Clinical trial NCT03491215
Conditions: Acute Graft Versus Host Disease
Keywords: Graft versus host disease GvHD acute graft versus host disease aGvHD Steroid refractory acute graft versus host disease SR-aGvHD Ruxolitinib INC424 allogeneic stem cell transplantation treatment naive
Sponsor: Novartis Pharmaceuticals
Start date: 2019-02-21; Completion date: 2023-02-02
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study was an open-label, single-arm, Phase I/II multi-center study to investigate the PK, activity and safety of ruxolitinib added to the patient's immunosuppressive regimen in infants, children, and adolescents ages ≥28 days to \<18 years old with either grade II-IV aGvHD or grade II-IV SR-aGvHD. The trial design included four age groups: Group 1 included patients ≥12y to \<18y, Group 2 included patients ≥6y to \<12y, Group 3 included patients ≥2y to \<6y, and Group 4 included patients ≥28days to \<2y.

Detailed description:
This Phase I/II, open-label, uncontrolled, single-arm, multi-center study investigated PK, activity and safety of ruxolitinib when added to the subject's immunosuppressive regimen in infants, children, and adolescents aged ≥ 28 days to \< 18 years with either grade II-IV treatment naive acute GvHD or grade II-IV SR-acute GvHD following allogeneic HSCT.

The trial subjects were grouped by age as follows:

* Group 1: subjects ≥ 12y to \< 18y,
* Group 2: subjects ≥ 6y to \< 12y
* Group 3: subjects ≥ 2y to \< 6y
* Group 4 was to include subjects ≥ 28 days to \< 2y

Subjects remained in the designated age group throughout the duration of the study, based on their age at the start of treatment. All subjects in this study were enrolled and treated for 24 weeks (approximately 6 months) or until early discontinuation.

All subjects were followed for an additional 18 months (total duration = 2 years from enrolment). Where the occurrence of acute GvHD flare require re-initiation of treatment or when extended tapering resulted in ruxolitinib not having been discontinued by the end of 24 weeks, subjects could continue to taper ruxolitinib beyond 24 weeks up to a maximum of 48 weeks.

Subjects ≥ 12 y to \< 18 y (Group 1) were treated with 10 mg BID, this dose was the RP2D, and was used to treat all subjects in this age group in Phase II of Study CINC424F12201. All other age groups were treated with the RP2D determined during Phase I of study CINC424F12201.

Therefore, all ≥12 to \<18 year old subjects were automatically enrolled in Phase II. The first 5 subjects treated in Group 1 underwent extensive PK sampling to inform the RP2D determination of the younger age groups in Phase I.

Arms: arm 1: All pediatric participants received ruxolitinib twice a day (BID) for a planned duration of 24 weeks in either tablet, capsule or oral solution (liquid), depending on the group they were in.
Interventions: intervention 1: Ruxolitinib
Intervention descriptions: intervention 1: All enrolled pediatric participants received ruxolitinib as a 5 mg tablet (adult and adolescent formulation) or an oral pediatric formulation (administered as oral solution or capsule dispersed in liquid).

Protocol documents:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................12
Amendment 3 ....................................................................................................................14
Amendment 2 ....................................................................................................................17
Amendment 1 ....................................................................................................................21
Protocol summary..............................................................................................................26
1
Introduction .......................................................................................................................30
1.1
Background............................................................................................................30
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment................................................................................................30
1.1.2
Introduction to investigational treatment(s) and other study 
treatment(s) ...........................................................................................32
1.2
Purpose ..................................................................................................................39
2
Objectives and endpoints...................................................................................................41
3
Study design ......................................................................................................................43
3.1
Phase I....................................................................................................................43
3.1.1
Determination of recommended Phase II dose .....................................44
3.2
Phase II ..................................................................................................................45
3.3
Study periods .........................................................................................................46
4
Rationale............................................................................................................................47
4.1
Rationale for study design .....................................................................................47
4.2
Rationale for dose/regimen and duration of treatment ..........................................48
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................49
4.4
Purpose and timing of interim analyses/design adaptations..................................49
4.5
Risks and benefits..................................................................................................49
4.6
Rationale for Public Health Emergency mitigation procedures ............................53
5
Population..........................................................................................................................53
5.1
Inclusion criteria ....................................................................................................54
5.2
Exclusion criteria...................................................................................................54
6
Treatment...........................................................................................................................56
6.1
Study treatment......................................................................................................56
6.1.1
Investigational and control drugs..........................................................57


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6.1.2
Additional study treatments ..................................................................58
6.1.3
Treatment arms/group ...........................................................................58
6.1.4
Guidelines for continuation of treatment ..............................................58
6.1.5
Treatment duration................................................................................58
6.2
Other treatment(s)..................................................................................................60
6.2.1
Concomitant therapy.............................................................................60
6.2.2
Prohibited medication ...........................................................................61
6.2.3
Rescue medication ................................................................................62
6.3
Subject numbering, treatment assignment, randomization....................................62
6.3.1
Subject numbering ................................................................................62
6.3.2
Treatment assignment, randomization ..................................................63
6.4
Treatment blinding.................................................................................................63
6.5
Dose escalation and dose modification..................................................................63
6.5.1
Dose escalation guidelines....................................................................63
6.5.2
Dose modifications................................................................................64
6.5.3
Follow-up for toxicities.........................................................................71
6.6
Additional treatment guidance...............................................................................73
6.6.1
Treatment compliance...........................................................................73
6.6.2
Emergency breaking of assigned treatment code..................................73
6.7
Preparation and dispensation.................................................................................73
6.7.1
Handling of study treatment and additional treatment..........................74
7
Informed consent procedures ............................................................................................75
8
Visit schedule and assessments .........................................................................................76
8.1
Screening ...............................................................................................................80
8.1.1
Eligibility screening ..............................................................................81
8.1.2
Information to be collected on screening failures.................................81
8.2
Subject demographics/other baseline characteristics.............................................81
8.3
Treatment Period ...................................................................................................82
8.4
Efficacy..................................................................................................................82
8.4.1
Staging and Response assessments.......................................................82
8.4.2
Appropriateness of efficacy assessments..............................................86
8.5
Safety.....................................................................................................................86
8.5.1
Physical examination ............................................................................86
8.5.2
Vital Signs.............................................................................................86
8.5.3
Height and weight .................................................................................86
8.5.4
Laboratory evaluations..........................................................................86
8.5.5
Pregnancy and assessments of fertility .................................................89


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8.6
Additional assessments..........................................................................................90
8.6.1
Pharmacokinetics ..................................................................................90
93
94
9
Discontinuation and completion........................................................................................94
9.1
Discontinuation from study treatment and from study..........................................94
9.1.1
Discontinuation of study treatment .......................................................94
9.1.2
Withdrawal of informed consent/ opposition to use data/biological 
samples..................................................................................................95
9.1.3
Lost to follow-up...................................................................................96
9.1.4
Early study termination by the sponsor.................................................96
9.1.5
Follow up for safety evaluations...........................................................97
9.2
Study completion and post-study treatment ..........................................................97
10 Safety monitoring reporting and committees ....................................................................98
10.1
Definition of adverse events and reporting requirements......................................98
10.1.1
Adverse events ......................................................................................98
10.1.2
Serious adverse events ........................................................................100
10.1.3
SAE reporting......................................................................................100
10.1.4
Pregnancy reporting ............................................................................101
10.1.5
Reporting of study treatment errors including misuse/abuse..............102
10.1.6
Laboratory Test Abnormalities ...........................................................102
10.1.7
Adverse events of special interest.......................................................102
10.2
Additional Safety Monitoring..............................................................................102
10.2.1
Liver safety monitoring.......................................................................102
10.3
Committees..........................................................................................................102
10.3.1
Data Monitoring Committee ...............................................................102
10.3.2 
Steering Committee.............................................................................103
11 Data Collection and Database management....................................................................103
11.1
Data collection.....................................................................................................103
11.2
Database management and quality control..........................................................103
11.3
Site monitoring ....................................................................................................104
11.4
Data Confidentiality.............................................................................................104
12 Data analysis and statistical methods ..............................................................................105
12.1
Analysis sets ........................................................................................................105
12.2
Subject demographics and other baseline characteristics....................................106
12.3
Treatments ...........................................................................................................106


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12.4
Analysis of the primary endpoint(s) ....................................................................106
12.4.1
Definition of primary endpoint(s).......................................................107
12.4.2
Statistical model, hypothesis, and method of analysis........................108
12.4.3
Handling of missing values/censoring/discontinuations.....................108
12.4.4
Sensitivity and Supportive analyses....................................................108
12.5
Analysis of secondary endpoints .........................................................................108
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)..................................108
12.5.2
Safety endpoints..................................................................................110
12.5.3
Other endpoints...................................................................................112
12.5.4
Pharmacokinetics ................................................................................112
113
113
114
12.7
Interim analyses...................................................................................................115
12.8
Sample size calculation........................................................................................115
12.8.1
Primary endpoint(s).............................................................................115
13 Ethical considerations and administrative procedures ....................................................117
13.1
Regulatory and ethical compliance......................................................................117
13.2
Responsibilities of the investigator and IRB/IEC................................................117
13.3
Publication of study protocol and results.............................................................117
13.4
Quality Control and Quality Assurance...............................................................117
14 Protocol adherence ..........................................................................................................118
14.1
Protocol Amendments .........................................................................................118
15 References .......................................................................................................................119
16 Appendices ......................................................................................................................123
16.1
Appendix 1: Infection Severity Grading..............................................................123
16.2
Appendix 2: Grading of Chronic GvHD (NIH Criteria) .....................................127
16.3
Appendix 3: Hematologic Disease Relapse.........................................................131
16.4
Appendix 4: HCT Specific Comorbidity Index Score.........................................133
16.5
Appendix 5: CIMBTR classification...................................................................134
16.6
Appendix 6: List of CYP3A4 inhibitors and inducers.........................................144
List of tables
Table 2-1
Objectives and related endpoints ..........................................................41
Table 3-1
Phase I: Age groups and dosing rationale.............................................44
Table 3-2
Phase II: Age groups and dosing rationale............................................45
Table 6-1
Dose and treatment schedule.................................................................57


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Table 6-2
Guidance for provisional doses (Example)...........................................64
Table 6-3
Criteria for interruption and re-initiation of ruxolitinib treatment 
for adverse events suspected to be drug-related....................................66
Table 6-4
Dose reduction steps for ruxolitinib......................................................70
Table 6-5
Dose re-escalation levels for ruxolitinib ...............................................70
Table 6-6
Assessments to determine cause of LFT abnormalities........................72
Table 6-7
Preparation and Dispensing...................................................................73
Table 6-8
Packaging and labeling .........................................................................74
Table 6-9
Supply and Storage of Study Treatment ...............................................74
Table 8-1
Assessment Schedule ............................................................................77
Table 8-2
Acute GvHD Staging Criteria (Harris et al 2016).................................83
Table 8-3
Response assessment.............................................................................84
Table 8-4
Local clinical laboratory parameters collection plan ............................86
Table 8-5
Ruxolitinib Pharmacokinetic blood collection for extensive PK*........91
Table 8-6
Ruxolitinib Pharmacokinetic blood collection log for sparse PK in 
Group 4..................................................................................................92
Table 8-7
Ruxolitinib Pharmacokinetic blood collection log for sparse PK*.......92
93
Table 12-1
Non-compartmental pharmacokinetic parameters of ruxolitinib........112
Table 12-2
Probability to have a 90% CI with lower limit ≥ 60% and 90% 
confidence intervals for different number of patients.........................116
Table 16-1
Severity grading table and recurrence interval definitions .................123
Table 16-2
Four age groups relevant to HCT........................................................126
Table 16-3
HCT Specific Comorbidity Index Score.............................................133
Table 16-4
CIBTMR disease risk index................................................................134
Table 16-5
List of CYP3A4 inhibitors and inducers.............................................144
List of figures
Figure 3-1
Study Design .........................................................................................44
Figure 3-2
Study Visit Schematic...........................................................................47


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List of abbreviations
aBFM
Augmented Berlin-Frankfurt-Munster 
ADR
Adverse Drug Reaction
ADV
Adenovirus
AE
adverse event
AESI
adverse event of special interest
aGvHD
Acute Graft vs. Host Disease
alloSCT
Allogeneic Stem Cell Transplantation
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
Absolute Neutrophils Count
anti-HBc
Hepatitis B core antibody
APC
Antigen-Presenting Cells
APPT
Activated partial thromboplastin time
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
ATG
Anti-thymocyte globulin
AUC
Area under the concentration-time curve
b.i.d.
twice a day
BAT
Best Available Therapy
BCC
Basal Cell Carcinoma
BCS
Biopharmaceutical Classification System
BLQ
Below the Limit of Quantitation
BM
Bone Marrow
BMI
Body Mass Index
BOR
Best Overall Response
BSA
Body Surface Area
BUN
blood urea nitrogen
cGvHD
chronic Graft vs. Host Disease
CI
Confidence Interval
CIBMTR
Center for International Blood and Marrow Transplant Research
CK
creatinine kinase
CLcr
Creatinine clearance
cm
centimeter
Cmax
Maximum concentration
CMO
Chief Medical Office 
CMV
cytomegalovirus
CNI
Calcineurin Inhibitor
CNS
Central Nervous System
CPO
Country Pharma Organization
CR
Complete response
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events


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CTD
Connective Tissue Disease
Ctrough
Minimum concentration
CTT
Clinical Trial Team
CV
coefficient of variation
CXCR3
Chemokine receptor 3
CYP3A
Cytochrome P450, family 3, subfamily A
DHEA
Dehydroepiandrosterone
DILI
Drug-Induced Liver Injury
DLCO
Diffusing capacity of the lung for carbon monoxide
DLI
donor leukocyte infusion
DMC
Data Monitoring Committee
DOR
Duration of Response
EBV
Epstein-Barr Virus
EC
Ethics committee
ECG
Electrocardiogram
ECP
Extracorporeal Photopheresis
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
EES
Efficacy Evaluable Set
EF
ejection fraction
EFS
Event-Free Survival
EOS
End of Study
EOT
End of Treatment
eSAE
Electronic Serious Adverse Event
ET
Essential Thrombocythemia
FAS
Full Analysis Set
FEV1
Forced expiratory volume in 1 second
FFS
Failure-Free Survival
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GFR
Glomular Filtration Rate
GGT
Gamma glutamyl transferase
GvHD
Graft vs. Host Disease
GvL
Graft vs. Leukemia
h
hour
h.nM
nanoMolar x hour
HBsAb
Heptatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCT
Hematopoietic Cell Transplantation
HCV
Hepatitis C Virus
HDL
High Density Lipoprotein
HDPE
High-density polyethylene
HHV-6
Human Herpes Virus
HIV
human immunodeficiency virus


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HLA
Human Leukocyte Antigen
HR
Hazard Ratio
HSCT
Hematopoietic stem cell transplantation
HSV
Herpes Simplex Virus
i.v.
intravenous
IB
Investigator Brochure
ICF
Informed consent form
ICH
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use
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
Intra-Uterine System
JAK
Janus kinase
LC-MS/MS
liquid chromatography-tandem mass spectrometry
LDH
lactate dehydrogenase
LDL
Low Density Lipoprotein
LFS
Leukemia-Free Survival
LFT
Liver function test
LLN
lower limit of normal
LLOQ
Lower limit of quantification
LMWH
Low Molecular Weight Heparin
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDS
Myelodysplastic Syndromes
MedDRA
Medical dictionary for regulatory activities
MF
Myelofibrosis
mg
milligram(s)
mL
milliliter(s)
MM
Multiple Myeloma
MMF
Mycophenolate mofetil
mPBSC
mobilized Peripheral Blood Stem Cells
MPNs
Myeloproliferative Neoplasms
MR
Malignancy Relapse/Progression
MSC
Mesenchymal Stromal Cells
MTD
Maximum Tolerated Dose
MTX
Methotrexate
NCA
Non-compartmental analysis
NG
Nasogastric
ng.h/mL
nanograms x hour/ milliliter


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NHL
Non-Hodgkin lymphoma
NIH
National Institutes of Health
NMSC
Non-Melanoma Skin Cancer
NR
No Response
NRM
Non Relapse Mortality
NSAID
Nonsteroidal anti-inflammatory drugs
OR
Overall Response
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PBPK
Physiologically based pharmacokinetic
PCR
Polymerase chain reaction
PD
pharmacodynamic(s)
PET
Positron emission tomography
PHI 
Protected Health Information
PIP
pediatric investigation plan
PK
pharmacokinetic(s)
PLL
Prolymphocytic leukemia
PLT
Platelets
PML
Progressive Multifocal Leuko-Encephalopathy
PR
Partial response
PS
Patient Safety
PT
Prothrombin Time 
PTT
Partial thromboplastin time
PV
Polycythemia Vera
QD
quaque die, once a day
QMS
Quality Management System
QOL
Quality of Life
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
RARS
Refractory Anaemia with Ring Sideroblasts
RBC
red blood cell(s)
REB
Research Ethics Board
RP2D
Recommended Phase II Dose
RSV
Respiratory Syncytial Virus
SAE
serious adverse event
SAP
Statistical analysis plan
SC
Steering Committee
SCC
Squamous Cell Carcinoma
SCT
Stem cell transplantation
SD
Standard Deviation
SDS
Standard Deviation Score, z-score
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase


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SLE
Systemic lupus erythematosus
SMQ
Standardized MedDRA Query
SOC
Standard of Care
SOP
Standard Operating Procedure(s)
SR-
aGvHD
Steroid Refractory acute Graft vs. Host Disease
SR-BOS
Bronchiolitis Obliterans Syndrome
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1/2
Half-life
TB
Tuberculosis
TBIL
Total Bilirubin
Tmax
Time to reach the peak concentration
TNF
Tumor Necrosis Factor
TYK2
Tyrosine kinase 2
UCB
Umbilical Cord Blood
ULN
upper limit of normal
VGPR
Very good partial response
VZV
Varicella Zoster
WBC
white blood cell(s)
WoC
Withdrawal of Consent


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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 patient.
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.
Cohort
A specific group of subjects fulfilling certain criteria
Discontinuation from Study 
Treatment
Point/time when the patient permanently stops receiving the study treatment for 
any reason (prior to the planned completion of study drug admnistration, if 
any). Patient 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 study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 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; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol).
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up), which applies 
across all arms of a study.
Group
Subdivision of patients based on age for this study. Four groups have been 
defined in the study as follows: 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)
Healthy Volunteer
A person with no known significant health problems who volunteers to be a 
study patient.
Investigational drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance”
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 each study drug package in studies that 
dispense study drug using an IRT system.
Medication pack number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system
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 or by nasogastric 
tube, to pediatric patients.
Other Treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy).


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Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease.
Patient/Subject
An individual with the condition of interest and/or who has consented to 
participate in this study (or has been consented by a legal representative).
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
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 administration and assessments; at this time all 
study drug administration is discontinued, and no further assessments are 
planned.
Randomization
The process of assigning trial patients to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias.
Screen Failure
A subject who is screened but is not treated or randomized
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.
Study completion
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later.
Study drug discontinuation
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal.
Study drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy.
Study treatment
Any drug administered to the study patients as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date
Subject
An individual who has consented to participate in this study (or has been 
consented by a legal representative).
Subject number
A number assigned to each subject who enrolls in the study. When combined 
with the center number, a unique identifier is created for each subject in the 
study.
Treatment Arm/Group
A treatment arm/group defines the dose and regimen or the combination and 
may consist of 1 or more cohorts.
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.
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 futher 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 3
Amendment rationale
As of 11Feb2021, CINC424F12201 completed enrollment with a total of 45 patients, which 
included 29% treatment-naive patients and 71% SR-aGvHD patients. Treatment by Group 
consisted of 18 patients in Group 1 (age ≥12y to < 18y), 12 patients in Group 2 (age ≥6y to 
<12y) and 15 patients in Group 3 (age ≥2y to <6y).
The main purpose of this amendment to include public health emergency disruption proofing 
language, to provide guidance on patient management, including withdrawal of consent, and to 
decrease the minimum enrollment requirement of treatment-naive patients from 40% to at least 
20% due to recruitment challenges. The sample remains representative of the study population 
and therefore the sample size was not re-estimated due to this modification.
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.
Glossary of terms: updated with additional terminology that appear throughout the protocol and 
require further explanation.
The word “participant” and/or “subject” has been updated throughout the document to “patient” 
in order to remain consistent throughout the protocol document.
Protocol Summary, Population: text modified to reflect enrollment of at least 20% treatment-
naive patients
Section 1.1.2.1: Updated to include approval of ruxolitinib for treatment of aGvHD and cGvHD.
Section 1.1.2.1 and Section 1.1.2.1.2: Updated the number of patients from approximately 370 
to more than 550 healthy 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 3.2: text modified to reflect the enrollment of at least 20% treatment naïve aGvHD 
patients
Section 4.5: text has been added to clarify that there is no substantial risk to subject safety as it 
relates to SARS-COV-2 and the COVID-19 pandemic
Section 4.6: Rationale for Public Health Emergency mitigation procedures have been added.
Section 5: text modified to reflect enrollment of at least 20% treatment naïve aGvHD patients 
in final study population


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Section 6.1.3: Updated to remove 40% total from either subpopulation due to change in 
treatment-naive and steroid refractory enrollment
Section 6.2.2: text added to include that the use of live attenuated vaccines is prohibited
Section 6.3.2: text updated to reference the minimum enrollment targets of treatment naïve 
aGvHD patients; text clarified to state that IRT enrollment will be capped to align with each 
subpopulation.
Section 6.5.2.1: text has been added to clarify that permanent treatment discontinuation from 
study treatment is mandatory for specific events indicated in Table 6-3 or listed in Section 9.1.1
Section 6.5.2.1.3: Header updated from “study treatment discontinuation” to “discontinuation 
from study treatment
Section 6.5.3.1 Updated to spell out T1D and CVD 
Section 7: Updates made to this section to align with protocol template version 5.0 and to 
include language on managing informed consent in case of a public health emergency
Section 8: Visit schedule and assessments updated to align with protocol template version 5.0 
including language on managing patients who discontinue from study or withdraw consent, 
language regarding managing visits in the event of a Public Health emergency, and an 
administrative correction to the word “subjects”.
Table 8-3 Updated to add “Opposition to use data / biological samples” per protocol template 
version 5.0
Table 8-5 Removal of “PK collection number/dose reference ID” 101
Section 8.5: Updates made to this section related to a public health emergency, to align with 
protocol template version 5.0
Section 9 and Section 9.1: Header updated to clarify “Study treatment discontinuation” and to 
distinguish between study discontinuation and study treatment discontinuation
Section 9.1.1:  text updated to distinguish between study treatment discontinuation and study 
discontinuation
Section 9.1.2: Header and section text updated to clarify withdrawal of informed consent and 
opposition to use data/biological samples; includes the option for patient to present opposition 
to use of data /biological samples at time of withdrawal of consent and a requirement that a 
request to withdraw consent should be in writing
Section 9.1.3: text added to distinguish between study treatment discontinuation and study 
discontinuation
Section 9.1.4: text added to clarify discontinuation from study treatment
Section 10: Header updated to include “and Committees”, per protocol template version 5.0
updates
Section 10.1.3: text updated with safety reporting timelines, per protocol template version 5.0; 
text updated to incorporate requirement that all SAEs will be collected until the end of long 
term follow up regardless of causality for patients enrolled in Denmark and Germany.


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Section 12.1: The definition of analysis sets were clarified to consider patients that have been 
treated with the full assigned dose as a result of co-administration with strong CYP3A4 or dual 
CYP3A4/CYP2C9 inhibitors.
Section 12.8: text modified to reflect enrollment of at least 20% treatment-naive patients. The 
sample size remains representative of the study population and therefore the sample size was 
not re-estimated due to this modification.
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 2
Amendment rationale
As of 14-Oct-2020, 30 patients have been enrolled into CINC424F12201, which includes 12
patients in Group 1 (age ≥12y to < 18y), 10 patients in Group 2 (age ≥6y to <12y) and 8 patients 
in Group 3 (age ≥2y to <6y).
The main purpose of amendment 2 is to update the guidelines regarding the management of 
ruxolitinib based on liver monitoring laboratory results, to update the inclusion criteria to allow 
for nasogastric tube administration of the pediatric formulation, to provide clarifications 
regarding the management of ruxolitinib tapering, to update contraception guidelines and 
pregnancy reporting requirements for female patients of child-bearing potential and to clarify 
requirements for ruxolitinib post-trial access.
The assessment of benefit and risk related to SARS-CoV-2 virus and the COVID-19 pandemic 
determined no substantial additional risk for patient safety at this time.
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:
Glossary of terms: the definition of “oral pediatric formulation” was added.
Amendment 1 rationale summary section: updated to further clarify that the patients in the 
safety and efficacy evaluations (increased to 45 patients) would be treated at the Recommended 
Phase II dose (RP2D).
Protocol Summary and Section 2, Secondary endpoints: clarification addressed regarding the 
acceptability and palatability assessments secondary endpoint as the “Responses from the
acceptability and palatability questionnaire for dose forms used after the first dose, 1 month 
and 6 months.” 
Section 1.1.2.1 and Section 1.1.2.1.2: Updated the number of patients from more than 8,500 to 
more than 10,250 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 Jagasia et al 2020 and Zeiser 
et al 2020.
Section 3 and Section 3.1.1: text added to clarify that patients may undergo extensive PK 
sampling “until the dose/exposure is confirmed”, should one or more patients not be evaluable.
Section 3.1.1: clarified criteria for intra-patient dose de-escalation in addition to the already 
referenced intra-patient dose escalation. 
Section 3.1.1 and Section 6.5.1: text added to clarify that a minimum of 5 patients within Phase 
I will undergo extensive PK sampling.
Section 3.2 and Table 3-2: text added to clarify that at least 45 patients treated with the 
confirmed RP2D will be enrolled in the study.


