fail that the subject was not treated.
8.2
Subject demographics/other baseline characteristics
Subject information to be collected at screening include:

Demography

Relevant medical history and current medical conditions

Prior and concomitant medications and non-drug therapies (including physical therapy, 
oxygen and blood transfusions)

Disease History – donor history, alloSCT history, aGvHD history, cGvHD history, 
including CIBMTR classification (Section 16.6)

HCT-specific comorbidity index score (Section 16.5)
Subjects will have the screening assessments performed before the start of study treatment as 
in Table 8-1:

Physical examination

Height

Weight

Vital signs

Laboratory assessments – Hematology, Chemistry, Urinalysis


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
Hepatitis viral load (HBV, HCV)

Hepatitis serology markers (HBV, HCV)

Pregnancy test (for applicable female subjects only (Section 8.4.2))

Infection monitoring

cGvHD staging

Second primary malignancy assessment

Hematologic underlying disease relapse/progression assessment

Graft failure assessment

Tanner staging (if not Tanner 5 at screening)
The investigator must confirm all the inclusion and exclusion criteria prior to contacting IRT 
for dose assignment. Once the subject’s eligibility is confirmed, the subject must have baseline 
assessments performed on Cycle 1 Day 1 prior to ruxolitinib initiation (Table 8-1).
Please refer to sections below for related assessments.
8.2.1
Treatment Period
The treatment period will begin on Cycle 1 Day 1, which is the baseline disease assessment 
visit. The primary efficacy endpoint assessment will be conducted on Cycle 7 Day 1 of the 
treatment period, with a window of +/- 7 days. The total duration on study for an individual 
subject will be 39 Cycles (156 weeks or approximately 36 months), inclusive of the treatment 
period and safety follow-up. Each cycle is a total of 28 days.
Study visits will occur at the following frequency in the treatment period, as specified in 
Table 8-1:

Cycle 1 Day 1

Every week in Cycle 1 (Day 8, 15, 22) (+/- 3 days)

Every 4 weeks from Cycle 2 Day 1 until Cycle 7 Day 1 (+/- 7 days)

Next visit after Cycle 7 Day 1 is Cycle 9 Day 1 (+/- 7 days)

Every 12 weeks from Cycle 9 Day 1 until Cycle 39 Day 1 (+/- 14 days)
The End of Treatment (EOT) visit is completed when a subject completes 39 cycles of the 
treatment period, or if a subject permanently discontinues ruxolitinib early.
All subjects must complete a safety follow-up visit, 30 days (+3 days) from the last dose of 
ruxolitinib.
If a subject permanently discontinues ruxolitinib early, after completing the EOT and safety 
follow-up visit, he/she should follow the early discontinued follow-up schedule as specified in 
Table 8-1. Visits should occur every 6 months (+/- 14 days) until the subject reaches 3 years 
from the time of first dose of ruxolitinib.
Refer to Figure 8-1.




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The chronic GvHD screening staging assessment is a global and organ-specific clinician 
assessment which focuses on symptom activity in chronic GvHD subjects. To classify the 
cGvHD severity, the staging assessment collects individual organ symptom scores (mouth, 
gastrointestinal, lungs, eyes, joints and fascia, liver, skin, genital tract). Assessments for all 
organs must be performed at screening. The list of organ-specific assessments and scoring can 
be found in Section 16.2. 
If there is any organ-specific abnormality present but explained entirely by non-GvHD 
documented cause, this should be indicated on the cGvHD Disease Staging eCRF and the 
applicable conditioned reported in the Medical History or Adverse Event eCRF.
Skin
Skin features are to be scored by % body surface area (BSA), presence of skin abnormalities 
(maculopapular rash/erythema, papulosquamous lesion or ichthyosis, lichen planus - like 
features, sclerotic features, keratosis pilaris – like GvHD) and other skin GvHD features not 
scored by BSA.
Mouth
Mouth features are to be scored by presence of lichen planus-like features and degree of oral 
intake limitation.
Eyes
The eye score is determined by assessing keratoconjunctivitis sicca (KCS), severity of dry eye 
symptoms and degree of vision impairment.
Gastrointestinal tract
The GI tract score is determined by assessing presence and degree of various symptoms 
(esophageal web/proximal structure or ring, dysphagia, anorexia, nausea, vomiting, diarrhea, 
weight loss, failure to thrive).
Liver
The liver score is based on ALT, alkaline phosphates, and total bilirubin.
Lungs
Both lung symptom score and a pulmonary function test should be performed for staging. The 
lung organ score is determined by the pulmonary function test; scores are derived from the 
forced expiratory volume in 1 second as a percentage (%FEV1) result. However, if the 
pulmonary function tests are not available or reliable, for example in young children or in very 
sick children, the lung symptom score alone can be substituted for lung scoring.


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Joints and Fascia
The joints and fascia score is determined by assessing range of motion and activity of daily 
living (ADL). Individual joints and fascia photographic range of motion (P-ROM) scores are 
collected for symptom severity of shoulder, elbow, wrist/finger, and ankle.
Genital Tract
The genital tract score is determined by assessing applicable signs and level of discomfort on 
exam.
8.3.1.2
Chronic GvHD Disease Assessment
The primary endpoint of the study is overall response rate at Cycle 7 Day 1 per NIH consensus 
criteria (Lee et al 2015).
Secondary endpoints include best overall response (BOR), duration of response (DOR), and 
overall response rate (ORR at end of cycle 3). The assessment will be performed by the treating 
physician according to the detailed schedule found in Table 8-1.
8.3.1.2.1 Baseline Organ involvement
The chronic GvHD assessment is a global and organ-specific clinician assessment which 
focuses on symptom activity in chronic GvHD subjects. The assessment collects individual 
organ symptoms (eyes, mouth, lungs, gastrointestinal, liver, skin, joints and fascia). Details and 
specifics of some organ assessments at C1D1 (baseline) differ to those for staging (for e.g. skin, 
gastrointestinal) and therefore cGvHD staging and baseline organ assessments must be 
completed independently. Assessments for all organs must be performed prior to treatment 
assignment at the Cycle 1 Day 1 visit (baseline). The list of organ-specific assessments and 
scoring can be found in Section 16.3.
Skin
Skin features are first to be assessed by % body surface area (BSA), presence of skin 
abnormalities (maculopapular rash/erythema, papulosquamous lesion or ichthyosis, lichen 
planus - like features, sclerotic features, keratosis pilaris – like, ), skin feature score, and skin 
and/or joint tightening severity. These assessments will populate the overall skin organ score in 
the eCRF.
Eyes
The eye score is determined by assessing severity of dry eye symptoms and degree of vision 
impairment.
Mouth
Mouth features are first to be scored by %BSA individually for any erythema, lichenoid, and 
ulcers. The total score for all mucosal changes will populate the overall mouth organ score in 
the eCRF.


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Liver
The baseline liver involvement is assessed using ALT, alkaline phosphates, and total bilirubin.
All three liver parameters must be obtained in order for the liver to be assessed. Liver 
parameters must be obtained comprehensively together with observed values, units and normal 
ranges documented. Note, staging criteria for liver differs to that of cGvHD liver organ 
assessments from baseline.
Gastrointestinal tract
Individual GI scores are to be collected for frequency of esophageal symptoms (dysphagia or 
odynophagia), upper GI symptoms (early satiety, anorexia, or nausea and vomiting), and lower 
GI (diarrhea). Individual GI scores refers to the week prior to the GI cGvHD assessment being 
performed.
Lungs
The lung baseline status is assessed by a pulmonary function test to determine the %FEV1 
(percentage) results and assessment of bronchiolitius obliterants. In addition, a lung score based 
on clinical symptoms is used. If available, the FEV1 value should be prioritized for response 
assessment. However, if the pulmonary function tests are not available or reliable, for example 
in young children or in sick children, the lung symptom score may be used for the response 
assessment.
Joints and Fascia
Individual joints and fascia scores are to be collected in addition to PROM for symptom severity 
of shoulder, elbow, wrist/finger, and ankle.
If there is any organ-specific abnormality present but explained entirely by non-GvHD 
documented cause, the individual organ should still be scored and the abnormality should be 
indicated on the cGvHD Assessment eCRF, and the applicable condition reported in the 
Medical History or Adverse Event eCRF.
As part of the chronic GvHD assessment, a biopsy of the organs involved may be performed 
per institutional practices at investigator’s discretion. If performed, the investigator will indicate 
the results in the appropriate eCRF pages.
8.3.1.2.2 Post-baseline organ involvement and cGVHD response assessment
The chronic GvHD assessment will be performed by the treating physician according to the 
detailed schedule found in Table 8-1. At each post-baseline assessment, each organ must be
assessed using the same criteria as for baseline. Additionally, the response evaluation of each 
organ should be made by comparing the current organ assessment versus the baseline organ 
status documented on Cycle 1 Day 1. A high level summary of organ-specific response 
assessment criteria as per NIH consensus guideline (Lee et al 2015) are listed in Table 8-2.
Table 8-3 summarizes the rules for overall response assessment based on organ-specific 
evaluations at each scheduled post-baseline visit. These overall response assessments will be 
used to derive response rates for the primary and secondary endpoints.


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More detailed instructions on organ-specific response assessment and overall response 
evaluation, including examples, are given in Section 16.4.
Table 8-2
Organs included for the post-baseline cGvHD response assessment
Organ
Evaluation by
Criteria for response assessment
Skin
NIH Skin Score, considering %BSA 
involvement and sclerotic features
Change of skin score
Eyes
NIH Eye Score
Change of Eye score
Mouth
NIH Modified OMRS (Sum of 
scores for erythema, lichenoid and 
ulcers)
Change of Oral Mucosa Rating Scale (OMRS)
Esophagus
NIH Esophagus Score
Change of Esophagus score
Upper GI
NIH Upper GI Score
Change of Upper GI score
Lower GI
NIH Lower GI Score
Change of Lower GI score
Liver
Lab results for ALT, alkaline 
phosphatase, and Total bilirubin
Change of values for ALT, alkaline phosphatase, 
and Total bilirubin
Lungs
NIH Lung score AND %FEV1
Change of %FEV1 (preferrable) or change in 
NIH lung symptom score
Joints and fascia
NIH Joint and Fascia Score and P-
ROM scores
Change of Joint and Fascia Score and P-ROM 
scores
Table 8-3
Post-baseline overall response evaluation based on all organs
Organ-specific response1
Skin
CR / not involved
PR or CR in at 
least one 
organ with 
baseline 
involvement 
AND no 
progression in 
any other 
organ (i.e. CR, 
PR, 
unchanged, or 
no 
involvement), 
assuming 
overall CR has 
not been 
achieved
PR or CR in 
one or more 
organ(s) with 
baseline 
involvement 
AND 
progression in 
one or more 
organs (incl. 
new 
occurrence in 
an organ with 
no baseline 
involvement)
Progression in 
one or more 
organ(s) with 
baseline 
involvement OR 
new occurrence 
in an organ with 
no baseline 
involvement 
AND no CR or
PR in any other 
organ
Organ-specific 
response 
‘unchanged’ for 
all organs (incl. 
no involvement)
Eyes
CR / not involved
Mouth
CR / not involved
Esophagus
CR / not involved
Upper GI
CR / not involved
Lower GI
CR / not involved
Liver
CR / not involved
Lungs
CR / not involved
Joints and 
fascia
CR / not involved
Overall 
response
CR
PR
Mixed 
response
Progression
Unchanged 
response
1 at least one organ must be involved at baseline. Organ-specific responses versus baseline status
Further assessments
Subjects will be also monitored for occurrence of cGvHD flares occurring during corticosteroid, 
CNI, or ruxolitinib taper.
The investigator should carefully record any action taken to manage cGvHD including start of 
tapering, initiation of any new systemic therapy, re-escalation of corticosteroids and the re-
escalated corticosteroid dose, and corticosteroid taper failure.


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The data should be entered in the appropriate eCRFs. Worsening of cGvHD, including 
occurrence of GvHD flare will be reported on appropriate specific eCRF and, not as an adverse 
event (Section 10.1.1).
Note: Additional assessments may be done as per institutional guidelines at investigator’s 
discretion. Chronic GvHD assessments performed at an unscheduled visit and leading to a 
change in the subject’s management during the treatment period or a change in subject’s 
response should be recorded in the eCRF.
8.3.1.3
Hematologic disease relapse/progression assessment
Subjects will be closely monitored for any evidence of underlying disease relapse or recurrence 
at each visit during the treatment period and the safety follow-up (if possible) as outlined in 
Table 8-1. If the subject has underlying disease relapse or recurrence during the safety follow-
up, the investigator should make every effort to collect the information and enter it into the 
appropriate eCRF.
The investigator will assess relapse and recurrence of the underlying disease and indicate if any 
therapy was instituted to treat persistent, progressive or relapsed underlying disease, including 
the withdrawal of immunosuppressive therapy, chemotherapy administration, and/or donor 
lymphocyte infusion.
Evaluation and/or evidence of underlying disease relapse/recurrence will be conducted 
according to local institutional practices. Available information on the underlying disease 
recurrence/relapse will be documented on the appropriate eCRF and not as an adverse event 
(Section 10.1.1).
8.3.2
Graft failure monitoring
Graft failure is defined as initial whole blood or marrow donor chimerism ≥5% declining to 
<5% on subsequent measurements.
Subjects must be closely monitored for any evidence of graft failure, including donor chimerism, 
as specified in Table 8-1.
If a subject experiences graft failure, Investigator should indicate any action taken to manage 
the graft including rapid taper of immunosuppression, administration of non-scheduled DLI, 
stem cell boost and/or chemotherapy or any other action taken.
Occurrence of graft failure will be reported on the appropriate specific eCRF and also as an 
adverse event (Section 10.1.1).
8.3.3
Appropriateness of efficacy assessments
Not applicable.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section (Section 10.1).


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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every week or more frequently if needed) for safety 
monitoring and discussion of the subject´s health status until it is safe for the subject to visit the 
site again.
Table 8-4
Safety Assessment
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, vascular, and neurological.
Information for all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to signing informed consent 
must be included in the Medical History part of the eCRF. Significant findings made after 
signing informed consent which meet the definition of an Adverse Event must be recorded 
on the Adverse Event section of the eCRF.
Vital sign
Vital signs include blood pressure (supine or seated position), pulse measurement and 
body temperature. Blood pressure should be measured following a 5 minute rest period 
and obtained in the same position and same arm throughout study participation.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes), will be measured at screening and at subsequent time points 
as specified in Table 8-1.
8.4.1
Laboratory evaluations
Table 8-5
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular 
Hemoglobin Concentration (MCHC), Mean Corpuscular Volume (MCV), Platelets (PLT), 
Red blood cells (RBC), White blood cells (WBC). RBC Morphology, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Absolute Neutrophil Count (ANC), 
Absolute Reticulocytes, Bands
Chemistry
Albumin, Alkaline phosphatase, ALT (Serum Glutamic Pyruvic Transaminase (SGPT), AST 
(Serum Glutamic Oxaloacetic Transaminase (SGOT), Gamma glutamyl transferase (GGT), 
Lactate Dehydrogenase (LDH), Bicarbonate, Calcium, Creatinine, Magnesium, 
Phosphorus, Chloride, Sodium, Potassium, Total Bilirubin, Direct Bilirubin, (Indirect 
Bilirubin only if Total Bilirubin out of range), Blood Urea Nitrogen (BUN) or Urea, Creatine 
kinase, Total Cholesterol, Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL), 
Total Protein, Triglycerides, Uric Acid, Amylase, Lipase, Glucose
Urinalysis
Macroscopic Panel (Dipstick)* (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
*Note: Any clinically significant findings per the Investigator's discretion on the 
macroscopic panel should be followed up with a microscopic evaluation.
Hepatitis 
markers
Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis B core antibody 
(baseline) and HBV DNA-PCR (baseline and during treatment period)
Hepatitis C virus antibody (baseline) and HCV RNA-PCR (baseline and during treatment 
period)
Additional viral 
testing as 
applicable
Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Human Herpes Virus (HHV-6), Herpes 
Simplex Virus (HSV), Varicella Zoster Virus (VZV), Adenovirus (ADV) and Severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load


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Test Category
Test Name
Pregnancy 
Test (for female,
child-bearing 
potential subjects 
only)
Serum at screening, End of Treatment (EOT) and Safety follow-up
Urine at all other time points
Per Investigator discretion, a serum pregnancy test can be performed in lieu of a urine 
pregnancy test.
A central laboratory will be used for analysis of biomarkers and pharmacokinetics. Details on 
the collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual.
All other laboratory assessments are to be performed locally. Normal reference ranges and 
results must be recorded in the eCRF.
Blood collection prioritization, based on volumes required for local and central laboratory 
collection, should be based on local recommendations or guidelines for limitations of acceptable 
blood volume extraction limits based on subject age and/or weight. The collection of biomarker 
samples should be prioritized in the order specified in Table 8-7.
8.4.1.1
Hematology
Hematology parameters (See Table 8-5) will be measured at screening and all scheduled visits 
as noted in Table 8-1.
8.4.1.2
Chemistry
Serum chemistries (See Table 8-5) will be measured at screening and all scheduled visits as 
stated in Table 8-1.
8.4.1.3
Urinalysis
Urinalysis will be performed using macroscopic evaluation (See Table 8-5) as outlined 
in Table 8-1.
Any significant findings as determined to be clinically significant by the Investigator on the 
macroscopic panel will be followed up with a microscopic evaluation.
8.4.1.4
Hematologic underlying disease relapse/progression assessment
Bleeding complications are important identified and potential risks in the setting of alloSCT 
due to profound thrombocytopenia and therefore will be monitored closely throughout the 
treatment period from Cycle 1 Day 1 and, at every visit until EOT and at the Early 
Discontinuation follow up visit as outlined in Table 8-1.
Bleeding will be reported as adverse event and the AE severity grade will be assessed according 
to Common Terminology Criteria for Adverse Events (CTCAE) grading as defined 
in Section 10.1.
8.4.1.5
Infection Monitoring
Infections (including opportunistic infections) are important risks identified with ruxolitinib 
cGvHD therapy and therefore will be monitored closely throughout the treatment period from 
Cycle 1 Day 1 and, at every visit until EOT and at the Safety follow up visit. Infections will 


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also be monitored for subjects that discontinue ruxolitinib early and follow the early 
discontinuation visit schedule as per Table 8-1.
Infections will be reported as adverse event and the AE severity grade will be assessed 
according to CTCAE grading as defined in Section 10.1.
In addition, Investigator will detail type of infection as well as method of diagnosis and assess 
the event according to the Infection severity grading (Section 16.1).
8.4.1.6
Viral reactivation monitoring
The Investigator must confirm that a subject has no evidence of active uncontrolled hepatitis B 
virus (HBV) or hepatitis C virus (HCV) at screening based on medical assessment by study 
investigator or delegate. Viral serology and viral load testing will be assessed once the subject 
has signed the informed consent form.
The following hepatitis serology markers will be assessed at screening:

Hepatitis B surface antigen (HBsAg)

Hepatitis B surface antibody (HBsAb)

Hepatitis B core antibody (anti-HBc)

HBV-deoxyribonucleic acid (DNA) polymerase chain reaction (PCR)

Hepatitis C virus antibody

HCV ribonucleic acid (RNA)-PCR
Serology hepatitis test results for HBV and HCV obtained as part of standard of care to confirm 
a subject is immune and not at risk for reactivation (i.e., hepatitis B surface antigen negative, 
surface antibody positive, or HCV antibody negative) within 28 days from screening may be 
used for purposes of eligibility and therefore baseline serology tests do not need to be repeated 
during the screening period
Viral load will be monitored throughout the study. The following PCR viral load (blood) will 
be assessed at screening, at Cycle 1 Day 1, Cycle 7 Day 1, every 6 months and EOT while the 
subject is on ruxolitinib treatment:

Hepatitis B and C
The results of the baseline viral load tests to assess HCV and HBV performed during screening 
may not become available by the time of randomization, as these specialized laboratory viral 
load tests may take up to several days. For eligibility purposes, the investigator or delegate must 
confirm the subject has no evidence of active uncontrolled HBV or HCV based on medical 
assessment.
If viral load tests were collected during the screening period (within 7 days from Cycle 1, Day 
1), and there is no evidence of uncontrolled HBV or HCV infection, viral load tests do not need 
to be repeated at Cycle 1 Day 1.
For details on the schedule of assessments, see Table 8-1. Additional viral testing may be 
performed as per local regulations.


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CMV, EBV, HHV-6, HSV, VZV, ADV and SAR-CoV-2 viral load may be reported as 
unplanned assessment results when applicable to a patient’s condition. Additional viral testing 
may be performed as per local guidelines.
8.4.1.7
Second primary malignancy assessment
Occurrence of any new malignancies other than the underlying hematologic disease, including 
non-melanoma skin cancer, will be monitored as outlined in Table 8-1.
Second primary malignancy will be reported as adverse event as defined in Section 10.1.
8.4.2
Pregnancy and assessments of fertility
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric subjects who are menarchal or who become 
menarchal during the study.
Serum pregnancy test will be performed for all females of child-bearing potential at screening, 
EOT and 30 days following the last dose of study treatment according to the schedule 
in Table 8-1. Urine pregnancy tests will be performed at other scheduled visits as outlined 
in Table 8-1. Per Investigator discretion, a serum pregnancy test can be performed in lieu of a 
urine pregnancy test as outlined in Table 8-1.
All menarchal girls and their parents/caregivers should be informed about the potential risks of
pregnancy and the need to prevent pregnancy during the study.
It is important to be sensitive in introducing this issue, as understanding and comprehension of 
puberty, sexual activity, pregnancy and contraception is influenced by age, as well as factors 
such as precocity, socio (educational) economic and familial background. These discussions 
with the subject and her parents/caregivers are therefore best performed by investigators 
familiar with the pediatric subject and her family and should be guided by requirements of the 
local regulatory authorities. These discussions should take into account the socio-economic, 
cultural factors and religious beliefs of the adolescent participant and her family. The 
investigator should also discuss the management of the pregnancy test results with the subject 
and her parents/caregivers. The privacy of the subject should be considered in accordance with 
the local law and ethics.
Additional pregnancy tests may be performed at the investigator’s discretion during the study. 
Subjects becoming pregnant must be discontinued from study drug. However, a subject may 
choose to remain in the study should she become pregnant, and be followed according to the 
protocol-defined study visits.
Female subjects of child-bearing potential who are or might become sexually active, must be 
informed of the potential teratogenic risk with ruxolitinib and the need for highly effective 
contraception to prevent pregnancy while on ruxolitinib therapy:
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (i.e., calendar, ovulation, symptothermal, post ovulation methods) and 
withdrawal are not acceptable methods of contraception.


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
Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception, females should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Contraception must be used during the study and for 30 days after stopping treatment. The 
decision on the contraceptive method should be reviewed at each study visit or at least every 3 
months to evaluate the individual need and compatibility of the method chosen.
If subjects cannot visit the site to have serum pregnancy tests during a Public Health emergency 
as declared by Local or Regional authorities i.e. pandemic, epidemic or natural disaster, that 
limits or prevents on-site study visits, urine pregnancy test kits may be used. Relevant subjects 
can perform the urine pregnancy test at home and report the result to the site. It is important 
that subjects are instructed to perform the urine pregnancy test first and only if the test result is 
negative proceed with the administration of the study treatment. A communication process 
should be established with the subject so that the Site is informed and can verify the pregnancy 
test results (e.g., following country specific measures).
8.4.3
Tanner staging
Assessments of reproductive development will be performed using the Tanner Staging scale at 
screening for subjects enrolled in Groups 1, 2 and 3. Tanner staging assessments are not 
required for subjects enrolled in Group 4. Additional Tanner Staging assessments will be based 
on the score at screening and subsequent scores:

Stage 5 = no additional Tanner Staging assessments needed.

Stage 4 or less = continue Tanner Staging assessments per Table 8-1.
8.5
Additional assessments
8.5.1
Pharmacokinetics
8.5.1.1
Pharmacokinetic blood collection and handling
On Day 1, blood sampling for PK of ruxolitinib will be performed in the first 5 subjects enrolled 
in Groups 1, 2 and 3 and in all subjects enrolled in Group 4 as indicated in Table 8-6. Pre-dose 
samples will be collected in all subjects enrolled in the study.
Subjects should be instructed not to take ruxolitinib at home on the days of the scheduled pre-
dose blood collection for PK samples. Dosing will be administered after pre-dose blood 
collection at these visits.
On the days of PK blood collection, subjects should be instructed to refrain from taking
corticosteroids until after the last PK samples are collected (i.e., approximately 6 hours post-
dose on Cycle 1 Day 1 and after the pre-dose sample collection on all other PK collection 
days).