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Section 3.3: text clarified to reference discontinuation criteria as referenced in Section 9.1.1.
Section 4.5: text added to clarify that viral load titer data will be documented “when results are 
available”.
Section 5.1: Inclusion Criteria #3; clarification text added, stating “or per physician decision in 
case institutional criteria are not available” to permit Investigator decision if steroid-refractory 
institutional criteria are not available.
Section 5.1: Inclusion criteria #5: permits the administration of the ruxolitinib pediatric 
formulation by nasogastric (NG) tube, if applicable.
Section 5.2: Exclusion Criteria #24; reference to local regulations regarding contraception 
methods added.
Section 6.1: text removed to better clarify that study treatment for SR-aGvHD patients includes 
concomitant use of corticosteroids +/- cyclosporine or tacrolimus. 
Section 6.1: text updated to state that patients “should” (instead of “may”) receive standard 
alloSCT supportive care, including anti-infective medications and transfusion support.
Section 6.1: previously omitted text was added to clarify the sentence “Other systemic 
medications used for prophylaxis of aGvHD may be continued after Day 1 only if “started” 
prior to diagnosis of aGvHD.”
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.
Section 6.1.1: the statements “Patients should remain on the same formulation throughout study 
participation” and “Any changes in formulation requires approval from the Sponsor” were 
added to provide guidance on the management of formulations used to dose patients in the 
study.
Section 6.1.1: statement removed and replaced with guidance to address dose adjustments based 
on age and BSA changes during study participation.
Section 6.1.1. and Table 6-1: text added to reference that the oral pediatric formulation can be 
administered orally or by nasogastric tube.
Section 6.1.5: text modified to clarify the criteria for managing study treatment based on patient
response at Day 28.
Section 6.1.5.1: example provided to further clarify tapering and dose reduction of ruxolitinib 
based on patient response.
Section 6.2.1.2, Section 6.2.2, and Section 6.5.2.1.4 and Section 16.6: the maximum 
fluconazole dose clarified as 6 mg/kg (maximum 200mg) daily to better represent pediatric 
dosing.
Section 6.2.2: Clarification added regarding the prohibited use of systemic nonsteroidal anti-
inflammatory drugs (NSAIDs).
Section 6.5.2.1.2: the word “non-hematological” added to provide clarification regarding action 
with ruxolitinib attributed to non-hematological AEs.




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Section 9.1.5: visit window (+ 3 days) assigned to the safety follow-up visit; text added to clarify 
that patients who remain on ruxolitinib at week 48 and obtain access to ruxolitinib outside of 
the study will not conduct the safety follow-up visit since study treatment will continue.
Section 9.2: criteria for access to post-trial treatment revised to align with post-trial access 
eligibility criteria.
Section 9.2: text added that permits a patient to switch ruxolitinib formulations upon completion 
of CINC424F12201 and enrollment into post-trial access.
Section 10.1.4: text added to clarify pregnancy reporting requirements.
Section 10.2.1: section added to ensure reference to Section 6.5.3.1 for liver safety monitoring.
Section 12.5.3: new section added, titled “Other Endpoints”; the Acceptability and Palatability 
assessment was removed from the safety endpoint section and listed under other endpoints to 
align with Section 8.6.
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 27-Feb-2019, 1 patient has been enrolled into the trial.
The main purpose of the amendment is to broaden the eligible patient population, modify study 
assessments and revise safety dose modifications based on feedback from investigators on 
current practices in the management of aGvHD. The number of patients will be expanded to a 
total of 45 patients treated at the Recommended Phase II dose (RP2D) , thus increasing the 
number of patients for safety and efficacy evaluation.
Inclusion/Exclusion Criteria
Inclusion Criteria #3:
The clinical confirmation of grades II-IV aGvHD for study inclusion purposes will be based on 
the investigator’s clinical assessment. Based on current clinical knowledge, the results of the 
biopsy may not be conclusive evidence of aGvHD diagnosis and therefore a negative biopsy 
result will not lead to patient discontinuation
Exclusion Criteria #5:
The revision of exclusion criterion #5 is to follow standard medical practice in determining the 
presence of active viral infection. This determination is based on the treating physician’s clinical 
assessment according to local institutional guidelines at the time of enrollment including but 
not limited to vital signs, physical examination, laboratory and relevant radiologic studies and 
viral load testing results when available. Should the screening viral load test results not be 
available prior to patient enrollment, the investigator may initiate study treatment due to this 
life-threatening disease. The investigator will assess presence of uncontrolled viral infection to 
determine patient eligibility based on his/her medical judgement
A patient is eligible for enrollment into this study if she/he has been treated with appropriate 
anti-viral therapy in the setting of an active viral infection and has responded to treatment such 
that the viral infection is considered well-controlled by the investigator.
Exclusion criterion #11:
Parameters for identifying severely impaired renal function in pediatric patients have been 
updated based on existing literature and current clinical practice worldwide.
Visit Schedule and Assessments 
DEXA scan:
While the DEXA scan serves to evaluate bone health in children as a conservative precautionary 
measure, its utility in predicting long-term bone health remains unclear. Acute inflammation in 
the bone marrow as well as treatment with high-dose corticosteroids could further confound the 
interpretation of this assessment to determine effects on bone. Additionally, based on 
toxicology safety studies using animals with a human equivalent age ≥12 years, as well as the 
clinical trials conducted in adult populations, there was no indication of detrimental effects by 
ruxolitinib on bone formation and structure. Further more performing DEXA scans, particularly 
in younger pediatric patients poses a significant logistical challenge as patients may have to be 




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PK sampling for the RP2D will take place on study Day 1, there will be no impact on the PK 
analysis. This proposed revision to the safety dose reduction for Group 2 will not have any 
impact on current provisional dosing schema in case RP2D is not confirmed.
Sample size: 
Following agreement with the European Medicines Agency’s (EMA) Paediatric Committee 
(PDCO), this pediatric study will include 6 additional patients in the Phase II increasing the 
total number of patients to 45 for safety and efficacy evaluation. An overall sample size of 45 
patients would increase from >80% to 90% the probability to have a 90% CI for ORR with 
lower limit ≥ 60%.
Post-Trial Access
As part of Novartis’ “Post-trial access” commitment, patients who meet particular criteria, and 
where permitted by and in accordance to local laws and regulations, will be given the possibility 
to continue ruxolitinib outside the study (if requested). This commitment has been implemented 
to support access to patients that may need ruxolitinib outside of the defined treatment period.
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:

Protocol summary updated with secondary endpoint of ORR at Day 14 for consistency 
with Table 2-1.

Section 1.1.2.1 Non-Clinical Experience updated to include additional safety data 
from toxicity studies clarifying that relevance to humans currently unknown.

Section 1.2 Additional rationale to justify the inclusion of treatment-naïve patients 
based on the potential benefit from the steroid-sparing effect given the associated 
risks with long-term exposure to steroids in children.

Section 2 Objectives and Endpoints, Protocol Summary and Section 12.5.1 efficacy 
and/or pharmacodynamic endpoints updated to include the secondary endpoint Best 
Overall Response (BOR) to align with commonly used efficacy end-points in GvHD.

Section 2 Objectives and Endpoints, Protocol Summary, Table 8-1, Section 8.6.2 
Biomarkers, Section 12.5 Analysis of secondary endpoints 
 

Figure 3-1, Section 3.2, Table 3-2, Section 6.3.2 and Section 12.8.1 updated to reflect 
total sample size of 45 patients in Phase II with updated rationale in Section 12.8.1.

Section 4.2: Added language to support the dose/regimen based on pharmacokinetic 
modeling to derive an optimal dose in pediatric aGvHD patients.

Section 4.5 Risks and benefits – Infections, Section 5.2 Exclusion criteria #5, Section 
8.5.4 Laboratory evaluations, Section 8.5.4.7 Viral reactivation monitoring: Removed 
requirement for viral load assessment at screening. Clarified baseline serology results 
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Protocol summary
Protocol number
CINC424F12201
Full Title
A Phase I/II open-label, single-arm, multi-center study of ruxolitinib added to 
corticosteroids in pediatric patients with grade II-IV acute graft vs. host disease after 
allogeneic hematopoietic stem cell transplantation
Brief title
Study of pharmacokinetics, activity and safety of ruxolitinib in pediatric patients with 
grade II-IV acute graft vs. host disease
Sponsor and 
Clinical Phase
Novartis
Phase I/II
Investigation type
Drug (INC424/ruxolitinib)
Study type
Interventional
Purpose and 
rationale
The purpose of the study is to assess safety, activity and pharmacokinetics of ruxolitinib 
treatment with corticosteroids in treatment-naïve and steroid refractory- acute Graft 
versus Host Disease (SR-aGvHD) patients aged ≥28 days to <18 years of age.
The rationale of the study is based on current knowledge of acute graft vs. host disease 
pathophysiology and published studies showing that ruxolitinib impairs antigen 
presenting cell function, inhibits donor T cell proliferation, suppresses adverse cytokine 
production, and improves survival and disease manifestations in GvHD mouse models. 
Further, published data has shown that ruxolitinib has evidence of clinical efficacy when 
added to immunosuppressive therapy in patients with steroid refractory acute graft vs. 
host disease. Clinical studies using ruxolitinib (10mg BID) alone or in comparison to best 
available therapy are currently underway in the SR-aGvHD setting for adult patients and 
adolescents ≥ 12 years of age. Recent data with ruxolitinib in SR-aGvHD pediatric 
patients (ages 1.6 y/o-16.4 y/o) have shown encouraging overall response rates 
compared to corticosteroids +/- Calcineurin Inhibitor (CNI) alone (Khandelwal et al 2017).
Primary 
Objective(s)

Phase I primary objectives: 

To assess pharmacokinetic (PK) parameters (i.e. AUC, Cmax, T1/2, Ctrough) of 
ruxolitinib for patients with aGvHD and SR-aGvHD

Define an age appropriate Recommended Phase II Dose (RP2D) for each of the 
groups 2-4 

Group 2: age ≥6y to <12y

Group 3: age ≥2y to <6y

Group 4: age ≥28 days to < 2y
All patients remain in the age group defined by the age at treatment start
Group 1 patients (age ≥12y to < 18y) are being treated with the same dose as that being 
used in the ongoing registration trial [CINC424C2301], and therefore are enrolled directly 
into the Ph II.

Phase II primary objective 

To measure the activity of ruxolitinib in patients with grade II-IV aGvHD or grade II-IV 
SR-aGvHD assessed by Overall Response Rate (ORR) at Day 28. ORR at Day 28, 
defined as the proportion of patients demonstrating a complete response (CR) or 
partial response (PR) without requirement for additional systemic therapies for an 
earlier progression, mixed response or non-response. Scoring of response will be 
relative to the organ stage at the start of the study treatment.
Secondary 
Objectives
The key secondary endpoint is to assess the rate of durable ORR at Day 56 by measuring 
the proportion of all patients who achieve a CR or PR at Day 28 and maintain a CR or PR 
at Day 56.
The other secondary endpoints are:

To estimate ORR at Day 14

To assess duration of response

To assess the cumulative steroid dose until Day 56

To evaluate the safety and tolerability of ruxolitinib


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
To assess Overall Survival (OS)

To assess Event-Free Survival (EFS)

To assess Failure-Free Survival (FFS)

To assess Non Relapse Mortality (NRM)

To assess incidence of Malignancy Relapse/Progression (MR)

To measure the incidence of cGvHD

To assess Best Overall Response (BOR)

To assess graft failure

To describe the responses from the acceptability and palatability questionnaire of the 
ruxolitinib formulation

Pharmacokinetic/Pharmacodynamic relationships
Study design
This trial is a Phase I/II open-label, single-arm, multi-center study of ruxolitinib added to 
corticosteroids in pediatric allogeneic stem cell transplant (alloSCT) recipients with grade 
II-IV acute graft vs. host disease. Patients will be enrolled into 4 groups based on age 
(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) to allow appropriate 
dosing based on available data. Group 1, being treated with the same dose as the 
ongoing registration trial (CINC424C2301 using 10mg BID), will be enrolled directly into 
the Phase II. The remaining groups will be enrolled in Phase I: Group 2 will have a 
starting dose of 5mg BID, Group 3 will have a starting dose of 4mg/m 2 BID, and the 
starting dose of Group 4 will be determined based on the PK data collected from Groups 
1-3.During the Phase I, the PK, safety and activity data for Groups 2-4 will be reviewed 
by the data monitoring committee (DMC). Should all of these parameters be considered 
appropriate by the DMC, the starting dose for each group will be confirmed as the RP2D 
for each age group, and then used as the starting dose for all future patients of that age 
group enrolled into the Phase II. All patients enrolled in the study will be treated for 24 
weeks (approximately 6 months) or until early discontinuation. All patients will also be 
followed for additional 18 months (total duration of study = up to 2 years from 
enrollment). Should the occurrence of aGvHD flare require treatment re-initiation or 
should ruxolitinib not be discontinued by the end of 24 weeks due to extended tapering, 
patients may continue to taper ruxolitinib beyond 24 weeks up to a maximum of 48 
weeks (approximately 12 months).
Population
The patient population will include male and female patients ages ≥28 days to <18 years, 
who have undergone alloSCT, have evidence of donor-derived myeloid engraftment 
(absolute neutrophil count (ANC) >1,000/µl and platelets > 20,000/µl), and have been 
diagnosed with either treatment naïve aGvHD grades II-IV or steroid-refractory aGvHD 
grades II-IV. The final study population must reflect at least 20% treatment naïve patients 
and 40% SR-aGvHD patients.
Key Inclusion 
criteria
For a full list of inclusion criteria, refer to Section 5.1. Key inclusion criteria include:
1.
Male or female patients age ≥28 days and <18 years at the time of informed consent.
2.
Patients who have undergone 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.
Patients with a clinically confirmed diagnosis of grades II-IV aGvHD within 48 hours 
prior to study treatment start. Patients may have either: Treatment-naïve aGvHD as 
per Table 8-2 (Harris et al 2016) OR Steroid refractory aGvHD as per institutional 
criteria, and the patient is currently receiving systemic corticosteroids.
4.
Evident myeloid engraftment with ANC > 1,000/µl and platelet count >20,000/µl.
(Use of growth factor supplementation and transfusion support is allowed.)
Key Exclusion 
criteria
For a full list of exclusion criteria, refer to Section 5.2. Key exclusion criteria include:
Has received the following systemic therapy for aGvHD:


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a) Treatment-naïve aGvHD patients have received any prior systemic treatment of 
aGvHD except for a maximum 72h of prior systemic corticosteroid therapy of 
methylprednisolone or equivalent after the onset of acute GvHD. Patients are allowed to 
have received prior GvHD prophylaxis which is not counted as systemic treatment (as 
long as the prophylaxis was started prior to the diagnosis of aGvHD);
OR
b) SR-aGvHD patients have received two or more prior systemic treatments for aGvHD 
in addition to corticosteroids
1.
Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome 
with both acute and chronic GvHD features (as defined by Jagasia et al 2015).
2.
Failed prior alloSCT within the past 6 months.
3.
Presence of relapsed primary malignancy, or who have been treated for relapse 
after the alloSCT was performed, or who may require rapid immune suppression 
withdrawal of immune suppression as pre-emergent treatment of early malignancy 
relapse.
4.
Acute GvHD occurring after non-scheduled donor leukocyte infusion (DLI) 
administered for pre-emptive treatment of malignancy recurrence. Note: Patients 
who have received a scheduled DLI as part of their transplant procedure and not for 
management of malignancy relapse are eligible.
5.
Any corticosteroid therapy for indications other than aGvHD at doses > 1 mg/kg/day 
methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of 
Screening. Routine corticosteroids administered during conditioning or cell infusion 
is allowed.
6.
Patients who received JAK inhibitor therapy for any indication after initiation of 
current alloSCT conditioning.
Investigational and 
reference therapy
Ruxolitinib (INC424)
Efficacy 
assessments
aGvHD assessment will be performed as per Table 8-2 (Harris et al 2016): organ 
assessment (skin; liver; upper GI; Lower GI) and overall grading to assess ORR at Day 
28 and durable ORR at Day 56.
In addition, other efficacy assessments include:
7.
cGvHD incidence
8.
Graft failure monitoring
9.
Hematologic disease relapse/ progression assessment
Pharmacokinetic 
assessments
10. Collection of Pharmacokinetic (PK) data (extensive or sparse sampling) based on 
age groups in Phases I/ II for PK parameters (AUC, Cmax, T1/2, Ctrough)
11. PK collection to assess RP2D in Groups 2-4
Key safety 
assessments
Key safety assessments include:
12. Adverse events (AEs) (including infection monitoring, bleeding)
13. Laboratory assessments
14. Physical examination
15. Vital signs
Other assessments
Additional assessments include:
17. Acceptability and palatability assessment
Data analysis
Data analysis of Phase I:
PK parameters (AUC, Cmax, Ctrough, T1/2, and other parameters, as appropriate) will be 
derived using non-compartmental methods in subjects with extensive sampling (Groups
1, 2, and 3). These parameters will then be used to define a RP2D for Groups 2, 3, and 4. 
The observed PK parameters (within group) will be summarized and compared to 
information obtained from adult and adolescent aGvHD patients treated with ruxolitinib on 
study CINC424C2301. Data from patients older than 2 years old will be combined and 


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analyzed by PBPK methods to determine the dose to be administered in patients younger 
than 2 years old (Group 4).
Data analysis of Phase II:
The response rates for ORR at Day 28 will be estimated with 90% confidence intervals on 
Efficacy Evaluable Set (EES). The confidence intervals will be calculated based on the 
exact method for binominal distribution. Summary statistics (frequencies and percentages) 
will be provided. No statistical hypothesis will be tested in this study.
The final analysis will be conducted on all patient data at the time the trial ends. No formal 
interim analysis is planned for this study. Further to the regular safety monitoring 
conducted by the DMC and the confirmation of RP2D, activity data will be analyzed when 
all patients (Phase I and Phase II) completed 24 weeks (approximately 6 months) of 
treatment or discontinued earlier.
PK data obtained from sparse sampling will be analyzed by a population PK approach 
along with data obtained in the Phase I part.
Key words
Graft versus host disease (GvHD), acute graft versus host disease (aGvHD), 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 
hematologic malignancies including leukemia, lymphoma, and myeloma. 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 initiate an adverse immune reaction leading to an 
inflammatory cascade with resultant tissue damage, organ failure, or even death.
GvHD can present as two distinct conditions, namely acute GvHD (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 Th1-Th2 shift of the cellular immune response, 
defective peripheral, and central tolerance mechanisms (i.e., 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).Among all patients undergoing allogeneic 
hematopoietic-cell transplantation, 30-50% have aGvHD (grades 1-4) and 14% have severe 
aGvHD (grades 3-4) (Zeiser and Blazar 2017) with signs and symptoms observed generally 
within 100 days after infusion of allogeneic grafts including donor bone marrow (BM), 
mobilized peripheral blood stem cells (mPBSC), or umbilical cord blood (UCB). This fairly 
high incidence of aGvHD is seen despite prophylaxis with two or more immunosuppressive 
agents such as calcineurin inhibitors (cyclosporine, tacrolimus), short-course methotrexate, 
mycophenolate mofetil, high-dose cyclophosphamide post-transplant, and anti-thymocyte 
globulin (ATG).
aGvHD target organs include the skin, liver, upper and lower gastrointestinal (GI) tract, with 
signs and symptoms including the following: maculopapular skin rash, erythroderma, nausea, 
vomiting, secretory diarrhea, cholestasis, hyperbilirubinemia, and/or jaundice. The extent of 
individual organ staging and overall grade of aGvHD is assessed at presentation as this is an 
important prognostic indicator (Harris et al 2016).
Biopsies of affected organs are often obtained in attempt to rule out non-GvHD etiologies that 
may be caused by concomitant medications or infections.


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Histologic evaluations of affected organs are highly specific, however the sensitivity is low 
(<60%), and as such aGvHD remains a clinical diagnosis based on careful integration of all 
available clinical information (Ross and Alousi 2012).
With the introduction of reduced intensity conditioning in the early 1990s, two subcategories 
of aGvHD emerged. The first, termed classic aGvHD, occurs in the majority (~90%) of patients 
within 100 days after alloSCT or donor leukocyte infusion (DLI), and the second, termed 
persistent, recurrent, or late aGvHD, occurs beyond 100 days after transplantation or DLI for 
an additional 4 to 8 weeks. Both subgroups occur without the presence of cGvHD 
manifestations, termed overlap syndrome (Pavletic and Fowler 2012). These observations have 
set the basis for current aGvHD grading that defines clinical manifestations, rather than time 
after transplantation, to define aGvHD.
GvHD is a disease of adults and pediatric patients. In fact, a large proportion of pediatric 
patients undergo alloSCT for treatment of malignancy and a rising number receive alloSCT for 
non-malignant 
diseases 
including 
bone 
marrow 
failure, 
immunodeficiency, 
hemoglobinopathies, and inherited metabolic disorders. Despite aGvHD prophylaxis with 
immunosuppressive agents, 20-50% of adult and pediatric patients develop grade II-IV aGvHD 
requiring high dose systemic corticosteroids added to calcineurin inhibitor (CNI) 
(Erbey et al 2016, Martin et al 2012; MacMillan et al 2010). Risk factors for GvHD include 
donor/recipient Human Leukocyte Antigen (HLA) mismatch, use of peripheral blood stem
cells/bone marrow from an HLA matched unrelated or HLA mismatched related donor, 
multiparious female donor to male recipient, and advanced age of the donor recipient  
(Flowers et al 2011, Zeiser and Blazar 2017).
Systemic steroids alone or in combination with calcineurin inhibitor have remained SOC as 
initial systemic treatment of aGvHD grades II-IV over 3 decades (Ruutu et al 2014). 
Unfortunately, only 30–50% of children respond to corticosteroids as initial therapy, and 
optimal 
initial 
or 
second-line 
therapies 
have 
not 
yet 
been 
determined 
(Carpenter and Macmillan 2010).
Treatments that are currently used for Grade II-IV steroid refractory aGvHD (SR-aGvHD) are 
mostly off-label and although they demonstrate initial responses in approximately 50% of 
patients, they are associated with aGvHD flare during attempted steroid taper. These second 
line treatments include the following: ATG, extracorporeal photopheresis (ECP), mesenchymal 
stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR 
inhibitors (everolimus or sirolimus), etanercept, or infliximab. Management of aGvHD flare 
necessitates administration of further high dose systemic corticosteroids over a more prolonged 
time period and/or additional new systemic immunosuppressive therapy leading to life-
threatening infections, and/or malignancy recurrence, with resultant two year survival rates 
ranging only approximately 20-30% (Martin et al 2012). As such, more effective treatment for 
aGvHD and SR-aGvHD grades II-IV in pediatric patients represents a very high unmet medical 
need.




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More than 14,000 patients have received ruxolitinib treatment in Novartis- and Incyte-
sponsored investigational clinical trials. 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 USA, Europe, 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, reticulocytes, eosinophils and lymphocytes 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.
Bone effects (fractures and reduced growth) have been observed in juvenile rat toxicity studies 
at 13 and 1.5 fold the adult patients exposure based on unbound Area under Curve (AUC) at 25 
mg BID, respectively (see Investigator Brochure (IB) for details). The relevance 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 IB.
1.1.2.1.2 Clinical experience
Ruxolitinib has been administered in clinical trials to more than 550 healthy volunteers as 
single, repeat single, or multiple doses for up to 10 days duration. Ruxolitinib has also been 
administered to 32 subjects with various degrees of renal impairment, 24 subjects with various 
degrees of hepatic impairment, and 50 patients with rheumatoid arthritis. More than 14,000 
patients have received ruxolitinib treatment in Novartis- and Incyte-sponsored investigational 
clinical trials cumulatively since the Development IBD (DIBD) (Refer to the most recent IB for 
details).


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Clinical Pharmacology
Clinical pharmacology of ruxolitinib has been characterized in healthy volunteers and in 
patients with MF, ET, 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 1-2 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 
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 CYP3A4 
to yield oxygenated and subsequent conjugated metabolites. Oxidative metabolites of 
ruxolitinib retain pharmacological activity albeit with one half to one fifth of the activity of the 
parent compound. Ex vivo pharmacokinetic/pharmacodynamic 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 patients with severe renal impairment (creatinine clearance (Clcr) < 30 mL/min), the 
recommended starting 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 patients 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.
Baseline elevations in inflammatory markers such as tumor necrosis factor alpha (TNFα), 
interleukin (IL)-6, and C-reactive protein (CRP) noted in patients with MF were associated with 
constitutional symptoms such as fatigue, pruritus, and night sweats. Decreases were observed 


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in these markers over the 24 weeks of treatment with ruxolitinib, with no evidence that patients 
became refractory to the effects of ruxolitinib treatment.
A thorough QT study was conducted in 50 healthy subjects. There was no indication of a 
QT/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 only clinical PK data in children available so far were described by (Loh et al 2015) in 
pediatric patients with relapsed or refractory solid tumors, leukemias, or MPNs enrolled in a 
Phase I study. In general, PK of ruxolitinib was similar in pediatric cancer patients (n=42, 
median age 14 years, range 2-21 years) compared to that in adult patients with myelofibrosis. 
In pediatric patients, peak plasma concentrations of ruxolitinib were achieved by 1 hour (range 
1–4 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 patients 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 
AUC 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 
pharmacodynamics.
Summary of Clinical Efficacy and Safety Data
The results from two phase III registration studies in myelofibrosis (COMFORT-I, COMFORT-
II) demonstrate the effectiveness of ruxolitinib in patients 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), and 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 3-4 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.


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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 patients 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 patients randomized to ruxolitinib versus control arm patients, with a hazard ratio 
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 patients treated with ruxolitinib compared 
with that for patients 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. There were no new or unexpected safety signals that occurred with the 
longer treatment exposure and follow-up period.
Consistent with its activity in myelofibrosis, ruxolitinib demonstrated in the RESPONSE 
pivotal study its efficacy in polycythemia vera patients who are resistant to or intolerant of 
hydroxyurea. Significantly more patients randomized to ruxolitinib than patients 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 patients randomized to ruxolitinib 
achieved hematocrit control (defined as a hematocrit <45% without the need for phlebotomy) 
at Week 32 when compared to patients randomized to BAT: 60.0% (95% CI: 50.2, 69.2) vs 
18.75% (95% CI: 12.7, 28.2), respectively. More patients randomized to ruxolitinib achieved 
at least 35% spleen volume reduction at Week 32 when compared to patients 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 patients randomized to ruxolitinib achieved the key secondary endpoint of 
complete hematological remission (hematocrit control, platelet count ≤400×109/L, and WBC 
count ≤ 10×109/L) at Week 32 when compared to patients randomized to BAT: 23.6% vs 8.0%, 
respectively (p=0.0028, when adjusted for baseline platelet and WBC status). The study is still 
ongoing and will continue for a total of 5 years.
In GvHD, two independent publications have reported encouraging early clinical data with 
ruxolitinib in SR-aGvHD and SR-cGvHD. The first included data from 6 SR-aGvHD patients 
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 (Spoerl et al 2014). Responses to ruxolitinib treatment 
in terms of improved GvHD grades and reduction of required corticosteroids were observed in 
all patients; no patient experienced GvHD flare during steroid taper requiring additional 
systemic therapy. Further early clinical experience with ruxolitinib in patients with SR-aGvHD 
was recently reported in a retrospective study that gathered experience in 95 SR-GvHD patients 
from 19 stem cell transplant centers (Zeiser et al 2015). In this study, 54 patients with SR-
aGvHD (all severe Grade III/IV) who had received a median of 3 previous GvHD therapies 
(range 1-7) received a ruxolitinib dose of 5-10 mg BID. Dose reductions were generally not 
required for worsening cytopenias after initiation of ruxolitinib therapy. The Overall Response 
Rate (ORR) in SR-aGvHD was 81.5% which included 46.3% of patients demonstrating 
complete remission. Median time to response was 1.5 weeks (range 1-11). Flare of aGvHD was 
observed in only 6.8% (3/44) of ruxolitinib-responsive patients during steroid taper. GvL was 
maintained with only 5 of 54 patients (9.3%) demonstrating relapse of the underlying 


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malignancy. The 6-month survival estimate was 79% (67.3-90.7% CI). Safety profile of 
ruxolitinib in SR-aGvHD was generally favorable. Although cytopenias were observed in 
55.5% of SR-aGvHD patients, cytopenias preceded ruxolitinib administration in 51.8% of these 
patients. CMV reactivation was observed in 30% of SR-aGvHD patients treated with 
ruxolitinib. This incidence rate compares favorably with that reported with other second line 
aGvHD agents including MMF, alemtuzumab, and others where CMV reactivation ranges from 
70 to 80% (Rager et al 2011).
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 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 (REACH2) support 
previously reported findings with ruxolitinib in patients with steroid-refractory acute GVHD. 
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 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 support previously 
reported findings with ruxolitinib in patients with steroid-refractory chronic GvHD. A total of 


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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 months; 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 80.9) 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 (in 15.2% of patients who received ruxolitinib and 10.1% of 
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).
. A non-randomized study of ruxolitinib in combination with a standard multi-agent 
chemotherapy regimen for the treatment of de novo B-ALL in pediatric patients who are not 
classified as very high or high risk (INCB18424-269) is ongoing. This study includes a dose-
finding design to determine the dose of ruxolitinib tolerated in combination with the augmented 
Berlin-Frankfurt-Munster (aBFM) regimen, followed by enrollment phase (Part 2) for 
assessment of efficacy.
In the aGvHD setting, a recent publication reported outcomes of pediatric patients with SR-
aGvHD treated with ruxolitinib. Patients weighing < 25 kg were empirically treated with 2.5 
mg BID, and in patients weighing ≥ 25 kg the starting dose was 5mg BID. As a general rule, 
treating physicians evaluated patients for dose escalation weekly, and if there was no evidence 
of toxicity or the need to initiate additional medications with similar adverse effect profile as 
ruxolitinib, the current dose was doubled, until a maximum dose of 10 mg twice daily was 
achieved (Khandelwal et al 2017). Thirteen patients with grades II (n = 2), III (n = 9), and IV 
(n = 2) aGvHD of median age 8.5 years (range, 1.6 to 16.5) were included in this retrospective 
analysis. Organs involved included GI (n = 6); skin (n = 1); skin and GI (n = 2); skin, GI, and 
ocular (n = 2); skin, GI, and liver (n = 1); and skin, GI, liver, and eye (n = 1). Acute GvHD was 
diagnosed at a median of 41 days (range, 20 to 169) after HSCT, and ruxolitinib was started at 
a median of 147 days (range, 55 to 538) after HSCT. The median number of immuno 
suppressive agents received before initiation of ruxolitinib, excluding agents for aGvHD 
prophylaxis, was 4 (range, 1 to 6) and included methylprednisolone at 2 mg/kg/day, 
basiliximab, infliximab, tocilizumab, alemtuzumab, extracorporeal photopheresis, and 
budesonide. Eleven patients were evaluated for response: overall response rate to ruxolitinib 
was 45%, with a CR of 9% (n=1) and partial response of 36% (n=4). No response was detected 
in 19% (n=2), and 36% (n=4) of children were treatment failures because of ruxolitinib toxicity.
Grades 2, 3, and 4 elevated alanine aminotransferase were observed in three patients. Two 
patients had grade 3 neutropenia, whereas 3 patients had grade 4 neutropenia; all patients 
required granulocyte colony-stimulating factor support. Three patients had grade 4 
thrombocytopenia; although all patients needed platelet transfusions, no patient experienced 


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life-threatening bleeding. All observed adverse effects resolved after discontinuation of 
ruxolitinib. Seven of 13 patients were alive at a median follow-up of 401 days (range, 219 to 
969) after HSCT. Four of these 7 patients were free of aGvHD symptoms, and 2 patients were 
off all immune suppression. Causes of death in 6 children included multi-organ failure because 
of ongoing severe aGvHD (n=3), central nervous system hemorrhage (n=1), and progressive 
bronchiolitis obliterans (n=2). The patient with central nervous system hemorrhage did not 
experience this complication because of thrombocytopenia due to ruxolitinib, but as a 
consequence of treatment for central nervous system post-transplant lymphoproliferative 
disorder. While these data are in patients with a much more advanced disease (median of 4 prior 
therapies) compared to the population intended in the ruxolitinib pediatric plan, they provide 
the first evidence of activity of ruxolitinib in the pediatric population.
1.2
Purpose
aGvHD pathophysiology begins with activation of host APC which in turn 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). Ruxolitinib has 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). Further, recently published data have shown evidence of clinical efficacy 
with ruxolitinib treatment when added to immunosuppressive therapy in patients with SR-
aGvHD (Zeiser et al 2015; Spoerl et al 2014). Clinical studies using ruxolitinib alone or in 
comparison to best available therapy are currently underway in the SR-aGvHD setting for adult 
patients and a proportion of adolescents ≥ 12 years of age.
While children are at less risk of developing aGvHD than adults, that risk is still significant 
especially when using alternative donor sources (Jacobsohn and Vogelsang 2007). Similar to
the adults, there are limited treatment options for Grade II-IV aGvHD including systemic 
corticosteroids as initial standard of care for pediatric patients. With only 30-50% of the 
children responding to corticosteroids, there is a high unmet medical need for optimal initial 
and second-line therapies in the pediatric population.
Recent data with ruxolitinib in SR-aGvHD pediatric patients have shown encouraging overall 
response rates compared to corticosteroids +/- CNI alone. Given this data (presented above) in 
the current setting of a lack of effective first- or second-line treatments for pediatric aGvHD, 
the study intends to assess safety, activity and pharmacokinetics of ruxolitinib treatment with 
corticosteroids in treatment-naïve and SR- aGvHD patients aged ≥28 days up to <18 years of 
age. It is expected that ruxolitinib will provide higher rates of disease response compared to 
steroids +/- CNI alone as upfront treatment of grade II-IV aGvHD. It is further expected that 
this response will be durable during steroid taper, representing a meaningful clinical benefit for 
patients.
Furthermore, treatment-naïve patients could potentially benefit from the steroid-sparing effect 
due to the risks associated with long-term exposure and toxic effects of steroids observed in 


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children. The expected mechanism of action as well as the safety profile of ruxolitinib in both 
treatment-naïve and SR-aGvHD are similar, given that the treatment-naïve patients have not 
been subjected to extensive pre-treatment for the underlying disease as compared to adults.
Expected meaningful clinical benefits in patients treated with ruxolitinib include its steroid 
sparing effect, reducing the proportion of patients experiencing flares during steroid tapering, 
reducing proportion of patients with infections and severity of infections, reducing 
hospitalization duration and requirement for re-admission, maintenance of graft vs. malignancy 
effect, and possible reduction of the proportion of patients developing cGvHD.


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2
Objectives and endpoints
Objectives and related endpoints are described in Table 2-1 below.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
1. Phase I
To assess pharmacokinetic (PK) parameters of ruxolitinib for patients 
with aGvHD and SR-aGvHD and define an age appropriate RP2D for 
each of the groups 2-4
2.
Group 2: age ≥6y to <12y
3.
Group 3: age ≥2y to <6y
4.
Group 4: age ≥28 days to < 2y
5.
Measurement of PK parameters in aGvHD and SR-aGvHD patients: AUC, Cmax, T1/2, 
Ctrough using extensive PK sampling in Groups 1-3 and sparse sampling in Group 4
6.
Age-based determination of RP2D for each of the groups 2-4, based on observed PK 
parameters.
7. Phase II
To measure the activity of ruxolitinib in patients with aGvHD or SR-
aGvHD assessed by Overall Response Rate (ORR) at Day 28.
8.
Overall response rate (ORR) at Day 28, defined as the proportion of patients 
demonstrating a complete response (CR) or partial response (PR) without requirement 
for additional systemic therapies for an earlier progression, mixed response or non-
response. Scoring of response will be relative to the organ stage at the start of the study 
treatment.
Secondary objective(s)
Endpoint(s) for secondary objective(s)
9. Key Secondary
To assess the rate of durable ORR at Day 56
10.
Proportion of all patients who achieve a CR or PR at Day 28 and maintain a CR or PR at 
Day 56
11.
To estimate ORR at Day 14
12.
Proportion of patients who achieved OR (CR+PR) at Day 14
13.
To assess pharmacokinetic/pharmacodynamic relationships
14.
PK parameters (such as AUC, Cmax, Ctrough) versus safety, efficacy, and PD 
biomarkers, as appropriate
15.
To assess Duration of response
16.
Duration of response (DOR) is assessed for responders only and is defined as the time 
from first response until aGvHD progression or the date of additional systemic therapies 
for aGvHD. Onset of chronic GvHD, or death without prior observation of aGvHD 
progression are considered as competing risks
17.
To assess the cumulative steroid dose until Day 56
18.
Weekly cumulative steroid dose for each patient up to Day 56


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Objective(s)
Endpoint(s)
19.
To evaluate the safety and tolerability of ruxolitinib
20.
Safety and tolerability including myelosuppression, infections, and bleeding will be 
assessed by monitoring the frequency, duration and severity of Adverse Events including 
occurrence of any second primary malignancies, infections, by performing physical 
exams, and evaluating changes in vital signs from baseline, routine serum chemistry, 
hematology results and coagulation profile
21.
To assess Overall Survival (OS)
22.
Overall survival, defined as the time from the start of treatment to the date of death due to 
any cause
23.
To assess Event-Free Survival (EFS)
24.
Event-free survival, defined as the time from start of treatment to the date of hematologic 
disease relapse/progression, graft failure, or death due to any cause
25.
To assess Failure-Free Survival (FFS)
26.
Failure-free survival, defined as the time from the start of treatment to date of 
hematologic disease relapse/progression, non-relapse mortality, or addition of new 
systemic aGvHD treatment
27.
To assess Non Relapse Mortality (NRM)
28.
Non-relapse mortality (NRM), defined as the time from start of treatment to date of death 
not preceded by hematologic disease relapse/progression
29.
To assess incidence of Malignancy Relapse/Progression (MR) 
30.
Malignancy Relapse/Progression (MR) (refer to Section 16.3 Appendix 3), defined as the 
time from start of treatment to hematologic malignancy relapse/progression. Calculated 
for patients with underlying hematologic malignant disease
31.
To measure the incidence of cGvHD 
32.
cGvHD, defined as the diagnosis of any cGvHD including mild, moderate, severe
33.
To estimate the rate of Best Overall Response (BOR)
34.
Proportion of patients who achieved OR (CR+PR) at any time point up to and including 
Day 28 and before the start of additional systemic therapy for aGvHD
35.
To assess graft failure
36.
Monitoring of donor cell chimerism, defined as initial whole blood or marrow donor 
chimerism >5% declining to <5% on subsequent measurements compared to baseline
37.
To describe the acceptability and palatability assessments of 
the ruxolitinib formulation
38.
Responses from the acceptability and palatability questionnaire for dose forms used after 
first dose, 1 month and 6 months


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3
Study design
This open-label, single-arm, Phase I/II multi-center study will investigate the PK, activity and 
safety of ruxolitinib added to the patient’s immunosuppressive regimen in infants, children, and 
adolescents ages ≥28 days to <18 years old with either grade II-IV aGvHD or grade II-IV SR-
aGvHD. This trial will utilize age groups: Group 1 includes patients ≥12y to <18y, Group 2 
includes patients ≥6y to <12y, Group 3 includes patients ≥2y to <6y, and Group 4 includes 
patients ≥28days to <2y. Patients 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 (Phase I/II) will be subject to the review of available PK, safety, and activity data in 
consultation with the data monitoring committee (DMC), Pediatric Committee (PDCO), and a 
final decision by the Sponsor.
All patients will be enrolled and treated for 24 weeks (approximately 6 months) or until early 
discontinuation. All patients will also be followed for additional 18 months (total duration = 2 
years from enrollment). Should the occurrence of aGvHD flare require treatment re-initiation 
or should ruxolitinib not be discontinued by the end of 24 weeks due to extended tapering, 
patients may continue taper ruxolitinib beyond 24 weeks up to a maximum of 48 weeks. As 
patients ≥12 y to < 18 y (Group 1) are already being included in [[CINC424C2301]], and treated 
with 10 mg BID, this dose is the recommended phase II dose (RP2D), and will be used to treat 
all patients in this age group. For the Ph II, all other age groups will be treated with the RP2D 
determined during the Ph I. Therefore, all ≥12 to <18 year old patients will automatically be 
enrolled in Phase II. It is planned that the first 5 patients treated in Group 1 will undergo 
extensive PK sampling to inform the RP2D determination of the younger age groups in the Ph 
I. Additional patients may undergo extensive sampling should one or more of the first 5 patients 
not be evaluable or until the dose/exposure is confirmed.
3.1
Phase I
Patients will be enrolled into 4 groups, based on age, to allow appropriate dosing based on 
available data Table 3-1.

Phase I (Figure 3-1): Full ruxolitinib concentration-time courses, safety and activity data 
will be collected over 28 days for Groups 2, 3 and 4. Groups 2 and 3 will be enrolled 
initially, and the PK data generated from all patients (including Group 1) will be used to 
inform the starting dose of Group 4. Therefore, Group 4 will only open after an RP2D has 
been defined for Group 2, and an RP2D has been defined for Group 3.

The PK and safety data will be used to assess the adequacy of the preliminary starting 
dose, which can be adapted if needed (i.e. to account for any potential difference between 
the expected and the observed ruxolitinib exposure).Should the exposure in Groups 2, 3 or 
4 not be confirmed following the PK sampling in 5 evaluable patients, at least an 
additional 5 patients will be enrolled in that specific age group until the dose/exposure is 
confirmed (i.e. selection of the RP2D for those ages based on exposure and safety review 
by the DMC).


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Table 3-1
Phase I: Age groups and dosing rationale
Group
Group 1
Group 2
Group 3
Group 4
Age Range
≥12y to < 18y
≥6y to < 12y
≥2y to < 6y
≥28 days to < 2y
N (Ph I)
Not applicable
5 evaluable
5 evaluable
Undefined
Preliminary dose
PBPK-derived 
equivalent 
predicted to yield 
similar exposure to 
10 mg BID adult 
dose =5 mg BID
PBPK-derived 
equivalent 
predicted to yield 
similar exposure to 
10 mg BID adult 
dose =4 mg/m2 BID
Will be generated 
based on PK data 
from groups 1-3
Figure 3-1
Study Design
3.1.1
Determination of recommended Phase II dose

Group 2 (age ≥6y to <12y) and Group 3 (age ≥2y to <6y): Physiologically based 
pharmacokinetic (PBPK) modeling will be used to derive a starting dosing for these 
patients, which is predicted to yield an exposure equivalent to that of a 10 mg BID in 
adults. The PBPK model will incorporate PK data from adult and adolescent patients 
with SR-aGvHD treated on study [CINC424C2301], and these predictions will be 
compared to existing data in pediatric patients from other indications (Loh et al 2015). 
The starting doses are thereby assigned as 5 mg BID (Group 2) and 4 mg/m2 BID 
(Group 3).

Group 4 (≥ 28 days to < 2 y): the absence of existing ruxolitinib PK data in this age 
group warrants a conservative approach. Therefore, the starting dose for Group 4 will 
be determined by using PK data generated in Groups 1, 2 and 3 (Table 3-1 and 
Table 3-2). These data will be used to inform the PBPK model in order to enable 
accurate predictions for these very young patients.


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Groups 2 and 3 will enroll a minimum of 5 patients each. Full ruxolitinib concentration-time 
courses, safety and activity data will be collected over 28 days. Should one or more of the 5 
patients not be evaluable, or until the dose/exposure is confirmed, additional patients may be 
enrolled to ensure a minimum of 5 evaluable patients per age group. This information will be 
used to assess the adequacy of this preliminary dose, which can be adapted if needed (e.g. to 
account for any potential difference between the expected and the observed ruxolitinib 
exposure).
If the exposure from the first 5 patients does not approximate the exposure of 10mg BID in 
adult and adolescent patients based on AUC and Cmax, at least an additional group of 5 patients 
will be enrolled in that specific age group. This second group of at least 5 patients may be 
administered a different starting dose to again target the 10mg BID adult exposure. This process 
will continue until the dose-exposure relationship is confirmed (i.e. selection of the RP2D for 
those ages based on exposure and safety review by the DMC). If the selected RP2D is higher 
than the starting dose assigned to the previous group of patients, intra-patient dose escalation is 
allowed (Section 6.5.1.1). Inversely, if the selected RP2D is lower than the starting dose 
assigned to the previous group of patients, intra-patient dose de-escalation is allowed.
As mentioned above, Group 1 (patients aged ≥12y to <18y) is excluded from this process as the 
starting dose is already confirmed at 10mg BID. The available PK data from these patients will 
however be used in the determination of the RP2D for the younger patients in Groups 2, 3, and 
4.
All Group 1 patients will be enrolled automatically into the Ph II, with the first 5 patients 
undergoing extensive PK. Once the RP2D is selected for Groups 2 and 3 any further eligible 
patients between the ages of ≥2y and <12y will be enrolled into the Phase II. At this point Group 
4 will begin enrolling patients in the Phase I. Further, once the RP2D is established in Group 4, 
enrollment to Phase II for this group will be initiated.
3.2
Phase II
The Phase II aims to measure the activity of ruxolitinib in these patients assessed by ORR at 
Day 28. The study’s primary endpoint for the Phase II is ORR without requirement for addition 
of new systemic immunosuppressive treatment will be assessed after 28 days of therapy, as Day 
28 ORR has been shown to correlate best with subsequent long-term survival 
(Levine et al 2010). A key secondary endpoint is the ORR at Day 56 after start of treatment, in 
order to assess the durability of the primary response.
The RP2D for all groups will be assessed for both activity and safety in Phase II, over a 24 week 
period. At least 45 patients will be enrolled in the study regardless of age, (at least 20% with
treatment naïve aGvHD and 40% with SR-aGvHD) and be treated with the confirmed RP2D. 
The sample size for the Phase II objective of measuring ORR at D28 is 45 evaluable patients 
regardless of age. Any patient receiving the confirmed RP2D during the Phase I will be counted 
towards the 45 patients (Table 3-2 and Figure 3-1). 
Table 3-2
Phase II: Age groups and dosing rationale
Group
Group 1
Group 2
Group 3
Group 4
Age Range
≥12y to < 18y
≥6y to < 12y
≥2y to < 6y
≥28 days to < 2y
N 
N=45 evaluable patients, treated with the confirmed RP2D


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Group
Group 1
Group 2
Group 3
Group 4
RP2D dose
Same as adult 
dose: 10 mg BID 
(All patients will be 
enrolled in Ph II)
Same as Phase I 
unless correction is 
needed to account 
for exposure 
variations
Same as Phase I 
unless correction is 
needed to account 
for exposure 
variations
Based on PK 
modeling from 
groups 1,2, and 3 
data in the PK part
3.3
Study periods
The study is comprised of the following periods:

Screening Period (Day -28 to Day -1)
Patients diagnosed with treatment-naïve or steroid refractory aGvHD will have screening 
activities and assessment of inclusion and exclusion criteria once the study informed consent is 
obtained. Upon confirmation of eligibility, the patients will be enrolled to the study.

Treatment Period (Day 1 to Week 24)
Study treatment will begin on Day 1. Subjects meeting eligibility requirements will be treated 
with ruxolitinib plus corticosteroids +/- CNI for 24 weeks (approximately 6 months) unless 
discontinuation criteria (See Section 9.1.1) or withdrawal from the study for other reasons 
occurs. Dose modifications are allowed for safety. Patients that have not discontinued 
ruxolitinib by the end of Week 24 or experience aGvHD flare may continue to receive treatment 
for a maximum of 48 weeks (See Section 6 for treatment details and dose modifications). In 
this case, the end of treatment for such patients will extend beyond Week 24 but MUST end by 
Week 48.
Study visits will occur per the following schedule to monitor tolerability and efficacy of the 
study treatments during the Treatment period:

Weekly visits from Day 1 up to Day 56;

Visits every 4 weeks beyond Day 56 and until Week 24 or End of Treatment (EOT), 
whichever occurs later.
A 30-day safety follow-up visit will be done for all patients after the last dose of ruxolitinib.

Long-term follow-up Period (From EOT to Month 24)
Recognizing that aGvHD is a complication of alloSCT that often leads to death within 2 years 
after the procedure, and that assessment of long-term safety and durable efficacy is clinically 
meaningful, all patients (responders and non-responders in both arms, regardless of when 
treatment was discontinued) will be followed to collect long term data including: survival, any 
relapse/progression of the underlying hematologic disease for which the alloSCT procedure was 
performed (refer to Section 16.3 Appendix 3), NRM, any occurrence of graft failure, EFS, any 
occurrence of cGvHD, and occurrence of any second primary malignancies.
Visits will be performed at 12, 18, and 24 months from the start of treatment (Day 1).
It is anticipated that unscheduled visits may be needed throughout the trial for evaluation and 
management of any aGvHD flare, worsening cytopenias, occurrence of serious infections, non-
hematologic toxicities, graft failure, hematologic disease progression or relapse.