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Table 8-6
Pharmacokinetic blood collection log
Cycle
Day of 
treatment
Scheduled time point
Dose 
reference 
Identification 
(ID)
PK Sample No
Sample 
volume [mL]
1
1
Post-dose 0.5 hour (± 15 
min)
1
1
1.2
1
1
Post-dose 2 hours (± 15 
min)
1
2
1.2
1
1
Post-dose 6 hours (± 120 
min)
1
3
1.2
1
8
Pre-dose
2
4
1.2
1
15
Pre-dose
3
5
1.2
1
22
Pre-dose
4
6
1.2
3
1
Pre-dose
5
7
1.2
5
1
Pre-dose
6
8
1.2
7
1
Pre-dose
7
9
1.2
Unschedule
d Sample
---
---
1001+
1.2
Refer to the Laboratory Manual for detailed instructions for the collection, handling, and 
shipment of PK samples.
8.5.1.2
Analytical method
The plasma samples from all subjects will be assayed for ruxolitinib concentrations using 
validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS).Values 
below the lower limit of quantification (LLOQ) of ruxolitinib at approximately 0.500 ng/mL 
will be reported at 0.0 ng/mL. Missing values will be labeled accordingly.
8.5.2
Biomarkers
In this study, we will be collecting blood for biomarkers (see Table 8-7 for a detailed sampling 
schedule). The collection of these samples is requested from all subjects enrolled on the study. 
Sample collection prioritization is provided (see Table 8-7) if all four requested biomarker 
samples are not able to be collected from a given subject.
Before, during study treatment, and at the end of treatment, biomarker samples will be collected 
to measure markers associated with bone remodeling. Two vials of blood with an approximate 
total volume of 2.2 mL of blood will be collected that will measure bone biomarkers as well as 
other markers related to cGvHD.
Additionally approximately 1.2 mL of blood will be collected to assess immune cell sub-
populations and approximately 1.1 mL to assess cytokines in order to investigate the effect of 
inflammatory and immune system state in the subject. In order to learn more about the effect of 
ruxolitinib on GvHD and understand disease biology, additional markers may also be tested.


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Table 8-7
Biomarker sample collection plan
Sample Type
Volume
Visit
Time point
Blood for bone 
biomarkers
(1st priority biomarker 
collection)
1.1 mL
Cycle 1 Day 1
Pre-dose
1.1 mL
Cycle 2 Day 1
Pre-dose
1.1 mL
Cycle 3 Day 1
Pre-dose
1.1 mL
Cycle 4 Day 1
Pre-dose
1.1 mL
Cycle 5 Day 1
Pre-dose
1.1 mL
Cycle 6 Day 1
Pre-dose
1.1 mL
Cycle 7 Day 1
Pre-dose
1.1 mL
Cycle 9 Day 1
Pre-dose
1.1 mL
Cycle 12 Day 1
Pre-dose
1.1 mL
Cycle 15 Day 1
Pre-dose
1.1 mL
Cycle 18 Day 1
Pre-dose
1.1 mL
Cycle 21 Day 1
Pre-dose
1.1 mL
Cycle 24 Day 1
Pre-dose
1.1 mL
Cycle 27 Day 1
Pre-dose
1.1 mL
Cycle 30 Day 1
Pre-dose
1.1 mL
Cycle 33 Day 1
Pre-dose
1.1 mL
Cycle 36 Day 1
Pre-dose
1.1 mL
Cycle 39 Day 1
Pre-dose
1.1 mL
End of Treatment
Anytime*
Blood for GvHD 
biomarker analysis
(1st priority biomarker 
collection – panel may 
also contain a bone 
biomarker)
1.1 mL
Cycle 1 Day 1
Pre-dose
1.1 mL
Cycle 1 Day 22
Pre-dose
1.1 mL
Cycle 2 Day 1
Pre-dose
1.1 mL
Cycle 3 Day 1
Pre-dose
1.1 mL
Cycle 4 Day 1
Pre-dose
1.1 mL
Cycle 5 Day 1
Pre-dose
1.1 mL
Cycle 6 Day 1
Pre-dose
1.1 mL
Cycle 7 Day 1
Pre-dose
1.1 mL
Cycle 9 Day 1
Pre-dose
1.1 mL
Cycle 12 Day 1
Pre-dose
1.1 mL
Cycle 15 Day 1
Pre-dose
1.1 mL
Cycle 18 Day 1
Pre-dose
1.1 mL
Cycle 21 Day 1
Pre-dose
1.1 mL
Cycle 24 Day 1
Pre-dose
1.1 mL
Cycle 27 Day 1
Pre-dose
1.1 mL
Cycle 30 Day 1
Pre-dose
1.1 mL
Cycle 33 Day 1
Pre-dose
1.1 mL
Cycle 36 Day 1
Pre-dose
1.1 mL
Cycle 39 Day 1
Pre-dose
1.1 mL
End of Treatment
Anytime*
Whole Blood for 
immune cell analysis
(2nd priority biomarker 
collection)
1.2 mL
Cycle 1 Day 1
Pre-dose
1.2 mL
Cycle 1 Day 22
Pre-dose
1.2 mL
Cycle 2 Day 1
Pre-dose
1.2 mL
Cycle 3 Day 1
Pre-dose
1.2 mL
Cycle 4 Day 1
Pre-dose


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Sample Type
Volume
Visit
Time point
1.2 mL
Cycle 5 Day 1
Pre-dose
1.2 mL
Cycle 6 Day 1
Pre-dose
1.2 mL
Cycle 7 Day 1
Pre-dose
1.2 mL
Cycle 9 Day 1
Pre-dose
1.2 mL
Cycle 12 Day 1
Pre-dose
1.2 mL
Cycle 15 Day 1
Pre-dose
1.2 mL
Cycle 18 Day 1
Pre-dose
1.2 mL
Cycle 21 Day 1
Pre-dose
1.2 mL
Cycle 24 Day 1
Pre-dose
1.2 mL
Cycle 27 Day 1
Pre-dose
1.2 mL
Cycle 30 Day 1
Pre-dose
1.2 mL
Cycle 33 Day 1
Pre-dose
1.2 mL
Cycle 36 Day 1
Pre-dose
1.2 mL
Cycle 39 Day 1
Pre-dose
1.2 mL
End of Treatment
Anytime*
Blood for cytokine 
analysis
(3rd priority biomarker 
collection)
1.1 mL
Cycle 1 Day 1
Pre-dose
1.1 mL
Cycle 1 Day 22
Pre-dose
1.1 mL
Cycle 2 Day 1
Pre-dose
1.1 mL
Cycle 3 Day 1
Pre-dose
1.1 mL
Cycle 4 Day 1
Pre-dose
1.1 mL
Cycle 5 Day 1
Pre-dose
1.1 mL
Cycle 6 Day 1
Pre-dose
1.1 mL
Cycle 7 Day 1
Pre-dose
1.1 mL
Cycle 9 Day 1
Pre-dose
1.1 mL
Cycle 12 Day 1
Pre-dose
1.1 mL
Cycle 15 Day 1
Pre-dose
1.1 mL
Cycle 18 Day 1
Pre-dose
1.1 mL
Cycle 21 Day 1
Pre-dose
1.1 mL
Cycle 24 Day 1
Pre-dose
1.1 mL
Cycle 27 Day 1
Pre-dose
1.1 mL
Cycle 30 Day 1
Pre-dose
1.1 mL
Cycle 33 Day 1
Pre-dose
1.1 mL
Cycle 36 Day 1
Pre-dose
1.1 mL
Cycle 39 Day 1
Pre-dose
1.1 mL
End of Treatment
Anytime*
* End of treatment sample will be collected anytime when treatment is permanently discontinued. No further 
biomarker sample collection is needed after the EOT sample collection.
These assessments will be performed at Novartis-designated laboratories. The sample collection 
date must be entered on the appropriate eCRF pages and/or requisition forms. Instructions for 
sample preparation and shipment will be provided in the [CINC424G12201 Laboratory 
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8.5.2.1
Additional biomarker assessments
Biomarker samples (blood or their derivatives) may be kept for up to 15 years to be used for 
additional studies related to ruxolitinib, GvHD, cancer or the initial disease leading to the bone 
marrow transplantation, including research to help develop ways to detect, monitor or treat 
GvHD, cancer or the initial disease leading to the bone marrow transplantation. A decision to 
perform such exploratory biomarker research studies would be based on outcome data from this 
study or from new scientific findings related to the drug class or disease, as well as assay 
availability. Subjects have the right to request that remaining sample material be destroyed by 
Novartis and should inform the Investigator of this decision. Novartis will be responsible for 
the destruction.
8.5.3
Other Assessments
8.5.3.1
Acceptability and Palatability questionnaire
Acceptability and palatability of ruxolitinib (only for subjects administered with the oral 
pediatric formulation starting treatment Day 1) will be evaluated from a questionnaire 
completed by subjects, with the help from parents or caregivers as needed at the following visits 
(as detailed in Table 8-1):

Cycle 1 Day 1 (after first dose)

Cycle 4 Day 1 (after morning dose)

Cycle 39 Day 1 (after morning dose) or End of Treatment (if subject discontinues 
ruxolitinib early)
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of investigational treatment for a subject occurs when treatment is stopped 
earlier than the protocol planned duration, and can be initiated by either the subject or the 
investigator.
The investigator must discontinue investigational treatment for a given subject if, he/she 
believes that continuation would negatively impact the subject's well-being.
In 
addition 
to 
mandatory 
investigational 
treatment 
discontinuation 
listed 
in Table 6-3, investigational treatment must also be discontinued under any of the following 
circumstances:

Lack of efficacy of chronic GvHD treatment (Section 16.4).

Lack of clinical benefit according to the Investigator.

Underlying disease recurrence, or relapse (Section 8.3.1.3).

Evidence of graft failure necessitating rapid taper of immunosuppression, administration 
of non-scheduled DLI, stem cell boost and/or chemotherapy, or other treatment that would 
expectedly affect chronic GvHD (Section 8.3.2).


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
The following deviations from the prescribed dose regimen for investigational treatment:

Dose hold > 21 days for ruxolitinib (Section 6.5.1).

Adverse events leading to investigational treatment discontinuation. (Section 6.5.1).

Pregnancy ( Section 8.4.2 )

Protocol deviation that results in a significant risk to the subject’s safety including use of 
prohibited treatment (Section 6.2.2).
Subjects who discontinue ruxolitinib should NOT be considered withdrawn from the study. The 
subject should return for the early discontinuation follow-up assessments as indicated 
in Table 8-1. Assessments will include:

Height and weight

Tanner staging (if appropriate)

Graft failure assessment

Hematologic underlying disease relapse/progression assessment

Infection monitoring

Second primary malignancy assessment

Survival follow-up
The follow-up for subjects that permanently discontinue ruxolitinib early includes visits every 
6 months until the subject reaches 3 years (39 cycles) from the date of their first ruxolitinib dose 
(see Table 8-1). In case the time between treatment discontinuation and 3 years (39 cycles) from 
the date of the first ruxolitinib dose is less than 6 months, subjects will be required to return for 
the one final early discontinuation follow-up visit as per Table 8-1.
Subjects with hematologic disease progression, graft failure, AE, patient safety (PS), or 
pregnancy may require abrupt cessation of ruxolitinib per Investigator discretion. Subjects 
should return for assessments as specified at the EOT visit in Table 8-1. The investigator must 
also contact the IRT to register the subject’s discontinuation from ruxolitinib. If they fail to 
return for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) 
should be made to contact them as specified in Section 9.1.3.
9.1.1.1
Replacement policy
Subjects who discontinue prematurely will not be replaced on this study. 
9.1.2
Withdrawal of informed consent/opposition to use data/biological 
samples
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent/opposition to use data /biological samples occurs only when a subject:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
subject’s data and biological samples)
and

No longer wishes to receive study treatment
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
Does not want to participate in the study anymore
and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent/exercise 
data privacy rights and record this information.
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. The Investigator shall clearly document if the subject has withdrawn his/her 
consent for the use of data in addition to a study discontinuation.
Withdrawal of consent impacts the ability to further contact the subject, collect follow up data 
(e.g. to respond to data queries) and potentially other country specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal of consent vs. study discontinuation 
based on the protocol definitions of these terms.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
For Japan: All biological samples not yet analyzed at the time of withdrawal may still be used 
for further testing/analysis in accordance with the terms of this protocol and of the informed 
consent form.
For European Union (EU) and rest of world (RoW): All biological samples not yet analyzed at 
the time of withdrawal will no longer be used, unless permitted by applicable law. They will be 
stored according to applicable legal requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological sample, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the subject, e.g. dates 
of telephone calls, registered letters, etc. A subject should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study.
Subjects lost to follow up should be recorded as such on the appropriate Disposition eCRF.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant or unacceptable safety risk to subjects enrolled in the study


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
Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development
Should early termination be necessary, subjects should be seen as soon as possible (provide 
instruction for contacting the subject, when the subject should stop taking drug, when the 
subject should come for a final visit) and treated as a prematurely withdrawn subject. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the subject’s interests. The investigator or 
Novartis depending on the local regulation will be responsible for informing IRBs/IECs of the 
early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject completes their Cycle 39 study visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
All subjects must have safety evaluations at least 30 days (+ 3 days) after the last dose of 
ruxolitinib. During the safety follow up, adverse events, concomitant medications, transfusions, 
and monitoring of infections will be recorded. If an adverse event or a serious adverse event is 
detected, it should be followed until its resolution or until it is judged to be permanent. See 
Table 8-1 for a complete list of assessments for the 30 day follow up visit.
Data collected should be added to the Adverse Events eCRF and the Concomitant Medications 
eCRF.
Subjects who meet the protocol criteria for treatment discontinuation for any reason as 
described in Section 9.1.1 will not be eligible to continue receiving ruxolitinib within the study. 
However, where permitted by and in accordance to local laws and regulations, and as part of 
Novartis post-trial access commitment, subjects who meet all of the following criteria:

Responded (CR or PR) to ruxolitinib at Cycle 7 Day 1,

Did not meet study discontinuation criteria 

are assessed by the Investigator to still be deriving clinical benefit from ruxolitinib,
may be given the possibility to continue ruxolitinib outside the study, if requested.
Similarly, subjects who are still receiving ruxolitinib at their end of their study treatment period 
(end of Cycle 39), and are deriving clinical benefit from ruxolitinib as assessed by the 
Investigator, may be given the possibility to continue ruxolitinib outside the study as part of the 
Novartis post-trial access program, as permitted by and in accordance to local laws and 
regulations.
Subjects who remain on ruxolitinib at the end of the treatment period (end of Cycle 39) and 
obtain access to ruxolitinib outside of the study will not conduct the safety follow-up visit since 
study treatment will continue.


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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the subject’s eCRF.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 to 5, will 
be used. Information about any deaths (related to an Adverse Event or not) will also be collected 
through a Death form.
Each adverse event should be evaluated to determine:
1. The severity grade (CTCAE Grade 1 to 5)
2. Its duration (Start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported.
3. Its relationship to the study treatment (related / not related). If the event is due to lack of 
efficacy or progression of underlying illness (i.e. progression of the study indication) the 
assessment of causality will usually be ‘Not suspected’. The rationale for this guidance is 
that the symptoms of a lack of efficacy or progression of underlying illness are not caused 
by the trial drug, they happen in spite of its administration and/or both lack of efficacy and 


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progression of underlying disease can only be evaluated meaningfully by an analysis of 
cohorts, not on a single subject.
4. Action taken with respect to study treatment (dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, unknown)
5. Whether Concomitant or additional treatment given due to this adverse event (yes / no)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 10.1.2
and which seriousness criteria have been met.
7. If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 
improvement to a lower grade is determined a new entry for this event should be reported 
in the eCRF noting the start date when the event improved from having been Grade 3 or 
Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose reduced

Drug interrupted/withdrawn
The following events, which are components of study endpoints: worsening of study indication 
(cGvHD) including occurrence of cGvHD flare as defined in Section 6.1.5.2.1, relapse or 
recurrence of underlying hematologic disease (including fatal outcomes), should not be reported 
as a serious adverse event and will be reported on specific eCRFs other than AE eCRF.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 


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baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above
Note that that progression of disease (including fatal outcomes), if documented by use of 
appropriate method as per 2014 NIH response criteria (Lee et al 2015), should not be reported 
as a serious adverse event.
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a progression/relapse of 
underlying hematologic disease.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
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All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until at least 30 days after the subject has stopped study 
treatment must be reported to Novartis safety immediately, without undue delay, under no 
circumstances later than within 24 hours of learning of its occurrence.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the Novartis study treatment, a chief medical office and patient safety 
(CMO&PS) department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant Ethics Committees (ECs) in 
accordance with Directive 2011/C 172/01 or as per national regulatory requirements in 
participating countries. The following events, which are components of study endpoints: 
worsening of study indication (chronic GvHD) including occurrence of cGvHD flare, relapse 
or recurrence of underlying disease (including fatal outcomes), should not be reported as a 
serious adverse event and will be reported on specific eCRFs other than AE eCRF. Adverse 
events separate from the events listed above (example, deep vein thrombosis at the time of 
progression or hemoptysis concurrent with finding of disease progression) will be reported as 
per usual guidelines used for such events with proper attribution regarding relatedness to the
drug.


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10.1.4
Pregnancy reporting
If a female trial subject becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial subject. The subject must be given 
adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis/Sponsor within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis/Sponsor Chief 
Medical Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the 
same form and should include an assessment of the possible relationship to the investigational 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European Medicines Agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record (DAR) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an 
AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.


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10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
For liver safety monitoring guidelines, refer to Section 6.5.2.1.
10.2.2
Data Monitoring Committee
This study will include a data monitoring committee (DMC) which will be constituted prior to 
the first subject receiving investigational treatment and will function independently of all other 
individuals associated with the conduct of this clinical trial, including the site investigators 
participating in the study.
The DMC will be responsible to review safety and PK data approximately every 6 months 
during the treatment period (after the first subject has started investigational treatment) and will 
recommend to Novartis whether to continue, modify or terminate a trial.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between Novartis and the DMC.
10.2.3
Steering Committee
A Steering Committee (SC) will be established for this study. The Steering Committee will be 
established comprising investigators participating in the trial, i.e. not being members of the 
DMC or Novartis representatives from the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require, and may provide advice 
retrospectively in the evaluation of the eligibility of a subject enrolled in the study. The SC will 
review protocol amendments as appropriate. Together with the clinical trial team, the SC will 
also develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter.
11
Data Collection and Database management
11.1
Data collection
This study will use Electronic Data Capture (EDC). Designated investigator staff will enter the 
data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs have 
been built using fully validated secure web-enabled software that conforms to 21 CFR Part 11 
requirements, Investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies in the eCRFs, allow 
modification and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on eCRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.


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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Blood samples for Biomarker and PK samples and/or data will be processed centrally and the 
results will be sent electronically to Novartis as described in the Data Transfer Specification.
11.2
Database management and quality control
Novartis personnel (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical conditions 
and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
Data about all study treatments dispensed to the subject and all IRT assigned dosage changes 
will be tracked using an Interactive Response Technology. The system will be supplied by a 
vendor(s), who will also manage the database. The data will be sent electronically to Novartis 
personnel (or designated CRO).
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked and made available for data analysis. Authorization is required prior to making 
any database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development.
For EDC studies, after database lock, the investigator will receive a compact disc – read only 
memory (CD-ROM) or paper copies of the patient data for archiving at the investigational site.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis/Clinical Research Associate (CRA) organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.


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The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, current medical conditions, laboratory data, electrocardiograms, and the results of 
any other tests or assessments. All information on eCRFs must be traceable to these source 
documents in the subject’s file. The investigator must also keep the original informed consent 
form signed by the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
The final analysis will be conducted and the clinical study report (CSR) written once all subjects 
have completed the study. Analysis cut-off date will be defined corresponding to the analysis 
time point and all data captured in the study up to that cut-off will be reported. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
If the starting dose is different from the assigned dose level due to co-administration of 
ruxolitinib with strong CYP3A4 inhibitors or dual CYP3A4/CYP2C9 inhibitors, these subjects 
will be included under the assigned dose level and considered that they have received the full 
assigned dose. This applies to Full Analysis Set, Safety Set and Pharmacokinetic analysis set as 
described below.
12.1
Analysis sets
12.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
and who received at least one dose of study treatment. 
12.1.2
Safety set
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined 
as the assigned dose level of ruxolitinib if the subject took at least one dose of that treatment or 
the first dose level received if the assigned dose level was never received.
12.1.3
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) includes all subjects who provide at least one evaluable 
PK concentration. For a concentration to be evaluable, subjects are required to:

Take the dose of ruxolitinib prior to PK sample


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
For post-dose samples on Cycle 1 Day 1: do not vomit within 2 hours after the dosing of 
ruxolitinib

For pre-dose samples: have the sample collected before the next dose administration of 
ruxolitinib
12.2
Subject demographics and other baseline characteristics
Baseline is the last non-missing assessment or procedure conducted prior to or on the treatment 
start date.
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by group for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by group.
The groups are defined in Figure 3-1.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in days to ruxolitinib will be summarized by means of descriptive 
statistics. The dose intensity (computed as the ratio of actual cumulative dose received and 
actual duration of exposure) for the ruxolitinib arm will be summarized.
The number of subjects with dose adjustments and the reasons will be summarized by group 
and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system by group.
12.4
Analysis of the primary endpoint(s)
The primary objective of the proposed study is to evaluate the activity of ruxolitinib added to 
standard dose corticosteroids +/- CNI in pediatric subjects with moderate or severe treatment 
naive-cGvHD or SR-cGvHD measured by Overall Response Rate (ORR) at Cycle 7 Day 1 
based on all subjects in the study. The analysis will be performed based on FAS.
12.4.1
Definition of primary endpoint(s)
The primary efficacy variable of the study is overall response rate (ORR) at Cycle 7 Day 1, 
defined as the proportion of subjects demonstrating a complete response (CR) or partial 
response (PR), according to the NIH Consensus Criteria (Lee et al 2015). Note that response is 
relative to the assessment of cGvHD at baseline.


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
Complete response is defined as complete resolution of all signs and symptoms of 
cGvHD in all evaluable organs without initiation of any new systemic therapy.

Partial response is defined as an improvement in at least one organ (e.g. improvement of 
1 or more points on a 4 to 7 point scale, or an improvement of 2 or more points on a 10 to 
12 point scale) without progression in other organs or sites, or initiation/ addition of new 
systemic therapies.

Lack of response is defined as unchanged, mixed response, or progression. (Please refer to 
Table 8-3 and Table 16-3for the definitions of "unchanged", "mixed response" and 
"progression".)
cGvHD Flare and cGvHD Recurrence are not considered as a treatment failure, unless they 
require a change or addition of another systemic treatment defined as below.

cGvHD Flare is defined as any increase in symptoms or therapy for cGvHD after an initial 
response (CR or PR). A cGvHD flare is not considered a treatment failure unless a change 
or addition of another systemic treatment, including CNIs, occurs.

cGvHD Recurrence is defined as the return of cGvHD disease after tapering off study 
treatment due to response. Following completion of a taper of systemic therapy, if 
worsening of cGvHD symptoms occur, the patient is allowed to resume treatment for 
cGvHD as per local institutional practice. For the statistical analyses, re-start of treatment 
for cGvHD is handled in the same way as addition or initiation of new systemic treatment.
12.4.2
Statistical model, hypothesis, and method of analysis
The response rates for ORR at Cycle 7 Day 1, will be estimated on the Full Analysis Set (FAS). 
Confidence intervals of 90% will be calculated based on the exact method for binominal 
distribution. Summary statistics (frequencies and percentages) will be provided.
12.4.3
Handling of missing values/censoring/discontinuations
Subjects with missing assessments that prevent the evaluation of the primary endpoint will be 
considered as non-responders. This includes missing cGvHD assessments at baseline and Cycle 
7 Day 1.
Subjects who discontinue study treatment should return for the regular assessments indicated 
in Section 9.1. Addition or initiation of a new systemic therapy before Cycle 7 Day 1 will be 
considered a treatment failure, and subjects will be counted as non-responder in the primary 
analysis.
12.4.4
Sensitivity and Supportive analyses
Supportive analysis will include:

A detailed description of response rates (CR, PR. Unchanged, mixed response and 
progression) at Cycle 7 Day 1

A detailed description of the organ-specific response for all organs at Cycle 7 Day 1

If at least 18 subjects are enrolled with either first line vs. SR-cGvHD respectively, the ORR 
will be explored for treatment naive and SR subgroup subjects.