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The core study ends after 24 weeks (approximately 6 months) after enrollment of the last subject 
into the Phase II, and the study will continue for up to a total of 2 years (i.e., 18 months of 
follow-up) to generate longer-term survival data.
Figure 3-2
Study Visit Schematic
4
Rationale
4.1
Rationale for study design
The scientific rationale for this study of ruxolitinib in pediatric patients with Grade II-IV 
aGvHD is based on the current knowledge of aGvHD pathophysiology that begins with the 
activation of host antigen-presenting cells (APC) by signals expressed by damaged tissues 
and/or pathogens. Activated host APC then present host antigens to donor immune cells, leading 
to donor T-cell proliferation and inflammatory cytokine production. The role of JAK/STAT 
signaling in the pathophysiology of GvHD was determined using the [B6 (H-2b) to Balb/c(H-
2d)] mouse model. In this model, interferon γ receptor (IFN-γR) signaling was shown to play a 
major role in T-cell trafficking to GvHD target organs via CXCR3. Mice transplanted with IFN-
γR -/- T cells had improved survival and less clinical GvHD compared with mice transplanted 
with wild-type T cells. Furthermore, pharmacologic inhibition of interferon signaling with a 
JAK/STAT signaling inhibitor, ruxolitinib, for 20 days resulted in the decreased expression of 
chemokine receptor 3 (CXCR3), reduced GvHD, and improved survival after allo-HSCT in 
mice (Choi et al 2012). The blockade of JAK/STAT signaling in wild-type T-cells using the 


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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-HSCT recipients increased FoxP3+ Tregs, 
which are linked to immunologic tolerance.
This signaling cascade in aGvHD determined in the mouse model and adult patients with 
GvHD, is expected to be the same in pediatric patients < 12 years of age as compared to patients 
≥12 years of age. As comparative data is being generated in an ongoing Ph III trial 
([CINC424C2301]) which enrolls patients ≥12 years of age, efficacy data from that study will 
be extrapolated to the pediatric population. Therefore, the current single-arm study aims to 
assess ruxolitinib and further characterize pharmacokinetics, safety and activity in pediatric 
patients (age ≥ 28 days to < 18 years) with treatment naïve aGvHD and SR-aGvHD. The 
primary endpoint for Phase II, overall response rate (ORR) without requirement for addition of 
new systemic immunosuppressive treatment will be assessed after 28 days of therapy, as Day 
28 ORR has been shown to correlate best with subsequent long-term survival (Levine et al
2010). A key secondary endpoint is to compare the ORR at Day 56 after start of treatment, in 
order to assess the durability of the primary response. The treatment phase will allow 
assessment of patient benefit and risk in terms of: i.)improvement or resolution of aGvHD 
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.) occurrence of cGvHD 
(Levine et al 2010).
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 of 2 years or older 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 CYPs in paediatrics) 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 


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(Shi et al 2011, Shi et al 2012)) were: 1.4 to 2.7 mg/m2 BID for the youngest patients (≥28 days 
to < 2y); 4 mg/m2 BID for ≥2y to < 6y; 5 mg BID for ≥6y to < 12y; 10 mg BID for ≥12y to < 
18y.
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 years old) becomes 
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 aGvHD including methylprednisolone (or equivalent 
prednisone) +/- cyclosporine or tacrolimus at standard dosing adjusted to therapeutic trough 
levels.
1.
Group 1: In the adolescent age group (≥12y to < 18y), the dose will be the same as adults 
(10 mg BID). 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 patients with various malignancies (Loh et al 2015). Adolescent 
patients treated at this dose of 10 mg BID and enrolled in the adult aGvHD study 
[CINC424C2301] will also provide PK data that will be used as additional information 
to confirm the adequacy of this dose.
2.
Group 2 and 3: For the younger groups (≥ 2 up to < 12 years), PBPK modeling will be 
used to derive dosing schemes predicted to yield exposure equivalent to that of 10 mg 
BID in adults.  The starting doses are thereby assigned as 5 mg BID (≥ 6y to < 12) and 
4 mg/m2 BID (≥ 2y to < 6y).
3.
Group 4: For the youngest patients (≥ 28 days to < 2 years), a conservative approach 
has been considered, given the information from the pharmacokinetic predictions as 
noted above and the absence of existing ruxolitinib PK data. Therefore, the starting dose 
for Group 4 will be determined using PK data generated in Groups 1, 2 and 3 
(Table 3-1 and Table 3-2). These data will enrich the PBPK model in order to enable 
reliable predictions in the 28 days to < 2 years age range.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable. No formal interim analysis is planned for this trial.
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 6.5.2. 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 


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and treatment discontinuation criteria. There may be unforeseen risks with ruxolitinib which 
could be serious. Refer to the most recent [Investigator Brochure].
The curative potential of alloSCT for patients with life-threatening hematologic disorders is 
significantly limited by aGvHD that occurs in a large proportion (>60%) of alloSCT recipients 
despite administration of multi-agent prophylactic immunosuppressive therapy. SR-aGvHD is 
associated with a very high mortality risk and available second-line therapies have not been 
shown to reduce mortality. Potential benefit of ruxolitinib for alloSCT patients with SR-aGvHD 
is based on published pre-clinical and encouraging early clinical data.
Important risks from ruxolitinib MPN clinical development and post-authorization experience 
to date include: myelosuppression (thrombocytopenia, anemia and leukopenia), infections 
(including tuberculosis, progressive multifocal leukoencephalopathy, hepatitis B reactivation 
and other opportunistic infections), bleeding and non-melanoma skin cancers. Additionally, in 
patients with hepatic and renal impairment, Area under Curve (AUC) and half-life of the 
metabolites of ruxolitinib increased and hence, these patients 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 in patients as these risks are also 
common in the alloSCT setting particularly patients with aGvHD. 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 remains unchanged.
Myelosuppression: Myelosuppression is a common occurrence in alloSCT patients with 
incidence higher at earlier time points when aGvHD occurs, e.g. first 6 weeks after graft 
infusion. Myelosuppression is observed prior to and during early donor engraftment, and in the 
setting of CMV reactivation as well as HHV-6 infection. In addition, medications used to treat 
these viral infections, particularly gancyclovir, are associated with myelosuppression. Case 
series in acute and chronic GvHD have identified worsening of myelosuppression in 
approximately 10-20% 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 ANC 
dropped below 500/mm3.
Myelosuppression is manageable in a-GvHD and SR-aGvHD patients by keeping the starting 
dose comparatively lower than in MF and with dose adjustment or dose holding based on ANC 
and platelet count (see Table 6-3). Patients will also be closely monitored for any evidence of 
secondary graft failure defined as initial whole blood or marrow donor chimerism >5% 
declining to <5% on subsequent measurements. In the Phase III clinical protocols in MPN 
patients, the concurrent use of hematopoietic growth factors was discouraged, but not 
prohibited. These same guidelines apply to this study as potential benefit of hematopoietic 
growth factors may exceed any risk. 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. aGvHD correlates strongly with the incidence 
and severity of bleeding episodes. Ruxolitinib dose adjustment or dose holding will be based 
on platelet count (see Table 6-3) and platelet transfusions may be given as clinically indicated.


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Use in patients with hepatic impairment: As the liver is a target organ in aGvHD 
pathophysiology, elevated liver function tests including bilirubin and AST/ALT cannot be used 
as a parameter to exclude aGvHD or SR-aGvHD patients or determine starting dose. Diagnostic 
evaluation and management of hepatic impairment in aGvHD patients treated on this study will 
follow institutional guidelines. The ruxolitinib starting dose in aGvHD patients is relatively low, 
e.g. 10 mg orally BID, and patients will be closely monitored for any signs of ruxolitinib-
associated hepatic toxicities. For patients with myeloproliferative disorders with hepatic 
impairment treated with ruxolitinib, the recommended starting dose, based on platelet count, is 
generally reduced by approximately 50%. However, in patients with SR aGvHD the starting 
ruxolitinib dose will not be reduced, as the dose is already low, and there is a need to ensure an 
adequate dose is administered to effectively treat SR aGvHD that is immediately life-
threatening.
Use in patients with renal impairment: Renal impairment is a common occurrence in patients 
with aGvHD 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 aGvHD and SR-aGvHD 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 SR-
aGvHD 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 transplant program guidelines and viral 
load titer data will be documented when results are available.
Patients are ineligible for enrollment if they have clinically active uncontrolled infection. Any 
bacterial, fungal, viral, parasitic, and non-microbiologically defined infection will be managed 
per institutional guidelines and severity graded by standard alloSCT criteria including 
recurrence intervals (see Appendix 1 (Table 16-1): Severity Grading Table & Recurrence 
Interval Definitions). This protocol will use, in addition to standard Common Terminology 
Criteria for Adverse Events (CTCAE) grading, the infection grading system developed and 
validated for alloSCT patients as this grading system is predictive of mortality 
(Cordonnier et al 2006, BMT Clinical Trials Network 2013).
All Grade 2 and 3 
microbiologically documented infections occurring after initiation of therapy will be reported 
by site of disease, date of onset, pathogen, and grade.
Tuberculosis: Tuberculosis (TB) is very rare in alloSCT patients as all patients are carefully 
screened prior to the transplant procedure and are not allowed to undergo alloSCT if TB is
present. Patients will be monitored for any clinical signs and symptoms of active TB infection, 
and appropriate treatment provided. Skin testing for TB will not be performed in this study of 
alloSCT patients as this assessment is non-informative due to anergy. Ruxolitinib therapy will 
not be administered in any patient with an active TB infection.
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 HHV-




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Supportive published data in pediatric patients: Although no existing clinical trial data is 
available among pediatric GvHD patients treated with ruxolitinib, there are several independent 
published reports suggesting no significant toxicities in this population.
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 3 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 (González Vicent et al 2019). 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 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).
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 patient 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.
5
Population
The patient population will include male and female patients ages ≥28 days to <18 years, who 
have undergone alloSCT, have evidence of donor-derived myeloid engraftment (ANC 
>1,000/µl and platelets > 20,000/µl), and have been diagnosed with either treatment naïve 
aGvHD grades II-IV or steroid-refractory aGvHD grades II-IV. The final study population must 
reflect at least 20% treatment naïve patients and 40% SR-aGvHD patients.


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The investigator or designee must ensure that only patients 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:

Male or female patients age ≥28 days and <18 years at the time of informed consent.

Patients who have undergone 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.

Patients with a clinically confirmed diagnosis of grades II-IV aGvHD within 48 hours 
prior to study treatment start. Patients may have either:
Treatment-naïve grades II-IV aGvHD as per Table 8-2 (Harris et al 2016)
OR
Steroid refractory grades II-IV aGvHD as per institutional criteria, or per physician 
decision in case institutional criteria are not available, and the patient is currently 
receiving systemic corticosteroids.

Evident myeloid engraftment with absolute neutrophil count (ANC) > 1000/µl and platelet 
count >20,000/µl. (Use of growth factor supplementation and transfusion support is 
allowed.)

Able to swallow study medication or administer the ruxolitinib oral pediatric formulation 
by nasogastric (NG) tube, if applicable.
1. Written Study Informed consent and/or assent from the patient, parent, or guardian at the 
time of Screening, i.e. at the time of treatment-naïve aGvHD or steroid refractory aGvHD 
diagnosis.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.

Has received the following systemic therapy for aGvHD:
a. Treatment-naïve aGvHD patients have received any prior systemic treatment of aGvHD 
except for a maximum 72h of prior systemic corticosteroid therapy of methylprednisolone 
or equivalent after the onset of acute GvHD. Patients are allowed to have received prior 
GvHD prophylaxis which is not counted as systemic treatment (as long as the prophylaxis 
was started prior to the diagnosis of aGvHD);
OR
b. SR-aGvHD patients have received two or more prior systemic treatment for aGvHD in 
addition to corticosteroids.

Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with 
both acute and chronic GvHD features (as defined by Jagasia et al 2015).

Failed prior alloSCT within the past 6 months.

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 


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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.

Evidence of uncontrolled Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) based on 
assessment of treating physician.

Evidence of clinically active tuberculosis (clinical diagnosis per local practice; skin testing 
is not required as not informative due to anergy).

Known human immunodeficiency virus infection (HIV).

Presence of 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.

Acute GvHD occurring after non-scheduled DLI administered for pre-emptive treatment 
of malignancy recurrence. Note: Patients who have received a scheduled DLI as part of 
their transplant procedure and not for management of malignancy relapse are eligible. 

Significant respiratory disease including patients who are on mechanical ventilation or 
who have resting O2 saturation <90% by pulse-oximetry on room-air.

Presence of severely impaired renal function (confirmed within 72 hrs prior to study 
treatment 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

Clinically significant or uncontrolled cardiac disease including any of the following:

Acute myocardial infarction within 6 months from Day 1 of study treatment 
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).

Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive 
disease of the liver (defined as persistent bilirubin abnormalities not attributable to 
aGvHD and ongoing organ dysfunction).

History of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, 
osteomyelitis, osteopenia, fibrous dyslpasia, osteomalacia etc. prior to the underlying 
diagnosis which resulted in the alloSCT.

History of endocrine or kidney related growth retardation prior to the underlying diagnosis 
which resulted in the alloSCT.


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
Any corticosteroid therapy for indications other than aGvHD at doses > 1 mg/kg/day 
methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of 
Screening. Routine corticosteroids administered during conditioning or cell infusion is 
allowed.

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). 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.

History of progressive multifocal leuko-encephalopathy (PML).

Patients who received JAK inhibitor therapy for any indication after initiation of 
current alloSCT conditioning.

Investigational treatment within 30 days prior to treatment initiation or within 5 half-
lives of the investigational product, whichever is greater.

Any condition that would, in the Investigator's judgment, interfere with full 
participation in the study, including administration of study treatment and attending 
required study visits; pose a significant risk to the patient; or interfere with 
interpretation of study data.

Known allergies, hypersensitivity, or intolerance to systemic immunosuppressive therapy 
or ruxolitinib (or any of its excipients).

Female patients who are pregnant or breast feeding.

Female patients of childbearing potential, (e.g., are menstruating) who do not agree to 
abstinence or, if sexually active, do not agree to the use of contraception as defined by 
Section 8.5.5.
If local regulations deviate from the contraception methods listed in Section 8.5.5. to prevent
pregnancy, local regulations apply and will be described in the ICF.
6
Treatment
6.1
Study treatment
The study treatment will be administered as a 5 mg tablet or as an oral pediatric formulation 
(taken in liquid form) twice a day for all patients.

Treatment-naïve aGvHD: In addition to ruxolitinib, treatment MUST include 
methylprednisolone (or equivalent prednisone) +/- cyclosporine or tacrolimus at standard 
dosing adjusted to therapeutic trough levels

SR-aGvHD: In addition to ruxolitinib, concomitant use of corticosteroids +/- cyclosporine 
or tacrolimus at standard dosing adjusted to therapeutic trough levels.
In addition to study treatment, patients should receive standard alloSCT supportive care 
including anti-infective medications and transfusion support. Continued use of systemic 
corticosteroids, CNI (cyclosporine or tacrolimus), and topical corticosteroid therapy per 
institutional guidelines is permitted. Other systemic medications used for prophylaxis of 
aGvHD may be continued after Day 1 only if started prior to diagnosis of aGvHD. For SR-


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aGvHD patients, cessation of other systemic treatment for aGvHD other than corticosteroids 
+/- CNI will be required prior to treatment initiation. Permitted concomitant therapies are 
described in Section 6.2.1.1 and Section 6.2.1.2.
6.1.1
Investigational and control drugs
Table 6-1
Dose and treatment schedule
Study treatments
Age groups
Pharmaceutical 
form and Route of 
Administration
Starting dose
Frequency and/or 
Regimen
Ruxolitinib 
(INC424)
Group 1
5-mg tablet for oral 
use OR
oral pediatric 
formulation for oral 
or NG use *
10 mg BID
(2 tablets BID) OR
10 mg BID oral 
pediatric 
formulation**
Twice per day
Ruxolitinib 
(INC424)
Group 2
5-mg tablet for oral 
use OR
oral pediatric 
formulation for oral 
or NG use*
5 mg BID
(1 tablet BID) OR
5 mg BID oral 
pediatric 
formulation**
Twice per day
Ruxolitinib 
(INC424)
Group 3
5-mg tablet for oral 
use OR
oral pediatric 
formulation for oral 
or NG use*
4 mg/m2 BID
(either tablet OR
oral pediatric 
formulation)**
Twice per day
Ruxolitinib 
(INC424)
Group 4
5-mg tablet for oral 
use OR
oral pediatric 
formulation for oral 
or NG use*
To be defined
Twice per day
*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 (taken in liquid form). Oral pediatric formulation 
should be dispensed according to instructions in the pharmacy manual. Refer to the pharmacy manual for 
nasogastric tube administration details.
Note:  Crushed tablet cannot be administered via nasogastric (NG) tube.
**BSA- based calculated doses should be administered as per instructions in the pharmacy manual.
The Investigator will instruct the patient to take the study treatment as per protocol.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record Case Report Form (CRF).
Ruxolitinib will be administered orally or by NG tube twice per day at the assigned starting 
doses based on age group, given as 5-mg tablets or equivalent dose as oral pediatric formulation. 
Patients should remain on the same formulation throughout study participation. Any changes in 
formulation requires approval from the Sponsor.
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 hospital 
personnel in an inpatient setting, or self-administered by the patient in an outpatient setting.


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Patients should be instructed not to take study treatment at home on the days of the scheduled 
pre-dose blood collection 
 
. Dosing will be administered after pre-dose blood collection at these visits.
At each study visit after Day 56, the Investigator may consider a ruxolitinib dose change based 
on the patient’s current age and/or BSA.  At the Investigator’s discretion, dosing may be 
adjusted if the newly calculated dose (based on the patient’s current age and/or BSA) is a >10% 
change from the current dose. 
6.1.2
Additional study treatments
The following non-investigational treatment will be taken by the patient as per standard of care:

CNI

Systemic corticosteroids
6.1.3
Treatment arms/group
This is a 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). In order to have data on both 
subpopulations, at least 20% treatment naïve aGvHD and at least 40% SR aGvHD patients will 
be enrolled overall in Phase I & Phase II.  The remaining enrollment can be from either 
subpopulation.
6.1.4
Guidelines for continuation of treatment
Refer to Section 6.5.2 on dose modifications and follow up for toxicities for guidelines for 
continuation of treatment.
6.1.5
Treatment duration
The planned duration of aGvHD treatment is 24 weeks (approximately 6 months).
The Treatment Period for each patient will begin on Study Day 1 and continue until the end of 
Week 24, unless treatment change for any reason including treatment failure, e.g. aGvHD 
progression, mixed response, or no response, or aGvHD flare failure as defined in 
Section 8.4.1.2, intolerable toxicity, death, or withdrawal from the study for other reasons 
occurs.
During the Treatment period, and beyond Day 28, patient’s treatment will be managed 
according to their response as follows:
For patients with response at Day 28 (see Table 8-3):

Patients responding to ruxolitinib will continue ruxolitinib until Day 56. These patients 
may be tapered off ruxolitinib as needed, starting no earlier than Day 56. The dose 
tapering strategy should be based on evaluation of the condition of the subject, current 
dosing regimen and the clinical judgment of the Investigator. (see Section 6.1.5.1.)

If a taper of ruxolitinib is considered appropriate, the taper should be completed no later 
than Week 24 unless prolonged tapering is indicated due to an aGvHD flare or other safety 
concern (see Section 6.1.5.1).


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For patients with a lack of response at Day 28 (see Table 8-3):

Patients must discontinue study treatment and be treated per Investigator’s judgement.
These patients will then enter the long-term follow-up period.
Patients responding to treatment will be tapered off immunosuppression (corticosteroids and 
CNI) as described in Section 6.1.5.1.
Tapering Guidelines
Tapering of immunosuppression will follow 2 steps: first taper of corticosteroids, followed with 
taper of CNI and/or ruxolitinib in responding patients. If applicable, the taper of CNI and 
ruxolitinib may be performed at the same time.
During the Treatment Period, immunosuppression taper guidelines are:
1. Corticosteroids: the taper of corticosteroids in patients demonstrating a PR or CR as 
observed by the Investigator must not be initiated earlier than Day 7, and should then be 
performed per institutional guidelines (e.g. 10% dose reduction every 5 days, beginning no 
earlier than Day 7 and continuing to approximately Day 56 to allow 7-8 week taper).
2. CNI (cyclosporine or tacrolimus): CNI taper is allowed in patients demonstrating a PR 
or CR, once off corticosteroids, and should then be performed per institutional guidelines 
(e.g. 25% dose reduction per month).
3. Ruxolitinib: ruxolitinib taper is allowed in patients demonstrating a PR or CR, once off 
corticosteroids, and must not start earlier than Day 56.
The following guidance may be followed based on evaluation of the condition of the patient, 
current dosing regimen and the clinical judgment of the Investigator: a 50% dose reduction 
every 2 months (approximately every 56 days), i.e., initial dose reduction from 10 mg BID to 5 
mg BID and, if sustained aGvHD stable disease is observed, patient is further tapered by a 
second 50% dosage reduction to 5 mg QD for an additional 56 days, prior to cessation. No 
further reductions will be allowed beyond once a day dose. Refer to Table 6-4.
It is expected that the taper of corticosteroids, CNI, and ruxolitinib will be completed by the 
end of Week 24. Should an aGvHD flare or other safety concern prevent taper from being 
complete by then, the dose of ruxolitinib may be maintained until Week 24. Ruxolitinib taper 
completion will be consequently delayed beyond Week 24, but must be complete by Week 48 
maximum.
All patients must be off corticosteroids, CNIs and ruxolitinib by the Week 48 maximum.
6.1.5.1.1 aGvHD flare
If aGvHD flares occurs during the taper of immunosuppressive medications prior to Day 56, 
the dose of corticosteroids may be re-escalated at the Investigator's discretion and will not be 
considered treatment failure, as long as criteria defined in Section 8.4.1.2 are not met. The taper 
of corticosteroids should be attempted again once the patient demonstrates a PR or CR. In these 
circumstances the taper of corticosteroids may extend beyond Day 56, delaying the initiation of 
CNI and/or ruxolitinib taper (as corticosteroid tapering must be completed prior to CNI and/or 
ruxolitinib taper). If aGvHD flare requires addition of a new systemic therapy due to inability 
to taper corticosteroids below methylprednisolone 0.5 mg/kg/day (or equivalent <0.6 
mg/kg/day of prednisone) for a minimum 7 days, OR due to re-escalation of corticosteroids to 


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methylprednisolone >2 mg/kg/day (or equivalent >2.5 mg/kg/day of prednisone), the patient 
will be considered to have experienced aGvHD flare failure, and new systemic treatment is 
indicated per Investigator’s judgement. Patients requiring new systemic treatment for aGvHD 
must discontinue study treatment (Section 9.1.1).
If aGvHD flare occurs after Day 56, patients may have their ruxolitinib dose increased to the 
prior dose level (maximum up to starting dose), their response monitored, and ruxolitinib taper 
attempted again if patients 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 patient will 
be considered to have experienced an aGvHD flare failure, and further treatment is allowed per 
Investigator’s judgment including: starting a new systemic treatment (refer to Section 9.1.1), or 
continuing ruxolitinib at the dose on which the patient was previously demonstrating a response 
(maximum up to starting dose) and may be continued up to Week 24.
If aGvHD flare occurs during ruxolitinib taper after Week 24 (i.e. in the case of a delayed end 
of ruxolitinib taper), the patient will discontinue study treatment and be treated per 
Investigator’s judgement.
If cGVHD signs and symptoms including overlap syndrome, de novo, or progressive disease 
develop during the taper of ruxolitinib, clinical management of cGvHD follows standard 
institutional guidelines. Ruxolitinib tapering schedule may be maintained for patient’s safety to 
avoid aGvHD flare. Ruxolitinib will not be administered for the treatment of cGvHD including 
overlap syndrome.
Treatment beyond disease progression
Not applicable
6.2
Other treatment(s)
6.2.1
Concomitant therapy
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 
in the concomitant medications / significant non-drug therapies.
Permitted concomitant therapy
Supportive treatments per institutional guidelines for management of alloSCT patients with 
aGvHD or SR-aGvHD are allowed. The patient 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) including over-the-counter and vitamins/herbal/natural 
medications must be listed on the Concomitant Medications electronic case report form (eCRF). 
Significant non-drug therapies (including physical therapy and blood transfusions) administered 
during the study must be listed on the significant non-drug therapies eCRF. Any prior 
medication received up to 30 days prior to the first dose of ruxolitinib must be recorded on the 
appropriate eCRF. Patients 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.


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In addition to assigned ruxolitinib, patients may receive standard alloSCT supportive care 
including anti-infective medications and transfusion support. Continued use of systemic 
corticosteroids, CNI (cyclosporine or tacrolimus), and topical corticosteroid therapy per 
institutional guidelines is permitted. Other systemic medications for aGvHD may be continued 
after Day 1 only if used for aGvHD prophylaxis prior to diagnosis of aGvHD. 
On the days of the PK blood collection, patients should be instructed to refrain from taking 
corticosteroids until after the last PK samples are collected (i.e. approximately 9 hours post-
dose on Week 1 Day 1 and approximately 2 hours post-dose 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 patients 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 100 
kg will be used.
Permitted concomitant therapy requiring caution and/or action
Patients 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, G-CSF, steroid pre-meds 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 patients treated with CYP450 
modulators (See Section 6.5.2).
Upon initiation of a strong CYP3A4 inhibitor or a dual CYP3A4/CYP2C9 inhibitor, including 
fluconazole up to a dose of 6 mg/kg (maximum 200 mg) daily, the dose of ruxolitinib may 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 patient 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 Table 6-3) and Investigator judgment, with 
appropriate corticosteroid immunosuppression provided to avoid aGvHD flare.
6.2.2
Prohibited medication
The following therapies are prohibited during the study until treatment discontinuation:
a.
Due to the high risk of bleeding in alloSCT patients with aGvHD or SR-aGvHD, systemic 
Nonsteroidal anti-inflammatory drugs (NSAIDs) and related medications that would 
expectedly reduce platelet function, and/or heparin, warfarin sodium (Coumadin®) 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 


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dose for e.g., prophylaxis of sinusoidal obstructive syndrome/veno-occlusive disease of 
the liver.
b. Concomitant use of another JAK inhibitor besides ruxolitinib.
c. 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 study treatment and until treatment discontinuation.
d. 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.
e. 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.
f.
Administration of fluconazole at daily doses higher than 6 mg/kg (maximum 200 mg)
(Section 6.5.2.1.4).
g. Addition of any new systemic immunosuppressive therapy after start of treatment may be 
decided by the Investigator (Section 6.1.5.1.1). In this case, the patient must discontinue 
study treatment (Section 9.1.1).
h. Considering the underlying population with immunocompromised state, use of live 
attenuated vaccines (i.e., against SARS-CoV-2) are prohibited while on study treatment.
6.2.3
Rescue medication
Not applicable
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
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 patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient 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 patient to register them into the IRT. Once 
assigned, the Subject No. must not be reused for any other subject and the Subject No. for that 
individual must not be changed, even if the patient is re-screened. If the patient 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 patient will not be entering the treatment phase of 
the study.


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6.3.2
Treatment assignment, randomization
This is a non-randomized study. The assignment of a patient to the appropriate dosing group 
will be based on age using the IRT and coordinated by the sponsor. In order to meet the 
minimum enrollment target of at least 20% of patients in the treatment naïve aGvHD 
subpopulation and 40% in the SR aGvHD subpopulation, the IRT system will cap enrollment 
into either subpopulation as required.
6.4
Treatment blinding
This is an open-label study. Therefore, treatment will be open to patients, investigator staff, 
persons performing the assessments, and the Clinical Trial Team (CTT).
6.5
Dose escalation and dose modification
6.5.1
Dose escalation guidelines
Group 2 (age ≥6y to <12y) and Group 3 (age ≥2y to <6y): PBPK modeling will be used to 
derive a starting dosing for these patients, which is predicted to yield an exposure equivalent to 
that of a 10 mg BID in adults. The PBPK model will incorporate PK data from adult and 
adolescent patients with SR-aGvHD treated on study [CINC424C2301], and these predictions 
will be compared to existing data in pediatric patients from other indications (Loh et al 2015).
The starting doses are thereby assigned as 5 mg BID (Group 2) and 4 mg/m2 BID (Group 3).
Group 4 (≥ 28 days to < 2 y): the absence of existing ruxolitinib PK data in this age group 
warrants a conservative approach. Therefore, the starting dose for Group 4 will be determined 
by using PK data generated in Groups 1, 2 and 3 (Table 3-1). These data will enhance the PBPK 
model in order to better predict PK in patients below 2 years of age.
Groups 2 and 3 will enroll a minimum of 5 patients each. Full ruxolitinib concentration-time 
courses, safety and activity data will be collected over 28 days. Should one or more of the 5 
patients not be evaluable, additional patients may be enrolled to ensure a minimum of 5 
evaluable patients per age group. This information will be used to assess the adequacy of this 
preliminary dose, which can be adapted if needed (e.g. to account for any potential difference 
between the expected and the observed ruxolitinib exposure).
If the exposure from a minimum of 5 patients does not approximate the exposure of 10mg BID 
in adult and adolescent patients based on AUC and Cmax, an additional group of 5 patients will 
be enrolled in that specific age group. This second group of 5 patients will be administered a 
different starting dose to again target the 10mg BID adult exposure. This process will continue 
until the dose-exposure relationship is confirmed (i.e. selection of the RP2D for those ages 
based on exposure and safety review by the DMC). If the selected RP2D is higher than the 
starting dose assigned to the previous group of patients, intra-patient dose escalation is allowed 
(Section 6.5.1.1.1).
As mentioned above, Group 1 (patients aged ≥12y to <18y) is excluded from this process as the 
starting dose is already confirmed at 10mg BID. The available PK data from these patients will 
however be used in the determination of the RP2D for the younger patients in Groups 2, 3, and 
4.


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All Group 1 patients will be enrolled automatically into the Ph II, with the first 5 patients 
undergoing extensive PK. Once the RP2D is selected for Groups 2 and 3 any further eligible 
patients between the ages of ≥2y and <12y will be enrolled into the Phase II. At this point Group 
4 will begin enrolling patients in the Phase I. Further, once the RP2D is established in Group 4, 
enrollment to Phase II for this group will be initiated.
The starting dose for Group 1 will not change, however the starting doses for other groups may 
be modified as per Table 6-2.
Table 6-2
Guidance for provisional doses (Example)
Dose level
Proposed Daily dose*
Increment from previous dose
-1
2.5 mg BID
- 50%
0
5 mg BID
(Starting dose)
+1
10 mg BID
+ 100%
Note: Example of provisional dose based on a starting dose of 5 mg BID for Group 2 is 
provided. Provisional doses for Group 3 and 4 will be based on applicable starting doses and 
follow the same guidance for dose level -1 and +1. Further, starting dose for Group 4 and RP2D 
confirmatory doses for Groups 2, 3 and 4 will be based on generated PK data and in consultation 
with the DMC.
Starting dose
Refer to Section 4.2 for more information.
6.5.1.1.1 Intra-patient dose escalation
If the selected RP2D is higher than the starting dose assigned to the previous group of patients, 
intra-patient dose escalation is allowed if the following conditions are met:

Inadequate activity is observed: lack of achieving a CR or PR

No treatment related toxicity has occurred resulting in dose interruption or dose reduction 
in the last 28 days
6.5.2
Dose modifications
A standardized dosing paradigm will be used to determine dose adjustments for safety and 
efficacy so that each patient is titrated to their most appropriate dose. These changes must be 
recorded on the Dosage Administration Record eCRF.
Dose adjustments for ruxolitinib safety
For patients who do not tolerate the protocol-specified dosing schedule, dose reductions and/or
interruptions are either recommended or mandated in order to allow the patients to continue the 
study treatment and maintain ruxolitinib dosing for optimal treatment of aGvHD. The objective 
of ruxolitinib dose adjustment rules described below is to optimize response for each individual 
patient (namely rapid resolution of aGvHD) while avoiding clinically relevant toxicities 
attributed to study drug. Deviations to mandatory dose interruptions and/or reductions are not 
allowed. Permanent treatment discontinuation from study treatment is mandatory for specific 
events indicated as such in Table 6-3 or listed in Section 9.1.1.


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The ruxolitinib dose will not exceed 10 mg BID.
6.5.2.1.1 Dose adjustments of ruxolitinib for hematologic safety
Dose reductions or interruptions for worsening cytopenias attributed to ruxolitinib are permitted 
in order to allow the patient to continue on the study treatment. Dose 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 patient while avoiding significant 
cytopenias.
For any patient who develops severe worsening cytopenias necessitating abrupt interruption of 
ruxolitinib, flare of aGvHD is expected to occur. To avoid significant aGvHD flare during 
abrupt ruxolitinib interruption, the patient’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 dose regimen of ruxolitinib for each patient that is 
necessary to obtain a clinical response, with increases in dose not more than one dose level 
every 2 weeks. Please refer to Table 6-5.
Treatment with ruxolitinib may be delayed up to 14 days to allow for resolution of toxicity. 
Patients may resume treatment if no medical condition or other circumstance exists that, in the 
opinion of the Investigator, would make the patient unsuitable for further participation in the 
study. The Investigator should contact the sponsor medical monitor to discuss cases where 
treatment has been delayed for more than 14 days before restarting treatment.
6.5.2.1.2 Dose adjustments of ruxolitinib for non-hematologic safety
Dose reductions or interruptions for non-hematologic toxicity are permitted in order to allow 
the patient to continue on the study treatment. 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 patient while avoiding significant non-
hematologic toxicities.
As organ toxicities are relatively common in alloSCT patients, any AE must be assessed to 
determine whether it is suspected to be related to ruxolitinib treatment. Ruxolitinib dose 
adjustments are only required for AEs that are suspected to be related to the study drug. This 
has particular relevance in evaluation of elevated creatinine, as 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 noted, to 
potentially alleviate the need for ruxolitinib dose reductions.
Ruxolitinib must be permanently discontinued upon any one of the following non-
hematological AEs 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:
1. The occurrence of a Grade 4 laboratory or non-laboratory abnormality attributable to 
ruxolitinib;


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2. The 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 outlined above are met prior to Day 
28, the patient will be considered to be a non-responder in terms of the Day 28 primary endpoint. 
Subsequent to Day 28, if any one or more of the treatment discontinuation criteria outlined 
above are met, the patient will be considered to be a non-responder in terms of the Day 56 
secondary endpoint.
In the event that any patient permanently discontinues the study treatment, regardless of reason, 
reasonable efforts should be made to have the patient return for an early termination visit and 
have the End of Treatment evaluations completed as described in Section 8. All patients 
completing/discontinuing study treatment at any time point will be followed in the Long-term 
follow-up period until they reach 2 years from Day 1.
The date any patient discontinued the study treatment and the specific reason for discontinuation 
will be recorded in the eCRF.
Table 6-3
Criteria for interruption and re-initiation of ruxolitinib treatment for 
adverse events suspected to be drug-related
Dose modifications for ruxolitinib for adverse events 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 (Table 6-4). If resolves to ≤ Grade 2, can resume 
initial dose level. If not resolved in ≤14 days the 
patient 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
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


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Dose modifications for ruxolitinib for adverse events suspected to be drug-related
Worst toxicity
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 patient 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: Hold dose and discontinue patient 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 patient from 
study treatment. The patient 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.
> 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.


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Dose modifications for ruxolitinib for adverse events suspected to be drug-related
Worst toxicity
Combined celevations of AST or ALT and total bilirubin
For patients 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 patients 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 patients 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 the 
Section 6.5.3.1 for additional follow-up evaluations as 
applicable.)
If causality assessment indicates that DILI is 
probable: Permanently discontinue patient 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: Hold dose and discontinue 
patient 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: Hold dose and discontinue patient from 
study treatment
Gastro intestinal
Pancreatitis
Grade 2
Recommendation: Maintain dose level
Grade ≥ 3
Mandatory: Hold dose and discontinue patient 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: Hold dose. Discontinue patient from study 
treatment


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Dose modifications for ruxolitinib for adverse events suspected to be drug-related
Worst toxicity
Skin and subcutaneous tissue disorders
Rash/photosensitivity
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, then increase by one dose 
level
If resolved in > 7 days, then maintain the reduced 
dose level
Grade 4
Mandatory: Hold dose. Discontinue patient 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: Hold dose and then discontinue 
from study treatment
All dose modifications should be based on the worst preceding toxicity.
For dose level refer to  Table 6-4 and Table 6-5.
a Common Toxicity 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 (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, patients will be discontinued permanently 
from study treatment.
*** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea.
Except for Group 1, all other dose reductions (Table 6-4) and dose re-escalations (Table 6-5) 
are examples and may not reflect the actual starting dose.


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Table 6-4
Dose reduction steps for ruxolitinib
Dose level/cohort
Proposed starting dose
First dose reduction
Second dose reduction
1
10mg BID
5mg BID
5mg QD
2
5mg BID
5mg QD OR 2.5mg BID
N/A
3
4mg/m2 BID*
2mg/m2 BID*
N/A
4
Starting dose BID*
50% Starting dose BID*
N/A
* BSA-based calculated doses should be administered as per instructions in the pharmacy manual.
Note: All dose reductions are 50%, no further reductions will be allowed beyond once a day dose.
Table 6-5
Dose re-escalation levels for ruxolitinib
Dose level/cohort
Reduced dose
First dose escalation
Second dose escalation
1
5mg QD
5mg BID
10mg BID
2
5mg QD OR 2.5mg BID
5mg BID
N/A
3
2mg/m2 BID*
4mg/m2 BID*
N/A
4
50% Starting dose BID*
Starting dose BID*
N/A
* BSA-based calculated doses should be administered as per instructions in the pharmacy manual.
6.5.2.1.3 Optional dose tapering strategy in the event of discontinuation from study 
treatment 
When a decision is made to permanently discontinue ruxolitinib therapy for reasons other than 
for hematologic/non-hematologic safety (e.g. when aGvHD complete response is observed), a 
dose tapering strategy may be followed, based on evaluation of the condition of the patient, 
current dosing regimen and the clinical judgment of the Investigator.
Following any abrupt interruption or discontinuation of ruxolitinib, symptoms of aGvHD 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 aGvHD flare 
anticipated after abrupt ruxolitinib discontinuation.
When a decision has been made to discontinue the patient 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 as least through the continued administration 
on ruxolitinib and until the safety follow-up visit is completed (30 days from last ruxolitinib 
dose intake or EOT visit, whichever occurs last) for AE monitoring.
6.5.2.1.4 Dose modification for ruxolitinib when combined with CYP450 modulators
In all cases when ruxolitinib is co-administered with CYP450 modulators, patients should be 
closely monitored and dose titrated based on safety (see Section 6.5.2.1.1 and 
Section 6.5.2.1.2).
See Section 16.6 Appendix 6 for a list of CYP3A4 inhibitors and inducers.


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Strong CYP3A4 inhibitors
A dose reduction of ruxolitinib (e.g. by 50% based on guidance for each age group inTable 6-
4) should be considered when using strong CYP3A4 inhibitors. No dose adjustment of 
ruxolitinib is needed for use with topical ketoconazole. See Section 6.2.1.2.
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% based on guidance for each age group in 
( Table 6-4) should 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.
CYP3A4 inducers
No dose adjustment is recommended when ruxolitinib is co-administered with CYP3A4 
inducers.
6.5.3
Follow-up for toxicities
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential 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 DILI 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:
a.
For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN
b. 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.
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.


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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 cause, and is already elevated at baseline, an 
increase in ALP 2 x baseline value may indicate liver damage.  In this situation, 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. 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
1.
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, 
HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
2.
CMV PCR (viral load) , EBV PCR (viral load), HSV PCR (viral 
load), ADV PCR(viral load)   
Autoimmune hepatitis
3.
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
4.
Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis
5.
Ultrasound or MRI
Hypoxic/ischemic hepatopathy
6.
Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease
7.
Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)
8.
Caeruloplasmin
Hemochromatosis
9.
Ferritin, transferrin
Alpha-1-antitrypsin deficiency
10. 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 
hepatitis).The possibility to perform a liver biopsy may be considered if clinically indicated.
Obtain PK sample, as close as possible to last dose, if possible.
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.


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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 a Serious Adverse Event (SAE) and reported as an 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
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
Compliance will be assured by administrations of the study treatment under the supervision of 
investigator or his/her designee, and will be verified by determinations of ruxolitinib in plasma.
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 patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
Table 6-7
Preparation and Dispensing 
Study Treatments
Dispensing
Preparation
INC424/ruxolitinib
Tablets or oral pediatric formulation including instructions for 
administration are dispensed by study personnel on an outpatient 
basis. Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least their next 
scheduled study visit
Not 
applicable
Study treatment should be administered to patients as per instructions in the pharmacy manual.
Study treatment, ruxolitinib, will be provided as global clinical open-label supply and will be packed and labeled 
under the responsibility of Novartis, Global Clinical Supply (GCS).
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and 
strength). Responsible site personnel will identify the study treatment package(s) to dispense 
by the medication number(s) assigned by IRT to the patient. Site personnel will add the patient 
number on the label. If the label has 2-parts (base plus tear-off label), immediately before 
dispensing the package to the patient, site personnel will detach the outer part of the label from 
the package and affix it to the patient’s source document.


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Table 6-8
Packaging and labeling 
Study Treatment
Packaging
Labeling (and dosing frequency)
INC424/ruxolitinib
Tablets in HDPE bottles OR oral 
pediatric formulation
Tablet: INC424 5mg or
Oral Pediatric Formulation: 
INC424 , dose strength
6.7.1
Handling of study treatment and additional treatment
Handling of study treatment
Study 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 study treatment must be stored according to the 
instructions specified on the labels and in the IB. Clinical supplies are to be dispensed only in 
accordance with the protocol. Technical complaints are to be reported to the respective Novartis 
CPO Quality Assurance.
The investigator should instruct the patient/caregiver to administer ruxolitinib in accordance 
with the instructions in the pharmacy manual.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study 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 study 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.
Table 6-9
Supply and Storage of Study Treatment 
Study treatments
Supply
Storage
INC424/ruxolitinib
Centrally supplied by Novartis
Refer to study treatment label
Handling of additional treatment
In the context of this protocol, the following non-investigational treatment will be taken by the 
patient as per standard of care, but will be monitored specifically because dose adjustments of 
these non-investigational treatments may contribute to the efficacy assessment:
1. CNI
2. Systemic corticosteroids
All dosages prescribed to the patient and all dose changes during the study must be recorded on 
the Dose Administration Record eCRF.
Details are described in the Monitoring Plan.


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7
Informed consent procedures
Eligible patients may only be included in the study after parents or guardians provide written 
(witnessed, where required by law or regulation), Institutional Review Board/Independent 
Ethics Committee/ Research Ethics Board (IRB/IEC/REB)-approved informed consent.
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) and assent form that is considered appropriate for this study and complies with the 
ICH E6 GCP guideline and regulatory requirements. Any changes to this ICF or the assent form 
as suggested by the investigator must be agreed to by Novartis before submission to the 
IRB/IEC/REB, and a copy of the approved version must be provided to the Novartis monitor 
after IRB/IEC/REB approval.
Information about common side effects already known about the investigational treatment can 
be
found in the Investigator's Brochure (IB). This information will be included in the patient / 
parental informed consent and should be discussed with the patient, parent/guardian 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 or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the patient and parent/guardian.
The following informed consents are included in this study:
1.
Main study patient, parent/guardian consent
2.
Adolescent assent
3.
Child assent
4.
As applicable, Pregnancy Outcomes Reporting Consent for female subjects
Females of child bearing potential should be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
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. 


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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 the patients and person obtaining informed consent, etc.).
8
Visit schedule and assessments
The assessment schedule (Table 8-1) 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.
Patients should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. (Refer to Section 8.3.) Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who discontinue from
study treatment are to return for the end of treatment visit as soon as possible, and attend the 
follow-up visits as indicated in the Assessment Schedule.
Patients who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must be recorded on the CRF.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
Screening Treatment1
Safety Follow-up
Long Term Follow-up2
Visit Name
Screening Day 1
Week 1-
Week 8 
(Weekly)
Week 12-
Week 24 
(Monthly)
Week 28-
Week 48 
(only in 
the case 
of taper or 
aGvHD 
flare, 
monthly)
EOT 
(Week 
24/Week 
48)3
Safety Follow-up 
visit
Month 
12
Month 
18
Month 
24
Weeks
-4
1
1 to 8
12 to 24
28 to 48
48
0
53
78
105
Days
-28 to -1
1
7 to 56
84 to 168 196 to 336 -
Last dose +30
365
546
730
Study Informed Consent/Assent
X
Inclusion / Exclusion criteria
X
Disease history (alloSCT and aGvHD history, 
CIBMTR risk assessment)
X
HCT-Specific Co-Morbidity Index Score
X
Demography
X
Other relevant Medical History
X
Prior/Concomitant Medications
X (From screening until safety follow up)
IWRS/IRT (Registration, EOT)
X
X
X 
(Monthly)
X
X
X
Physical Examination
S
S
S
S
S
S
Body Height
X
X
X (Week 
24)
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X




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Period
Screening Treatment1
Safety Follow-up
Long Term Follow-up2
Visit Name
Screening Day 1
Week 1-
Week 8 
(Weekly)
Week 12-
Week 24 
(Monthly)
Week 28-
Week 48 
(only in 
the case 
of taper or 
aGvHD 
flare, 
monthly)
EOT 
(Week 
24/Week 
48)3
Safety Follow-up 
visit
Month 
12
Month 
18
Month 
24
Weeks
-4
1
1 to 8
12 to 24
28 to 48
48
0
53
78
105
Days
-28 to -1
1
7 to 56
84 to 168 196 to 336 -
Last dose +30
365
546
730
PK blood sampling
X (see 
Section 
8.6.1.1)
X (See 
Section 
8.6.1.1)
X (See 
Section 
8.6.1.1)
Survival Follow-up
X
X
X
Disposition
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
1 From Day 1 to Week 24/End of Study Treatment (EOT) Weekly visits from Week 1 to Week 8 (Day 56) Monthly visit (every 28 days) after Day 56 until Week 24 or 
EOT, whichever occurs later
2 (See Section 9.1.5 for details)
3 EOT visit occurs when the patient discontinues study treatment. If EOT occurs before Week 24 the patient will still follow the visit schedule as planned and then 
continue to the follow up phase.
5 For applicable female patients only (Section 8.5.5). Per Investigator discretion, a serum pregnancy test can be performed in lieu of a urine pregnancy test.
6 Only for patients administered with oral pediatric formulation starting treatment Day 1 (Section 8.6.3.1)


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8.1
Screening
Molecular pre-screening
Not Applicable
Screening
Patients diagnosed with either aGvHD (grades II-IV) or SR-aGvHD (grades II-IV) after 
alloSCT will be consented to the study prior to any study procedures being performed.
Screening period will begin once the patient has signed the Study Informed Consent and 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 treatment initiation on Day 1. 
Laboratory assessments should be performed within 72 hours of treatment initiation. Continued 
use of systemic corticosteroids, CNI (cyclosporine or tacrolimus), and topical corticosteroid 
therapy per institutional guidelines is permitted. Other systemic medications for aGvHD may 
be continued after Day 1 only if used for aGvHD prophylaxis prior to diagnosis of aGvHD. For 
SR-aGvHD patients, cessation of other systemic treatment for aGvHD other than 
corticosteroids +/- CNI will be required prior to treatment initiation.
A patient 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 patient will not be required to 
sign another ICF, and the original patient ID number assigned by the investigator will be used.
All baseline assessments should be performed on Day 1 as per Table 8-1. Laboratory 
assessments performed within 72 hours of Day 1 need not be repeated.
A patient is considered a screen failure in the event that the laboratory test(s) cannot be available 
within the screening period, or the retest(s) do not meet the entrance criteria or the patient’s 
medical condition has changed significantly during the screening period so that the 
inclusion/exclusion criteria are no longer met, more details outlined on Section 5.
A new study ICF will need to be signed if the investigator chooses to re-screen the patient after 
a patient has screen failed. The subject number will remain unchanged and patient will be 
entered in the IRT as re-screen. All required screening activities must be performed when the 
patient is rescreened for participation in the study. An individual patient may only be rescreened 
once for the study.
Patients 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
Patients must meet all eligibility criteria at screening in order to proceed with the dose 
assignment and enter the Treatment Period of the study.
Patient 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 will the site follow 
instructions to enter the patient into the IRT system to be assigned to a dose based on 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 patient information into the eCRF.
8.1.2
Information to be collected on screening failures
Patients who sign the study informed consent, but fail to be started on study treatment for any 
reason will be considered a screen failure.
The reason for not starting on treatment will be entered on the appropriate Disposition CRF 
pages.
The demographic information, informed consent, and Inclusion/Exclusion CRFs must also be 
completed for all Screen Failure patients. In addition, the aGvHD/SR-aGvHD assessment at 
screening will also be recorded in the CRF with overall grade and staging to better characterize 
the aGvHD/SR-aGvHD population screened for this trial.
No other data will be entered into the clinical database for patients who are screen failures, 
unless the patient 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 patient was not treated.
8.2
Subject demographics/other baseline characteristics
Patient information to be collected at screening include:
a. Demography
b. Complete Medical History and current medical conditions
c. Prior and concomitant medications and non-therapies (including physical therapy, oxygen 
and blood transfusions)
d. Disease History – disease treatment history, donor background, stem cell transplant and 
GvHD disease history including CIMBTR classification (Section 16.5 Appendix 5) and 
HCT specific comorbidity index score (Section 16.4 Appendix 4)
Patient will have the screening assessments performed before the start of study treatment as in 
Table 8-1: 

Physical examination including height, weight, vital signs

Laboratory assessments – Hematology, Chemistry, Coagulation, Urinalysis

Hepatitis serology markers

Pregnancy test (for applicable female patients only, Section 8.5.5)

Graft failure assessment




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Table 8-2
Acute GvHD Staging Criteria (Harris et al 2016)
Stage 
Skin
(Active Erythema 
Only)
Liver
(Bilirubin)
Upper GI
Lower GI
(stool output/day)
Stage 0
No active 
(erythematous)
GVHD rash
< 2mg/dL
No or intermittent 
nausea, vomiting, 
or anorexia
Adult: <500mL/day 
or < 3 episodes/day
Child: 
<10mL/kg/day or < 
4 episodes/day
Stage 1
Maculopapular rash
< 25% BSA
2 – 3 mg/dL
Persistent nausea, 
vomiting, or 
anorexia
Adult: 500-999 
mL/day or 3-4 
episodes/day
Child: 10-19.9 
mL/kg/day or 4-6 
episodes/day
Stage 2
Maculopapular rash 
< 25-50% BSA
3.1 – 6 mg/dL
Adult: 1000-
1500mL/day or 5-7 
episodes/day
Child: 20-
30mL/kg/day or 7-
10 episodes/day
Stage 3
Maculopapular rash 
> 50% BSA
6.1 – 15 mg/dL
Adult: 
>1500mL/day or > 
7 episodes/day
Child: 
>30mL/kg/day or > 
10 episodes/day
Stage 4
Generalized 
erythroderma 
(>50% BSA) plus 
bullous formation 
and desquamation 
> 5% BSA
> 15 mg/dL
Severe abdominal 
pain with or without 
ileus or grossly 
bloody stool 
(regardless of stool 
volume)
Overall clinical grade (based on most severe target organ involvement):
Grade 0: No stage 1-4 of any organ.
Grade I: Stage 1-2 skin without liver, upper GI or lower GI involvement.
Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI.
Grade III: Stage 2-3 liver and/or stage 2-3 lower GI with stage 0-3 skin and/or stage 0-1 upper GI.
Grade IV: Stage 4 skin, liver or lower GI involvement, with stage 0-1 upper GI.
aGvHD assessment
aGvHD grading will be performed by the investigator on a weekly basis for the first 8 weeks 
after treatment assignment and then every 28 days thereafter during the treatment period and at 
EOT visit as outlined in Table 8-1.
aGvHD assessment will be performed as per Table 8-2 (Harris et al 2016): organ assessment 
(skin; liver; upper GI; Lower GI) and overall grading at the time of the evaluation should be 
reported according to Table 8-2.
In addition, biopsy of the organ involved may be performed per institutional practices at 
investigator’s discretion for aGvHD management. If performed, the investigator will indicate 
the results once available.