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12.5
Analysis of secondary endpoints
The secondary objectives in this study include the assessment of: failure free survival (FFS), 
ORR at Cycle 4 Day 1 (end of Cycle 3), duration of response, overall survival (OS), non-relapse 
mortality (NRM), best overall response (BOR), cumulative incidence of malignancy 
relapse/recurrence (MR), reduction and successful tapering of corticosteroid treatment (Cycle 
7 Day 1), pharmacokinetics, safety and graft failure.
12.5.1
Secondary efficacy objective(s)
Failure Free Survival
FFS is a composite time to event endpoint incorporating the following FFS events: i) relapse or 
recurrence of underlying disease or death due of underlying disease, ii.) non-relapse mortality, 
or iii.) addition or initiation of another systemic therapy for cGvHD.
The FFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 3, 6, 12, 18, 24 and 36 month FFS estimates and 95% confidence intervals 
(Brookmeyer and Crowley J. 1982) will be presented based on FAS.
The cumulative incidence curve of each of the three FFS components (considering the other 
two components as a competing risk) as well as estimates at 3, 6, 12, 18, 24 and 36 months will 
also be presented with 95% confidence intervals.
Best overall response (BOR)
Best overall response (BOR) is defined as proportion of subjects who achieved overall response 
(CR or PR) at any time point until Cycle 7 Day 1 or the start of additional systemic therapy for 
cGvHD.
BOR and its 90% confidence interval will be presented based on FAS.
ORR at Cycle 4 Day 1 (end of Cycle 3)
ORR (CR+PR) at Cycle 4 Day 1 and its 90% confidence interval will be presented based FAS.
Duration of Response
Duration of response (DOR) is assessed for responders only. DOR is defined as the time from 
first response until cGvHD progression, death, or the date of additional systemic therapies for 
cGvHD. Subjects without event will be censored at the last contact date. Kaplan-Meier method 
and the Kaplan-Meier curves, medians, 3, 6, 12, 18, 24 and 36 months survival probabilities 
with 95% confidence intervals will be presented based on FAS.
Overall survival (OS)
The OS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 3, 6, 12, 24 and 36 month survival probabilities and 95% confidence intervals 
(Brookmeyer and Crowley J. 1982) will be presented based on all subjects in the study.


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Non-Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time from date of treatment assignment to date of 
death not preceded by underlying disease relapse/recurrence. Cumulative incidence of NRM 
and derived probabilities at Months 1, 2, 6, 12, 18, 24 & 36 will be estimated based on all 
subjects in the study, considering underlying disease relapse/recurrence as competing events.
Incidence of Malignancy Relapse/Recurrence (MR)
The cumulative incidence curve for MR and estimates at 3, 6, 12, 18, 24 and 36 months with 
95% confidence intervals will be presented for subjects with underlying hematologic malignant 
disease, accounting for NRM as the competing risk. In addition, the proportion of subjects who 
had hematologic malignancy relapse/recurrence and its 95% confidence interval at 3, 6, 12, 18, 
24 and 36 months will be presented for subjects with underlying hematologic malignant disease.
Reduction of daily corticosteroid dose
This will be assessed by the proportion of subjects with ≥50% reduction from baseline in daily 
corticosteroid dose at Cycle 7 Day 1, based on all subjects enrolled in the study.
A sensitivity analysis of the same endpoint, to exclude dose interruption of corticosteroids due 
to AE, might be planned in the Statistical Analysis Plan (SAP) per the alignment across the 
REACH studies.
Reduction to low dose corticosteroids
This will be assessed by the proportion of subjects with reduction from baseline in daily 
corticosteroid dose to methylprednisolone-equivalent steroid dose of ≤0.2mg/kg/day (or 
equivalent dose of ≤0.25mg/kg/day prednisone or prednisolone) at Cycle 7 Day 1, based on all 
subjects enrolled in the study.
A sensitivity analysis of the same endpoint, to exclude dose interruption of corticosteroids due 
to AE, might be planned in the SAP per the alignment across the REACH studies.
Graft Failure
This will be assessed by donor cell chimerism, defined as initial whole blood or marrow donor 
chimerism for those who had ≥5% donor cell chimerism at baseline. If donor cell chimerism 
declines to <5% on subsequent measurements, graft failure is declared. The percentage of graft 
failure with 95% confidence intervals at 3, 6, 12, 18, 24 and 36 months will be presented. Case 
descriptions will be used in case of very few subjects with graft failure (e.g. less than 5 subjects).
12.5.2
Safety endpoints
For all safety analyses, the safety analysis set will be used. All listings and tables will be 
presented by group.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose of 
study medication.


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2. On-treatment period: from day of first dose of ruxolitinib to 30 days after date of last actual 
administration of assigned treatment.
3. Post-treatment period: starting at Day 31 after last dose of study medication.
For safety evaluations (except for AE), the last available assessment on or before the date of 
start of study treatment is taken as the “baseline” assessment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for (AEs) will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
12.5.2.1 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
12.5.2.2 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE version 4.03, results will be 
categorized as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and chemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE v4.03 
grades if applicable and the classifications relative to the laboratory normal ranges.
For laboratory tests where grades are defined by CTCAE v4.03:

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value.


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For laboratory tests where grades are not defined by CTCAE v4.03:

Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the analysis plan.
12.5.2.3 Vital signs
All vital signs data will be listed by group, patient, and visit/time and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by group and visit/time.
12.5.2.4 Development (Growth and sexual maturation)
Graphical displays of percentile of height and weight over time will be provided for signal 
detection of impact on growth development. In case of a signal, the following further analyses 
may be provided. 
Height and Body Mass Index (BMI) will be summarized at 6-month intervals, using the 
standard deviation scores (SDS, also called z-score), velocity and velocity SDS. SDS will be 
calculated based on published referenced height and BMI information.
Height/BMI SDS and height/weight velocity SDS will be summarized using descriptive 
statistics (mean, standard deviation, range) for each time window, as well as by presenting 
number of patients with SDS values lower/higher than 5th/95th percentiles respectively. All 
height/BMI SDS, velocity and velocity SDS data will be listed.
Sexual maturation will be monitored by Tanner staging. The age at which Tanner Stages 2 to 5 
are achieved by gender will be summarized descriptively. All tanner stage data will be listed.
12.5.3
Pharmacokinetics
Pharmacokinetic analysis set (PAS) will be used in all pharmacokinetic data analysis and PK 
summary statistics.
Pharmacokinetic variables:
Ruxolitinib concentration sparse profiles will be summarized by time point. Pharmacokinetic 
parameters, e.g. AUC0-12h and Cmax and Ctrough, will be determined using Population PK 
method(s) for ruxolitinib, and methods detailed in an independent analysis plan.
Statistical methods for pharmacokinetic analyses
Ruxolitinib concentrations data will be listed by age group and formulation. Descriptive 
summary statistics will be provided by age group/formulation at each scheduled time point. 
Summary statistics will include n (number of subjects with non-missing values), mean 
(arithmetic and geometric), standard deviation (SD), coefficient of variation (CV%) (arithmetic 
and geometric), median, minimum and maximum. Individual profiles with median by age 
group/formulation as well as arithmetic mean with SD and geometric mean ruxolitinib plasma 
concentration versus time profiles by treatment will be displayed graphically.


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Ruxolitinib plasma PK parameters data will be listed by age group/formulation. Descriptive 
statistics (n, arithmetic mean, SD, CV% for mean, geometric mean, geometric CV%, median, 
minimum and maximum) will be provided for all PK parameters by age group/formulation.
Population PK approach Concentration results from the sparse sampling will be analyzed 
using nonlinear mixed effects modeling (population PK) or other model-based approaches, as 
appropriate, and key pharmacokinetic parameters will be derived for the study population from 
sparse concentration-time data e.g. AUC, Cmax, Ctrough. Details of the analysis method will 
be developed in an independent PK analysis plan and the population PK analysis will be 
documented in a separate report.
During modeling of the pharmacokinetics of study treatment, the broad principles outlined in 
the Food and Drug Administration (FDA) guidance will be followed (Guidance for Industry: 
Population Pharmacokinetics; fda.gov/cder/guidance/1852fnl.pdf).
Exposure-Response analysis
A detailed description of exposure-response analysis will be developed in an independent 
analysis plan, and the analysis will be documented in a separate report. Briefly, the objectives 
are to:

Characterize the exposure-efficacy relationship of ruxolitinib in terms of concentration-
effect and dose-effect (effect: overall response rate at Cycle 7 Day 1; Overall survival at 
Cycle 4 Day 1, Cycle 7 Day 1 and 12 months). Exposure metrics will be described in further 
details in the analysis plan.

Characterize the exposure-safety relationship of ruxolitinib in terms of concentration-AEs 
and/or dose-AEs (AEs: frequency of AEs, severity of AEs, AEs of special interest, time to 
onset of AEs). Exposure metrics will be described in further details in the analysis plan

Exposure-Biomarker – immune cell subsets, inflammatory cytokine levels and soluble 
cGvHD biomarkers
12.5.3.1 Data handling principles
Plasma concentration values below the limit of quantification (BLQ) will be set to zero by the 
Bioanalyst, and will be displayed as zero in the listings and flagged. BLQ values will be treated 
as zero in any calculations of summary statistics, and treated as missing for the calculation of 
the geometric means and their coefficient of variation (CV%).
Any missing concentration will not be imputed.
12.5.4
Biomarkers
Since this clinical trial was not designed to address specific biomarkers-related hypotheses, the 
analysis of this data should be viewed as exploratory and hypotheses generating.
Circulating levels of bone biomarkers, GvHD markers, immune cell markers and cytokines will 
be assessed with time to evaluate the impact ruxolitinib over time. Some of the disease linked 
biomarkers will also be assessed for the impact of ruxolitinib on the disease.
Additional analyses that may be performed after the completion of the end-of-study CSR will 
be documented in separate reports. These analyses may include but are not limited to the meta-


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analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in an addendum of the 
SAP or in a stand-alone analysis plan document, as appropriate.
While the goal of the biomarkers is to provide supportive data for the clinical study, there may 
be circumstances when a decision is made to stop a sample collection, or not perform or 
discontinue the analysis of blood due to either practical or strategic reasons (e.g., issues related 
to the quality and or quantity of samples, or issues related to the assay that preclude the analysis 
of samples). Under such circumstances, the number of samples may be inadequate to perform 
a rigorous data analysis and the available data will only be listed.
12.5.4.1 Outline of the data analysis
In general, continuous variables will be summarized using means, medians, quartiles, standard 
deviations, minimums, and maximums. Categorical variables will be summarized using 
frequency counts and percentages. Analysis may be presented be presented overall (combining 
both cohorts) or by cohorts. Data transformations (e.g., log transformation) may be applied as 
appropriate in order to summarize and analyze the data adequately.
12.5.4.2 Data handling principles
Relevant aspects of data handling will be addressed in the SAP.
12.5.4.3 Data analysis principles
12.5.4.3.1
Analysis sets
The FAS will be used unless otherwise specified (e.g. for associations with safety end-points 
the safety analysis set will be used).
12.5.4.3.2
Basic tables, figures and listings
Levels and changes from baseline will be summarized at each visit for each continuous 
biomarker (e.g., immune cell characterization, cytokines, cGvHD biomarkers, bone 
biomarkers) when it is measured. Both absolute change and relative change will be tabulated. 
In addition, a longitudinal plot of the average change over time (mean +/- standard error of 
mean) will be produced for each biomarker in order to assess dynamic changes in the biomarker 
over time.
In order to assess the PD relationship between biomarker changes and PK parameters scatter 
plots for each post-baseline visit may be produced. The relationship between efficacy (e.g. 
response) and biomarker changes over time will be examined through strip plots for each post-
baseline visit.
The relationship between time-to event efficacy end-points (e.g., OS) and biomarker (baseline 
status; categorized baseline level or change from baseline) may also be examined through 
Kaplan-Meier plots. All biomarker data will be listed.
Details of tables, figures and listings will be described in the SAP.


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12.6
Analysis of exploratory endpoints
The data analysis for the following exploratory objectives will be described in an addendum of 
the Statistical Analysis Plan or in a stand-alone analysis plan document, as appropriate:

To evaluate effect of ruxolitinib on cytokines, cGvHD biomarkers and immune cell subset

To evaluate effect of ruxolitinib on markers of bone development in pediatric subjects

To evaluate systemic corticosteroid-free response rate.
12.6.1
Acceptability and Palatability assessment
All acceptability and palatability assessment data will be listed by group and subjects.
12.7
Interim analyses
In order to summarize one year of safety data, in addition to the primary efficacy analysis, an 
interim CSR will be reported when all subjects have completed 1 year of treatment or 
discontinued earlier. The final analysis will be performed and the final CSR produced after all 
subjects have discontinued from the study.
Since the data for the primary efficacy assessment, ORR at Cycle 7 Day 1, will already be final 
once all subjects have completed 6 months of treatment, and in this clinical trial it is not planned 
to test specific hypotheses related to the efficacy endpoint(s), but to provide estimates of 
efficacy endpoints, no alpha adjustment will be made for the analysis of the primary endpoint.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
The sample size for the primary objective of measuring ORR at Cycle 7 Day 1 is approximately
42 subjects, regardless of age.
The sample size calculation is based on the ORR at Cycle 7 Day 1, and the calculation will 
consider the Saw-Toothed behavior of power waving for single binomial proportion using an 
exact method (Chernick and Liu 2002 ; Published online: 01 Jan 2012). Considering the 
response rate of children using corticosteroids is 30% to 50% (Wolff et al 2011), we assume the 
true ORR at Cycle 7 Day 1 of the study population is 70%, and therefore, a minimum sample 
size of 42 subjects would provide >80% probability to have a 90% CI with lower limit ≥ 50%. 
Table 12-1 provides estimates of the probability to have a 90% CI with lower limit ≥ 50%, 
minimum number of responders required and two-sided 90% Clopper-Pearson CIs for various 
sample sizes.
Table 12-1
Probability to have a 90% CI with lower limit ≥ 50% and 90% 
confidence intervals for different number of subjects
Sample size
Minimum No. 
of responders
Response 
Rate
Probability to 
have a 90% CI 
with lower 
limit ≥ 50%
90% CI
30
20
0.67
0.730
0.501
0.807
31
21
0.68
0.688
0.515
0.813
32
22
0.69
0.644
0.528
0.820


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Sample size
Minimum No. 
of responders
Response 
Rate
Probability to 
have a 90% CI 
with lower 
limit ≥ 50%
90% CI
33
22
0.67
0.733
0.509
0.801
34
23
0.68
0.693
0.522
0.807
35
23
0.66
0.773
0.504
0.789
36
24
0.67
0.737
0.517
0.795
37
24
0.65
0.807
0.500
0.778
38
25
0.66
0.774
0.512
0.784
39
26
0.67
0.740
0.523
0.790
40
26
0.65
0.807
0.508
0.774
41
27
0.66
0.776
0.519
0.780
42
27
0.64
0.836
0.505
0.765
43
28
0.65
0.808
0.515
0.771
44
28
0.64
0.861
0.501
0.757
45
29
0.64
0.836
0.511
0.763
46
30
0.65
0.809
0.521
0.768
47
30
0.64
0.860
0.508
0.755
48
31
0.65
0.836
0.517
0.760
49
31
0.63
0.881
0.505
0.747
50
32
0.64
0.859
0.514
0.753
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.


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13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last subject last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.


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Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
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Flowers ME, Martin PJ (2015) How we treat chronic graft-versus-host disease. Blood; p. 606-
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health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow 
Transplant Survivor Study. Blood; 108(8), pp.2867-2873.
Frémond ML, Rodero MP, Jeremiah N, et al (2016) Efficacy of the Janus kinase 1/2 inhibitor 
ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations 
in 3 children. J. Allergy Clin. Immunol; p. 1752-1755.
Greinix HT, Loddenkemper C, Pavletic SZ, et al (2011) Diagnosis and staging of chronic 
graft-versus-host disease in the clinical practice. Biology of Blood and Marrow 
Transplantation; 17(2), pp.167-175.
Heine A, Held SA, Daecke SN, et al (2013) The JAK-inhibitor ruxolitinib impairs dendritic 
cell function in vitro and in vivo. Blood; pp.blood-2013.
Jagasia MH, Greinix HT, Arora M, et al (2015) National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. 
The 2014 Diagnosis and Staging Working Group report. Biology of Blood and Marrow 
Transplantation; 21(3), pp.389-401.
Jagasia M, Perales MA, Schroeder MA, et al. (2020) Ruxolitinib for the treatment of steroid-
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135(20):17391749. 
Kaufman GP, Aksamit AJ, Klein CJ, et al (2014) Progressive multifocal 
leukoencephalopathy: a rare infectious complication following allogeneic hematopoietic cell 
transplantation (HCT). European journal of haematology; 92(1), pp.83-87.
Khandelwal P, Teusink-Cross A, Davies SM, et al (2017) Ruxolitinib as Salvage Therapy in 
Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell 
Transplant Patients. Biol. Blood Marrow Transplant; p. 1122-1127.
Khoury HJ, Langston AA, Kota VK, et al (2018) Ruxolitinib: a steroid sparing agent in 
chronic graft-versus-host disease. Bone Marrow Transplant; 126(23): p.1938.
Lee JH, Lee JH, Choi SJ, et al (2003) Graft-versus-host disease (GVHD)-specific survival and 
duration of systemic immunosuppressive treatment in patients who developed chronic GVHD 
following allogeneic haematopoietic cell transplantation. British journal of haematology; 
122(4), pp.637-644.


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Lee SJ, Flowers ME (2008) Recognizing and managing chronic graft-versus-host disease. 
ASH Education Program Book; 2008(1), pp.134-141.
Lee SJ, Wolff D, Kitko C, et al (2015) 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. Biology of Blood and Marrow Transplantation; 21(6), pp.984-999.
Loh ML, Tasian SK, Rabin KR, et al (2015). A phase 1 dosing study of ruxolitinib in children
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Children's Oncology Group phase 1 consortium study (ADVL1011). Pediatric blood & 
cancer; 62(10), pp.1717-1724.
Mahmood I (2014) Dosing in children: a critical review of the pharmacokinetic allometric 
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Pharmacokinet; p. 327-46.
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The 2014 Clinical Trial Design Working Group Report. Biology of Blood and Marrow 
Transplantation; 21(8), pp.1343-1359.
Mohty B, Mohty M (2011) Long-term complications and side effects after allogeneic 
hematopoietic stem cell transplantation: an update. Blood cancer journal; 1(4), p.e16.
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51(6), p.778.
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validation of NIH response criteria in 39 patients receiving imatinib for steroid-refractory 
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Transplant Recipients: A Population-Based Cohort Study. JAMA dermatology; 152(2), 
pp.177-183.
Paczesny S, Hanauer D, Sun Y, et al (2010). New perspectives on the biology of acute 
GVHD. Bone marrow transplantation; 45(1), p.1.
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pp.374-384.
Sorror ML, Maris MB, Storb R, et al (2005) Hematopoietic cell transplantation (HCT)-
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Zecca M, Prete A, Rondelli R, et al (2002) Chronic graft-versus-host disease in children: 
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Disease. N Engl J Med; 382:1800-1810


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16
Appendices
16.1
Appendix 1: Infection Severity Grading
Table 16-1
Infection severity grading table and recurrence interval definitions
Type of Infection/ 
Severity Grade
Grade 1
Grade 2
Grade 3
Bacterial infections
Bacterial focus NOS 
requiring no more than 
14 days of therapy for 
treatment (e.g urinary 
tract infection)
Bacteremia,except 
Coagulase-Negative 
Staphylococci (CoNS) 
without severe sepsis ***
Bacteremia with deep 
organ involvement (e.g. 
with new or worsening 
pulmonary infiltrates; 
endocarditis)
Coag Neg Staph (S. epi), 
Corynebacterium, or 
Proprioniobacterium 
bacteremia
Bacterial focus with 
persistent signs, 
symptoms or persistent 
positive cultures requiring 
greater than 14 days of 
therapy
Severe sepsis with 
bacteremia.
Cellulitis responding to 
initial therapy within 14 
days
Cellulitis requiring a 
change in therapy due to 
progression Localized or 
diffuse infections 
requiring incision with or 
without drain placement
Fasciitis requiring 
debridement
Any pneumonia 
documented or presumed 
to be bacterial
Pneumonia requiring 
intubation
Brain abscess or 
meningitis without 
bacteremia
C. Difficile toxin positive 
stool with diarrhea < 1L 
without abdominal pain 
(child < 20 mL/kg)
C. Difficile toxin positive 
stool with diarrhea > 1L 
(child > 20 mL/kg) or with 
abdominal pain
C. Difficile toxin positive 
stool with toxic dilatation 
or renal insufficiency 
with/without diarrhea
Fungal infections
Superficial candida 
infection (e.g. oral thrush, 
vaginal candidiasis)
Candida esophagitis 
(biopsy proven).
Fungemia including 
Candidemia
Proven or probable 
fungal sinusistis 
confirmed radiologically 
without orbital, brain or 
bone involvement.
Proven or probable 
invasive fungal infections 
(e.g., Aspergillus, Mucor, 
Fusarium, 
Scedosporium).
Fungal infections 
(continued)
Disseminated infections 
(defined as multifocal 
pneumonia, presence of 
urinary or blood antigen, 
and/or CNS involvement) 
with Histoplasmosis, 
Blastomycosis, 
Coccidiomycosis, or 
Cryptococcus.
Pneumocystis jiroveci
pneumonia (regardless of 
partial pressure of 
oxygen (PaO2) level)


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Type of Infection/ 
Severity Grade
Grade 1
Grade 2
Grade 3
Viral infections
Mucous HSV infection
Dermatomal Zoster
VZV infection with 3 or 
more dermatomes
Severe VZV infection 
(coagulopathy or organ 
involvement)
Asymptomatic CMV 
viremia untreated or a 
CMV viremia with viral 
load decline by at least 
2/3 of the baseline value 
after 2 weeks of therapy
Clinically active CMV 
infection (e.g. symptoms, 
cytopenias) or CMV 
Viremia not decreasing 
by at least 2/3 of the 
baseline value after 2 
weeks of therapy
CMV end-organ 
involvement 
(pneumonitis, enteritis, 
retinitis)
EBV reactivation not
treated with rituximab
EBV reactivation 
requiring institution of 
therapy with rituximab
EBV Post-Transplant 
Lymphoproliferative 
Disorder (PTLD)
Adenoviral conjunctivitis 
asymptomatic viruria, 
asymptomatic stool 
shedding and viremia not 
requiring treatment
Adenoviral upper 
respiratory infection, 
viremia, or symptomatic 
viruria requiring treatment
Adenovirus with end-
organ involvement 
(except conjunctivitis and 
upper respiratory tract)
Asymptomatic HHV-6 
viremia untreated or an 
HHV-6 viremia with a 
viral load decline by at 
least 0.5 log after 2 
weeks of therapy
Clinically active HHV-6 
infection (e.g. symptoms, 
cytopenias) or HHV-6 
viremia without viral load 
decline 0.5 log after 2 
weeks of therapy
Polyoma BK Virus (BK) 
viremia or viruria with 
cystitis not requiring 
intervention
BK viremia or viruia with 
clinical consequence 
requiring prolonged 
therapy and/or surgical 
intervention
Viral infections 
(continued)
Enterocolitis with enteric 
viruses
Symptomatic upper tract 
respiratory virus
Lower tract respiratory 
viruses
Viremia (virus not 
otherwise specified) not 
requiring therapy
Any viremia (virus not 
otherwise specified) 
requiring therapy
Any viral encephalitis or 
meningitis
Parasitic infections
CNS or other organ 
toxoplasmosis
Strongyloides 
hyperinfection
Nonmicrobiologically 
defined infections
Uncomplicated fever with 
negative cultures 
responding within 14 
days
Clinically documented 
infection not requiring 
inpatient management
Pneumonia or 
bronchopneumonia not 
requiring mechanical 
ventilation
Any acute pneumonia 
requiring mechanical 
ventilation
Typhlitis
Severe sepsis*** without 
an identified organism


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Type of Infection/ 
Severity Grade
Grade 1
Grade 2
Grade 3
*Concomitant or multimicrobial infections are graded according to the grade of the infection with the higher 
grade of severity.
**Therapy includes both oral (PO) and intravenous (IV) formulations :
Adults:
Hypotension

A systolic blood pressure of <90 mm Hg or a reduction of >40 mm hg from baseline in the 
absence of other causes for hypotension.
Multiple Organ Dysfunction Syndrome

2 or more of the following: Renal failure requiring dialysis, respiratory failure requiring 
bipap or intubation, heart failure requiring pressors, liver failure.
Pediatrics:

Pediatric systemic inflammatory response syndrome (SIRS) definition and suspected or 
proven infection and cardiovascular dysfunction or acute respiratory distress syndrome 
(ARDS) or TWO or MORE other organ dysfunctions.
Pediatric SIRS definition:
Two or more of the following, one of which must be abnormal temperature or leukocyte count
1. Core temperature >38.5°C or < 36°C .
2. Tachycardia, otherwise unexplained persistent in absence of external stimulus, chronic 
drugs or painful stimuli. or bradycardia, in < 1 year old, otherwise unexplained persistent.
3. Tachypnea or mechanical ventilation for an acute process not related to underlying 
neuromuscular disease or general anesthesia.
4. Leukocytosis or leukopenia for age (not secondary to chemotherapy) or >10% bands.
Pediatric organ dysfunction criteria:
Cardiovavascular: despite administration of fluid bolus >40 mL/kg in 1 hour:

Hypotension <5th percentile for age

Pressors at any dose

Two of the following:

Capillary refill > 5 secs

Core to peripheral temperature gap > 3°C

Urine output < 0.5 mL/kg/hr

Unexplained metabolic acidosis (Base deficit > 5.0 mEq/L)

Blood lactate > 2 x ULN
Respiratory:

ARDS or


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
Intubated or

>50% fractioned of inspired oxygen (FiO2) to maintain oxygen saturation (SaO2) > 92%
Neurological:

Glasgow Coma Score (GCS) < 11 or

Acute change in mental status with a decrease in GCS >3 pts from abnormal baseline
Renal:

Serum creatinine > 2 x ULN for age or 2-fold increase in baseline creatinine
Hepatic:

Total bilirubin > 4 mg/dL or

ALT >2 x ULN for age
Table 16-2
Four age groups relevant to HCT
Age
Tachycardia 
(beats per 
minute)
Bradycardia 
(beats per 
minute)
Tachypnea 
(breaths/min)
Leukocytosis / 
Leukopenia 
(WBC)
Hypotension 
Systolic Blood 
Pressure 
(mmHg)
1 mo to 1 yr
>180
<90
>34
>17.5 to <5.0
<100
2 yr to 5 yr
>140
NA
>22
>15.5 to <6.0
<94
6 yr to 12 yr
>130
NA
>18
>13.5 to <4.5
<105
13 yr to < 18 yr
>110
NA
>14
>11 to <4.5
<117
Disseminated Infections:
1. Two or more non-contiguous sites with the SAME organism.
2. A disseminated infection can occur at any level of severity, but most will be grade 2 or 3.
Recurrence Intervals to Determine Whether an Infection is the Same or New:
1. CMV, HSV, EBV, HHV-6: 2 months (< 60 days)
2. VZV, Herpes Zoster Virus (HZV): 2 weeks (< 14 days)
3. Bacterial, non-C. difficile: 1 week (< 7 days)
4. Bacterial, C. difficile: 1 month (< 30 days)
5. Yeast: 2 weeks (< 14 days)
6. Molds: 3 months (< 90 days)
7. Helicobacter: 1 year (< 365 days)
8. Adenovirus, Enterovirus, Influenza, Respiratory Syncytial Virus (RSV), Parainfluenza, 
Rhinovirus: 2 weeks (< 14 days)
9. Polyomavirus (BK virus): 2 months (< 60 days)
For infections coded as “Disseminated” per the Infection Form, any previous infection with the 
same organism but different site within the recurrence interval for that organism will be counted 
as part of the disseminated infection.
Not applicable (NA)
BMT Clinical Trials Network (2013)




















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16.4.2.1 Liver
Liver response assessment is based on the following chemistry lab parameters: Alanine 
aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (BILI). All three liver 
parameters must be obtained in order for the liver to be assessed.
Observed lab values and corresponding ULN at baseline should be documented. Observed post-
baseline values will be compared to observed baseline values in order to determine the liver 
response for the post-baseline visit. The steps to apply the rules per NIH criteria and some 
examples are displayed in Figure 16-1, Figure 16-2 and Figure 16-3.
Example 1 (Figure 16-2):

At baseline ALT and AP are increased (> ULN) and BILI is within the normal range.

At the post-baseline visit ALT and BILI are within the normal ranges and the value of AP 
decreased from baseline by 56%: Therefore, the liver response for this visit is assessed as 
‘partial response (PR)’.
Example 2 (Figure 16-3):

At baseline Alkaline Phosphatase (AP) is increased (> ULN), whereas ALT and BILI are 
within the normal range.

At the post-baseline visit all 3 parameters are increased (> ULN) but the absolute increase 
for each of the parameters is less than the corresponding value of 2 x ULN. Therefore, the 
Week 4 liver response is considered as ‘unchanged’ from baseline.
Table 16-3
Response determination for chronic GvHD by organ at post-baseline 
assessment (comparison vs. baseline)
Organ
Complete 
response1
Partial 
response1
Progression1
No involvement/unchanged
Baseline
Post-baseline
Skin
NIH Skin Score 
0 after previous 
involvement
Decrease in 
NIH Skin Score 
by 1 or more 
points
Increase in NIH 
Skin Score by 1 
or more points, 
except 0 to 1
Score = 0
Score = 0 or 1
Equal Scores at both time points
Eyes
NIH Eye Score 
0 after previous 
involvement
Decrease in 
NIH Eye Score 
by 1 or more 
points
Increase in NIH 
Eye Score by 1 
or more points, 
except 0 to 1
Score = 0
Score = 0 or 1
Equal Scores at both time points
Mouth
NIH Modified 
OMRS 0 after 
previous 
involvement
Decrease in 
NIH Modified 
OMRS of 2 or 
more points
Increase in NIH 
Modified OMRS 
of 2 or more 
points
Equal OMRS at both time points 
(including Score=0) or change of 
OMRS from baseline less than 2 
points
Esophagus
NIH Esophagus 
Score 0 after 
previous 
involvement
Decrease in 
NIH Esophagus 
Score by 1 or 
more points
Increase in NIH 
Esophagus 
Score by 1 or 
more points, 
except 0 to 1
Score = 0
Score = 0 or 1
Equal Scores at both time points
Upper GI
NIH Upper GI 
Score 0 after 
previous 
involvement
Decrease in 
NIH Upper GI 
Score by 1 or 
more points
Increase in NIH 
Upper GI Score 
by 1 or more 
points, except 0 
to 1
Score = 0
Score = 0 or 1
Equal Scores at both time points
Lower GI
Score = 0
Score = 0 or 1


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Organ
Complete 
response1
Partial 
response1
Progression1
No involvement/unchanged
Baseline
Post-baseline
NIH Lower GI 
Score 0 after 
previous 
involvement
Decrease in 
NIH Lower GI 
Score by 1 or 
more points
Increase in NIH 
Lower GI Score 
by 1 or more 
points, except 
from 0 to 1
Equal Scores at both time points
Liver
Normal ALT, 
alkaline 
phosphatase, 
and Total 
bilirubin after 
previous 
elevation of 1 or 
more
Decrease by 
50%
Increase by 2 x 
ULN
See text
Lungs2
Normal %FEV1 
after previous 
involvement
If PFTs not 
available, NIH 
Lung Symptom 
Score 0 after 
previous 
involvement
Increase by 
10% predicted 
absolute value 
of %FEV1 If 
PFTs not 
available, 
decrease in NIH 
Lung Symptom 
Score by 1 or 
more points
Decrease by 
10% predicted 
absolute value 
of %FEV1
If PFTs not 
available, 
increase in NIH 
Lung Symptom 
Score by 1 or 
more points, 
except 0 to 1
Change of %FEV1 from baseline < 
10% (see text for additional rules)
If PFTs not available,
Score = 0
Score = 0 or 1
Equal scores at both time points
Joints and 
fascia
Both NIH Joint 
and Fascia 
Score 0 and P-
ROM score 25 
after previous 
involvement by 
at least 1 
measure
Decrease in 
NIH Joint and 
Fascia Score by 
1 or more 
points or 
increase in P-
ROM score by 
1 point for any 
site
Increase in NIH 
Joint and 
Fascia Score by 
1 or more 
points or 
decrease in P-
ROM score by 
1 point for any 
site
J&F Score=0 
and P-ROM 
Score=25
J&F Score=0 
and P-ROM 
Score=25
Any situation that does not qualify 
for response or progression (see 
text)
1 response definition as per Table 4 in the published NIH criteria, see Lee et al 2015, ULN indicates upper limit 
of normal.
2 Lung response assessment is determined based on an improvement (e.g. 50% to 60%) or worsening (e.g. 
50% to 40%) in %FEV1 of 10% or more predicted absolute value. 








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16.4.2.3 Joints and fascia
NIH Joint and Fascia score as well as photographic range of motion (P-ROM) score are 
evaluated.
Involvement at baseline is defined as NIH Joint and Fascia score ≥ 1
A decrease (i.e. worsening) of any site in P-ROM is considered as progression (irrespective of 
the change in the NIH Joints and Fascia score). Similarly, an increase (worsening) in the NIH 
Joints and Fascia score is considered as progression (irrespective of the change in any of the 4 
P-ROMs)
Accordingly, a partial response is only possible if:

at least one site in P-ROM increased by 1 or more points

and all other sites remain unchanged compared to baseline

and NIH Joints and Fascia score is equal to or decreased from baseline
OR

Decrease of the NIH Joints and Fascia Score from baseline with NO worsening in P-ROM 
for any site
Example for progression
Baseline
Post-baseline
NIH Joints and Fascia 
Score
1
1
equal
P-ROM
Shoulder
6
6
equal
Elbow
6
5
decrease
Wrist/finger
6
6
equal
Ankle
3
4
increase
TOTAL
21
21
Example for partial response
Baseline
Post-baseline
NIH Score
1
1
equal
P-ROM
Shoulder
6
6
equal
Elbow
6
6
equal
Wrist/finger
6
6
equal
Ankle
3
4
increase
TOTAL
21
22
Photographic Range of Motion (P-ROM)




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Total BSA 
involved (%)
Score %BSA
Sclerotic 
involvement?
Type of 
sclerotic 
involvement
Skin feature 
score
Skin Score1
19% to 50%
2
yes
Superficial only 
(able to pinch)
2
2
19% to 50%
2
yes
Unable to 
pinch
(“Hidebound”) 
Deep sclerotic 
features 
Impaired 
mobility 
Ulceration
3
3
More than 50%
3
no
NA
0
3
More than 50%
3
yes
Superficial only 
(able to pinch)
2
3
More than 50%
3
yes
Unable to 
pinch
(“Hidebound”) 
Deep sclerotic 
features 
Impaired 
mobility 
Ulceration
3
3
1 Overall skin score to be used for the response assessment taken as worst of Score for %BSA and Skin 
feature score
NA = not applicable
16.4.3
Efficacy Assessments - Overall response assessment at one time 
point
Following the NIH working group recommendations the overall response evaluation (at each 
scheduled post-baseline time point/assessment) will be based on the evaluations for skin, eyes, 
mouth, esophagus, upper GI, lower GI, liver, lungs and joints/fascia. For each post-baseline 
assessment comparison will be made to baseline (C1D1).

Complete response is defined as complete resolution of all signs and symptoms of cGvHD 
in all evaluable organs without addition of new systemic therapy, including CNIs.

Partial response is defined as an improvement in at least one organ (e.g. improvement of 1 
or more points on a 4 to 7 point scale, or an improvement of 2 or more points on a 10 to 12 
point scale) without progression in other organs or sites, or initiation/addition of new 
systemic therapies.

Lack of response is defined as unchanged, mixed response, or progression.

Progression is defined as worsening of at least one organ and no improvement (CR or PR) 
in any other organ.

Mixed response is a CR or PR in at least 1 organ accompanied by progression in another 
organ.

Unchanged response is defined as stable disease or absence of improvement in any organ 
involved by cGvHD.


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cGvHD Flare: is defined as any increase in symptoms or therapy for cGvHD after an initial 
response (CR or PR). A cGvHD flare is not considered a treatment failure unless a change of 
therapy or addition of another systemic treatment, including CNIs, occurs.
cGvHD Recurrence is defined as the return of cGvHD disease after tapering off study treatment 
due to response. Following completion of a taper of systemic therapy, if worsening of cGvHD 
symptoms occur, the patient is allowed to resume treatment for cGvHD as per local institutional 
practice. For the statistical analyses re-start of treatment for cGvHD is handled in the same way 
as addition or initiation of new systemic treatment.
Table 16-5 summarizes the rules for overall response assessment based on organ-specific 
evaluations at a scheduled post-baseline visit (e.g. the primary endpoint at Month 6 – Cycle 7 
Day 1).
Table 16-5
Overall response evaluation
Organ-specific response1
Skin
CR / not involved
PR or CR in at 
least one organ 
with baseline 
involvement 
AND no 
progression in 
any other organ 
(i.e. CR, PR, 
unchanged, no 
involvement), 
assuming 
overall CR has 
not been 
achieved
PR or CR in 
one or more 
organ(s) with 
baseline 
involvement 
AND 
progression in 
one or more 
organs (incl. 
new occurrence 
in an organ with 
no baseline 
involvement)
Progression in 
one or more 
organ(s) with 
baseline 
involvement OR 
new occurrence 
in an organ with 
no baseline 
involvement 
AND no CR or 
PR in any other 
organ
Organ-specific 
response 
‘unchanged’ for 
all organs (incl. 
no 
involvement )
Eyes
CR / not involved
Mouth
CR / not involved
Esophagus
CR / not involved
Upper GI
CR / not involved
Lower GI
CR / not involved
Liver
CR / not involved
Lungs
CR / not involved
Joints and 
fascia
CR / not involved
Overall 
response
CR
PR
Mixed 
response
Progression
Unchanged 
response
1 at least one organ must be involved at baseline. Organ-specific response versus baseline status.
Source: Lee S, 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. 2015:984-999
16.5
Appendix 5: HCT-Specific Comorbidity Index Score
Table 16-6
HCT-Specific Comorbidity Index Score
Comorbidities
Definition
Score
Migraine/headache
0
Osteoporosis
0
Osteoarthritis
0
Hypertension
0
Gastrointestinal
Including inflammatory bowel disease
0
Mild pulmonary
DLCO and/or FEV1 > 81-90% or Dyspnea on moderate activity
0
Mild renal
Serum creatinine 1.2-2 mg/dL
0
Endocrine
0


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Comorbidities
Definition
Score
Bleeding
0
Coagulopathy
Deep venous thrombosis or pulmonary embolism
0
Asthma
0
Arrhythmia
1
Myocardial
Coronary artery disease, congestive heart failure, history of medically 
documented myocardial infarction, EF ≤50%
1
Mild hepatic
Chronic hepatitis, bilirubin > ULN to 1.5 x ULN, or AST/ALT > ULN to 
2.5 x ULN
1
Cerebro-vascular 
accident
History of transient ischemic attack or cerebro-vascular accident
1
Morbid obesity
1
Diabetes
Hypoglycemic but not diet alone
1
Depression/anxiety
1
Infection
Requiring continuation of antibacterial treatment after day 0
1
Rheumatologic
SLE, RA, polymyositis, mixed CTD, polymyalgia rheumatica
2
Moderate pulmonary
DLCO and/or FEV1 66% to 80% or Dyspnea on slight activity
2
Peptic ulcer
subjects who have required treatment
2
Moderate-severe renal
Serum creatinine > 2 mg/dL, on dialysis, or prior renal transplantation
2
Valvular heart disease
Except mitral valve prolapse
3
Prior solid tumor
Treated at any time in the subject’s past history, excluding non-
melanoma skin cancer
3
Moderate-severe hepatic
Liver cirrhosis, Bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN
3
Severe pulmonary
DLCO and/or FEV1 ≤ 65% or Dyspnea at rest or requiring oxygen
3
Source: Sorror et al 2005
Total score is the sum of all comorbidities present at time of transplantation.
AST: aspartate aminotransferase; ALT; alanine aminotransferase; CTD: connective tissue 
disease; DLCO: diffusing capacity of the lung for carbon monoxide; EF: ejection fraction; 
FEV1: forced expiratory volume in 1 second; RA: rheumatoid arthritis; SLE: systemic lupus 
erythematosus; ULN: upper limit of normal.


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16.6
Appendix 6: CIBMTR Classification
Table 16-7
CIBMTR disease risk index
ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
AML and ALL precursor B-
lymphoblastic lymphoma/leukemia 
(per WHO reclassified from 
lymphoma) precursor T-
lymphoblastic lymphoma/leukemia
Low risk: CR 1
First complete remission (CR1):A treatment 
response where all of the following criteria are 
met for at least four weeks*†: Hematological: no 
blast cells in the peripheral blood, < 5% blasts in 
the bone marrow, no blasts with Auer rods (AML 
only), normal maturation of all cellular 
components in the marrow, normal CBC and ANC 
of > 1,000/µL Platelets ≥ 100,000/µL*† 
Transfusion independent No other signs or 
symptoms of disease, including extramedullary 
disease (e.g., central nervous system or soft 
tissue involvement) Include recipients with 
persistent cytogenetic abnormality who otherwise 
meet all the criteria of CR. CIBMTR collects 
information about cytogenetic and molecular 
testing for those in CR (hematologic CR), 
however these are only relevant for RFI reporting 
in as much as the center’s judge importance of 
residual cytogenetic abnormalities in determining 
current status beyond the hematic criteria. *In 
some cases, there may not be a four-week 
interval between the completion of treatment for 
disease and the disease assessment immediately 
prior to the HSCT. If this is the case, CR should 
still be reported as the status at transplantation. 
Although this is an exception to the general 
condition that CR is “durable” beyond four weeks, 
the status of CR represents the “best 
assessment” prior to HSCT. Similarly, sufficient 
time may not have elapsed to allow for platelet 
recovery to normal levels and physician judgment 
is required to interpret whether residual low 
platelet counts may reflect residual disease. 
NOTE: Recipients with MDS that transformed to 
AML If the recipient has residual MDS following 
treatment for AML, report the AML disease status 
as either PIF or relapse (i.e., the recipient cannot 
be in an AML CR if there is evidence of MDS at 
the time of assessment).
AML and ALL (con‟t)
Intermediate risk:
CR2, CR3+
Complete remission 2nd or greater (CR2/+)†: 
Recipient achieved CR as defined above, 
relapsed and achieved CR again. Final pre-HSCT 
status must be CR.


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ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
AML and ALL (con‟t)
High risk (not in 
remission): Never 
treated Primary 
Induction Failure
(PIF) Relapse
Never treated: The recipient was diagnosed with 
acute leukemia and never treated. For example, 
this disease status may be appropriate if MDS 
was initially diagnosed and treated, the MDS then 
transformed into AML, and a decision was made 
to proceed immediately to transplant instead of 
treating the AML with therapy. Primary Induction 
Failure (PIF): The recipient was treated for acute 
leukemia but never achieved durable* complete 
remission with any therapy (*including relapsed 
<1 mo from CR1 determination). The term “PIF” is 
not limited to the number of treatments used 
unsuccessfully. Relapse: Recurrence of disease 
after CR. Relapse is defined as: ≥ 5% blasts in 
the marrow Extramedullary disease 
Reappearance of cytogenetic abnormalities 
and/or molecular markers associated with the 
diagnosis that, in the judgement of a physician, 
are at a level representing relapse. Although 
CIBMTR collects information upon the number of 
the relapse, this information is not needed for the 
ASBMT RFI
CML
Low risk:
Hematologic CR1 
CP1
Hematologic CR 1 deriving from first Chronic 
Phase (never in AP or BP). A treatment response 
where all of the following criteria are met: White 
blood count is less than 10 x 109/L, without 
immature granulocytes and with less than 5% 
basophils Platelet count less than 450 x 109/L 
Non-palpable spleen First chronic phase (CP1):
Recipient was in chronic phase from diagnosis to 
the start of the preparative regimen, never in AP 
or BP. Characterized by: Relatively few blasts 
(<10%) present in the blood and bone marrow. 
Symptoms are often not present. The chronic 
phase may last several months to years 
depending on the individual recipient and the 
treatment received. Although CIBMTR collects 
additional information regarding cytogenetic and 
molecular response, this information is not 
needed to complete the RFI.
CML (con’t)
Intermediate risk:
CP2 Hematologic 
CR2 Hematologic 
CR deriving from AP 
or BP AP1
Second chronic phase (CP2): Recipient had one 
AP or BP (see BP definition in high risk group) 
and was treated back into CP or hematologic CR. 
Hematologic CR2: A hematologic CR occurring 
after treatment for progression from a first 
hematologic CR (eg hematologic CR, progress to 
CP/AP or BP, then treated back into hematologic 
CR). Hematologic CR deriving from AP or BP: 
Hematologic CR occurring after treatment for a 
single previous episode of AP or BP. Accelerated 
Phase 1 (AP1): One or more of the following 
must be present (WHO definition): 10% to 19% 
blasts in blood or marrow ≥ 20% basophils in 
peripheral blood Clonal cytogenetic abnormalities 
in addition to the single Philadelphia chromosome 
(clonal evolution) Increasing spleen size, 
unresponsive to therapy Increasing WBC, 
unresponsive to therapy Thrombocytopenia 


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ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
(platelets < 100,000) unrelated to therapy 
Thrombocytosis (platelets > 1,000,000) 
unresponsive to therapy
CML (con’t)
High risk: CP3/+, 
Hematologic CR3/+ 
AP2/+ BP (Blast 
phase)
Third chronic phase (CP3): Recipients had two 
or more AP/BP and was treated back into CP or 
hematologic CR Hematologic CR3: Recipients 
who have achieved two prior hematologic CRs, 
progressed, and achieved a third hematologic CR 
after treatment. Second accelerated phase 
(AP2/+): e.g. 1) recipient was in BP and treated 
back into AP. 2) CP1->AP1->CP2->AP2, 3) CP1-
>AP1->CP2->AP2->CP3. Blast Phase/Crisis (BP): 
≥ 20% blasts (formerly ≥ 30%) in the peripheral 
blood or bone marrow Extramedullary blastic 
infiltrates (i.e., myeloid sarcoma, granulocytic 
sarcoma, or chloroma)
CLL (includes PLL) (report 
Hairy Cell Leukemia as "other", 
see last row of table)
Low risk: CR 
(includes CR2 or 
subsequent CR) 
nPR
Complete remission (CR): The disease is 
completely absent and no relapse occurred prior 
to the preparative regimen. Requires all the 
following: ● No lymphadenopathy ● No 
organomegaly ● Neutrophils > 1.5 x 109/L ● 
Platelets > 100 x 109/L ● Hemoglobin 11g/dL ● 
Lymphocytes < 4 x 109/L/L ● Bone marrow < 30% 
lymphocytes ● Absence of constitutional 
symptoms Nodular Partial Remission (nPR)
complete response with persistent lymphoid 
nodules in bone marrow.
CLL (con’t)
Intermediate risk: 
PR Never treated 
Relapse (untreated)
Partial remission (PR): Reduction of more than 
50% in the disease burden regardless of the 
number of lines of therapy received. Requires all 
of the following: ● 50% decrease in peripheral 
blood lymphocyte count from pretreatment value 
● 50% reduction in lymphadenopathy if present 
pretreatment ● 50% reduction in liver and spleen 
size if enlarged pretreatment AND one or more of 
the following: ● Neutrophils ≥ 2.5x109/L or 50% 
above baseline Platelets > 100x109/L or 50% 
improvement over baseline ● Hemoglobin > 11.0 
g/dL or 50% improvement over baseline Never 
Treated: The recipient was diagnosed with 
leukemia and never treated. Relapse 
(untreated): The re-appearance of disease after 
complete recovery (previous CR). Relapse should 
be determined by one or more diagnostic tests.
CLL (con't)
High risk: NR/SD 
Progression
No Response/Stable disease (NR/SD): No 
change OR Less than 50% change in disease. 
Not complete response, partial response, or 
progressive disease. Progression: Increase in 
disease burden or new sites of disease. Requires 
one or more of the following: ≥ 50% increase in 
the sum of the products of ≥ 2 lymph nodes (≥ 1 
node must be ≥ 2 cm) or new nodes ≥ 50% 
increase in liver or spleen size, or new 
hepatomegaly or splenomegaly ≥ 50% increase in 
absolute lymphocyte count to ≥ 5 x 109/L 
Transformation to a more aggressive histology, 
e.g. transform to diffuse large B-cell lymphoma 
known as Richter’s transformation.


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ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
MDS (Note all MPD are reported 
as “other‟. JMML has its own 
category on the ASBMT RFI 
Outcomes Data table)
Low risk: RA RARS 
RCMD RCMD/RS 
MDS Unclassifiable 
isolated 5q-
syndrome
RA/RARS/RCMD/RS/ MDS-NOS and <5% blasts, 
isolated 5q-syndrome/
MDS (con’t)
High risk: RAEB 
RAEB-T RAEB-1 
RAEB-2 CMML
RAEB/RAEB-T/RAEB-1/RAEB-2/ CMML NOTE: 
RAEB and RAEB-T have been replaced in current 
WHO nomenclature by RAEB-1 or RAEB-2
Hodgkin Disease/Hodgkin 
Lymphoma†
Low Risk: CR1 
CRU1
CR1 Confirmed: Complete disappearance of all 
known disease for ≥ 4 weeks†. The term 
“confirmed” is defined as a laboratory and/or 
pathological or radiographic determination. CR1 
Unconfirmed (CRU1): Complete disappearance 
of all known disease for ≥ 4 weeks with the 
exception of persistent scan abnormalities of 
unknown significance†. The term “unconfirmed” is 
defined as scan abnormalities of unknown 
significance that are not biopsied or otherwise 
evaluated.
Hodgkin Disease/Hodgkin 
Lymphoma† (con’t)
Intermediate risk:
CR2/+ CRU2/+ PR 
without prior CR 
(PR1) PR with prior 
CR (PR2+) (includes 
any sensitive 
relapse)
CR2+ Confirmed: The recipient relapsed, then 
achieved complete absence of disease for at least 
one month without radiographic evidence of 
disease†. CR2+ Unconfirmed (CRU2+): The 
recipient has achieved a second or subsequent 
complete response but has persistent 
radiographic abnormalities of unknown 
significance Partial remission- (PR): Reductions 
of ≥ 50% in greatest diameter of all sites of known 
disease and no new sites. Partial response may 
be represented as PR1, PR2, etc. There are 
differing interpretations of what the number after 
“PR” represents. To avoid confusion, distinguish 
the type of PR with the following: “without prior 
CR” and “with prior CR”. This includes any 
relapse that is sensitive to chemotherapy, which 
by definition is achievement of at least a PR to 
therapy.
Hodgkin Disease/Hodgkin 
Lymphoma† (con’t)
High risk: Never 
treated Primary 
Refractory (PIF res) 
Relapse untreated 
(any number) 
Relapse resistant 
(any number)
Never Treated: The recipient was diagnosed with 
lymphoma and never treated. Primary refractory
(less than partial response to initial therapy or PR 
not maintained at time of HSCT). The response of 
the lymphoma to treatment is less than in a partial 
response (PR). This status would also include 
recipients who achieved a prior PR (but never 
CR) but are not currently in PR. Relapse: The 
recipient obtained CR/CRU, but relapsed (any 
sensitivity, includes PR with prior CR). 
Recurrence of disease after CR. This may involve 
an increase in size of known disease or new sites 
of disease. Patients who have any relapse AND 
have resistant or untreated or unknown sensitivity 
to chemotherapy.