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Response to study treatment will be assessed by the investigator at every visit during the 
treatment period (Section 8.3). Response assessment by the investigator at Day 28 and at Day 
56 will support respectively, the primary and key secondary endpoint assessments for this trial.
Patients will be also monitored for aGvHD flares occurring during steroid, CNI, and ruxolitinib 
taper.
Investigator should carefully record any action taken to manage aGvHD including start of 
tapering, initiation of any new systemic therapy, re-escalation of corticosteroids and the re-
escalated steroid dose, and steroid taper failure.
The data should be entered in the appropriate CRFs. Worsening of aGvHD, including 
occurrence of GvHD flare will be reported on appropriate specific CRF and, not as an adverse 
event (Section 10.1.1).
Note: Additional assessments may be done as per institutional guidelines at investigator’s 
discretion. aGvHD assessments performed at unscheduled visit and leading to a change in 
patient’s management or a change in patient’s response should be recorded in the CRF.
Table 8-3
Response assessment
Efficacy assessments:
aGvHD response assessment will be made with respect to the organ stage at screening and Day 1:
4.
Complete response is defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates 
complete resolution of all signs and symptoms of aGvHD in all evaluable organs without administration of 
additional systemic therapy for any earlier progression, mixed response or non-response of aGvHD.
5.
Partial response is defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or 
symptoms without progression in other organs or sites without administration of additional systemic therapy 
for an earlier progression, mixed response or non-response of aGvHD.
6.
Lack of response is defined as no response, mixed response, or progression.
7.
No response is defined as absence of improvement in any organ involved by aGvHD, without worsening 
in any involved organ.
8.
Mixed response is defined as improvement of at least 1 stage in the severity of aGvHD in one organ 
accompanied by progression in another organ or development of signs or symptoms of aGvHD in a new 
organ.
9.
Progression is defined as worsening in 1 or more organs by 1 or more stages without improvement in any 
involved organ.
Patients requiring additional systemic therapy for aGvHD will be classified as non-responders.
aGvHD Flare is defined as any increase in signs or symptoms of aGvHD that is sustained for >24h after an 
initial response (CR or PR) and requires re-escalation of immunosuppressive therapy (e.g. corticosteroid, CNI 
and/or ruxolitinib dosing). While all aGvHD flares will be captured on study whether occurring during steroid, 
CNI, or ruxolitinib taper, only flares that fulfill either one the following criteria will be considered a failure of 
treatment:
1. Addition of new systemic therapy for aGvHD due to inability to taper corticosteroids below 
methylprednisolone 0.5 mg/kg/day (or equivalent <0.6 mg/kg/day of prednisone) for a minimum 7 days,
OR
2. Addition of new systemic therapy for aGvHD due to re-escalation of corticosteroids to methylprednisolone >2 
mg/kg/day (or equivalent >2.5 mg/kg/day of prednisone).
aGvHD assessments will be performed by the treating team according to standard criteria (Harris et al 2016) as 
described in Table 8-3. Disease assessments must continue per the schedule of visits weekly until Day 56, 
unless withdrawal of consent/ Opposition to use data/biological samples or death occurs, even in patients who 
are withdrawn from treatment unless consent for these assessments is specifically withdrawn.


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At later time points after Day 56 after the start of the study treatment, signs and symptoms of cGvHD may be 
observed. cGvHD signs and symptoms may occur in up to 50% of patients based on published literature. 
Patients will be evaluated for any signs or symptoms of cGvHD and scored using NIH Consensus Criteria 
(Lee et al 2015) as described in Section 16.2 (Appendix 2). Development of cGvHD signs or symptoms is not 
considered a treatment failure of aGvHD. Treatment of cGvHD will follow institutional standards of procedure 
and Investigator preference. Ruxolitinib must not be administered for treatment of cGvHD. For patients 
receiving ruxolitinib at the time of onset of cGvHD, ruxolitinib taper will follow guidelines per Section 6.1.5.1.
Chronic GvHD Assessment
Occurrence of definitive and possible manifestations of cGvHD will be assessed monthly after 
Day 1 during the treatment period and at EOT. Patients will continue to be assessed for 
occurrence of cGVHD during the Long Term Follow-up period at Month 12, at Month 18 and 
at Month 24 (see Table 8-1). Occurrence of cGvHD will be reported on appropriate specific 
CRF and, not as an adverse event Section 8.4.1.3. Ruxolitinib taper is initiated or continued as 
outlined in the tapering guidelines (Section 6.1.5.1).
Investigator will assess cGvHD as per NIH consensus guidelines for cGVHD (Section 16.2
Appendix 2): overall grading (mild, moderate, severe) at the time of cGvHD diagnosis which 
will be reported in corresponding CRF.
In addition, investigator should indicate if a systemic treatment is initiated for cGvHD in 
appropriate CRF(s).
Graft Failure Monitoring
Patients will also be monitored for any evidence of graft failure at screening, each visit after 
Day 1 during the Treatment and Long Term Follow-Up periods.
In addition, considering that graft failure is defined as initial whole blood or marrow donor 
chimerism >5% declining to <5% on subsequent measurements, donor chimerism will be also 
closely monitored.
If a patient 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).
Hematologic disease relapse/progression assessment
Patients will be closely monitored for any evidence of underlying hematologic disease relapse 
or progression at each visit from Day 1 during the Treatment period and the Long Term Follow-
Up period as outlined in Table 8-1.
The investigator will assess relapse and progression of the underlying hematologic disease 
according definitions outlined in Section 16.3 (Appendix 3), and indicate if any therapy was 
instituted to treat persistent, progressive or relapsed hematologic disease, including the 
withdrawal of immunosuppressive therapy, chemotherapy administration, and/or donor 
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Evaluation and/or evidence of malignancy relapse/progression will be conducted according to 
local institutional practices. Available information on the malignant hematologic disease 
progression/relapse will be documented in the appropriate CRF and, not as an adverse event 
(Section 10.1.1).
8.4.2
Appropriateness of efficacy assessments
Not Applicable
8.5
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 Section 10.1.
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 patient´s health status until it is safe for the patient to visit the 
site again.
8.5.1
Physical examination
A physical exam, as per local standard of care, will be performed during screening, all scheduled 
study visits up to EOT during Treatment period Table 8-1.
Occurrences of bleeding must be recorded on the Adverse Event page of the patient’s eCRF.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s eCRF. Significant new findings that begin or 
worsen after informed consent must be recorded on the Adverse Event page of the patient’s 
eCRF
8.5.2
Vital Signs
Vital signs include blood pressure (supine or seated position), pulse measurement, and body 
temperature.
8.5.3
Height and weight
Height and body weight (in indoor clothing, but without shoes) will be measured at screening 
and at subsequent time points as specified in Table 8-1.
8.5.4
Laboratory evaluations
Table 8-4
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, Red 
blood cells (RBC), White blood cells (WBC). RBC Morphology, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Absolute Neutrophil Count (ANC), 
Absolute Reticulocytes, Bands


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Test Category
Test Name
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (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 findings on dipstick will be followed up with a microscopic evaluation (Red Blood 
Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
Coagulation
Prothrombin time (PT), International normalized ratio (INR), Partial thromboplastin time 
(PTT) or Activated partial thromboplastin time (APTT), D-Dimer, Fibrinogen
Hepatitis 
markers
Hepatitis B surface antigen, Hepatitis B surface antigen 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)
Note:
Prior HBV and HCV serology test results obtained as part of standard of care prior to 
alloSCT (i.e., hepatitis B or C surface antigen negative, surface antibody positive) may be 
used. Baseline serology tests do not need to be repeated during the Screening 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) and Adenovirus (ADV) viral load
Pregnancy Test
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 and recorded in the eCRF.
Hematology
Hematology parameters (See Table 8-4) will be measured at screening and all scheduled visits 
during treatment period up to EOT as noted in Table 8-1.
Clinical Chemistry
Serum chemistries (See Table 8-4) will be measured at screening and all scheduled visits during 
treatment period up to EOT as stated in Table 8-1.
Urinalysis
Urinalysis will be performed using macroscopic evaluation (See Table 8-4) at screening and 
scheduled visits during treatment period up to EOT as outlined in Table 8-1.
Any significant findings on the macroscopic panel will be followed up with a microscopic 
evaluation.


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Coagulation
Coagulation parameters (See Table 8-4) will be measured at screening, scheduled visits during 
treatment period up to EOT as outlined in Table 8-1.
Bleeding
Bleeding complications are important identified and potential risks in the setting of alloSCT
due to profound thrombocytopenia and/or coagulopathy and therefore will be monitored closely 
throughout the treatment period from Day 1 and, at every visit until EOT and at the Safety 
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 CTCAE grading as defined in Section 10.1.
Infection Monitoring
Infections (including opportunistic infections) are important risks identified with ruxolitinib 
aGvHD therapy and therefore will be monitored closely throughout the treatment period from 
Day 1 and, at every visit until EOT and at the Safety follow up visit.
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 Appendix 1).
Viral reactivation monitoring
Investigator must confirm patient has no evidence of active uncontrolled hepatitis B virus 
(HBV) or hepatitis C virus (HCV) at screening based on medical assessment.
Viral serology and viral load testing will be assessed once the patient has signed the informed 
consent form and during screening.
The following hepatitis serology markers will be assessed at screening:
1.
Hepatitis B surface antigen (HBsAg)
2.
Hepatitis B surface antibody (HBsAb)
3.
Hepatitis B core antibody (anti-HBc)
4.
HBV-DNA
5.
Hepatitis C virus antibody
6.
HCV RNA-PCR
Serology hepatitis test results obtained as part of standard of care prior to alloSCT (i.e., hepatitis 
B surface antigen negative, surface antibody positive, or HCV antibody) may be used and 
baseline serology tests do not need to be repeated during the Screening period. Viral serology 
can be performed throughout the study as per local guidelines.
Viral load will be monitored throughout the study. The following PCR viral load (blood) will 
be assessed at screening and every 6 months while the patient is on ruxolitinib treatment:


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1.
Hepatitis B and C
Viral load results obtained as part of standard of care within 3 days of the Screening visit may 
be used as baseline results and do not need to be repeated during the Screening period.
The results of the baseline viral load tests to assess HBV and HCV performed during screening 
may not become available by the time of enrollment, as these specialized laboratory viral load 
test results may take up to several days. For eligibility purposes, the investigator must confirm 
the patient has no evidence of active uncontrolled HBV or HCV.
For details on the schedule of assessments, see Table 8-1. 
CMV, EBV, HHV-6, HSV, VZV and ADV 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.
Second primary malignancy monitoring
Occurrence of any new malignancies other than the underlying hematologic disease, including 
non-melanoma skin cancer, will be monitored closely up to 24 months after Day 1 (from Day 
1 throughout the treatment period and Long Term Follow-Up period outlined in Table 8-1).
Second primary malignancy will be reported as adverse event as defined in Section 10.1.
8.5.5
Pregnancy and assessments of fertility
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric patients 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 (monthly) 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 patient 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 patientand her family. The investigator should 
also discuss the management of the pregnancy test results with the patient and her 
parents/caregivers. The privacy of the patient 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. 
Patients becoming pregnant must be discontinued from study drug. However, a patient may 




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2.
All Phase II patients will have samples collected as per Table 8-7.
3.
Group 4:
1. All patients will have samples collected as per Table 8-6.
Table 8-5
Ruxolitinib Pharmacokinetic blood collection for extensive PK*
Treatment 
Period
Week of 
treatment
Day of 
treatment
Scheduled 
timepoint
PK collection number
/ Dose reference ID
PK 
Sample 
No
Sample 
volume** 
[mL]
1
1
1
Pre-dose
1
1
1.2
Post-dose 
0.5 hour (± 
15 min)
1
--
2
1.2
Post-dose 
1 hour (± 
15 min)
1
--
3
1.2
Post-dose 
1.5 hours 
(± 15 min)
1
--
4
1.2
Post-dose 
2 hours (± 
15 min)
1
--
5
1.2
Post-dose 
4 hours (± 
1 hr)
1
--
6
1.2
Post-dose 
6 hours (± 
1 hr)
1
--
7
1.2
Post-dose 
9 hours (± 
1 hr)
1
--
8
1.2
1
1
7
Pre-dose
2
201a
9
1.2
Post-dose 
2 hour (± 
15 min)
2
--
10
1.2
1
2
14
Pre-dose
3
301a
11
1.2
Post-dose 
2 hour (± 
15 min)
3
--
12
1.2
1
4
28
Pre-dose
4
401a
13
1.2
Post-dose 
2 hour (± 
15 min)
4
--
14
1.2
Unscheduled Sample
---
---
1001+
1.2
a Dose reference IDs to collect previous dose information for PK trough samples.
* For Group 1 only, the first 5 patients enrolled will undergo extensive PK sampling. ** A maximum of 
approximately 17 mL blood will be collected in 28 days.


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Table 8-6
Ruxolitinib Pharmacokinetic blood collection log for sparse PK in 
Group 4
Treatment 
Period
Week of 
treatment
Day of 
treatment
Scheduled 
timepoint
PK collection number
/ Dose reference ID
PK 
Sample 
No
Sample 
volume* 
[mL]
1
1
1
Post-dose 2 
hour (± 15 
min)
10
--
100
1.2
1
1
7
Pre-dose
11
1101a
101
1.2
Post-dose 2 
hour (± 15 
min)
11
--
102
1.2
1
2
14
Pre-dose
12
1201a
103
1.2
Post-dose 2 
hour (± 15 
min)
12
--
104
1.2
1
4
28
Pre-dose
13
1301a
105
1.2
Post-dose 2 
hour (± 15 
min)
13
--
106
1.2
Unscheduled Sample
---
---
1001+
1.2
a Dose reference IDs to collect previous dose information for PK trough samples.
*A maximum of approximately 9 mL blood will be collected in 28 days.
Table 8-7
Ruxolitinib Pharmacokinetic blood collection log for sparse PK*
Treatment 
Period
Week of 
treatment
Day of 
treatment
Scheduled 
timepoint
PK collection number
/ Dose reference ID
PK 
Sample 
No
Sample 
volume** 
[mL]
1
4
28
Pre-dose
20
2001a
200
1.2
Post-dose 2 
hour (± 15 
min)
20
201
1.2
1
8
56
Pre-dose
21
2101a
202
1.2
Post-dose 2 
hour (± 15 
min)
21
--
203
1.2
1
12
84
Pre-dose
22
2201a
204
1.2
Post-dose 2 
hour (± 15 
min)
22
--
205
1.2
1
20
140
Pre-dose
23
2301a
206
1.2
Post-dose 2 
hour (± 15 
min)
23
--
207
1.2
1
24
168
Pre-dose
24
2401a
208
1.2
Post-dose 2 
hour (± 15 
min)
24
--
209
1.2
Unscheduled Sample
---
---
1001+
1.2
a Dose reference IDs to collect previous dose information for PK trough samples.
* For Group 1 only, following extensive PK sampling for first 5 patients, the remaining will have sparse samples 
collected. **A maximum of approximately 12 mL blood will be collected in 24 weeks.


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Refer to the [[Laboratory Manual]] for detailed instructions for the collection, handling, and 
shipment of PK samples.
Analytical method
The plasma samples from all patients 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.


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8.6.3
Other Assessments
Acceptability and palatability questionnaire
Acceptability and palatability of the study drug (only for patients administered with oral 
pediatric formulation starting treatment Day 1) will be evaluated from a questionnaire 
completed by patients, with the help from parents or caregivers as needed at the following visits 
(as detailed in Table 8-1): 
1.
Day 1 (after first dose)
2.
Week 4 (1 month) (after either morning or evening dose of that visit date)
3.
Week 24 (6 months) (after either morning or evening dose of that visit date)
9
Discontinuation and completion
9.1
Discontinuation from study treatment and from study
9.1.1
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reason.
The investigator may discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being.
In addition to mandatory discontinuation from study treatment listed in Table 6-3, 
discontinuation from study treatment is required under any of the following circumstances:


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1.
Lack of response of aGvHD treatment at Day 28 (Section 6.1.5) (Section 12.4.1)
2.
Patients requiring new systemic therapy for aGvHD at any time (Section 6.1.5.1.1)
3.
aGvHD flare occurring during ruxolitinib taper after Week 24 (Section 6.1.5.1.1)
4.
Development of signs or symptoms of cGvHD including de novo, overlap, or 
progressive onset (Section 8.4.1.3)
5.
Underlying hematological disease progression or relapse (Section 8.4.1.5)
6.
Evidence of graft failure necessitating rapid taper of immunosuppression, 
administration of non-scheduled DLI, stem cell boost, chemotherapy, or other 
treatment that would expectedly affect aGvHD,
7.
Adverse events leading to discontinuation from study treatment (Section 6.5.2)
8.
Pregnancy (Section 8.5.5)
9.
Protocol deviation that results in a significant risk to the patient’s safety including use 
of prohibited treatment (Section 6.2.2)
10.
Patient has not weaned off corticosteroids, CNIs and ruxolitinib by Week 48 
(Section 6.1.5.1.)
Patients who discontinue ruxolitinib study treatment for reasons other than achieving a CR or 
PR should NOT be considered withdrawn from the study and will enter the Long Term Follow-
Up after completion of the Safety Follow Up visit Section 9.1.5 and assessments at the end of 
Week 24. All other patients (including patients that discontinue ruxolitinib prior to Week 24 for 
achieving a CR or PR) will enter Long-term follow-up and continue to follow the Visit 
Evaluation Schedule as outlined in the Table 8-1. Patients who develop cGvHD must 
discontinue from the study, and may utilize a ruxolitinib tapering strategy per Section 6.1.5.1. 
Patients with hematologic disease progression, graft failure, AE, patient safety, or pregnancy 
may require abrupt cessation of ruxolitinib study treatment per Investigator discretion. Patients 
should return for assessments as specified at the EOT visit in Table 8-1. The investigator must 
also contact the IRT to register the patient’s discontinuation from study treatment.
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 9.1.5.
Replacement policy
Patients who discontinue prematurely will not be replaced on this study. 
9.1.2
Withdrawal of informed consent/ opposition to use data/biological 
samples
Patients 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 patient:
1.
Explicitly requests to stop use of their biological samples and/or data (opposition to 
use patient’s data and biological samples)
and
2.
No longer wishes to receive study treatment
and


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3.
does not want to participate in the study any longer, and does not allow further 
collection of personal data.
This request should be in writing (depending on local regulations) and recorded in the source 
documentation.
Withdrawal of consent impacts ability to further contact the patient, 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 vs. discontinuation based on the protocol 
definitions of these terms.
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision to withdraw their 
consent/exercise data privacy rights and record this information. The investigator shall clearly 
document if the patient has withdrawn his/her consent for the use of data in addition to a study 
discontinuation.
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 patient are not allowed unless safety findings require 
communication or follow up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’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 EU and 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 patients 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 samples, the investigator should show "due 
diligence" by contacting the patient, family or family physician as agreed in the informed 
consent and by documenting in the source documents steps taken to contact the patient, e.g. 
dates of telephone calls, registered letters, etc.
A patient should not be considered lost to follow-up until due diligence has been completed. 
Patients lost to follow up should be recorded as such on the appropriate Disposition CRF.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time based on the occurrence of any of the 
following:

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.
In taking the decision to terminate, Novartis will always consider subject welfare and safety. 
Should early termination be necessary, the patient must be seen as soon as possible and be 
treated as a patient who discontinued from study treatment. The same assessments should be 
performed as described in Section 9.1.1 for a discontinued or withdrawn patient. 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 patient’s interests. The Investigator or 
sponsor, depending on local regulation, will be responsible for informing IRBs and/or ECs of 
the early termination of the trial.
9.1.5
Follow up for safety evaluations
1.
Safety Follow-up Visit
All patients must have a follow-up visit for safety evaluations 30 days (+ 3 day visit window)
following the last dose of study treatment based on discontinuation from Treatment Period.
At the Safety Follow-Up visit, adverse events and therapies after treatment discontinuation will 
be reviewed. In addition, serum pregnancy will be collected for female patients of child-bearing 
potential. Refer to Table 8-1. Patients who remain on ruxolitinib at Week 48 and obtain access
to ruxolitinib outside of the study will not complete the safety follow-up visit since study 
treatment will continue.
1.
Long-term safety Follow-up
All patients who discontinue study treatment (responders, non-responders, completing or 
prematurely discontinued from treatment period for any reasons as outlined above) will enter 
in the Long Term Follow-Up period, which lasts up to 24 months from start of study treatment 
(Day 1). Patients who prematurely discontinue ruxolitinib prior to Week 24 (without achieving 
CR or PR), must have assessments performed at the end of Week 24 (Table 8-1) and 
subsequently enter the Long Term follow-up period.
Visits are scheduled every six months (+/- 1 month from scheduled visit) starting Month 12 
followed by subsequent visits at Month 18 and Month 24. Patients who may have an End of 
Treatment at Week 48 due to extended taper or aGvHD flare, will have the long-term follow up 
at Month 18 and 24 only.
Information to be collected during Long-Term follow-up is detailed in Table 8-1. Data collected 
should be entered in the appropriate eCRF. Unscheduled visits may be performed as necessary. 
Additional assessments may be done as per institutional guidelines at investigator’s discretion 
at any time during the trial.
9.2
Study completion and post-study treatment
End of Study (EoS) will occur when all patients have reached Month 24 (i.e., the end of the 
long term follow-up observation period), unless the patient discontinues earlier.


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The final analysis will occur once all patients have completed the Long Term Follow-Up period 
to 24 months. All available data from all patients up to EoS, inclusive of OS, will be reported 
in a final Clinical Study Report (CSR).
Patients who meet the protocol criteria for treatment discontinuation 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, patients who meet all of the following criteria may 
be given the possibility to continue ruxolitinib outside the study, if requested:
1.
Responded (CR or PR; Refer to Table 8-3) to ruxolitinib at Day 28
2.
Did not meet study discontinuation criteria (Section 9.1.1)
3.
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.
Subjects who have not completed ruxolitinib tapering at the end of their study treatment period 
(Week 48) and are still deriving clinical benefit from ruxolitinib as assessed by the Investigator, 
may be considered to have completed the study and may be given the possibility to continue 
ruxolitinib outside of the study. If a patient meets the criteria for post-trial access, the 
Investigator may consider a ruxolitinib formulation change upon completion of 
CINC424F12201 and upon enrollment into post-trial access.
10
Safety monitoring reporting and committees
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
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 patient’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.


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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 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1.
The severity grade (CTCAE Grade 1-5)
2.
Its duration (Start and end dates)
3.
Its relationship to the study treatment (related / not related)
4.
Action taken with respect to study treatment (dose increased, 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
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.
The following events, which are components of study endpoints: worsening of study indication 
(aGvHD) including occurrence of aGvHD flare as defined in Section 6.1.5.1.1, occurrence of 
chronic GvHD, or progression/relapse of underlying hematologic disease (including fatal 
outcomes) as defined in Section 16.3 (Appendix 3), should not be reported as a serious adverse 
event and will be reported on specific CRFs 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 
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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:
1.
Fatal
2.
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).
1.
Results in persistent or significant disability/incapacity
2.
Constitutes a congenital anomaly/birth defect
3.
Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
1.
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
2.
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
3.
Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition
4.
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
5.
Occurrence of chronic GvHD
6.
Progression/relapse of underlying hematologic disease (including fatal outcomes) as 
defined in Section 16.3 Appendix 3.
7.
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
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 disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided study informed consent and until at least 30 days after the patient has 




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Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
10.1.5
Reporting of study treatment errors including misuse/abuse
Not applicable
10.1.6
Laboratory Test Abnormalities
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
10.1.7
Adverse events of special interest
Please refer to the ruxolitinib [Investigator Brochure] for safety information and selected 
adverse events, or the product label as applicable.
Adverse events of special interest (AESI) are selected categories of risks consisting of pooled 
AEs that are similar in nature, for which there is a specific clinical interest as a result of signals 
identified during the conduct of earlier trials with ruxolitinib. Such events on the basis of an 
ongoing review of the safety data and discussed in detail in the [Clinical Summary Preparation 
Document, RMP Pooling Plan and Statistical Methodology].
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
For liver safety monitoring guidelines, refer to Section 6.5.3.1.
10.3
Committees
10.3.1
Data Monitoring Committee
This study will institute a data monitoring committee (DMC) which 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 constituted prior to the first patient 


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receiving treatment. The DMC will be responsible to review safety data approximately every 6 
months during the Ph II (after the first patient has started study treatment). Additionally, during 
the Phase I, the DMC will review each age group data to determine an age appropriate RP2D. 
This data will include all PK data, safety, and activity data which will be collected over the first 
28 days of the Phase I for that age group under review. There may be additional DMC reviews 
based on enrollment in each group in the Phase I for adequate and timely assessment of the age-
appropriate RP2D. This includes but does not limit the role of the DMC to evaluate these and 
additional activity data and to provide recommendations to the sponsor to continue modify or 
stop the study early. The DMC will make a recommendation as to whether the safety and 
activity data is supportive of enrolling Group 4 into this 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 the sponsor and the DMC.
10.3.2 
Steering Committee
A Steering Committee (SC) will be established for this study. Further details on the functions
and responsibilities will be outlined in the Steering Committee charter.
11
Data Collection and Database management
11.1
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the 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 and, allow modification or 
verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.
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
For studies using eCRFs, Novartis personnel (or designated Clinical 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 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.