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ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
NHL (Indolent/ Low Grade) †
Includes the following diseases: 
splenic marginal zone B-cell 
lymphoma, extranodal marginal 
zone B-cell lymphoma of MALT 
type, nodal marginal zone B-cell 
lymphoma, follicular lymphoma 
(Grade I-III and unknown) 
Waldenstrom 
macroglobulinemia
(lymphoplasmacytic lymphoma) 
should be reported as ‘Other’
Low risk: CR1 
CRU1
CR1 Confirmed: Complete disappearance of all 
known disease for ≥ 4 weeks†. The term 
“confirmed” is defined as a laboratory and/or 
pathological or radiographic determination. CR1 
Unconfirmed (CRU1): Complete disappearance 
of all known disease for ≥ 4 weeks with the 
exception of persistent scan abnormalities of 
unknown significance†. The term “unconfirmed” is 
defined as scan abnormalities of unknown 
significance that are not biopsied or otherwise 
evaluated.
Intermediate risk:
CR2/+, CRU2/+ PR 
with prior CR PR 
without prior CR 
(includes any 
sensitive relapse) 
Never Treated
CR2+ Confirmed: The recipient relapsed, then 
achieved complete absence of disease for at least 
one month without radiographic evidence of 
disease†. CR2+ Unconfirmed (CRU2+): The 
recipient has achieved a second or subsequent 
complete response but has persistent 
radiographic abnormalities of unknown 
significance. Partial remission- (PR): Reductions 
of ≥ 50% in greatest diameter of all sites of known 
disease and no new sites. Partial response may 
be represented as PR1, PR2, etc. There are 
differing interpretations of what the number after 
“PR” represents. To avoid confusion, distinguish 
the type of PR with the following: “without prior 
CR” and “with prior CR”. This includes any 
relapse that is sensitive to chemotherapy, which 
by definition is achievement of at least a PR to 
therapy. Never Treated: The recipient has never 
been treated for NHL. No chemotherapy was 
given within the 6 months prior to the preparative 
regimen (disease untreated, REL unt).
NHL (Indolent/Low Grade) (con’t)
High risk: Primary 
Refractory Relapse 
untreated (any 
number) Relapse 
resistant (any 
number)
Primary refractory (less than partial response to 
initial therapy or PR not maintained at time of 
HSCT). The response of the lymphoma to 
treatment is less than in a partial response (PR). 
This status would also include recipients who 
achieved a prior PR (but never CR) but are not 
currently in PR. Relapse: The recipient obtained 
CR/CRU, but relapsed (any sensitivity, includes 
PR with prior CR). Recurrence of disease after 
CR. This may involve an increase in size of 
known disease or new sites of disease. Patients 
who have any relapse AND have resistant or 
untreated or unknown sensitivity to 
chemotherapy.
NHL (Aggressive/ Intermediate 
and High Grade) Includes the 
following diseases: mantle cell 
lymphoma, diffuse large B-cell 
lymphoma, Burkitt’s 
lymphoma/Burkitt cell leukemia, 
high grade B-cell lymphoma, 
Burkitt- like (provisional entity), 
adult T-cell lymphoma/leukemia 
(HTLV1+), aggressive NK-cell 
leukemia, extranodal NK/T-cell 
Low risk: CR1 
CRU1
CR1 Confirmed: Complete disappearance of all 
known disease for ≥ 4 weeks†. The term 
“confirmed” is defined as a laboratory and/or 
pathological or radiographic determination. CR1 
Unconfirmed (CRU1): Complete disappearance 
of all known disease for ≥ 4 weeks with the 
exception of persistent scan abnormalities of 
unknown significance†. The term “unconfirmed” is 
defined as scan abnormalities of unknown 
significance that are not biopsied or otherwise 
evaluated.


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ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
lymphoma, hepatosplenic 
gamma- delta T-cell lymphoma, 
subcutaneous panniculitis T-cell 
lymphoma, anaplastic large-cell 
lymphoma – T/null cell – primary 
cutaneous type, peripheral T-cell 
lymphoma unspecified, 
angioimmunoblastic T- cell 
lymphoma (AILD), anaplastic 
large cell T/null cell–primary 
systemic type, large T-cell 
granular lymphocytic leukemia, 
mycosis fungoides/Sezary 
syndrome and other T-NK cell 
lymphoma.– nasal type, 
enteropathy type T-cell
NHL (Aggressive/ Intermediate 
and High Grade) (con’t)
Intermediate risk: 
CR2/+, CRU2/+ PR 
with prior CR PR 
without prior CR 
(includes any 
sensitive relapse)
CR2+ Confirmed: The recipient relapsed, then 
achieved complete absence of disease for at least 
one month without radiographic evidence of 
disease†. CR2+ Unconfirmed (CRU2+): The 
recipient has achieved a second or subsequent 
complete response but has persistent 
radiographic abnormalities of unknown 
significance Partial remission- (PR): Reductions 
of ≥ 50% in greatest diameter of all sites of known 
disease and no new sites. Partial response may 
be represented as PR1, PR2, etc. There are 
differing interpretations of what the number after 
“PR” represents. To avoid confusion, distinguish 
the type of PR with the following: “without prior 
CR” and “with prior CR”. This includes any 
relapse that is sensitive to chemotherapy, which 
by definition is achievement of at least a PR to 
therapy.
NHL (Aggressive/ Intermediate 
and High Grade) (con’t)
High risk: Primary 
refractory Relapse 
untreated (any 
number) Relapse 
resistant (any 
number) Never 
Treated
Primary refractory (less than partial response to 
initial therapy or PR not maintained at time of 
HSCT). The response of the lymphoma to 
treatment is less than in a partial response (PR). 
This status would also include recipients who 
achieved a prior PR (but never CR) but are not 
currently in PR. Relapse: The recipient obtained 
CR/CRU, but relapsed (any sensitivity, includes 
PR with prior CR). Recurrence of disease after 
CR. This may involve an increase in size of 
known disease or new sites of disease. Patients 
who have any relapse AND have resistant or 
untreated or unknown sensitivity to 
chemotherapy. Never Treated: The recipient has 
never been treated for NHL. No chemotherapy 
was given within the 6 months prior to the 
preparative regimen (disease untreated, REL 
unt).
Multiple Myeloma (report plasma 
cell leukemia, solitary 
plasmacytoma, primary 
amyloidosis or other plasma cell 
disorders as „other‟)
Low risk: CR1 
(includes first sCR) 
VGPR 1 (eg VGPR 
without prior CR) 
PR1 (eg PR without 
prior CR)
CR1, (CR) A treatment response where all of 
the following criteria are met: Negative 
immunofixation on serum and urine samples; 
Disappearance of any soft tissue plasmacytomas; 
< 5% plasma cells in the bone marrow 
(confirmation with repeat bone marrow biopsy not 


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needed) CR requires two consecutive
assessments† made at any time before the 
institution of any new therapy, and no known 
evidence of progressive or new bone lesions if 
radiographic studies were performed; 
radiographic studies are not required to satisfy 
CR requirements. Stringent Complete Remission 
(sCR) Follow criteria for CR as defined above 
PLUS Normal free light chain ratio AND Absence 
of clonal cells in the bone marrow by 
immunohistochemistry or immunoflourescence 
(confirmation with repeat bone marrow biopsy not 
needed). (An abnormal kappa/lambda ratio by 
immunohistochemistry and or 
immunofluorescence requires a minimum of 100 
plasma cells for analysis. An abnormal ration 
reflecting the presence of an abnormal clone is 
kappa/lambda of >4:1 or < 1:2) Very Good 
Partial Response (VGPR) Serum and urine M 
protein detectable by immunofixation but not on 
electrophoresis, or >= 90% reduction in serum M-
protein and urine M protein level < 100 mg/24h 
PR without prior CR (PR1). Both of the following 
must be present: ≥ 50% reduction in serum M-
protein; Reduction in 24-hour urinary M-protein by 
≥ 90% or to < 200 mg/24 hours. If the serum and 
urine M-protein are not measurable (i.e., do not 
meet any of the following criteria: Serum M-
protein ≥ 1 g/dL; Urine M-protein ≥ 200 mg/24 
hours; Then a ≥ 50% decrease in the difference 
between involved and uninvolved free light chain 
levels is required in place of the M-protein criteria 
(provided the serum-free light chain assay shows 
involved level ≥ 10 mg/dL and the serum-free light 
chain ratio is abnormal) .
Multiple Myeloma (con’t)
Low risk: (con’t) 
CR1 (includes first 
sCR) VGPR 1 (eg 
VGPR without prior 
CR) PR1 (eg PR 
without prior CR)
If serum and urine M-protein and serum-free light 
chains are not measurable, a ≥50% reduction in 
plasma cells is required in place of M-protein, 
provided the baseline bone marrow plasma cell 
percentage was ≥ 30%. In addition to the above 
listed criteria, a ≥ 50% reduction in the size of soft 
tissue plasmacytomas is also required, if present 
at baseline. VGPR and PR requires two 
consecutive assessments† made at any time 
before the institution of any new therapy, and no 
known evidence of progressive or new bone 
lesions if radiographic studies were performed; 
radiographic studies are not required to satisfy PR 
requirements. For recipients otherwise meeting 
the criteria for CR, but with no documented 
marrow with <5% plasma cells , status must be 
classified as PR.


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ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
Multiple Myeloma (con’t)
High risk: Relapse 
from CR (untreated) 
CR2/+ sCR2/+ 
VGPR2/+ PR2/+ 
(with prior CR) SD 
Progression Never 
treated PR2/+
Relapse from CR (untreated) Requires one or 
more of the following: Reappearance of serum or 
urine M-protein by immunofixation or 
electrophoresis Development of ≥ 5% plasma 
cells in the bone marrow (relapse from CR has a 
5% cutoff vs. 10% for other categories of relapse) 
Appearance of any other sign of progression 
(e.g., new plasmacytoma, lytic bone lesion, 
hypercalcemia) Relapse requires two consecutive 
assessments made at any time before 
classification as relapse, and/or the institution of 
any new therapy† CR2/+: Same criteria as, 
Myeloma low risk CR‟, except a relapse must 
have occurred and recipient was treated back into 
CR. sCR2/+: see sCR definition for MM, except a 
relapse must have occurred and recipient was 
treated back into sCR VGPR2/+: See VGPR 
definition. PR2/+ (with prior CR): Same criteria as 
‘Myeloma low risk PR’, except a relapse must 
have occurred and treatment back into PR.
Multiple Myeloma (con’t)
High risk (Con’t):
Relapse from CR 
(untreated) CR2/+ 
sCR2/+VGPR2/+ 
PR2/+ (with prior 
CR) SD Progression 
Never treated PR2/+
SD: Does not meet the criteria for CR, VGPR, PR, 
or PD. SD requires two consecutive assessments 
made at any time before the institution of any new 
therapy, and no known evidence of progressive or 
new bone lesions if radiographic studies were 
performed; radiographic studies are not required 
to satisfy SD requirements Progression:
Requires one or more of the following: Increase of 
≥ 25% from the lowest response value achieved; 
Serum M-component (including an absolute 
increase ≥ 0.5 g/dL) (for progressive disease, 
serum M-component increases of ≥ 1 g/dL are 
sufficient to define relapse if the starting M-
component is ≥ 5 g/dL); Urine M-component with 
an absolute increase ≥ 200 mg/24 hours. For 
recipients without measurable serum and urine M-
protein levels: the difference between involved 
and uninvolved free light chain levels with an 
absolute increase > 10 mg/dL; Bone marrow 
plasma cell percentage with absolute percentage 
≥ 10%; Definite development of new bone lesions 
or soft tissue plasmacytomas, or definite increase 
in the size of any existing bone lesions or soft 
tissue plasmacytomas; Development of 
hypercalcemia (corrected serum calcium > 11.5 
mg/dL or 2.65 mmol) that can be attributed solely 
to the plasma cell proliferative disorder; PD 
requires two consecutive assessments made at 
any time before classification as disease 
progression, and/or the institution of any new 
therapy†.
Solid Tumors: Adult Includes: 
breast cancer, Ewings sarcoma, 
germ cell cancers, 
neuroblastoma, ovarian cancer, 
rhabdomyosarcoma, testicular 
cancer, renal cell carcinoma and 
any other solid tumors
All clinical status 
at HCT


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ASBMT RFI 
Classification
CIBMTR Classification^
Solid Tumors: Pediatric 
Neuroblastoma
Intermediate Risk 
CR1 CRU1 VGPR1 
PR1 (PR without 
prior CR) Adjuvant
Note addition of RECIST criteria. RECIST criteria 
are based on the sum of the longest diameter of 
measured lesions, rather than product of two 
dimensions of measured lesions. First Complete 
remission (CR1): The recipient has achieved 
complete absence of disease. RECIST adds: 
Disappearance of all target lesions for a period of 
at least one month. Adjuvant treatment is 
excluded from this definition First Complete 
Response Unconfirmed (CRU1) Disappearance 
of all signs and symptoms of disease with 
normalization of all biochemical and radiologic 
parameters, but with persistent, unchanging 
imaging abnormalities of unknown significance. 
RECIST: Complete response with persistent 
imaging abnormalities of unknown significance 
(CRU) First very good partial response
(VGPR): The recipient has obtained a reduction of 
more than 90% in the disease burden after only 
one line of therapy. First Partial response: (Note 
1st PR would include any first VGPR) No prior 
CR, reduction of more than 50% in the disease 
burden regardless of the number of lines of 
therapy received. Decrease of ≥ 50% in total 
tumor load of the lesions that have been 
measured for at least 4 weeks RECIST: Partial 
response (PR) – At least 30% decrease in the 
sum of the longest diameter of measured lesions 
(target lesions) taking as reference the baseline 
sum of longest diameters Adjuvant: High-dose 
treatment with transplantation delivered in the 
absence of any known residual disease with an 
adjuvant intent. Metastatic recipients (any status) 
should never be considered as adjuvant. 
Treatment given after the primary cancer 
treatment to increase the chances of a cure. 
Adjuvant cancer therapy may include 
chemotherapy, radiation therapy, hormone 
therapy, or biological therapy.


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ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
Solid Tumors: Pediatric 
Neuroblastoma (con’t)
High Risk CR2/+ 
CRU2/+ PR2/+ (with 
prior CR) NR/SD PD 
Relapse (untreated) 
Never treated
Note CR definitions for Neuroblastoma above. 
2nd Partial response or more (PR with prior 
CR, any number): (Note includes VGPR after 
prior CR) One prior CR, reduction of more than 
50% in the disease burden regardless of the 
number of lines of therapy received after relapse 
Decrease of ≥50% in total tumor load of the 
lesions that have been measured for at least 4 
weeks. RECIST: Partial response (PR) – At least 
30% decrease in the sum of the longest diameter 
of measured lesions (target lesions) taking as 
reference the baseline sum of longest diameters 
Progressive Disease (PD) Increase of ≥ 25% in 
the size of one or more measurable lesions, or 
the appearance of new lesions. RECIST: At least 
a 20% increase in the sum of the longest 
diameter of measured lesions (target lesions), 
taking as reference the smallest sum of the 
longest diameters recorded since the treatment 
started or the appearance of one or more new 
lesions Relapse (untreated) The reappearance 
of disease after complete recovery. Should be 
determined by one or more diagnostic tests. 
Never Treated (upfront): Recipient has not 
received any treatment for Neuroblastoma prior to 
the preparative regimen. This disease status at 
transplant should rarely be used No 
Response/Stable Disease (NR/SD) Disease has 
been treated and the size of one or more lesions 
has neither increased 25% or more in the size of 
one or more lesions, nor has total tumor size 
decreased 50% or more. RECIST: Stable disease 
(SD) – Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum of the longest 
diameters since the treatment started
All Other Solid Tumors –
Pediatrics Includes all other solid 
tumors except neuroblastoma
Intermediate Risk –
same as 
Neuroblastoma 
(above) CR1 CRU1 
VGPR1 PR1 (PR 
without prior CR) 
Adjuvant
See Neuroblastoma above.
All Other Solid Tumors –
Pediatrics (con’t) Includes all 
other solid tumors except 
neuroblastoma
High Risk – same 
as Neuroblastoma 
(above) CR2/+ 
CRU2/+ PR with 
prior CR NR/SD PD 
Relapse Never 
treated
See Neuroblastoma above.
Non-Malignant Disease – Adults Includes: severe aplastic anemia, and any other non-malignant diseases.
Non-Malignant Disease - Pediatrics Includes: histiocytic disorders, Immunodeficiencies, Inborn errors of 
metabolism, congenital bone marrow failure, acquired aplastic anemia, thalassemia major, sickle cell anemia 
and any other non-cancerous diseases.
Other Includes any hematologic disorder or solid tumor not included in above (e.g. other plasma cell disorders, 
amyloidosis, plasma cell leukemia, hairy cell leukemia, myeloproliferative diseases).


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ASBMT Diagnosis Category
ASBMT RFI 
Classification
CIBMTR Classification^
Center for International Blood and Marrow Transplant Research (CIBTMR), The American Society for Blood 
and Marrow Transplantation (ASBMT), Request for information (RFI), Myelodysplastic Syndrome (MDS), 
Chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), refractory anemia with ring sideroblasts 
(RARS), refractory cytopenia with multilineage dysplasia (RCMD), refractory cytopenia with multilineage 
dysplasia with ring sideroblasts (RCMD/RS), Relpase (REL), non-Hodgkin lymphoma (NHL), natural killer (NK), 
natural killer T-cell (NK/T), very good partial response (VGPR), Hodgkin's lymphoma (HL)
2014 and 2015 Update: No substantive changes from the 2011 through 2014 documents. 2011 Update: No 
changes from the 2010 document. 2010 Updates: † Several diseases (eg AML, MM, NHL and HL) require an 
observation period of response of at least 4 weeks or two independent assessments in order to strictly be 
considered to have achieved that level of response. However, in many cases, transplantation is conducted 
before this time has fully elapsed, or subsequent assessment can be completed. In these circumstances, the 
best response determined before the transplantation or based upon the last assessment before transplantation 
should be used. ^ CIBMTR has included instructions from the CIBMTR TED manual for reference, along with 
the CIBMTR “matching” disease classifications in bold font 2009 and 2010 Updates: General updates to align 
ASBMT risk categories with disease status collected on CIBMTR TED forms Matching disease text to the 
revised TED Forms per WHO. criteria (e.g. precursor B-lymphoblastic lymphoma/leukemia moved to ALL from 
Lymphoma) Matching response text to the revised TED Forms Preparative regimen replaces conditioning 
Referring to revised CIBMTR Disease Forms for detailed criteria Distinguishing PR1/1st PR to PR without prior 
CR and PR2/2nd PR to PR with prior CR Waldenstrom macroglobulinemia moved to “Other‟ from Plasma Cell 
Disorders, and better description of diseases fitting into “Other” category. Moved mycosis fungoides/Sezary 
syndrome to the aggressive/intermediate diagnosis category. Adding Response Evaluation Criteria in Solid 
Tumors (RECIST) criteria for solid tumors Added details from the CIBMTR TED instruction manual. Date 
created: 3/4/03 Date(s) of Revision: 2/27/04; 12/1/04; 11/17/05; 10/23/06; 11/15/07; 9/26/09; 10/18/10, 
11/23/11, 11/4/12, 12/3/13; 1/13/14, 2/16/15, 3/23/16. Copyright 2016, American Society for Blood and Marrow 
Transplantation
16.7
Appendix 7: List of CYP3A4 inhibitors and inducers
Table 16-8
List of CYP3A inhibitors and inducers
Category
Drug Names
Strong inhibitorsa of CYP3A
boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, eltegravir/ritonavir, grapefruit juice1, idelalisib, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, LCL161, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, sequinavir/ritonavir, telaprevir, telithromycin, 
voriconazole, indinavir/ritonavir, tipranoavir/ritonavir, troleandomycin
Moderate inhibitorsb of CYP3A
amprenavir, aprepitant, atazanavir, atazanavir/ritonavir, casopitant, 
cimetidine, ciprofloxacin, crizotinib, cyclosporine, duranavir, 
darunavir/ritonavir, diltiazem, dronedarone, erythromycin, 
faldaprevilr, fluconazole2, fosamprenavir, grapefruit juice1, imatinib, 
lomitapide, netupitant,nilotinib, schisandra sphenanthera3, tofisopam, 
verapamil
Strong inducersc of CYP3A
avasimibe, carbamazepine, enzalutamide, mitotane,phenytoin, 
rifampin, St. John’s wort3, rifabutin, phenobarbital
Moderate inducersd of CYP3A
bosentan, efavirenz, etravirine, genistein3, lersivirine, lopinavir, 
modafinil, nafcillin, ritonavir, semagacestat4, talviraline4, thioridazine, 
tipranavir
The list of CYP inhibitors and inducers was compiled from the FDA’s “Guidance for Industry 
(U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation an
d Research (CDER) Center for Biologics Evaluation and Research), Drug Interaction Studies;” from the Indiana 
University School of Medicine’s “Clinically Relevant” Table and from the University of Washington’s Drug 
Interaction Database. Note that this may not be an exhaustive list. Please refer to footnotes.
1 Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.


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Category
Drug Names
2 Fluconazole is a dual CYP3A4 and CYP2C9 inhibitor. Fluconazole is a strong CYP2C9 inhibitor based on the 
AUC ratio of omeprazole, which is also metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor.
3 Herbal product.
4 Drugs not available in the US Market.
a A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by equal or more than 5-fold.
b A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold
c A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate 
for that CYP by equal or more than 80%.
d A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that 
CYP by 50-80%.
Dual CYP2C9/CYP3A4 inhibitor:
Fluconazole: Avoid the concomitant use of ruxolitinib with fluconazole doses > 6 mg/kg 
(maximum 200mg) daily; if clinically necessary to use doses ≥ 200 mg daily, consultation with 
Sponsor is required. Refer to Section 6.2.1.1.