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Biomarker and PK samples and/or data will be processed centrally, and the results will be sent 
electronically to Novartis (or a designated CRO).
Data about all study treatments dispensed to the patient 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 violations 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 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, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol 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.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.
11.4
Data Confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:
1.
What protected health information (PHI) will be collected from subjects in this study?
2.
Who will have access to that information and why?
3.
Who will use or disclose that information?
4.
The rights of a research subject to revoke their authorization for use of their PHI.


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential patient 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
12
Data analysis and statistical methods
The final analysis will be conducted and the clinical study report (CSR) written once all patients 
have completed the study (i.e. completed the long-term follow-up period of Month 24) or 
discontinued earlier. 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.
12.1
Analysis sets
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 patients 
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 Efficacy Evaluable Set as 
described below.
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received at least one dose of study treatment. Patients will be analyzed according to 
the treatment they have been assigned to.
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the assigned dose level of ruxolitinib if the patient 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 patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to:
1.
Take the dose of ruxolitinib prior to PK sample.
2.
For pre-dose samples, do not vomit within 2 hours after the dosing of ruxolitinib prior 
to sampling; for post-dose samples, do not vomit within 2 hours after the dosing of 
ruxolitinib.
The PAS will be used for Non-compartmental analysis (NCA) for patients where extensive PK 
sampling is obtained. This analysis set will also be used for any exposure-response analysis 


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The Efficacy Evaluable Set (EES) comprises all patients to whom study treatment has been 
assigned at the Recommended Phase 2 dose (RP2D) of ruxolitinib and who received at least 
one dose of study treatment at that dose level. If the starting dose is different from the RP2D 
due to co-administration of ruxolitinib with strong
CYP3A4 inhibitors or dual
CYP3A4/CYP2C9 inhibitors, these patients will be included in the EES.
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 Table 3-1 and Table 3-2. If the Phase I preliminary dose is different 
to RP2D, baseline characteristic data will be listed and summarized by age group and dose level.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized 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 patients 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.
If the Phase I preliminary dose is different to RP2D, treatment data will be listed and 
summarized by age group and dose level.
12.4
Analysis of the primary endpoint(s)
The primary objective of the Phase I is to assess pharmacokinetic (PK) parameters of ruxolitinib 
for patients with aGvHD and SR-aGvHD and define an age appropriate RP2D for each of the 
groups 2-4. The primary objective of the Phase II is to measure the activity of ruxolitinib in 
patients with aGvHD or SR-aGvHD assessed by Overall Response Rate (ORR) at Day 28.


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12.4.1
Definition of primary endpoint(s)
The primary endpoint of the Phase I is the list of following PK parameters (AUC, Cmax, T1/2, 
Ctrough, and other parameters, as appropriate) which will be derived using non-compartmental 
methods in subjects with extensive sampling (Groups 1, 2, and 3). These parameters will then 
be used to define a RP2D for Groups 2, 3, and 4. The observed PK parameters (within group) 
will be summarized and compared to information obtained from adult and adolescent aGvHD 
patients treated with ruxolitinib on study [[CINC424C2301]]. Data from patients older than 2 
years old will be combined and analyzed by PBPK methods to determine the dose to be 
administered in patients younger than 2 years old (Group 4).
The primary endpoint for the Phase II is the overall response rate (ORR) at Day 28, defined as 
the proportion of patients with complete response (CR) or partial response (PR) without 
requirement for additional systemic therapies for an earlier progression, mixed response or non-
response as per Table 8-3 (Harris et al 2016). Note that response is relative to the assessment of
aGvHD at the start of study treatment.

Complete-response is defined as a score of 0 for the aGvHD grading in all evaluable 
organs that indicates complete resolution of all signs and symptoms of aGvHD in all 
evaluable organs without administration of additional systemic therapies for any earlier 
progression, mixed response or non-response of aGvHD.

Partial response is defined as improvement of 1 stage in 1 or more organs involved with 
aGvHD signs or symptoms without progression in other organs or sites without 
administration of additional systemic therapies for an earlier progression, mixed response 
or non-response of aGvHD.

Lack of response is defined as no response, mixed response, or progression.

No response is defined as absence of improvement in any organ involved by aGvHD, 
without worsening in any involved organ.

Mixed response is defined as improvement of at least 1 stage in the severity of aGvHD in 
at least one organ accompanied by progression in another organ or development of signs 
or symptoms of aGvHD in a new organ.

Progression is defined as worsening in 1 or more organs by 1 or more stages without 
improvement in any involved organ
Patients requiring additional systemic therapy for aGvHD will be classified as non-responders, 
and patients with missing baseline or Day 28 aGvHD response assessment will be considered 
as treatment non-responders.
aGvHD Flare is defined as any increase in signs or symptoms of aGvHD that is sustained for 
>24h after an initial response (CR or PR) and requires re-escalation of immunosuppressive 
therapy (e.g. corticosteroid, CNI and/or ruxolitinib dosing). While all aGvHD flares will be 
captured on study whether occurring during steroid, CNI or ruxolitinib taper. Only flares in 
GvHD that require new additional systemic therapy, will be considered aGvHD flare failure.
Acute GvHD will be assessed as per Table 8-2 (Harris et al 2016). Grade will be calculated 
based on the staging of the organs and recorded on the eCRF by the Investigator. The 
Investigator reported grade will be used for all analyses. Grade and response will be calculated 
by the sponsor for the purposes of data review and sensitivity analysis.


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12.4.2
Statistical model, hypothesis, and method of analysis
Pharmacokinetic parameters for patients in Groups 1, 2, 3 and 4 (who are part of the PAS) will 
be compared to adult information from study [[CINC424C2301]] through the use of ANOVA 
methods. The geometric mean ratio with 90% CI will be provided.
The response rates for ORR at Day 28 will be estimated on the Efficacy Evaluable Set (EES). 
90% confidence intervals 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
Patients with missing assessments that prevent the evaluation of the ORR will be considered 
non-responders. This includes aGvHD response assessments at baseline and Days 28, 56. 
Patients who discontinue the study treatment prior to the completion of the Day 28 visit will be 
considered non-responders.
The following analysis windows will be applied to the target day for assessments on overall 
response, where target day for Week X is X*7.
Baseline assessment is the last aGvHD assessment prior to or at the start of study treatment 
(Day 1).
Weeks 1, 2, 3, 4, 5, 6, 7, 8: -3 days/+3 days
Weeks 12 to 48: -13 days/+14 days
12.4.4
Sensitivity and Supportive analyses
As supportive analyses, the estimate of response rates ORR at Day 28 will be presented by 
diagnosis (treatment naïve aGvHD and SR-aGvHD) on the EES.
12.5
Analysis of secondary endpoints 
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
The main secondary objective of the study is to estimate the proportions of all patients who 
achieve a complete response (CR) or partial response (PR) at Day 28 and maintain a CR or PR 
at Day 56. A patient will not be considered a durable responder at Day 56 if any of the following 
events occurs prior to or at Day 56:

No CR or PR at Day 28 or at Day 56.

aGvHD progression or additional systemic therapy for aGvHD
The durable response rates for ORR at Day 56 will be estimated with 90% confidence intervals 
on EES. Summary statistics (frequencies and percentages). The confidence intervals will be 
calculated based on the exact method for binominal distribution.
All secondary efficacy endpoint analyses will be analyzed using the EES.

Overall Response Rate at Day 14, will be derived in the same way as the primary variable 
ORR at Day 28.

Duration of response (DOR)


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Duration of response will be calculated for patients whose overall response at Day 28 is CR or 
PR according to updated standard criteria (Harris et al 2016). The start date is the date of first 
documented response of CR or PR (i.e., the start date of response), and the end date is defined 
as the date of progression or the date of addition of systemic therapies for aGvHD, since this 
constitutes a non-response.
Death without prior observation of aGvHD progression and onset of chronic GvHD are 
considered to be competing risks.
Duration of response will be censored at the last response assessment prior to or at the analysis 
cut-off date, if no events/competing risk occurred before or at of cut-off date.
DOR will be listed and summarized for all patients on the EES with overall response of CR or 
PR at Day 28.

Overall survival (OS)
Overall survival is defined as the time from date of the start of study treatment 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 (on or before the cut-off date).
The OS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 1, 2, 6, 12, 18 and 24 month survival estimates and 95% confidence intervals 
will be presented.

Event Free Survival (EFS)
Event-free survival is defined as the time from the study treatment start date to the date of 
hematologic disease relapse/progression, graft failure or death due to any cause. If a patient is 
not known to have any event, then EFS will be censored at the latest date the patient was known 
to be alive (on or before the cut-off date). The EFS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians, 1, 2, 6, 12, 18 and 24 month 
survival estimates and 95% confidence intervals will be presented.

Failure Free Survival (FFS)
Failure-free survival is defined as the time from the study treatment start date to date of 
hematologic disease relapse/progression, non-relapse mortality or addition of new systemic 
aGvHD treatment.
Cumulative incidence of FFS at 1, 2, 6, 12, 18 and 24 months will be estimated, considering 
each event as a competing risk for the other two. Onset of chronic GvHD is considered as a 
competing risk for all three types of failure.

Non-relapse mortality (NRM)
Non-relapse mortality is defined as the time from the study treatment start date to date of death 
not 
preceded 
by 
hematologic 
disease 
relapse/progression. 
Hematologic 
disease 
relapse/progression is considered a competing risk for NRM with the date of hematologic 
disease relapse/progression being the earlier of documented hematologic disease 
relapse/progression or institution of therapy to treat potential hematologic disease 
relapse/progression. If a patient is not known to have died or to have relapsed/progressed, then 
NRM will be censored at the latest date the patient was known to be alive (on or before the cut-
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NRM will be analyzed on the EES for all patients. The cumulative incidence curve for NRM as 
well as estimates at 1, 2, 6, 12, 18 and 24 months with 95% confidence intervals will be 
presented.

Incidence of Malignancy Relapse/Progression (MR)
Malignancy relapse/progression is defined as the time from the study treatment start date to date 
of hematologic malignancy relapse/progression. Deaths not preceded by hematologic 
malignancy relapse/progression are competing risks. If a patient is not known to have event or 
competing risks, then MR will be censored at the latest date the patient was known to be alive 
(on or before the cut-off date). The cumulative incidence of MR will be estimated for patients 
with underlying hematologic malignant disease, accounting for NRM as the competing risk.
In addition, the proportion of patients who had hematologic malignancy relapse/progression 
and its 95% confidence interval will be presented for patients with underlying hematologic 
malignant disease.

Best Overall Response (BOR)
Best overall response rate, is defined as the proportion of patients with complete response 
(CR) or partial response (PR) at any time point (up to and including Day 28 and before the 
start of additional systemic therapy for aGvHD).

Cumulative steroid dosing until Day 56
Overall and weekly cumulative steroid dose for each patient up to Day 56 will be tabulated.

Incidence of cGvHD
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe. Incidence 
of cGvHD is the time from the start of treatment to onset of cGvHD. Cumulative incidence of 
cGvHD will be estimated, accounting for deaths without prior onset of cGvHD and hematologic 
disease relapse/progression as the competing risks. If a patient is not known to have event or 
competing risks, then the incidence of cGvHD will be censored at the latest date the patient was 
known to be alive (on or before the cut-off date).
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
group. If the Phase I preliminary dose is different to RP2D, the safety data will be listed and 
summarized by age group and dose level. 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 study treatment to 30 days 
after the date of the last actual administration of any study treatment.


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Adverse events
All information obtained on adverse events will be displayed by group for all patients on safety 
set.
The number (and percentage) of patients with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of study treatment but 
increased in severity based on preferred term) will be summarized in the following ways:

by group, primary system organ class and preferred term.

by group, primary system organ class, preferred term and maximum severity (based on 
CTCAE grades).

by group, Standardized MedDRA Query (SMQ) and preferred term
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.
The number (and proportion) of subjects with adverse events of special interest (AESI) such as 
worsening cytopenias, infections etc. during the on-treatment period will be summarized by 
group.
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.
The proportion of patients developing Grade 2 to 3 infections using infection severity 
(Section 16.1 Appendix 1) during the aGvHD treatment period Day 1 to Day 56 will be 
summarized in addition to standard CTCAE grading. In addition, proportion of patients 
developing second primary malignancies will be summarized based on the entire study period. 
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
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.
Clinical laboratory evaluations
All laboratory data will be listed by group, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. Shift tables using the low/normal/high/ (low and high) 
classification will be used to compare baseline to the worst on-treatment value.
Tolerability
The number and percentage of patients who have a dose increase, reduction, or interruption will 
be summarized.


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12.5.3
Other endpoints
Acceptability and Palatability assessment
All acceptability and palatability assessment data will be listed by group and patient for all 
patients on safety analysis set.
12.5.4
Pharmacokinetics
In patients with extensive PK sampling on Day 1 (samples 1 to 8 described in Section 8.6.1.1), 
PK parameters of ruxolitinib will be calculated by non-compartmental methods using Phoenix 
WinNonlin (Pharsight, Mountain View, CA) software. Additional PK parameters may be 
estimated as needed. The following parameters will be calculated (Table 12-1).
Table 12-1
Non-compartmental pharmacokinetic parameters of ruxolitinib
AUClast
The AUC from time zero to the last measurable concentration sampling time (Tlast)
AUCinf
The AUC from time zero extrapolated to infinity
AUC0-12
The AUC from time zero extrapolated to 12 hours
Cmax
The maximum (peak) observed plasma drug concentration
Ctrough
The minimum observed plasma concentration at the end of an administration interval 
(corresponding to the pre-dose concentration prior to the following administration)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (Lambda_z ) of a semi 
logarithmic concentration-time curve
CL/F
The total body clearance of drug from the plasma
Vz/F
The apparent volume of distribution during terminal phase (associated with Lambda_z)
Plasma concentrations obtained from the sparse sampling schedules (described in 
Section 8.6.1.1) will be analyzed using a population PK approach along with data obtained in 
the Phase I.
Statistical methods for pharmacokinetic analyses
Ruxolitinib concentrations data will be listed by group. Descriptive summary statistics will be 
provided by group at each scheduled time point. Summary statistics will include n (number of 
patients with non-missing values), mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Individual profiles with median by dose level 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 group. Descriptive statistics (n, 
arithmetic mean, standard deviation (SD), coefficient of variation (CV)% for mean, geometric 
mean, geometric CV%, median, minimum and maximum) will be provided for all PK 
parameters by dose level except for Tmax where median, minimum and maximum will be 
presented.
If the Phase I preliminary dose is different to RP2D, PK data will be listed and summarized by 
age group and dose level.


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Population PK approach on pooled Phase I and Phase II data
Concentration results from the sparse sampling performed in the Phase II will be added to those 
from Phase I and analyzed further using nonlinear mixed effects modeling (population PK) or 
other model-based approaches, as appropriate. Details of the analysis method will be developed 
in a 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 FDA guidance will be followed (Guidance for Industry: Population Pharmacokinetics 
Fed 1999).
Exposure-Response analysis
A detailed description of exposure-response analysis will be developed in the analysis plan. 
Briefly, the objectives are to:

Characterize the exposure-efficacy relationship of ruxolitinib with efficacy response 
defined as overall response rate at Day 28, durable response at Day 56, and Overall survival. 
Exposure metrics will be described in further details in the analysis plan.

Characterize the exposure-safety relationship of ruxolitinib with safety response defined as 
1st occurrence AEs, 1st occurrence of G3/4 AEs, 1st occurrence of AEs of interest, and 
appropriate liver function parameters. Exposure metrics will be described in further details 
in the SAP.

Exposure-Biomarker –
Average steady-state exposures and/or other PK parameters for the population may be 
computed by the population PK model accounting for dose modifications or dose interruptions 
up to the day prior to the day of assessments. Population PK derived parameters may be used 
for exposure-response analysis by appropriate methods.
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 PK parameter or concentration will not be imputed.


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12.7
Interim analyses
No formal interim analysis is planned for this study. However, summaries of safety and PK data 
will be produced to support the regular safety monitoring conducted by the DMC and the 
confirmation of RP2D. Efficacy data may also be analyzed
when all patients (Phase I and Phase II) have completed 24 weeks (approximately 6 months) of 
treatment or discontinued earlier. The final analysis will be conducted when all patients have 
completed Month 24 (i.e., the end of the long-term follow-up period), unless the patients 
discontinue earlier.
In this clinical trial it is not planned to test specific efficacy hypotheses but to provide estimates 
of efficacy endpoints for the pediatric study population and therefore no-alpha adjustment will 
be made for earlier estimates of efficacy endpoints. However, the data for the primary efficacy 
assessment, ORR at Day 28 will already be final once all patients have completed 6 months of 
treatment.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
In Phase I, 5 patients will be enrolled to each age group with no minimum for Group 4. A 
minimum of 5 patients in Group 1 will also undergo extensive PK sampling during Phase II. 
Should one or more of the 5 patients not be evaluable for PK analysis, additional patients may 
be enrolled to ensure a minimum of 5 evaluable PK profiles for Groups 1, 2 and 3.
A comparison of PK parameters (Cmax) from 5 pediatric patients (in Groups 2 and 3 separately) 
to ~25 adult patients (from study [[CINC424C2301]]) will be performed. With expected 
similarity in the point estimates across groups (geo-mean ratio, GMR = 1), and accounting for 
expected higher variability in the pediatric patients (CV% ~55.7%, (Loh et al 2015, detailed 
data on file) compared to ~40% in adults), the confidence interval for a GMR of 1 would be 
[0.609;1.641] which demonstrates clinically relevant comparability of exposure to adult 
exposure (within 2-fold).
Therefore, with a minimum of 5 evaluable profiles in each of Groups 2 and 3, combined with 5 
evaluable profiles from Group 1 and further sparse PK samples in the Phase II of the study, 
there is sufficient precision to support the PK objectives of the study.
Should the exposure in Group 2, 3 or 4 not be confirmed following the PK sampling in at least 
5 patients, additional patients will be enrolled in that specific age group until the dose/exposure 
is confirmed (i.e., selection of the RP2D for those ages based on exposure and safety review by 
the DMC). Once the RP2D is selected for Groups 2 and 3 any further eligible patients between 
the ages of 2 years and 12 years will be enrolled into the Phase II, and Group 4 will begin 
enrolling patients in the Phase I.


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Although several studies of treatments for aGvHD and SR-aGvHD have included pediatric 
patients, it is difficult to find recent estimates for steroid response in de novo aGvHD pediatric 
patients or BAT response in SR-aGvHD pediatric patients. A review of 443 patients (including 
175 patients < 20 years), reported a CR/PR rate of 55% at Day 28, no association with ORR 
rate and patient age was found (MacMillan et al 2010). Other papers report response rates in 
the ranges 50-60% for de novo and SR-aGvHD (Martin et al 2012).
The sample size for the Phase II objective of measuring ORR at D28 is 45 patients regardless 
of age. Of these there must be at least 20% of the patients with treatment naïve aGvHD and 
40% of the patients with SR-aGvHD to ensure the sample is representative of the study 
population. The remaining can be filled with either diagnosis. Any patient receiving the 
confirmed RP2D during the Phase I will be counted towards the 45 patients.
The sample size calculation for the Ph II activity objective is based on the ORR at Day 28. 
Assuming the true ORR at Day 28 of the study population is 80%, an overall sample size of 45 
patients would have 90% probability to have a 90% CI for ORR with lower limit ≥ 60%. In 
addition, considering the Saw-Toothed behavior of power waving for single binomial 
proportion using an exact method (Chernick and Liu 2002) a minimum sample size of 45 
subjects would provide >85% probability to have a 90% CI with lower limit ≥ 60%.
Chernick and Liu 2002 Table 12-2 provides estimates of the probability to have a 90% CI with 
lower limit ≥ 60% , minimum number of responders required to have a 90% CI with lower limit 
of ≥ 60% and two-sided 90% Clopper-Pearson CIs for various sample sizes. Patients treated at 
the RP2D from the Phase I contribute to this analysis.
Table 12-2
Probability to have a 90% CI with lower limit ≥ 60% and 90% 
confidence intervals for different number of patients
Sample 
size
Minimum No. of responders
Response 
Rate
Probability to have 
a 90% CI with 
lower limit ≥ 60%
90% CI
37
28
0.76
0.809
0.614
0.867
38
29
0.76
0.784
0.623
0.871
39
29
0.74
0.859
0.604
0.854
40
30
0.75
0.839
0.613
0.858
41
31
0.76
0.818
0.621
0.861
42
31
0.74
0.882
0.604
0.846
43
32
0.74
0.864
0.612
0.849
44
33
0.75
0.846
0.620
0.853
45
33
0.73
0.901
0.604
0.838
46
34
0.74
0.886
0.612
0.842
47
35
0.74
0.869
0.619
0.846
48
35
0.73
0.916
0.604
0.832
49
36
0.73
0.903
0.612
0.835
50
37
0.74
0.889
0.619
0.838


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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 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.
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 and finalization of the clinical 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 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.


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Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
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/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
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/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
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 (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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MacMillan ML, DeFor TE, Weisdorf DJ (2010) The best endpoint for acute GVHD treatment 
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Disease. N Engl J Med. 385: 228-238. 


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Appendices
16.1
Appendix 1: Infection Severity Grading
Table 16-1
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 
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 d/t 
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.


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Type of Infection/ 
Severity Grade
Grade 1
Grade 2
Grade 3
Pneumocystis jiroveci
pneumonia (regardless of 
PaO2 level)
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 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
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


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Type of Infection/ 
Severity Grade
Grade 1
Grade 2
Grade 3
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
*Concomitant or multimicrobial infections are graded according to the grade of the infection with the higher 
grade of severity. 
**Therapy includes both PO and IV formulations 
***Severe Sepsis:
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 SIRS definition and suspected or proven infection and cardiovascular dysfunction or 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 >38.5C or < 36C
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 > 3oC

Urine output < 0.5 mL/kg/hr

Unexplained metabolic acidosis (Base deficit > 5.0 mEq/L)

Blood lactate > 2 x ULN
Respiratory:

ARDS or

Intubated or

>50% FiO2 to maintain SaO2 > 92%
Neurological:

Glasgow Coma Score < 11 or

Acute change in mental status with a decrease in GSC >3 pts from abnormal baseline


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Type of Infection/ 
Severity Grade
Grade 1
Grade 2
Grade 3
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 agea
Table 16-2
Four age groups relevant to HCT
Age
Tachycardia 
(bpm)
Bradycardia 
(bpm)
Tachypnea 
(breaths/min)
Leukocytosis / 
Leukopenia (WBC)
Hypotension 
Systolic BP 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:
3.CMV, HSV, EBV, HHV6: 2 months (< 60 days)
4.VZV, HZV: 2 weeks (< 14 days)
5.Bacterial, non-C. difficile: 1 week (< 7 days)
6.Bacterial, C. difficile: 1 month (< 30 days)
7.Yeast: 2 weeks (< 14 days)
8.Molds: 3 months (< 90 days)
9.Helicobacter: 1 year (< 365 days)
10.Adenovirus, Enterovirus, Influenza, RSV, Parainfluenza, Rhinovirus: 2 weeks (< 14 days)
11.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.


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Appendix 2: Grading of Chronic GvHD (NIH Criteria)
The definition for mild, moderate, and severe chronic GvHD is as follows:
Grading of chronic GvHD as described by Jagasia et al. (Jagasia et al 2015) should be 
performed as described below.


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Organ scoring of chronic GvHD. ECOG indicates Eastern Cooperative Oncology Group; KPS, 
Karnofsky Performance Status; LPS, Lansky Performance Status; BSA, body surface area; 
ADL, activities of daily living; LFTs, liver function tests; AP, alkaline phosphatase; ALT, 
alanine aminotransferase; ULN, normal upper limit. *Weight loss within 3 months. Skin scoring 
should use both percentage of BSA involved by disease signs and the cutaneous features scales. 
When a discrepancy exists between the percentage of total body surface (BSA) score and the 
skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired 
mobility or ulceration (Score 3), the higher level should be used for the final skin scoring. To 
be completed by specialist or trained medical providers. **Lung scoring should be performed 
using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final 
lung scoring where there is discrepancy between symptoms and FEV1 scores.