SAP_001.pdf: 


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Statistical Analysis Plan
CINC424G12201
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
18-Dec-
2019
Prior to 
DB lock
Creation of 
final version
N/A – First version
NA
24-Mar-
2022
Prior to 
DB lock
Amendment 
1
This SAP has been updated after 
protocol Amendment version 2 
(release date 19-Nov-2020) and 
creation of TFL Shells.
Main changes:
• Additional analysis set “Listing 
only set” 
• Definition of analysis sets updated 
to consider patients with lower 
starting dose as a result of co-
administration with strong 
CYP3A4/CYP2C9 inhibitors
• Additional exploratory endpoint 
“Steroid-free remission at Cycle 7 
Day 1”
• Clarification of subgroup analyses 
by regions to add Japan and Turkey 
as separate region; number of 
subgroup analyses reduced
• Analyses to investigate impact of 
COVID-19 pandemic added
• Further changes for clarification 
purposes and/or to align with other 
studies in the project
Section: 
1.2
2.1 – 2.4
2.7, 2.8, 2.13
App. 5.3
19-Nov-
2022
Prior to 
DB lock
Amendment 
2
Update to align with protocol 
Amendment version 2 (release date 
09-Sep-2022) and to clarify some 
specifications after dry run. 
Main changes:
• Exploratory endpoint “Steroid-free 
remission at Cycle 7 Day 1” 
changed into “Systemic 
corticosteroid-free response” and 
derivation clarified
• Sensitivity analysis for primary 
endpoint added 
Sections:
1.2
2.1.1, 2.2, 
2.4.1, 2.5.4
2.7
2.8.4
2.13
4
App. 5.4.3


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Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
• Analysis of BOR up to data cut-off 
date added and analysis of DOR up 
to data cut-off date added 
accordingly
• Analysis of time to first occurrence 
of infections using Kaplan-Meier 
methodology removed
• Specified how to analyze patients 
who change formulation during 
treatment
• Update of protocol deviation codes 
in the analysis set definitions (Tab. 
2-3), but content of definition keeps 
unchanged 
• More detailed specifications how to 
identify new or additional systemic 
therapy
• Simplified derivation of dose 
reduction 
• Criteria for notable vital signs 
clarified
07-Oct-
2024
Prior to 
final 
DB lock
Final CSR
Main changes:
• Analyses identified that don’t need 
to be repeated for the final CSR 
• Definition of on-treatment period 
for safety analyses clarified, 
especially for subjects who tapered 
off ruxolitinib treatment.
• Definition for duration of follow-up 
added.
• Duration of exposure incl./excl. 
taper off periods added in presence 
of subjects who tapered off 
ruxolitinib and re-started after 
cGvHD recurrence.
Definition of dose intensity adapted 
accordingly.
• Analysis of prohibited concomitant 
medications removed since table on 
corresponding PD is sufficient.
Sections:
General
2.1.1
2.4.1
2.4.1
2.4.2


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Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
• Definition of duration of response 
updated according to what was 
used in the iCSR (specified in CSR 
Section 16.1.9 “Changes to the 
planned analysis”) 
• Analyses on reduction of 
corticosteroid dose updated to 
consider data up to end of study
• Analysis for safety disclosure 
updated to report events for on-
treatment and post-treatment 
period, separately.
• Criteria for notably abnormal vital 
signs updated according to the 
analysis in the iCSR (specified in 
CSR Section 16.1.9 “Changes to 
the planned analysis”)
• Specifications for analysis of time 
to first occurrence of infection 
clarified.
• Shift table for height, weight, BMI 
(high/normal/low) added.
• All specification for biomarker 
analyses moved into a separate 
analysis plan
• Specification added how to identify 
subjects who tapered off ruxolitinib 
for the analysis of cGvHD 
recurrence following completion of 
a taper of ruxolitinib.
• Analysis of systemic 
corticosteroid-free response rate 
clarified for subjects who didn’t 
receive steroids at baseline.
2.7.1
2.7.1/2.7.2
2.8.1.1
2.8.4.2
2.8.4.3
2.8.4.5
2.12
2.13
2.13


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Table of contents
Table of contents..................................................................................................................5
List of abbreviations ............................................................................................................7
1
Introduction..........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints..............................................................................10
2
Statistical methods .............................................................................................................13
2.1
Data analysis general information..........................................................................13
2.1.1
General definitions ................................................................................14
2.2
Analysis sets...........................................................................................................17
2.2.1
Subgroup of interest ..............................................................................19
2.3
Patient disposition, demographics and other baseline characteristics....................20
2.3.1
Patient disposition .................................................................................21
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................21
2.4.1
Study treatment / compliance................................................................21
2.4.2
Prior, concomitant and post therapies ...................................................24
2.5
Analysis of the primary objective..........................................................................26
2.5.1
Primary endpoint ...................................................................................26
2.5.2
Statistical hypothesis, model, and method of analysis ..........................26
2.5.3
Handling of missing values/censoring/discontinuations .......................27
2.5.4
Supportive analyses...............................................................................27
2.6
Analysis of the key secondary objective................................................................28
2.7
Analysis of secondary efficacy objective(s) ..........................................................28
2.7.1
Secondary endpoints..............................................................................28
2.7.2
Statistical hypothesis, model, and method of analysis ..........................30
2.7.3
Handling of missing values/censoring/discontinuations .......................31
2.8
Safety analyses.......................................................................................................32
2.8.1
Adverse events (AEs)............................................................................32
2.8.2
Deaths....................................................................................................33
2.8.3
Laboratory data......................................................................................34
2.8.4
Other safety data....................................................................................34
2.9
Pharmacokinetic endpoints ....................................................................................38
2.10
PD and PK/PD analyses.........................................................................................39
2.11
Patient-reported outcomes......................................................................................39
2.12
Biomarkers.............................................................................................................39
2.13
Other Exploratory analyses....................................................................................39


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2.14
Interim analysis......................................................................................................40
3
Sample size calculation......................................................................................................40
4
Change to protocol specified analyses...............................................................................41
5
Appendix............................................................................................................................42
5.1
Imputation rules .....................................................................................................42
5.1.1
Study drug .............................................................................................42
5.1.2
AE date imputation................................................................................43
5.2
AEs coding/grading................................................................................................44
5.3
Laboratory parameters derivations.........................................................................44
5.4
Statistical models ...................................................................................................45
5.4.1
Primary analysis ....................................................................................45
5.4.2
Key secondary analysis .........................................................................45
5.4.3
Definition of new or additional systemic treatment of cGvHD ............45
6
Reference ...........................................................................................................................46


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List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
aGvHD
Acute Graft vs. Host Disease
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
cGvHD
chronic Graft vs. Host Disease
CIBMTR
Center for International Blood and Marrow Transplant Research
CMV
Cytomegalovirus
CR
Complete Response
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
FFS
Failure-Free Survival
GvHD
Graft vs. Host Disease
HCT
Hematopoietic Cell Transplantation
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NRM
Non Relapse Mortality
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic analysis set
PD
Pharmacodynamics
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial response 
PRO
Patient-reported Outcomes
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
WBC
White Blood Cells
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the final Clinical Study 
Report (CSR) of study CINC424G12201, a Phase II open-label, single-arm, multi-center study 
of ruxolitinib added to corticosteroids in pediatric subjects with moderate and severe chronic 
graft vs. host disease after allogeneic stem cell transplantation. Specification of analyses done 
for the interim CSR but not repeated for the final CSR are kept in this document which can be 
seen as cumulative SAP. These are those analyses for which no new or updated data are 
available (for example, all efficacy at Cycle 7 Day 1, all demographic and baseline disease 
characteristics). Analyses that are not repeated for the final CSR are indicated in Tab. 1-1 and/or 
in the corresponding sections.
This SAP is based on protocol CINC424G12201 version 02, dated 09-Sep-2022.
•
Changes implemented in this SAP version compared to previous versions are indicated 
in the document history table above. The major changes compared to the previous 
version are: 
•
Analyses specified that don’t need to be repeated in the final CSR 
•
Definition of on-treatment period for safety analyses clarified, especially for subjects 
who tapered off ruxolitinib treatment.
•
Duration of exposure incl./excl. taper off periods added in presence of subjects who 
tapered off ruxolitinib. Definition of dose intensity adapted accordingly.
•
Definition for duration of follow-up added.
•
Changes specified in the interim CSR Section 16.1.9 “changes to the analysis plan” 
are implemented into the SAP, which are the updated 
o
Definition of duration of response and
o
Criteria for notably abnormal vital signs.
•
Analyses on reduction of corticosteroid dose updated to consider data up to end of 
study.
•
Analysis for safety disclosure updated to report events for on-treatment and post-
treatment period, separately.
•
Shift table for height, weight, BMI (high/normal/low) added.
•
All specification for biomarker analyses moved into a separate analysis plan.
•
Specification added how to identify subjects who tapered off ruxolitnitb for the 
analysis of cGvHD recurrence following completion of a taper of ruxolitinib. 
•
Analysis of systemic corticosteroid-free response rate clarified for subjects who didn’t 
receive steroids at baseline.
All decisions regarding final analysis, as defined in the SAP document, have been made prior 
to final database lock of the study data.
1.1
Study design
This open-label, single-arm, Phase II multi-center study will investigate the activity, 
pharmacokinetics and safety of ruxolitinib added to the subject's immunosuppressive regimen 
among infants, children, and adolescents aged ≥ 28 days to < 18 years old with either moderate 


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to severe treatment-naive cGvHD or SR-cGvHD. Approximately 42 subjects will be enrolled 
in this study. Subjects will be grouped according to their age as follows: Group 1 includes 
subjects ≥ 12y to < 18y, Group 2 includes subjects ≥ 6y to <12 y, Group 3 includes subjects ≥ 
2y to < 6y, and Group 4 includes subjects ≥ 28days to < 2y. Subjects will remain in the age 
group throughout the study based on the age at the time of start of treatment. Enrollment 
initiation into the youngest age group, Group 4, will be subject to the availability of data in this 
age group from study [CINC424F12201], as well as a review of available PK, safety, and 
clinical activity data generated from Groups 1 to 3 in the current study, in consultation with the 
data monitoring committee (DMC) and a final decision by the Sponsor. At least 5 evaluable 
subjects per Group are needed for the primary analysis in Groups 1, 2 and 3. No minimum 
number of evaluable subjects are needed in Group 4.
As shown in Figure 1-1, after a screening period from Day -28 to Day -1, eligible subjects will 
begin the investigational treatment (ruxolitinib) on Cycle 1 Day 1 and will be treated for up to 
a maximum of 3 years (39 cycles/week 156) or until early discontinuation. Subjects who 
discontinue ruxolitinib for any reason earlier than 39 cycles will be followed every 6 months 
until 3 years from their first dose of ruxolitinib is reached. Subjects who tapered off ruxolitinib 
and all immunosuppressive therapy due to achieving a CR or PR will continue to follow the 
currently assigned Visit Evaluation Schedule (Table 8-1), including all safety and efficacy 
assessments. 
Figure 1-1
Study Design
Refer to protocol Section 8.2.1 for details of the treatment period study visits. All subjects 
continuing to receive ruxolitinib treatment benefit following 3 years of treatment will be given 
the possibility to continue ruxolitinib outside the study, from another source, where permitted 
in accordance with local laws and regulations.


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The ruxolitinib dose is based on the preliminary efficacy and safety data generated with this 
dose in subjects with steroid-refractory graft vs. host disease (SR-GvHD) (Zeiser et al 2015), 
and based on PK/safety data generated from the Phase III trials CINC424C2301 and 
CINC424D2301. As subjects ≥ 12 y to < 18 y are already being treated with 10 mg BID in 
CINC424D2301, this dose is the recommended phase II dose (RP2D), and will be used to treat 
all subjects in this age group.
Pediatric subjects enrolled in the ongoing pediatric aGvHD study [CINC424F12201] will 
provide PK data that will be used to confirm the adequacy of the doses described above and 
thus patients < 12 years will only be enrolled in Groups 2 to 4 in the current study once the dose 
is confirmed in the appropriate age group. If a different dose is confirmed in the pediatric 
aGvHD study [CINC424F12201], the dose will need to be adjusted accordingly in the current 
study. Subjects enrolled in the adult aGvHD study [CINC424C2301] and cGvHD study 
[CINC424D2301] may also provide PK data that will be used as additional information to 
confirm adequacy of this dose.
An interim CSR will be reported when all subjects have completed 1 year of treatment or 
discontinued earlier, at which time the primary efficacy assessment, ORR at Cycle 7 Day 1, 
will already be final.
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Analysis
Analysis 
incl. in 
final CSR
Primary objective(s)
Endpoint(s) for primary objective(s)
Primary 
Analysis
•
To evaluate the activity of 
ruxolitinib added to 
standard dose 
corticosteroids +/- CNI in 
pediatric subjects with 
moderate or severe 
treatment naive-cGvHD 
or SR-cGvHD measured 
by overall response rate 
(ORR) at Cycle 7 Day 1 
based on all subjects in 
the study.
•
Overall response rate (ORR) at 
Cycle 7 Day 1, defined as the 
proportion of subjects 
demonstrating a complete 
response (CR) or partial response 
(PR) without the requirement of 
additional systemic therapies for 
an earlier progression, mixed 
response or non-response. The 
response is assessed per NIH 
consensus criteria (Lee et al 
2015), and scoring of response 
will be relative to the organ stage 
at the start of study treatment.
•
Refer to 
Section 
2.5.1
No
Secondary objective(s)
Endpoint(s) for secondary 
objective(s)
Secondary 
analysis
•
To assess 
pharmacokinetics (PK) of 
ruxolitinib in  treatment-
•
Ruxolitinib concentrations by 
timepoint
•
Refer to 
Section 
2.9
No


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Objective(s)
Endpoint(s)
Analysis
Analysis 
incl. in 
final CSR
naïve cGvHD and SR-
cGvHD pediatric subjects
•
To evaluate the safety of 
ruxolitinib 
•
Safety and tolerability will be 
assessed by monitoring the 
frequency, duration and severity 
of Adverse Events, including 
occurrence of any second primary 
malignancies or infections, and by 
performing physical exams and 
evaluating changes in vital signs, 
tanner stage, chemistry and 
hematology results from baseline.
•
Refer to 
Section 
2.8
Yes
•
To assess duration of 
response (DOR)
•
Duration of response (DOR) is 
assessed for responders only. 
DOR is defined as the time from 
first response until cGvHD 
progression, death, or the date of 
addition of systemic therapies for 
cGvHD.
Yes
•
To estimate ORR at end 
of Cycle 3
•
Proportion of subjects who 
achieve OR (CR+PR) at Cycle 4 
Day 1
No
•
To assess best overall 
response (BOR)
•
Proportion of subjects who 
achieved OR (CR+PR) at any 
time point (until Cycle 7 Day 1 or 
the start of additional systemic 
therapy for cGvHD)
No repeat 
of BOR at 
C7D1, but 
for BOR up 
to study 
end
•
To estimate the failure 
free survival (FFS)
•
Composite time to event endpoint 
incorporating the following FFS 
events: i) relapse or recurrence of 
underlying disease or death due 
to underlying disease, ii) non-
relapse mortality, or iii) addition or 
initiation of another systemic 
therapy for cGvHD.
Yes
•
To assess cumulative 
incidence of malignancy 
relapse/recurrence (MR)
•
Malignancy relapse/recurrence 
(MR) is defined as the time from 
date of treatment assignment to 
hematologic malignancy 
relapse/recurrence. Calculated for 
subjects with underlying 
hematologic malignant disease.
Yes
•
To assess non-relapse 
mortality (NRM)
•
Non-relapse mortality (NRM), 
defined as the time from date of 
treatment assignment to date of 
death not preceded by underlying 
disease relapse/recurrence.
•
Refer to 
Section 
2.7.2
Yes


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Objective(s)
Endpoint(s)
Analysis
Analysis 
incl. in 
final CSR
•
To assess overall 
survival (OS)
•
Overall survival, defined as the 
time from the date of treatment 
assignment to the date of death 
due to any cause. 
Yes
•
To assess a reduction of 
at least ≥ 50% in daily 
corticosteroid use at 
Cycle 7 Day 1
•
Proportion of subjects with ≥ 50% 
reduction from baseline in daily 
corticosteroid dose at Cycle 7 Day 
1
No repeat 
of the data 
up to C7D1, 
but analysis 
will be done 
considering 
data up to 
study end
•
To assess a reduction to 
a low dose corticosteroid 
dose at Cycle 7 Day 1
•
Proportion of subjects with 
reduction from baseline in daily 
corticosteroid dose to ≤ 0.2 
mg/kg/day methylprednisolone (or 
equivalent dose of ≤ 0.25 
mg/kg/day prednisone or 
prednisolone) at Cycle 7 Day 1
No repeat 
of the data 
up to C7D1, 
but analysis 
will be done 
considering 
data up to 
study end
•
To assess graft failure
•
Assess using donor cell 
chimerism, defined as initial whole 
blood or marrow donor chimerism 
for those who had ≥ 5% donor cell 
chimerism at baseline. If donor 
cell chimerism declines to 
< 5% on subsequent 
measurements, the graft failure is 
declared.
Yes
Exploratory objective(s)
Endpoint(s) for exploratory 
objective(s)
•
To describe the 
responses from the 
acceptability and 
palatability questionnaire 
of ruxolitinib oral pediatric 
formulation
•
Responses from the acceptability 
and palatability questionnaire for 
the oral pediatric dose formulation 
after Cycle 1 (first dose), Cycle 4 
and Cycle 39, as applicable.
•
Refer to 
Section 
2.8.4.4
Yes
•
To assess 
pharmacokinetic (PK) / 
pharmacodynamic (PD) 
relationships
•
Pharmacokinetic parameters 
derived by population PK analysis 
from sparse concentration-time 
data, e.g., AUC, Cmax, Ctrough
•
Refer to 
Section 
2.10
No
•
To evaluate effect of 
ruxolitinib on cytokines, 
cGvHD biomarkers and 
immune cell subsets
•
Assess changes in immune cell 
subsets, inflammatory cytokine 
levels, and soluble cGvHD 
biomarkers. 
•
Refer to 
Section 
2.12
Yes 
(in separate 
report)
•
To evaluate effect of 
ruxolitinib on markers of 
•
Assess changes in soluble 
markers for bone resorption and 
•
Refer to 
Section 
2.12
Yes 
(in separate 
report)


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Objective(s)
Endpoint(s)
Analysis
Analysis 
incl. in 
final CSR
bone development in 
pediatric subjects
formation, including but not limited 
to CTX, Osteopontin, and BALP
•
To explore cGvHD 
recurrence following 
completion of a taper of 
systemic therapy
•
Time to recurrence, assessed for 
patients with completion of a taper 
of systemic therapy only. 
•
Refer to 
Section 
2.13
Yes
•
To evaluate systemic 
corticosteroid-free 
response rate
•
Proportion of subjects who 
achieved OR (CR or PR) at any 
time point without systemic 
corticosteroid therapy for at least 
one month prior to the disease 
assessment. 
•
Refer to 
Section 
2.13
Yes
2
Statistical methods
2.1
Data analysis general information
The interim and final analysis will be performed by Novartis. SAS version 9.4 or later and/or R 
version 3.0.2 or later will be used to perform all data analyses and to generate tables, figures 
and listings.
The analysis cutoff date for the interim analysis of study data will be established when all 
patients have completed 1 year of treatment or discontinued earlier. The analysis cutoff date for 
the final analysis of study data will be established when all patients have completed the study.
All statistical analyses will be performed using all data collected in the database up to the data 
cutoff date. All data with an assessment date or event start date (e.g. vital sign assessment date 
or start date of an adverse event) prior to or on the cutoff date will be included in the analysis. 
Any data collected beyond the cutoff date will not be included in the analysis and will not be 
used for any derivations.
All events with start date before or on the cutoff date and end date after the cutoff date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cutoff 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed.  
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency 
tables; a missing category will be included as applicable. Percentages will be calculated using 
the number of patients in the relevant population or subgroup as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate


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descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum).
2.1.1
General definitions 
Investigational treatment and study treatment
Investigational treatment, will refer to the ruxolitinib only, while other study treatment will 
refer to concomitant use of corticosteroids to treat treatment-naive cGvHD or SR-cGvHD. 
Study treatment, will include both Investigational treatment and other study treatment.
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of ruxolitinib was administered as per the DAR eCRF. The date of first administration of 
study treatment will also be referred as start of study treatment.
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of ruxolitinib was administered as per DAR eCRF. The date of last administration of study 
treatment will also be referred as end of study treatment.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
 •   The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;
•
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference start date for all assessments (e.g. safety, efficacy, PK, biomarker, etc.) is the 
start of study treatment. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is  reported in 
years, duration in days will be divided by 365.25.
Baseline
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment. 


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If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods for safety analyses
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of ruxolitinib.
2. On-treatment period: from day of first dose of ruxolitinib to 30 days after date of last 
actual administration of assigned treatment. 
3. post-treatment period: starting at Day 31 after last administration of ruxolitinib.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on-treatment and 
post-treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) 
will summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).  
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged. In analyses 
for the safety disclosure, all AEs collected in the post-treatment period will be included and 
reported separately.
Subjects who taper off ruxolitinib due to achieving a CR or PR continue efficacy and safety 
assessments until their EoT visit which may be only after Cycle 39 unless the subject 
discontinues from study earlier. Safety data from these patients collected after the last study 
drug intake date + 30 days and before EoT visit will not be included in any safety analyses 
based on the on-treatment period as defined above. Nevertheless, these data will be listed and 
flagged in all listings (AEs, lab, vital signs). Subject who tapered off ruxolitinib are identified 
as they have reason “responder” for ruxolitinib permanent discontinuation on the exposure CRF.
For subjects who tapered off study treatment and later re-started ruxolitinib treatment after a 
cGvHD recurrence, the on-treatment period is from date of first dose of ruxolitinib to very last 
dose + 30 days including the period without treatment, which are collected in the database as 
dose interruption. Safety data (e.g. AEs, labs) collected during this period without treatment 
will be included in the summary tables as treatment emergent events. 
Windows for multiple assessments 
In order to summarize data collected over time (including unscheduled visits), the assessments 
will be time slotted. The following general rule will be applied in creating the assessment 
windows: If more than one assessment is done within the same time window, the assessment 
performed closest to the target date will be used. If two assessments within a time window are 
equidistant from the target date, then the earlier of the two  assessments will be used. If multiple 
assessments on the same date then the worst case will be used.  Data from all assessments 
(scheduled and unscheduled), including multiple assessments, will be listed.


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The following time windows are defined for descriptive summary on cGvHD assessment, 
biomarkers, and safety (Table 2-1) by visit. The end of treatment assessment will be mapped 
into the time points as needed.
Table 2-1
Time windows for cGvHD assessment and safety assessment (lab, 
vital sign, etc.)
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline 
On or before Study Day 1
≤ Study Day 1 
Cycle 1 Day 8
Study Day 8
Study Days 5 – 11
Cycle 1 Day 15
Study Day 15
Study Days 12 – 18
Cycle 1 Day 22
Study Day 22
Study Days 19 – 25
Cycle 2 Day 1
Study Day 29
Study Days 26 – 39
Cycle 3 Day 1
Study Day 57
Study Days 47 – 67
Cycle 4 Day 1
Study Day 85
Study Days 75 – 95
Cycle 5 Day 1
Study Day 113
Study Days 103 – 123
Cycle 6 Day 1
Study Day 141
Study Days 131 – 151
Cycle 7 Day 1
Study Day 169
Study Days 159 – 179   
Cycle 9 Day 1
Study Day 225
Study Days 211 – 239
Cycle 12 Day 1
Study Day 309
Study Days 295 – 323 
         every 12 weeks
+ 84 day 
+84 days to lower and upper bound
Cycle 39 Day 1
Study Day 1065
Study Days 1051 – 1179
Safety follow-up
30 days after last dose
Last dose date + 30
Study Day 1 = start date of study treatment;
EOT assessments are mapped to the time points as needed.
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-2
Last contact date data sources
Source data
Conditions
Last contact date/last date patient was known to 
be alive from Survival Follow-up page 
Patient status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from new cGvHD treatment since 
discontinuation from study treatment
Non-missing medication/procedure term.
Start/End* dates from drug administration 
record/concomitant medication record 
Non-missing dose. Doses of 0 are allowed.
Date of discontinuation from end of treatment 
pages
No condition.
- cGvHD assessment date
Non-missing assessment.


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Source data
Conditions
- any specific efficacy assessment date if 
available (e.g. graft failure assessment, 
hematologic disease relapse/progression 
assessment)
Laboratory/PK collection dates/Biomarker 
collection dates
Sample collection marked as ‘done’.
Vital signs date
At least one non-missing parameter value.
Assessment date of development information 
(e.g. tanner staging)
Evaluation is marked as ‘done’.
Collection date of acceptability and palatability 
questionnaire 
Assessment performed is “Yes”.
Start/End dates of AE 
Non-missing verbatim term
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring if coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of patients in the analysis of overall survival,  
failure free survival, non-relapse mortality, and malignancy relapse/recurrence.
2.2
Analysis sets
If the starting dose is different from the assigned dose level due to co-administration of 
ruxolitinib with strong CYP3A4/CYP2C9 inhibitors, these subjects will be included under the 
assigned dose level and considered that they have received the full assigned dose. This applies 
to Full Analysis Set, Safety Set, and Pharmacokinetic analysis set as described below.
If the treatment formulation (tablet/liquid) changed during treatment, the subject will be 
considered under the formulation she/he started treatment. Nevertheless, a change in 
formulation will be flagged and may be considered for PK analyses. 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
and who received at least one dose of study treatment. 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined 
as the assigned dose level of ruxolitinib if the subject took at least one dose of that treatment or 
the first dose level received if the assigned dose level was never received.
The Pharmacokinetic analysis set (PAS) includes all subjects who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, subjects are required to:
•
Take the dose of ruxolitinib prior to PK sample


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•
For post-dose samples on Cycle 1 Day 1: do not vomit within 2 hours after the dosing of 
ruxolitinib
•
For pre-dose samples: have the sample collected before the next dose administration of 
ruxolitinib; do not vomit within 2 hours after the previous dosing of ruxolitinib prior to 
sampling.
The Listing only Set contains only those patients who are not eligible for efficacy analyses due 
to PD “Patient enrolled and treated beyond local regulatory requirements”. These patients will 
also not be included in safety summary analyses, but all safety data will be provided in listings, 
separately from the listings of all other patients. 
Patient Classification: 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific patient classification rules defined in 
Table 2-3. 
Patients with protocol deviation OTH12 “Patient enrolled and treated beyond local regulatory 
requirements” will only be included in the “Listing only Set” and not in any other analysis set.
Table 2-3
Patient classification based on protocol deviations and non-PD 
criteria
Analysis set
Protocol deviations 
leading to exclusion
Non protocol deviation leading to exclusion
FAS 
INCL01A, OTH12
Not applicable
Safety Set
INCL01A, OTH12
No dose of study treatment 
PK Analysis Set
INCL01A, OTH12, 
TRT01/ TRT02 
No dose of ruxolitinib, No evaluable PK 
concentration
Listing only Set
OTH12 (include only 
patients with this PD)
Not applicable
INCL01A - Written informed consent was not obtained
OTH12 - Patient enrolled and treated beyond local regulatory requirements
TRT01 - Starting dose of study drug (ruxolitinib) not per protocol-defined age-based schedule (Group 1 and 2).
TRT02 - Starting dose of study drug (ruxolitinib) not per protocol-defined age-based schedule (Group 3 and 4).
Withdrawal of Informed Consent
Any data collected in the clinical database before a patient signed informed consent or after a 
patient withdraws informed consent from all further participation in the trial, will not be 
included in the analysis. The informed consent data and the date on which a patient withdraws 
full consent is recorded in the eCRF.  


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2.2.1
Subgroup of interest
Efficacy
Subgroup analyses for efficacy endpoints will not be repreated for the final CSR.
The primary efficacy endpoint will be summarized by the following subgroups: 
•
Age group (please refer to Section 1.1 for the definition)
•
Age group and formulation (tablet vs liquid)
•
Treatment Naive cGvHD vs SR-cGvHD
•
Region EU+ROW except Turkey / Turkey / Asia excl. Japan / Japan
Note: ROW includes US, Canada, Australia and other countries (e.g. Russia). 
•
Chronic GvHD severity at baseline, moderate vs. severe (as reported on the staging CRF 
and not from the GvHD Disease History page).
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 90% confidence intervals will be provided. 
Safety
Key safety analyses will be repeated on the Safety Set in the following subgroups: 
•
Age group (please refer to Section 1.1 for the definition)
•
Treatment-naive cGvHD vs. SR-cGvHD
•
Region EU+ROW except Turkey / Turkey / Asia excl. Japan / Japan 
•
Chronic GvHD severity (moderate vs. severe)
For the final CSR safety subgroup analyses will be repeated for age groups and treatment-
naïve cGvHD vs. SR-cGvHD only.
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to or more commonly observed in a subgroup of patients.  The following 
summaries will be presented by subgroup:
•
Overview of adverse events
•
Serious AEs, irrespective of causality, by primary system organ class and preferred term
•
On-treatment deaths, by primary system organ class and preferred term 
These additional analyses will be provided only by age groups and by treatment-naive vs SR 
cGvHD:
•
AEs, irrespective of causality, by primary system organ class and preferred term
•
AEs with suspected relationship to investigational treatment, by primary system organ 
class and preferred term
•
Serious AEs with suspected relationship to investigational treatment, by primary system 
organ class and preferred term
•
Overview of adverse events of special interests


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Japanese patients
Analyses on the subgroup of Japanese patients will not be repeated for the final CSR.
Subgroup analyses may also be performed for the patients treated in Japan. No selection will 
be done on the basis of ethnicity, the purpose being to evaluate the population of patients living 
in Japan, not a specific ethnic set of patients. The analysis will be done the same way as in 
region subgroup specified above. 
2.3
Patient disposition, demographics and other baseline 
characteristics
Analyses on demographics, eligibility criteria, baseline disease characteristics, and other 
baseline data like medical history and prior treatments will not be repeated for the final CSR. 
The only analyses that need to be updated for the final CSR Section 14.1 are the tables on 
disposition and protocol deviations, as well as analysis sets.
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by Age group and for all patients, 
and listings will be reported by Age group to assess baseline comparability. No inferential 
statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by Age 
group. Categorical data (e.g. gender, race, ethnicity) will be summarized by frequency counts 
and percentages; the number and percentage of patients with missing data will be provided. 
Continuous data (e.g. age, weight, height, body surface area, body mass index) will be 
summarized by descriptive statistics (N, mean, median, standard deviation, minimum and 
maximum). 
Diagnosis and extent of disease
Summary statistics will be tabulated for diagnosis and extent of disease in underlying disease, 
stem cell transplant and chronic GvHD. 
For underlying disease, the analysis will include the following: primary diagnosis category and 
subcategory, details of primary diagnosis, time since diagnosis of underlying disease, CIBMTR 
risk assessment.
For transplant related disease history, the analysis will include the following: conditioning 
regimen type, total HCT-specific comorbidity index score, time since transplant, time from 
diagnosis of underlying disease to transplant, stem cell type, donor information including age, 
gender, HLA typing method, HLA match score, source of grafts (HLA matched related donor, 
unrelated UCB (umbilical cord blood), related haploidentical, HLA matched/mismatched URD 
(unrelated donor)),  T-cell depleted (Y/N), total nucleated cell dose. 


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For cGvHD disease history, the analysis will include the following: prior diagnosis of aGvHD, 
time since initial diagnosis of cGvHD, overall severity of initial cGvHD,  cGvHD severity at 
baseline (study entry), time since steroid refractory cGvHD, cGvHD organ involvement, steroid 
dose at baseline (study entry).
Medical history
Medical history and ongoing conditions, including underlying disease conditions and symptoms 
entered on eCRF will be summarized and listed by Age group.  The summaries will be presented 
by primary system organ class (SOC), preferred term (PT) and Age group. Medical history and 
current medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. The MedDRA version used for reporting will be specified in the CSR 
and as a footnote in the applicable tables/listings.
Other
All data collected at baseline including Tanner Staging will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
Age group and for all patients. The number (%) of treated  patients will be presented overall 
and by Age group. The number (%) of screened and not-treated patients and the reasons for 
screening failure will also be displayed. The number (%) of patients in the FAS who are still on 
treatment, who discontinued the treatment phases as well as the reason for discontinuation, and 
the long term follow-up will be presented overall and by Age group.
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category overall and by Age group for the FAS. All protocol deviations will be listed.
To assess the impact of COVID-19 pandemic on the conduct of the study, COVID-19 specific 
protocol deviations will be summarized and listed separately.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
Age group.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure to ruxolitinib will be summarized by Age group and by means of 
descriptive statistics. It will also be categorized into time intervals; frequency counts and 
percentages will be presented for the number (%) of patients in each interval. 


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Total daily dose, actual cumulative dose, dose intensity (DI) and relative dose intensity (RDI) 
will be summarized for ruxolitinib by Age group. 
The number (%) of patients who have dose reductions or interruptions, and the reasons, will be 
summarized for ruxolitinib by Age group.
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced by Age group.  
The Safety Set will be used for all summaries and listings of study treatment.
If more than one dose and/or formulation is assigned within one Age group, then summaries 
and listings will be reported by Age group as well as doses/formulation within the Age group
Duration of follow-up
The duration of follow-up time is defined as (date of last contact) – (date of first administration 
of investigational treatment) + 1. 
Duration of exposure to investigational treatment
Duration of exposure to investigational treatment (days) = (last date of exposure to 
investigational treatment) – (date of first administration of investigational treatment) + 1. 
If any subjects tapered off ruxolitinib and re-started ruxolitinib treatment due to cGvHD 
recurrence, two different definitions of duration of exposure will be distinguished:
•
Duration of exposure including taper off periods is defined as the time from first to 
very last date of ruxolitinib treatment, which includes the interveningperiod without 
treatment.
•
Duration of exposure excluding taper off periods is defined as above but deduct the 
interveningperiod without treatment for subjects who taper off and restart after cGvHD 
recurrence. These periods are captured as dose interruption with reason “dose tapering 
following response”.
Summary of duration of exposure of investigational treatment in days will include categorical 
summaries (based on clinically meaningful time intervals) and continuous summaries (i.e. 
mean, standard deviation etc.) using appropriate units of time.
Duration of exposure to investigational treatment in patient-years 
The duration of exposure to investigational treatment in patient-years is a total of the duration 
of exposure to investigational treatment in years from all the patients in the Age group. 
Duration of exposure to systemic corticosteroid 
Duration of exposure to systemic corticosteroid treatment (days) = (last date of exposure to 
systemic corticosteroid) – (date of first administration of systemic corticosteroid) + 1. 
Duration of exposure to systemic corticosteroid in patient-years 
The duration of exposure to systemic corticosteroid in patient-years is a total of the duration of 
exposure to systemic corticosteroid in years from all the patients in the Age group. 


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Cumulative dose
The planned cumulative dose for ruxolitinib refers to the total planned dose per protocol up to 
the last dose date. 
The actual cumulative dose of ruxolitinib refers to the total actual dose of ruxolitinib as 
documented in the Study Treatment eCRF. 
For patients who did not take any drug the cumulative dose is by definition equal to zero.
Dose intensity and relative dose intensity of ruxolitinib
Subjects receive ruxolitinib in doses twice a day (bid). For purposes of reporting dose intensity, 
a summary over the dose by day (total daily dose) is provided.
Dose intensity (DI) of ruxolitinib for patients with non-zero duration of exposure is defined as 
follows: 
DI (mg / day or mg/m^2/day) = Actual cumulative dose (mg or mg/m^2) of ruxolitinib / 
Duration of exposure to ruxolitinib (days).
In case the study includes subjects who taper off ruxolitinib and later re-start ruxolitinib 
treatment due to cGvHD recurrence, the duration of exposure excluding “taper off periods” will 
be used as denominator for dose intensity.
For patients who did not take any drug, the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (mg/day or mg/m^2/day) = Planned Cumulative dose (mg or mg/m^2) / Duration of 
exposure (days).
The PDI of ruxolitinib with daily dose schedule is according to protocol for the three age groups:
•
Age group 1: 20 mg/day
•
Age group 2: 10 mg/day
•
Age group 3: 8 mg/m2/day using the baseline BSA
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg / day or mg/m^2/day)  / PDI (mg / day or mg/m^2/day).  
The total daily dose, actual cumulative dose, DI and RDI up to last date of exposure to study 
treatment will be summarized.
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose reduction, or interruptions, and the reasons, will be 
summarized for ruxolitinib by Age group. Separate summaries will be generated for patients 
with dose change due to dose tapering (change of dose due to efficacy of treatment) and patients 
with dose change due to other reasons (potential safety concerns). The number of patients who 
have dose permanent discontinuations and the reasons will be summarized by Age group.
‘Type of change’ and ‘Dose permanently discontinued’ fields from the Study Treatment CRF 
pages will be used to determine the dose change, dose interruptions, and permanent 
discontinuations respectively.


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The corresponding fields ‘Reason for Change’ and ‘Reason for Permanent Discontinuation’ 
will be used to summarize the reasons.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption. 
Dose Reduction: A dose changed when the actual total daily dose is lower than the previous  
actual total daily dose A dose change due to dose tapering (change of dose due to efficacy of 
treatment) will not be considered as a dose reduction. Only dose changes that are indicated on 
the CRF as due to reason other than dose tapering, are taken into consideration. Number of 
reductions will be derived programmatically based on the change and the direction of the change.
2.4.2
Prior, concomitant and post therapies
Analyses on prior treatments or prophylaxis will not be repeated for the final CSR. 
2.4.2.1
Prior prophylaxis
The number and percentage of patients who received any prophylaxis (e.g. CNI) prior to start 
of study treatment will be summarized by lowest ATC class, preferred term and group using 
FAS. 
Listings will be generated for prophylaxis.
2.4.2.2
Systemic corticosteroid prior to start of study treatment
The number and percentage of patients who received systemic corticosteroids prior to study 
start will be summarized by Age group with number of days on steroids and peak daily dose, 
where doses of methylprednisolone will be converted to prednisone equivalents (see Section 
2.4.2.3).
2.4.2.3
Systemic corticosteroid during study treatment
As per protocol the steroid doses of methylprednisolone will be converted to prednisone 
equivalents by multiplying the methylprednisolone dose by 1.25. Prednisone doses for each 
subject are converted to mg/kg/day.
The duration of exposure will be summarized for systemic corticosteroid by Age group and 
disease history of treatment naive-cGvHD or SR-cGvHD at baseline. It will be categorized into 
time intervals; frequency counts and percentages will be presented for the number (%) of 
patients in each interval. The actual cumulative dose, dose intensity and relative dose intensity 
(relative to the starting dose of corticosteroids) will be summarized up to the Cycle 7 Day 1 
visit. Graphical display (box plots) will also be generated. These analyses will be based on 
Safety Set. 
For the final CSR these analyses will be done considering data up to end of study/LPLV date.


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2.4.2.4
Additional systemic cGvHD therapy
New additional systemic cGvHD therapy (medications and procedures) since start of study 
treatment will be listed and summarized by lowest ATC class, preferred term, overall and by 
Age group by means of frequency counts and percentages using FAS.
Initiation of systemic CNI at the time of or after start of study treatment despite absence of lack 
of efficacy will be counted as new additional systemic treatment. Note: Although the protocol 
does not explicitly prohibit initiation of systemic CNI at time of randomization or initiation of 
study treatment potential impact of CNI on efficacy outcome in responders cannot be excluded.
See Appendix Section 5.4.3 for more detailed specifications.
2.4.2.5
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy includes medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system and summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. The summaries using Safety Set will 
include:
•
Medications starting on or after the start of study treatment but no later than end of on-
treatment period; and
•
Medications starting prior to start of study treatment and continuing after the start of study 
treatment.
All concomitant therapies will be listed using Safety Set. Any concomitant therapies starting 
and ending prior to the start of study treatment or starting beyond end of on-treatment period 
will be flagged in the listing. 
In addition, a subset of concomitant medications i.e. hemopoietic cytokines and transfusions 
(red blood cells and platelets) will be grouped and summarized by Age group.
2.4.2.5.1 Calcineurin inhibitors (CNIs) during study treatment
The duration of exposure will be summarized for systemic CNIs (cyclosporine or tacrolimus) 
up to end of on-treatment period by Age group. It will also be categorized into time intervals; 
frequency counts and percentages will be presented for the number (%) of patients in each 
interval. These analyses will be based on Safety Set.


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2.5
Analysis of the primary objective
Analyses of the primary endpoint and related supportive analyses will not be repeated for the 
final CSR, if data has not changed compared to interim database lock.
The primary objective of the study is to evaluate the activity of ruxolitinib added to standard 
dose corticosteroids +/- CNI in pediatric subjects with moderate or severe treatment naive-
cGvHD or SR-cGvHD measured by Overall Response Rate (ORR) at Cycle 7 Day 1 based 
on all subjects in the study. The analysis will be performed based on FAS.
2.5.1
Primary endpoint
The primary efficacy variable of the study is overall response rate (ORR) at Cycle 7 Day 1, 
defined as the proportion of subjects demonstrating a complete response (CR) or partial 
response (PR), according to the NIH Consensus Criteria (Lee et al 2015) as reported in the CRF. 
Note that response is relative to the assessment of cGvHD at baseline.
•
Complete response is defined as complete resolution of all signs and symptoms of 
cGvHD in all evaluable organs without initiation of any new systemic therapy.
•
Partial response is defined as an improvement in at least one organ (e.g. improvement of 
1 or more points on a 4 to 7 point scale, or an improvement of 2 or more points on a 10 to 
12 point scale) without progression in other organs or sites, or initiation/ addition of new 
systemic therapies.
•
Lack of response is defined as unchanged, mixed response, or progression. (Please refer 
to Table 8-3 and Table 16-3 in the protocol for the definitions of "unchanged", "mixed 
response" and "progression".)
cGvHD Flare and cGvHD Recurrence are not considered as a treatment failure, unless they 
require a change or addition of another systemic treatment defined as below.
•
cGvHD Flare is defined as any increase in symptoms or therapy for cGvHD after an 
initial response (CR or PR). A cGvHD flare is not considered a treatment failure unless a 
change or addition of another systemic treatment, including CNIs, occurs.
•
cGvHD Recurrence is defined as the return of cGvHD disease after tapering off study 
treatment due to response. Following completion of a taper of systemic therapy, if 
worsening of cGvHD symptoms occur, the patient is allowed to resume treatment for 
cGvHD as per local institutional practice. For the statistical analyses, re-start of treatment 
for cGvHD is handled in the same way as addition or initiation of new systemic treatment.
2.5.2
Statistical hypothesis, model, and method of analysis
The response rates for ORR at Cycle 7 Day 1, will be estimated on the Full Analysis Set (FAS) 
for all the patients, when all subjects have completed 1 year of treatment or discontinued earlier. 
Confidence intervals of 90% will be calculated based on the exact method (Clopper and Pearson 
1934) for binominal distribution. Summary statistics (frequencies and percentages) will be 
provided. It is not planned to test any specific hypotheses related to the efficacy endpoint(s), 
but to provide estimates of efficacy endpoints in the pediatric population.


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2.5.3
Handling of missing values/censoring/discontinuations
Patients with missing assessments that prevent the evaluation of the primary endpoint will be 
considered non-responders. This includes missing overall cGvHD response assessments at 
baseline and/or Cycle 7 Day 1. The time window for the Cycle 7 Day 1 visit is defined in Table 
2-1 above.  
No data imputation will be applied. Patients who discontinue study treatment should return for 
the regular assessments indicated in Protocol Section 9.1. Addition or initiation of a new 
systemic therapy before Cycle 7 Day 1 will be considered a treatment failure, and patients will 
be counted as non-responder in the primary analysis.
2.5.4
Supportive analyses
Supportive analysis will include:
•
A detailed description of response rates (CR, PR. Unchanged, mixed response and 
progression) at Cycle 7 Day 1
•
A detailed description of the organ-specific response for all organs at Cycle 7 Day 1
•
If at least 18 subjects are enrolled with either first line vs. SR-cGvHD respectively, the 
ORR will be explored for treatment naive and SR subgroup subjects. 
This and further subgroups are described in Section 2.2.1.
The supportive analyses will be performed on the FAS. 
In addition, a sensitivity analysis will be done, where subjects with protocol deviations that may 
affect the primary endpoint are excluded from the analysis. These are following:
•
Prohibited concomitant medication administered during treatment period (COMD01)
•
Treatment naive or steroid refractory cGvHD corticosteroid treatment criteria not met 
(INCL04B)
•
Missing individual organ assessment at C1D1 (unless not possible) (OTH02)
•
Missing individual organ assessment at C4D1 or C7D1 (unless not possible) (OTH03)
•
Starting dose of study drug (ruxolitinib) not per protocol-defined age-based schedule 
(Group 1 and 2) (TRT01)
•
Starting dose of study drug (ruxolitinib) not per protocol-defined age-based schedule 
(Group 3 and 4) (TRT02)
•
In treatment naive cGvHD subjects, in addition to ruxolitinib, methylprednisolone (or 
equivalent prednisone) treatment was initially not given as part of study treatment 
(TRT03)
•
Patient did not take the ruxolitinib assigned dose (TRT08)
•
The ruxolitinib dose assigned on C1D1 (based on age) was changed before the subject 
completed C7D1 assessments (excluding dose adjustments for safety) (TRT09)


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•
Corticosteroid taper was initiated earlier than allowed as per protocol (excluding dose 
adjustments for safety) (TRT13)
•
Subject had a dose interruption of >21 days from ruxolitinib but was not permanently 
discontinued from ruxolitinib (WITH01)
•
Individual organ response assessment / overall response assessment not as per protocol 
response criteria (OTH14)
•
Patient was not compliant with study drug (Ruxolitinib); More than 7 days of 
consecutive insufficient treatment or overdosing or cumulated insufficient treatment 
over a period of 24 weeks is observed (TRT16)
Supportive analysis will be purely exploratory and are intended to explore the consistency of 
treatment effect. No inferential statistics (p-values) will be produced for the  subgroups.
2.6
Analysis of the key secondary objective
No key secondary objective has been planned.
2.7
Analysis of secondary efficacy objective(s)
The secondary objectives in this study include the assessment of: failure free survival (FFS), 
ORR at Cycle 4 Day 1 (end of Cycle 3), duration of response (DOR), overall survival (OS), 
non-relapse mortality (NRM), best overall response (BOR), cumulative incidence of 
malignancy relapse/recurrence (MR), reduction and successful tapering of corticosteroid 
treatment (Cycle 7 Day 1) and graft failure.
2.7.1
Secondary endpoints
Failure Free Survival
FFS is a composite time to event endpoint incorporating the following FFS events: i) relapse or 
recurrence of underlying disease or death due of underlying disease, ii.) non-relapse mortality, 
or iii.) addition or initiation of another systemic therapy for cGvHD. If a patient did not 
experience any of these events, FFS will be censored at the latest contact data (on or before the 
cut-off date). 
Best overall response (BOR)
Analyses of BOR at Cycle 7 Day 1 will not be repeated, whereas BOR up to end of study will 
be analyzed for the final CSR.
Best overall response (BOR) is defined as proportion of subjects who achieved overall response 
(CR or PR) at any time point up to and including Cycle 7 Day 1 and before the start of additional 
systemic therapy for cGvHD. 
An additional analysis will include all response assessments up to End of Treatment of the 
subjects or data cut-off date and before the start of additional systemic therapy for cGvHD. Note, 


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for subjects who tapered off, all response assessments, including those collected after 
ruxolitinib discontinuation, will be considered for the analysis. 
BOR will be calculated based on the FAS using local investigators’ overall response 
assessments.
ORR at Cycle 4 Day 1 (end of Cycle 3)
Analysis of ORR at Cycle 4 Day 1 will not be repeated for the final CSR.
ORR at Cycle 4 Day 1, defined as the proportion of patients with complete response (CR) or 
partial response (PR), according to the NIH Consensus Criteria (Lee 2015). ORR will be 
calculated based on the FAS using local investigators’ overall response assessed at the Cycle 4 
Day 1 visit and taking into account initiation or addition of new systemic therapy before this 
time point.
Duration of Response
Duration of response (DOR) is assessed only for responders up to Cycle 7 Day 1 (i.e. all subjects 
with BOR = CR or PR considering response assessments up to Cycle 7 Day 1). DOR is defined 
as the time from first response until cGvHD progression, death, or the date of additional 
systemic therapies for cGvHD. Subjects without event will be censored at the date of their last 
response assessment prior to or at the analysis cut-off date if no events occurred on or before 
12 weeks (84 days) after the last GvHD assessment.
An additional analysis of duration of response for responders up to data cut-off date will be 
done on all subjects with BOR considering all response assessments up to End of Treatment of 
the subjects or data cut-off date. Note, for subjects who tapered off, all response assessments 
up to End of Treatment even those collected after ruxolitinib discontinuation will be considered 
for the analysis.
Overall survival (OS)
Overall survival is defined as the time from date of treatment assignment to date of death due 
to any cause. If a patient is not known to have died, then OS will be censored at the latest date 
the patient was known to be alive (last contact date on or before the cut-off date). 
Non-Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time from date of treatment assignment to date of 
death not preceded by underlying malignant or non-malignant disease relapse/recurrence. 
Underlying disease relapse/recurrence is considered as competing events. If a patient is not 
known to have died or experienced the competing event, then NRM will be censored at the 
latest date the patient was known to be event-free (last contact date on or before the cut-off 
date).
Incidence of Malignancy Relapse/Recurrence (MR)
Incidence of Malignancy Relapse/Recurrence (MR), defined as the time from date of treatment 
assignment to date of relapse/recurrence of the underlying hematologic malignancy disease. 
NRM is considered as competing event. If a patient is not known to have a hematologic 
malignancy relapse/recurrence or died without relapse/recurrence, then incidence of MR will 


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be censored at the latest date the patient was known to be event-free (last contact date on or 
before the cut-off date).
Reduction of daily corticosteroid dose
Reduction of daily corticosteroid dose, is defined as the proportion of patients with ≥50% 
reduction from baseline in daily corticosteroid dose due to disease improvement at Cycle 7 
Day 1. 
For the final CSR the analyses will be done considering data up to end of study.
Reduction to low dose corticosteroids
Reduction to low dose corticosteroids, is defined as the proportion of subjects with reduction 
from baseline in daily corticosteroid dose to methylprednisolone-equivalent steroid dose of 
≤0.2mg/kg/day (or equivalent dose of ≤0.25mg/kg/day prednisone or prednisolone) due to 
disease improvement at Cycle 7 Day 1. 
For the final CSR the analyses will be done considering data up to end of study.
Graft Failure
This will be assessed by donor cell chimerism, defined as initial whole blood or marrow donor 
chimerism for those who had ≥ 5% donor cell chimerism at baseline. If donor cell chimerism 
declines to < 5% on subsequent measurements, graft failure is declared. 
2.7.2
Statistical hypothesis, model, and method of analysis
Failure Free Survival
The FFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 3, 6, 12, 18, 24 and 36 months FFS estimates and 95% confidence intervals 
(Brookmeyer and Crowley J. 1982) will be presented based on all subjects in the FAS.
The cumulative incidence curve of each of the three FFS components (considering the other 
two components as a competing risk) as well as estimates at 3, 6, 12, 18, 24 and 36 months will 
also be presented with 95% confidence intervals.
Best overall response (BOR)
BOR up to Cycle 7 Day 1 as well as BOR up to data cut-off date and its 90% confidence interval 
will be presented based on all subjects in the FAS.
ORR at Cycle 4 Day 1 (end of Cycle 3)
ORR (CR+PR) at Cycle 4 Day 1 and its 90% confidence interval will be presented based on all 
subjects in the FAS.
Duration of Response
Duration of response will be calculated for all patients with BOR = CR or PR up to Cycle 7 
Day 1 as well as for all patients with BOR up to data cut-off date = CR or PR. Kaplan-Meier 
method and the Kaplan-Meier curves, medians, 3, 6, 12, 18, 24 and 36 months survival 


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probabilities with 95% confidence intervals will be presented based on these responder subjects 
in the FAS.
Overall survival (OS)
The OS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 3, 6, 12, 24 and 36 month survival probabilities and 95% confidence intervals 
(Brookmeyer and Crowley J. 1982) will be presented based on all subjects in the FAS.
Non-Relapse Mortality (NRM)
Cumulative incidence of NRM and derived probabilities at Months 1, 2, 6, 12, 18, 24 and 36 
with 95% confidence intervals will be estimated based on all subjects in the FAS, considering 
underlying disease relapse/recurrence as competing events (Gooley et al. 1999).
Incidence of Malignancy Relapse/Recurrence (MR)
The cumulative incidence curve for MR and estimates at 3, 6, 12, 18, 24 and 36 months with 
95% confidence intervals will be presented for subjects with underlying hematologic malignant 
disease, accounting for NRM as the competing risk. In addition, the proportion of subjects who 
had hematologic malignancy relapse/recurrence and its 95% confidence interval at 3, 6, 12, 18, 
24 and 36 months will be presented for subjects with underlying hematologic malignant disease.
Reduction of daily corticosteroid dose
The proportion of subjects with ≥ 50% reduction from baseline in daily corticosteroid dose due 
to disease improvement at Cycle 7 Day 1, and its 95% confidence interval will be presented 
based on all subjects in the FAS. For the final CSR the analyses will be done considering data 
up to end of study.
Reduction to low dose corticosteroids
The proportion of subjects with reduction from baseline in daily corticosteroid dose to 
methylprednisolone-equivalent steroid dose of ≤0.2mg/kg/day (or equivalent dose of 
≤0.25mg/kg/day prednisone or prednisolone) due to disease improvement at Cycle 7 Day 1, and 
its 95% confidence interval will be presented based on all subjects in the FAS. For the final 
CSR the analyses will be done considering data up to end of study.
Graft Failure
The percentage of graft failure with 95% confidence intervals at 3, 6, 12, 18, 24 and 36 months 
will be presented based on all subjects in the FAS. In case of very few patients with graft failure 
(e.g. less than 5 patients), case descriptions using listings will be provided instead.
2.7.3
Handling of missing values/censoring/discontinuations
Patients with missing assessments that prevent the evaluation of the ORR at Cycle 4 Day 1 and 
BOR will be considered non-responders. This includes missing overall cGvHD response 
assessments at baseline and/or Cycle 4 Day 1. The time window for the Cycle 4 Day 1 visit is 
defined in Table 2-1 above.  


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2.8
Safety analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
Age group. For safety evaluations (except for AE), the last available assessment on or before 
the date of start of study treatment is taken as the “baseline” assessment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for (AEs) will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent Aes).
The on-treatment period lasts from the date of first administration of ruxolitinib to 30 days after 
the date of the last actual administration of ruxolitinib, see definitions in Section 2.1.1.
2.8.1
Adverse events (AEs)
For reporting of AEs, the overall observation period will be divided into mutually exclusive 
categories, including pre-treatment, on-treatment, post-treatment periods as defined in Section 
2.1.1.
AE summaries will include all Aes occurring (new or worsening) during on-treatment period. 
All Aes collected in the AE eCRF page will be listed along with the information collected on 
those Aes e.g. AE relationship to study drug, AE outcome etc. Aes with start date outside of 
on-treatment period will be flagged in the listings. 
Aes will be summarized by number and percentage of patients having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically, and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on the descending frequency in the ruxolitinib arm. 
The following adverse event summaries will be produced by group; overview of adverse events 
and deaths, Aes by SOC and PT, summarized by relationship (all Aes and Aes related to study 
treatment), seriousness (SAEs and non-SAEs), leading to treatment discontinuation, leading to 
dose interruption/adjustment, and leading to fatal outcome. 
In addition, summary table and listing will be provided for COVID-19 related Aes.
2.8.1.1
Adverse events of clinical trial safety disclosure 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables of on-
treatment/post-treatment adverse events which are not serious adverse events with an incidence 


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greater than 5% and  on-treatment/post-treatment deaths, serious adverse events and SAEs 
suspected to be related to study treatment will be provided by system organ class and preferred 
term on the safety set population. Events that occurred during on-treatment period and those in 
post-treatment period (see definitions in Section 2.1.1) will be reported separately.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
•
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
•
more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
2.8.1.2
Adverse events of special interest / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound ruxolitinib. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 
level terms) and/or PTs (preferred terms). Customized SMQs (CMQs) may also be used. A 
CMQ is a customized group of search terms which defines a medical concept for which there 
is no official SMQ available or the available SMQ does not completely fit the need. It may 
include a combination of single terms and/or an existing SMQ, narrow or broad. 
For each AESI, number and percentage of patients with at least one event of the AESI occurring 
during on-treatment period will be summarized. Summaries of AESIs will be provided by group 
(specifying grade, SAE, relationship, leading to treatment discontinuation, leading to dose 
adjustment/interruption, hospitalization, death etc.). 
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated. 
In addition to summarizing infections by CTCAE grade, they will also be summarized using 
infection severity (protocol Appendix 1) for the on-treatment period. A listing of infection with 
infection severity will be generated and the events with start date outside of on-treatment period 
will be flagged. 
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by Age group, system organ class and preferred term. 
All deaths will be listed, and deaths occurred outside of on-treatment period will be flagged. A 
separate listing of deaths prior to starting treatment will be provided for all screened patients.


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2.8.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than end of the on-treatment periods.
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.  The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and Age group):
•
Shift tables using CTC grades to compare baseline to the worst on-treatment  value 
•
For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The following listings will be produced for the laboratory data:
•
Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  
•
Listing of all CTC grade 3 or 4 laboratory toxicities
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
produced.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Not applicable.
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height or body length (cm), weight (kg), body temperature 
(°C), pulse (beats per minute), systolic and diastolic blood pressure (mmHg). The body surface 
area (BSA in m2) and body mass index (BMI in kg/m2) are derived using the following formulas:
BSA: (Height (cm) x Weight (kg) / 3600)0.5
BMI: Weight (kg) / Height2 (m2)


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Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings. 
Clinically notable vital sign criteria for blood pressure or weight (see below) are based on the 
height of the subject. Since height might not be measured at each visit, the last available height 
value before that assessment date will be used instead, i.e. using LOCF as imputation method.
Data analysis
For analysis of vital signs the clinically notable vital sign criteria depending on the patient’s age 
are provided in Table 2-4 below. Criteria should be applied according to the age at vital sign 
assessment rather than age at baseline.
Table 2-4
Criteria for notably abnormal vital signs
Clinically notable criteria
Vital sign (unit)
High
Low
Systolic blood pressure 
[mmHg]
≥ 95th percentile of the age and 
height group1
≤ 5th percentile of the age and 
height group1
Diastolic blood pressure 
[mmHg]
≥ 95th percentile of the age and 
height group1
≤ 5th percentile of the age and 
height group1
Body temperature [°C]
≥ 38.4°C
≤ 35.0°C
Pulse rate [bpm]2
12-<18 months
18-<24 months
2-<3 years
3-<4 years
4-<6 years
6-<8 years
8-<12 years
12-<15 years
≥ 15 years
> 140
> 135
> 128
> 123
> 117
> 111
> 103
> 96
> 92
12-<18 months
18-<24 months
2-<3 years
3-<4 years
4-<6 years
6-<8 years
8-<12 years
12-<15 years
≥ 15 years
< 103
< 98
< 92
< 86
< 81
< 74
< 67
< 62
< 58
Weight3
increase from baseline of ≥ 2 BMI-
for-age/gender percentile categories
decrease from baseline of ≥ 2 
BMI-for-age/gender percentile 
categories
Height4
increase from baseline of ≥ 2 height-
for-age/gender percentile categories
decrease from baseline of ≥ 2 
height-for-age/gender 
percentile categories
bpm=beats per minute; CDC= Centers for Disease Controls and prevention
1 Blood pressure percentiles are calculated for each blood BP record using the method described in Appendix 
B of the following reference: The Fourth Report on Diagnosis, Evaluation and Treatment of High Blood 
Pressure in Children and Adolescents. Pediatrics 2004; 114; 555.
2 Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children from 
birth to 18 years of age: a systematic review of observational studies. Lancet 2011; 377: 1011-18. 
3 BMI-for-age/gender percentiles categories (P3, P5, P10, P25, P50, P75, P85, P90, P95, P97) are obtained 
from the CDC Growth Charts.
4 Height-for-age/gender percentiles categories (P3, P5, P10, P25, P50, P75, P90, P95, P97) are obtained from 
the CDC Growth Charts.


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The number and percentage of patients with notable vital sign values (high/low) will be 
presented.
Graphical presentations of vital signs (e.g., body weight, body mass index, systolic blood 
pressure, diastolic blood pressure) over time for change from baseline may be produced via 
boxplots based on time windows and corresponding tables displaying the statistics used for the 
box plots by the selected time points.     
A listing of all vital sign assessments will be produced and notable values will be flagged. In 
the listing, the assessments collected outside of on-treatment period will be flagged. 
2.8.4.3
Cumulative incidence of severity grade ≥ 3 infection
Time to first occurrence of infection is defined as time from start of study treatment to the date 
of first occurrence of an infection of severity grade ≥ 3, i.e. time in days is calculated as (start 
date of first occurrence of infection with CTC grade ≥ 3) – (start of study treatment) +1. 
The cumulative incidence analysis will consider death or discontinuation from study treatment 
(due to any reason) without prior infection as competing risks. 
In the absence of an event during the on-treatment period, the censoring date applied will be 
the earliest of the following dates: 
•
data cut-off date
•
withdrawal of informed consent date
whereas dates for competing risks are:
•
death date
•
end date of on-treatment period
Cumulative incidence curves for time to grade ≥ 3 infections as well as summary tables for the 
number of subjects with event/competing risk/censored and cumulative incidence estimates at 
1, 2, 6 months etc. with 95% confidence intervals will be presented overall and for each age 
group (if sufficient number of patients are available in the age groups) as well as by treatment-
naive vs SR-cGvHD.
2.8.4.4
Acceptability and Palatability assessment
All acceptability and palatability assessment data of all subjects using liquid formulation will 
be summarized and listed by Age group in the final study report. 
2.8.4.5
Development (Growth and sexual maturation)
Growth
Graphical displays of percentile of height and weight over time will be provided for signal 
detection of impact on growth development. In case of a signal, further analyses may be 
provided. 
In addition, a shift tables for height, weight, and BMI will be provided using following 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment 
value. Low: below the 5th percentile, Normal: between 5th and 95th percentiles, High: above 
the 95th percentile. Percentiles are based on CDC Growth Charts, derivation is described below.


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Height and BMI will be summarized at 6-month intervals, using the standard deviation scores 
(SDS, also called z-score), velocity and velocity SDS as appropriate. The relevant height and 
weight values for each 6-month period are defined using time windows, according to Table 2-
1. The z-scores will allow identification of potential outliers.
SDS will be calculated using the current formulae provided by the CDC as follows:
Calculate zind = 
where:
•
X is height in centimeters or BMI in kilograms/m2,
•
L, M and S are height or BMI-, sex- and age-specific reference values from the CDC 
Growth Charts.
The CDC Height-for-age and BMI-for-age L, M and S reference values for males and females 
are available under https://www.cdc.gov/growthcharts. The age category immediately above 
the patient’s exact age should be used. SDS is actually a Z score that measures the distance from 
the population mean in units of standard deviations. That is, SDS < 0 refers to values lower than 
the population mean, and for example SDS ≤ -1.645 refers to values in the lowest 5%. The 
percentile  can be derived from the z-score by a normal distribution.
Height velocity is defined as follows:
Height velocity (cm/6-months) = (height in time window k – height in time window k-1) ÷ 
([assessment date in time window k – assessment date in time window k-1] ÷ [365.25/2]), 
and similarly for weight velocity. 
Velocity SDS is calculated as (velocity – mean) / SD, where mean and SD are obtained as the 
height-, weight-, sex- and age-specific values (Baumgartner et al 1986), where the age category 
immediately above the patient’s exact age (at the assessment date in time window k) should be 
used. Velocity SDS will only be calculated for time window k if data also exists for time 
window k-1, since calculating across multiple units of 6 months requires more than one 
reference value to be taken into account. 
All height/length, weight, BMI, standardized scores (percentile and SDS) will be listed.
Sexual maturation 
Sexual maturation will be monitored by the Tanner stages. Tanner stage includes two 
components for boys, namely genitalia stage and pubic hair stage, and two components for girls: 
breast development stage and pubic hair stage. The overall Tanner stage is derived by the 
maximum of the two stages (Tanner stage of pubic hair and Tanner stage of genitalia/breast 
development) from the same assessment.
Tanner stage will only be analyzed among pre-pubescent patients. Therefore, analysis will be 
based on patients from the Safety Set who were classified as Tanner Stage 4 or lower at the 
latest assessment prior to the start of study treatment.


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It is expected that data will become available during the trial on a proportion of patients as they 
go through puberty attaining higher levels of the Tanner Stage. The age at which Tanner Stages 
2-5 are achieved, and the age at menarche (females), will be displayed graphically and 
summarized descriptively (if sufficient number of patients are available). 
All available sexual maturation data will be included in the figures and listed.
2.9
Pharmacokinetic endpoints  
Analyses of PK data will not be repeated for the final CSR, since no PK samples were collected 
since interim CSR analyses..
Pharmacokinetic analysis set (PAS) will be used in all pharmacokinetic data analysis and PK 
summary statistics.
Pharmacokinetic variables:
Ruxolitinib concentration sparse profiles will be summarized by time point. Pharmacokinetic 
parameters, e.g. AUC0-12h and Cmax and Ctrough, may be determined using Population PK 
method(s) for ruxolitinib, and methods detailed in an independent analysis plan.
Statistical methods for pharmacokinetic analyses
Ruxolitinib concentrations data will be listed by Age group and formulation. Descriptive 
summary statistics will be provided by Age group/formulation at each scheduled time point. 
Summary statistics will include n (number of subjects with non-missing values), mean 
(arithmetic and geometric), standard deviation (SD), coefficient of variation (CV%) (arithmetic 
and geometric), median, minimum and maximum. Individual profiles with median by Age 
group/formulation as well as arithmetic mean with SD and geometric mean ruxolitinib plasma 
concentration versus time profiles by treatment will be displayed graphically.
Ruxolitinib plasma PK parameters data will be listed by Age group/formulation. Descriptive 
statistics (n, arithmetic mean, SD, CV% for mean, geometric mean, geometric CV%, median, 
minimum and maximum) will be provided for all PK parameters by Age group/formulation.
Population PK approach Concentration results from the sparse sampling will be analyzed 
using nonlinear mixed effects modeling (population PK) or other model-based approaches, as 
appropriate, and key pharmacokinetic parameters may be derived for the study population from 
sparse concentration-time data e.g. AUC, Cmax, Ctrough. Details of the analysis method will 
be developed in an independent PK analysis plan and the population PK analysis will be 
documented in a separate report.
During modeling of the pharmacokinetics of study treatment, the broad principles outlined in 
the Food and Drug Administration (FDA) guidance will be followed (Guidance for Industry: 
Population Pharmacokinetics; fda.gov/cder/guidance/1852fnl.pdf).
Data handling principles
All concentration values below the lower limit of quantitation (LLOQ) are set to zero by the 
Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values will be 
treated as zero in any calculations of summary statistics, and treated as missing for the 


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calculation of the geometric means and their CV%. The number of non-zero concentrations will 
also be reported in the summary statistics.
Missing values for any PK data will not be imputed and will be treated as missing.
2.10
PD and PK/PD analyses
Analyses of PK data will not be repeated for the final CSR.
Exposure-Response analysis
A detailed description of exposure-response analysis may be developed in an independent 
analysis plan if the data permits, and the analysis will be documented in a separate report. 
Briefly, the objectives are to:
•
Characterize the exposure-efficacy relationship of ruxolitinib in terms of concentration-
effect and dose-effect (effect: overall response rate at Cycle 7 Day 1; Overall survival at 
Cycle 4 Day 1, Cycle 7 Day 1 and 12 months). Exposure metrics will be described in 
further detail in the analysis plan.
•
Characterize the exposure-safety relationship of ruxolitinib in terms of concentration-AEs 
and/or dose-AEs (AEs: frequency of AEs, severity of AEs, AEs of special interest, time to 
onset of AEs). Exposure metrics will be described in further details in the analysis plan
•
Explore exposure-biomarker relationships as appropriate – immune cell subsets, 
inflammatory cytokine levels and soluble cGvHD biomarkers.
2.11
Patient-reported outcomes
Not applicable.
2.12
Biomarkers
Specified in a separate analysis plan and reported in a separate biomarker report.
2.13
Other Exploratory analyses
Chronic GvHD recurrence following completion of a taper of ruxolitinib
This analysis is performed only for patients who taper off ruxolitinib due to achieving a CR or 
PR. These subjects will be identified as they have reason “responder” for ruxolitinib permanent 
discontinuation on the exposure CRF. It’s planned to do this analysis at time of final CSR and 
only if sufficient number of subjects with cGvHD recurrence after tapering off occurred.
Time to recurrence is defined as the time from completion of a taper of systemic therapy until 
cGvHD recurrence. Patients without event will be censored at the last contact date. Kaplan-


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Meier method and the Kaplan-Meier curves as well as survival probabilities at appropriate time 
points will be presented with 95% confidence intervals (Brookmeyer and Crowley 1982). 
In case of single subjects (less than 5 subjects) with cGvHD recurrence after tapering off, data 
will be reported in listing only.
Systemic corticosteroid-free response rate
Systemic corticosteroid-free response rate is defined as the proportion of subjects taking no 
systemic corticosteroid therapy since at least 1 month (i.e. time between date of last 
corticosteroid drug intake and response assessment data is ≥ 30 days) and  demonstrating a 
complete response (CR) or partial response (PR), at any time post-baseline. Subjects who didn’t 
receive corticosteroids at baseline and still not taking corticosteroids at time of response will be 
considered as corticosteroid-free responder. Initiation of any new systemic therapy after 
cGvHD flare or recurrence, regardless when, means treatment failure and the subject is 
considered as non-responder. The endpoint is similar to the primary endpoint ORR, but 
considers all subjects who could not taper off systemic corticosteroids as non-responder 
regardless if they are in CR or PR, and considers all response assessments up to End of 
Treatment of the subject or data cut-off date.
Systemic corticosteroid-free response rate and its 90% confidence interval will be presented 
based on all subjects in the FAS and by subgroup of treatment naive cGvHD vs SR-cGvHD.
2.14
Interim analysis
In order to summarize one year of safety data, in addition to the primary efficacy analysis, an 
interim CSR will be reported when all subjects have completed 1 year of treatment or 
discontinued earlier. The final analysis will be performed and the final CSR produced after all 
subjects have discontinued from the study. The same SAP will be used for both the interim and 
final analysis.
Since the data for the primary efficacy assessment, ORR at Cycle 7 Day 1, will already be final 
once all subjects have completed 6 months of treatment, and in this clinical trial it is not planned 
to test specific hypotheses related to the efficacy endpoint(s), but to provide estimates of 
efficacy endpoints, no alpha adjustment will be made for the analysis of the primary endpoint.
3
Sample size calculation
The sample size for the primary objective of measuring ORR at Cycle 7 Day 1 is approximately 
42 subjects, regardless of age.
The sample size calculation is based on the ORR at Cycle 7 Day 1, and the calculation will 
consider the Saw-Toothed behavior of power waving for single binomial proportion using an 
exact method (Chernick and Liu 2002). Considering the response rate of children using 
corticosteroids is 30% to 50% (Wolff et al 2011), we assume the true ORR at Cycle 7 Day 1 of 
the study population is 70%, and therefore, a minimum sample size of 42 subjects would 
provide >80% probability to have a 90% CI with lower limit ≥ 50%. Table 3-1 provides 


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estimates of the probability to have a 90% CI with lower limit ≥ 50%, minimum number of 
responders required and two-sided 90% Clopper-Pearson CIs for various sample sizes.
Table 3-1
Probability to have a 90% CI with lower limit ≥ 50% and 90% 
confidence intervals for different number of subjects
Sample size
Minimum No.
of 
responders
Response 
Rate
Probability to have a 90% 
CI with lower limit ≥ 50%
90% CI
30
20
0.67
0.730
0.501
0.807
31
21
0.68
0.688
0.515
0.813
32
22
0.69
0.644
0.528
0.820
33
22
0.67
0.733
0.509
0.801
34
23
0.68
0.693
0.522
0.807
35
23
0.66
0.773
0.504
0.789
36
24
0.67
0.737
0.517
0.795
37
24
0.65
0.807
0.500
0.778
38
25
0.66
0.774
0.512
0.784
39
26
0.67
0.740
0.523
0.790
40
26
0.65
0.807
0.508
0.774
41
27
0.66
0.776
0.519
0.780
42
27
0.64
0.836
0.505
0.765
43
28
0.65
0.808
0.515
0.771
44
28
0.64
0.861
0.501
0.757
45
29
0.64
0.836
0.511
0.763
46
30
0.65
0.809
0.521
0.768
47
30
0.64
0.860
0.508
0.755
48
31
0.65
0.836
0.517
0.760
49
31
0.63
0.881
0.505
0.747
50
32
0.64
0.859
0.514
0.753
4
Change to protocol specified analyses
One exploratory analysis endpoints is added: 
Chronic GvHD recurrence following completion of a taper of systemic therapy (see Section 
2.13).


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5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date. 
Scenario 1 should not be applied for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available: 
Please note that date of assessment on EOT eCRF might be very different from last date of 
dose. 
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
            Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
            Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
            Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment: 
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.


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5.1.2
AE date imputation
Table 5-5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year
•
No imputation will be done for completely missing dates
day, month
•
If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 
•
If available year > year of study treatment start date then 01JanYYYY
•
If available year < year of study treatment start date then 01JulYYYY
day
•
If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.
•
If available month and year > month and year of study treatment start 
date then 01MONYYYY  
•
If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule 
(* if end date of the on-treatment period not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year
•
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 
day, month
•
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day
•
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications. 


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5.1.2.1
Other imputations
Incomplete date of initial diagnosis of cGvHD 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
The latest available MedDRA version at the time of the analyses should be used. The MedDRA 
version used should be specified in the footnote of relevant tables.  
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 4.03 at the time of analysis will be used. For laboratory 
tests where grades are not defined by CTCAE v4.03, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
CTCAE Grade 5 is not defined for laboratory values. For laboratory tests that are graded for 
both low and high values, summaries will be done separately and labelled by direction, e.g., 
sodium will be summarized as hyponatremia and hypernatremia.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) will 
be assigned as described above for grading.


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Statistical Analysis Plan
CINC424G12201
5.4
Statistical models
5.4.1
Primary analysis
Confidence interval for ORR
Responses will be summarized in terms of percentage rates with two-sided 90% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ 
with EXACT statement [Clopper and Pearson 1934]).
5.4.2
Key secondary analysis
Not applicable.
5.4.3
Definition of new or additional systemic treatment of cGvHD
The data source to search for the new or additional systemic therapy would be from eCRFs of 
“Prior and Concomitant Medication” (CONMED) or eCRFs “Prior or Concomitant non-drug 
therapies/procedures”. 
Systemic therapies are identified using the Route (if CMROUTE is Intramuscular, Intravenous, 
Oral, Subcutaneous, or Parenteral). Therapies with CMROUTE = ‘ORAL’ will be considered 
as systemic only if in addition CMADMIN = “SYSTEMIC”.
Any of the following therapies represent new or additional systemic therapy for cGvHD:
•
Any CNI therapy being initiated newly as ‘treatment for cGvHD’ or ‘treatment for SR-
cGvHD’ after the baseline (as recorded on CONMED). That means when a subject starts 
a new systemic therapy during study treatment for the indication ‘treatment for cGvHD’ 
or ‘treatment for SR-cGvHD’, or a subject received the same therapy before as 
prophylaxis and then changed to treatment of cGvHD/SR-cGvHD as indication, this 
will be considered as new or additional systemic treatment. 
CNI therapy given as ‘treatment for cGvHD’ or ‘treatment for SR-cGvHD’ that started 
after Cycle 1 Day 1 will be considered as new or additional systemic treatment, even if 
the same therapy was given as treatment for (SR-) cGvHD already before start of study 
treatment but the patient was not receiving such therapy on Cycle 1 Day 1. Whereas a 
stop of such therapy after Cycle 1 Day 1 and later re-start of the same therapy will not 
be considered as new or additional therapy.
Change of the drug within the defined group of CNIs or only change of the dose is not 
considered as new CNI treatment.
•
Any other systemic treatments (excluding CNI and steroids) being initiated newly as 
‘treatment for cGvHD’ or ‘treatment for SR-cGvHD’ after the baseline and documented 
in CONMED (according to the same definitions as for CNI treatments above).
•
Any other non-drug therapy/procedure being initiated newly as ‘treatment for cGvHD’ 
or ‘treatment for SR-cGvHD’ after the baseline (according to the same definitions as for 
CNI above) and documented on concomitant non-drug therapies/procedures (e.g. ECP).


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Statistical Analysis Plan
CINC424G12201
Changes in the systemic corticosteroid therapy (captured on study treatment eCRF), e.g. change 
of the drug, the dose or any interruption and re-start, will not be taken into account for 
identification of new or additional systemic therapy, nor will any other corticosteroid therapy 
(in CONMED) be considered.
6
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