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Appendix 3: Hematologic Disease Relapse
Malignancy relapse/progression is defined as follows: 
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS 
consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not 
by biopsy. Progression of disease applies to patients with lymphoproliferative diseases 
(lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation. The 
event is defined as increase in size of prior sites of disease or evidence of new sites of disease, 
documented or not by biopsy.
Acute leukemia and MDS – Relapse will be diagnosed when there is:
Reappearance of leukemia blast cells in the peripheral blood; or,
>5% blasts in the bone marrow, not attributable to another cause (e.g. bone marrow 
regeneration)
The appearance of previous or new dysplastic changes (MDS specific) within the bone marrow 
with or without falling donor chimerism; or
The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid or
The reappearance of cytogenetic abnormalities present prior to transplantation
Lymphoproliferative Diseases – Relapse or progression will be diagnosed when there is:
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected 
site will only be considered relapsed or progressive disease after confirmation with other 
modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules 
identified by CT are mostly benign. Thus, a therapeutic decision should not be made solely on 
the basis of the PET without histologic confirmation.
At least a 50% increase from nadir in the sum of the product diameters of any previously 
involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or hepatic 
nodules). To be considered progressive disease, a lymph node with a diameter of the short axis 
of less than 1.0 cm must increase by > 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm 
in the long axis.
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was 
PET positive before therapy unless the lesion is too small to be detected with current PET 
systems (<1.5 cm in its long axis by CT).
In addition to the criteria above, patients with CLL who present in complete remission prior to 
transplantation may fulfill the relapse definition if there is reappearance of circulating malignant 
cells that are phenotypically characteristic of CLL.
Non-Malignant Hematologic Disease progression is defined as follows: 
Sickle Cell Disease- Progression will be diagnosed when there is:
Recurrent signs/symptoms of disease in the setting of graft failure and autologous recovery 
including but not limited to: recurrence of painful crises, ongoing hemolysis, chest syndrome, 
stroke, and/or progression of sickle nephropathy,


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Thalassemia (including beta, alpha, epsilon)- Progression will be diagnosed when there is:
Recurrent signs/symptoms of disease in the setting of graft failure and autologous recovery 
including but not limited to: severe hemolytic anemia requiring ongoing RBC transfusion 
support.
Severe Aplastic Anemia- Progression will be diagnosed when there is:
Recurrent signs/symptoms of disease in the setting of graft failure and autologous recovery 
including but not limited to: severe pancytopenia requiring ongoing RBC/platelet transfusion 
support.
*Institution of any therapy to treat persistent, progressive or relapsed hematologic 
disease, including the withdrawal of immunosuppressive therapy, chemotherapy 
administration, or donor lymphocyte infusion, will be considered evidence of 
relapse/progression regardless of whether the criteria described above were met


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Appendix 4: HCT Specific Comorbidity Index Score
Table 16-3
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 > 80% or Dyspnea on moderate activity
0
Mild renal
Serum creatinine 1.2-2 mg/dL
0
Endocrine
0
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
Requiring treatment
1
Depression/anxiety
1
Infection
Requiring continuation of treatment after day 0
1
Rheumatologic
SLE, RA, polymyositis, mixed CTD, polymyalgia rheumatica
2
Moderate pulmonary
DLCO and/or FEV1 66% - 80% or Dyspnea on slight activity
2
Peptic ulcer
Patients 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
Requiring treatment with chemotherapy
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
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.
Source: Sorror ML, Maris MB, Storb R, et al: Hematopoietic cell transplantation (HCT)-
specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 
106(8): 2912-9, 2015


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Appendix 5: CIMBTR classification
Table 16-4
CIBTMR disease risk index
ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
AML and ALL precursor B-
lymphoblastic 
lymphoma/leukemia {per 
W.H.O. 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.
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 


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ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
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): 10-19% 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 
(platelets < 100,000) unrelated to therapy 


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ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
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 


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ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
x 109/L Transformation to a more aggressive 
histology, e.g. transform to diffuse large B-
cell lymphoma known as Richter’s 
transformation.
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 


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ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
resistant or untreated or unknown sensitivity 
to chemotherapy.
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 
andHigh Grade) Includes the 
following diseases: mantle cell 
lymphoma, diffuse large B-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. 


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ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
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 
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
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.
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 


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Protocol No. CINC424F12201
ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
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 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 


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ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
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.
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 


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ASBMT Diagnosis Category 
ASBMT RFI Classification
CIBMTR Classification^
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
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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Protocol No. CINC424F12201
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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Protocol No. CINC424F12201
16.6
Appendix 6: List of CYP3A4 inhibitors and inducers
Table 16-5
List of CYP3A4 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, cyclosporin, 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, 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. 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 200 mg) daily; If clinically necessary to use doses ≥ 6 mg/kg daily consultation with 
Sponsor is required. Please refer to Section 6.2.1.2 (Permitted concomitant therapy requiring 
caution and/or action).

SAP_001.pdf: 
Clinical Development
INC424/Ruxolitinib/JAKAVI®
CINC424F12201 / NCT03491215
A Phase I/II open-label, single-arm, multi-center study of 
ruxolitinib added to corticosteroids in pediatric patients 
with grade II-IV acute graft vs. host disease after allogeneic 
hematopoietic stem cell transplantation
Statistical Analysis Plan (SAP)- Amendment 3
Author:
Trial Statistician;
Document type:
SAP Documentation
Document status:
Final version 4.0
Release date:
10-Mar-2023
Number of pages:
49
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
CINC424F12201
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
Jun.27.2018
First 
version
Final version 1.0
NA
Feb22, 
2022
Amendment 
1
Final version 2.0
Changes to align with protocol 
Amendment 1 and 2
Section 
1.1, 
1.2, 1.3, 1.4, 
2.1.1, 2.8.4.5, 
2.9, 
2.13.2, 
2.14, 3
Clarification was required 
2.2, 
2.4.2, 
2.5.4, 
2.7.1, 
2.7.2,2.8.4.2,
2.10, 2.12
Change the notable vital signs to 
follow the latest WHO criteria 
2.8.4.2
Jun27 2022
Amendment 
2
Final version 3.0
Delete Table 2-3 in Analysis sets to 
remove INC01 and add clarification 
that patients with dual CYP3A4/
CYP2C9
inhibitors
will 
be
considered as treated with full 
assigned dose.
Sections: 
1 
and 2.2
Section 3.8.4.2 on graft failure was 
deleted from safety and moved in 
analysis of secondary efficacy
Section 
3.8.4.2 
deleted and 
moved in 
secondary 
endpoints.
06Mar2023
Amendment 
3
Final version 4.0
Update to align with protocol 
Amendment version 3 (release date 
24-Jun-2022) and to clarify some 
specifications after dry run. 
Main changes:
Clarify the last contact date 

 
 
 
Sections
1.1.1
3.2


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SAP
CINC424F12201
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
Add subgroup analysis by 
formulation, treatment naïve vs 
SR-aGvHD 
 
for efficacy and safety analysis
Add listing on COVID-related PDs
Analysis of BOR added up to data 
cut-off date 
Provide clarification on exposure, 
and derivation of planed dose 
intensity and dose changes
Clarify the use of CRF pages for 
Calcineurin Inhibitors (CNI)
treatment
Clinical notable vital signs criteria 
were updated to align within the 
project
Analysis of time to first occurrence 
of infections using Kaplan-Meier 
methodoloy removed
More detailed specifications how 
to identify new or additional 
systemic therapy
3.2.1
3.3.1
3.7.1, 3.7.2
3.4.1
3.4.2.4
3.8.4.2
3.8.4.3
3.4.2.5
App 6.4.3


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SAP
CINC424F12201
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
2
Study design ........................................................................................................................8
2.1
Phase I......................................................................................................................9
2.1.1
Determination of recommended Phase II dose .....................................10
2.2
Phase II ..................................................................................................................11
2.3
Study objectives and endpoints .............................................................................12
3
Statistical methods.............................................................................................................13
3.1
Data analysis general information .........................................................................13
3.1.1
General definitions................................................................................14
3.2
Analysis sets ..........................................................................................................17
3.2.1
Subgroup of interest ..............................................................................18
3.3
Patient disposition, demographics and other baseline characteristics ...................19
3.3.1
Patient disposition.................................................................................20
3.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................21
3.4.1
Study treatment / compliance................................................................21
3.4.2
Prior, concomitant and post therapies...................................................23
3.5
Analysis of the primary objective..........................................................................25
3.5.1
Primary endpoint...................................................................................25
3.5.2
Statistical hypothesis, model, and method of analysis..........................26
3.5.3
Handling of missing values/censoring/discontinuations.......................26
3.5.4
Supportive analyses...............................................................................26
3.6
Analysis of the key secondary objective ...............................................................27
3.6.1
Key secondary endpoint........................................................................27
3.6.2
Statistical hypothesis, model, and method of analysis..........................27
3.6.3
Handling of missing values/censoring/discontinuations.......................27
3.7
Analysis of secondary efficacy objective(s)..........................................................27
3.7.1
Secondary endpoints .............................................................................27
3.7.2
Statistical hypothesis, model, and method of analysis..........................29
3.7.3
Handling of missing values/censoring/discontinuations.......................30
3.8
Safety analyses.......................................................................................................31
3.8.1
Adverse events (AEs)............................................................................31
3.8.2
Deaths....................................................................................................32
3.8.3
Laboratory data .....................................................................................32


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3.8.4
Other safety data ...................................................................................33
3.9
Pharmacokinetic endpoints....................................................................................36
3.10
PD and PK/PD analyses.........................................................................................37
3.11
Patient-reported outcomes .....................................................................................38
.38
.........................................................39
39
40
3.14
Interim analysis......................................................................................................41
4
Sample size calculation .....................................................................................................41
5
Change to protocol specified analyses ..............................................................................42
6
Appendix ...........................................................................................................................43
6.1
Imputation rules.....................................................................................................43
6.1.1
Study drug.............................................................................................43
6.1.2
AE, ConMeds and safety assessment date imputation..........................44
6.2
AEs coding/grading ...............................................................................................45
6.3
Laboratory parameters derivations ........................................................................45
6.4
Statistical models...................................................................................................46
6.4.1
Primary analysis....................................................................................46
6.4.2
Key secondary analysis.........................................................................46
7
Reference...........................................................................................................................48


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
BAT
Best Available Therapy
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
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 Clinical Study Report 
(CSR) of study CINC424F12201, A Phase I/II open-label, single-arm, multi-center study of 
ruxolitinib added to corticosteroids in pediatric patients with grade II-IV acute graft vs. host 
disease after allogeneic hematopoietic stem cell transplantation.
SAP Amendment 3
The main purpose of SAP amendment 3 is to align with protocol amendment 3, provide more 
detailed specifications and to keep consistency across GvHD indication.
Major changes of SAP amendment 3 included:

Clarification on last contact date

 
 

To add BOR up to data cut-off date

To add subgroup analysis by formulation, treatment naïve vs SR-aGvHD and 
 
 for efficacy and safety analysis

Add a listing for COVID-related PDs

To provide clarifications on derivations for exposure, Planed Dose intensity and dose 
reductions

To clarify the use of the CRF pages for derivation of the CNI treatment

To change the clinical notable criteria of vital signs 

To remove analysis of time to first occurrence of infections 

To provide  more detailed specifications on how to identify any new or additional 
systemic therapy
SAP amendments 1 and 2
The content of SAP amendment 1 was based on protocol CINC424F12201, versions 1 and 2.  
SAP Amendment 2 was also an amendment of SAP version 01, SAP amendment 1 . 
The main purpose of SAP amendment 1 was to align with all the changes made in Protocol 
amendments 1 and 2. 
Major changes of SAP amendment 1 included:

Updates in the sample size from 39 to 45 subjects.

The definition of analysis sets were updated to consider subjects that have been treated 
with the full assigned dose as a result of co-administration with strong CYP3A4 or dual 
(clarified at SAP amendment 2) CYP3A4/CYP2C9 inhibitors, 


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
 
Finally a few more changes in SAP amendment 1 were made for clarification purposes and/or 
for consistency purposes across GvHD indications:

The analyses sets were clarified to include only patients who signed informed concent 
(standard approach).

The presentation of prior and concomitant medications were updated to follow project 
requirements

The key secondary objective was clarified as per project requirements

Presentation of graft failure assessment was clarified as part of other safety analysis. 

Sensitivity analysis was added to primary objective in order to exclude patients with 
protocol deviations on aGvHD assessments due to not strictly following the standard 
criteria 

The notable vital sings were updated to  follow the latest version of WHO growth criteria

The presentation of prior and concomitant criteria were updated to follow project 
requirements

 as well as some PK analysis were clarified that will be explored 
using a seperate SAP and seperate CSR report.
The main purpose of the SAP amendment 2 was to remove patients clasifications based on PD 
criteria since these were not applicable in the study. All patients who signed written informed 
consent were included in analyses sets.  Therefore, Table 2-3 in Analysis sets section has been 
deleted from the SAP.  Another change made in SAP amendment 2 was to move graft failure 
analysis from safety to efficacy analysis section.
All decisions regarding final analysis, as defined in the SAP document, have been made prior 
to final database lock of the study data.
2
Study design
This open-label, single-arm, Phase I/II multi-center study will investigate the PK, activity and 
safety of ruxolitinib added to the patient’s immunosuppressive regimen in infants, children, and 
adolescents ages ≥28 days to <18 years old with either grade II-IV aGvHD or grade II-IV SR-
aGvHD. This trial will utilize age groups: Group 1 includes patients ≥12y to <18y, Group 2 
includes patients ≥6y to <12y, Group 3 includes patients ≥2y to <6y, and Group 4 includes 
patients ≥28days to <2y. Patients 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 (Phase I/II) will be subject to the review of available PK, safety, and activity data in 
consultation with the data monitoring committee (DMC), Pediatric Committee (PDCO), and a 
final decision by the Sponsor.
All patients will be enrolled and treated for 24 weeks (approximately 6 months) or until early 
discontinuation. All patients will also be followed for an additional 18 months (total duration = 
2 years from enrollment). Should the occurrence of aGvHD flare require treatment re-initiation 


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or should ruxolitinib not be discontinued by the end of 24 weeks due to extended tapering, 
patients may continue taper ruxolitinib beyond 24 weeks up to a maximum of 48 weeks. As 
patients ≥12 y to < 18 y are already being included in [CINC424C2301], and treated with 10 
mg BID, this dose is the recommended phase II dose (RP2D), and will be used to treat all 
patients in this age group. For the Phase II, all other age groups will be treated with the RP2D 
determined during the Phase I. Therefore, all ≥12 to <18 year old patients will automatically be 
enrolled in the Phase II. It is planned that the first 5 patients treated in Group 1 will undergo 
extensive PK sampling to inform the RP2D determination of the younger age groups in the Ph 
I. Additional patients may undergo extensive sampling should one or more of the first 5 patients 
not be evaluable or until the dose/exposure is confirmed.
2.1
Phase I
Patients will be enrolled into 4 groups, based on age, to allow appropriate dosing based on 
available data Table 1-1.

Phase I (Figure 1-1): Full ruxolitinib concentration-time courses, safety and activity data 
will be collected over 28 days for Groups 2, 3 and 4. Groups 2 and 3 will be enrolled 
initially, and the PK data generated from all patients (including Group 1) will be used to 
inform the starting dose of Group 4. Therefore, Group 4 will only open after an RP2D has 
been defined for Group 2, and an RP2D has been defined for Group 3.

The PK and safety data will be used to assess the adequacy of the starting dose, which can 
be adapted if needed (e.g. to account for any potential difference between the expected 
and the observed ruxolitinib exposure).

Should the exposure in Groups 2, 3 or 4 not be confirmed following the PK sampling in 5 
evaluable patients, at least an additional 5 patients will be enrolled in that specific age 
group until the dose/exposure is confirmed (ie selection of the RP2D for those ages based 
on exposure and safety review by the DMC).

Ruxolitinib will be administered either as tablet or as an oral pediatric formulation 
(capsule/liquid) twice a day”.
Table 2-1
Phase I: Age groups and dosing rationale
Group
Group 1
Group 2
Group 3
Group 4
Age 
Range
≥12y to < 
18y
≥6y to < 12y
≥2y to < 6y
≥28 days to < 2y
N (Ph I)
Not 
applicable
5 evaluable
5 evaluable
Undefined
Starting
dose
PBPK-derived equivalent 
predicted to yield similar 
exposure to 10 mg BID 
adult dose =5 mg BID
(Tablet /capsule 
formulation)
PBPK-derived equivalent 
predicted to yield similar 
exposure to 10 mg BID 
adult dose =4 mg/m2 BID
(Capsule/ Liquid 
formulation)
Will be 
generated based 
on PK data from 
groups 1-3
Figure 2-1
Study Design


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2.1.1
Determination of recommended Phase II dose

Group 2 (age ≥6y to <12y) and Group 3 (age ≥2y to <6y): Physiologically based 
pharmacokinetic (PBPK) modeling will be used to derive a starting dosing for these patients, 
which is predicted to yield an exposure equivalent to that of a 10 mg BID in adults. The 
PBPK model will incorporate PK data from adult and adolescent patients with SR-aGvHD 
treated on study [CINC424C2301], and these predictions will be compared to existing data 
in pediatric patients from other indications (Loh et al 2015). The starting doses are thereby 
assigned as 5 mg BID (Group 2) and 4 mg/m2 BID (Group 3).

Group 4 (≥ 28 days to < 2 y): the absence of existing ruxolitinib PK data in this age group 
warrants a conservative approach. Therefore, the starting dose for Group 4 will be 
determined by using PK data generated in Groups 1, 2 and 3 (Table 3-1 and Table 3-2). 
These data will be used to inform the PBPK model in order to enable accurate predictions 
for these very young patients.
Groups 2 and 3 will enroll a minimum of 5 patients each. Full ruxolitinib concentration-time 
courses, safety and activity data will be collected over 28 days. Should one or more of the 5 
patients not be evaluable, or until the dose/exposure is confirmed, additional patients may be 
enrolled to ensure a minimum of 5 evaluable patients per age group. This information will be 
used to assess the adequacy of this starting dose, which can be adapted if needed (e.g. to account 
for any potential difference between the expected and the observed ruxolitinib exposure).
If the exposure from the first 5 patients does not approximate the exposure of 10mg BID in 
adult and adolescent patients based on AUC and Cmax, at least an additional group of 5 patients 
will be enrolled in that specific age group. This second group of at least 5 patients will be 
administered a different starting dose to again target the 10mg BID adult exposure. This process 
will continue until the dose-exposure relationship is confirmed (i.e selection of the RP2D for 


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those ages based on exposure and safety review by the DMC). If the selected RP2D is higher 
than the starting dose assigned to the previous group of patients, intra-patient dose escalation is 
allowed (Section 6.5.1.1). Inversely, if the selected RP2D is lower than the starting dose 
assigned to the previous group of patients, intra-patient dose de-escalation is allowed.
As mentioned above, Group 1 (patients aged ≥12y to <18y) is excluded from this process as the 
starting dose is already confirmed at 10mg BID. The available PK data from these patients will 
however be used in the determination of the RP2D for the younger patients in Groups 2, 3, and 
4.
All Group 1 patients will be enrolled automatically into the Ph II, with the first 5 patients 
undergoing extensive PK. Once the RP2D is selected for Groups 2 and 3 any further eligible 
patients between the ages of ≥2y and <12y will be enrolled into the Phase II. At this point Group 
4 will begin enrolling patients in the Phase I. Further, once the RP2D is established in Group 4, 
enrollment to Phase II for this group will be initiated.
2.2
Phase II
The Phase II aims to measure the activity of ruxolitinib in these patients assessed by overall 
response rate (ORR) at Day 28, as Day 28 ORR has been shown to correlate best with 
subsequent long-term survival (Levine et al 2010). The study’s primary endpoint for the Phase 
II is Investgator reported ORR without requirement for addition of new systemic 
immunosuppressive treatment assessed 28 days after start of therapy. A key secondary endpoint 
is the ORR at Day 56 after start of treatment, in order to assess the durability of the primary 
response. Best Overall Response (BOR) up to or at Day 28 will also be calculated.
The RP2D for all groups will be assessed for both activity and safety in  Phase II, over a 24 
week period. At least 45 patients will be enrolled in the study regardless of age, with at least 
20% of treatment naïve aGvHD and 40% with SR-aGvHD patients and be treated with the 
confirmed RP2D. The sample size for the Phase II objective of measuring ORR at D28 is 45
evaluable patients regardless of age. Any patient receiving the confirmed RP2D during the 
Phase I will be counted towards the 45 patients (Table 1-2 and Figure 1-1).
Table 2-2
Phase II: Age groups and dosing rationale
Group
Group 1
Group 2
Group 3
Group 4
Age Range
≥12y to < 18y
≥6y to < 12y
≥2y to < 6y
≥28 days to < 2y
N 
N=45 evaluable patients treated with the confirmed RP2D
RP2D 
dose 
Same as adult 
dose: 10 mg BID 
(All patients will be 
enrolled in Ph II)
Same as Phase I 
unless correction is 
needed to account for 
exposure variations
Same as Phase I unless 
correction is needed to 
account for exposure 
variations
Based on PK 
modeling from 
group 1,2, and 3 
data in the PK part
No formal interim analysis is planned for this study. However, summaries of safety and PK data 
will be produced to support the regular safety monitoring conducted by the DMC and the 
confirmation of RP2D. Efficacy data may also be analyzed when all patients (Phase I and Phase 
II) have completed 24 weeks (approximately 6 months) of treatment or discontinued earlier. 
The final analysis will be conducted and the clinical study report (CSR) written once all patients 
have completed the study (i.e. completed the long-term follow-up period of Month 24) or 


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discontinued earlier. Analysis cutoff date will be defined corresponding to the analysis time 
point and all data captured in the study up to that cutoff will be reported. 
2.3
Study objectives and endpoints
Objectives and related endpoints are described in Table 2-3 below.
Table 2-3
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Phase I
To assess pharmacokinetic (PK) parameters 
of ruxolitinib for patients with aGvHD and SR-
aGvHD and define an age appropriate RP2D 
for each of the groups 2-4

Group 2: age ≥6y to <12y

Group 3: age ≥2y to <6y

Group 4: age ≥28days to < 2y

Measurement of PK parameters in aGvHD and SR-
aGvHD patients: AUC, Cmax, T1/2, Ctrough using 
extensive PK sampling in Groups 1-3 and sparse 
sampling in Group 4

Age-based determination of RP2D for each of the 
groups 2-4, based on observed PK parameters.

Phase II
To measure the activity of ruxolitinib in 
patients with aGvHD or SR-aGvHD assessed 
by Overall Response Rate (ORR) at Day 28.

Overall response rate (ORR) at Day 28, defined as 
the proportion of patients demonstrating a complete 
response (CR) or partial response (PR) without 
requirement for additional systemic therapies for an 
earlier progression, mixed response or non-
response. Scoring of response will be relative to the 
organ stage at the start of the study treatment.
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Key Secondary
To assess the rate of durable ORR at Day 56

Proportion of all patients who achieve a CR or PR at 
Day 28 and maintain a CR or PR at Day 56

To estimate ORR at Day 14

Proportion of patients who achieved ORR (CR+PR) 
at Day 14

To assess pharmacokinetic/pharmacodynamic 
relationships

PK parameters (such as AUC, Cmax, Ctrough) 
versus safety, efficacy, and PD biomarkers, as 
appropriate

To assess Duration of response

Duration of response (DOR) is assessed for 
responders only and is defined as the time from first 
response until aGvHD progression or the date of 
additional systemic therapies for aGvHD. Onset of 
chronic GvHD, or death without prior observation of 
aGvHD progression are considered as competing 
risks

To assess the cumulative steroid dose until 
Day 56

Weekly cumulative steroid dose for each patient up 
to Day 56

To evaluate the safety and tolerability of 
ruxolitinib

Safety and tolerability including myelosuppression, 
infections, and bleeding will be assessed by 
monitoring the frequency, duration and severity of 
Adverse Events including occurrence of any second 
primary malignancies, infections, by performing 
physical exams, and evaluating changes in vital 
signs from baseline, routine serum chemistry, 
hematology results and coagulation profile

To assess Overall Survival (OS)

Overall survival, defined as the time from the start of 
treatment to the date of death due to any cause

To assess Event-Free Survival (EFS)

Event-free survival, defined as the time from start of 
treatment to the date of hematologic disease 


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Objective(s)
Endpoint(s)
relapse/progression, graft failure, or death due to 
any cause

To assess Failure-Free Survival (FFS)

Failure-free survival, defined as the time from the 
start of treatment to date of hematologic disease 
relapse/progression, non-relapse mortality, or 
addition of new systemic aGvHD treatment

To assess Non Relapse Mortality (NRM)

Non-relapse mortality (NRM), defined as the time 
from start of treatment to date of death not preceded 
by hematologic disease relapse/progression

To assess incidence of Malignancy 
Relapse/Progression (MR) 

Malignancy Relapse/Progression (MR) (refer to 
protocol Appendix 3), defined as the time from start 
of treatment to hematologic malignancy 
relapse/progression. Calculated for patients with 
underlying hematologic malignant disease

To measure the incidence of cGvHD 

cGvHD, defined as the diagnosis of any cGvHD 
including mild, moderate, severe

To estimate the rate of Best Overall Response 
(BOR)

Proportion of patients who achieved OR (CR+PR) at 
any time point up to and including Day 28 and 
before the start of additional systemic therapy for 
aGvHD

To assess graft failure

Monitoring of donor cell chimerism, defined as initial 
whole blood or marrow donor chimerism >5% 
declining to <5% on subsequent measurements 
compared to baseline

To describe the acceptability and palatability 
assessments of the ruxolitinib formulation

Responses from the acceptability and 
palatability questionnaire for dose forms used 
after first dose, 1 month and 6 months
3
Statistical methods
The 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.
3.1
Data analysis general information
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.


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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
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum).
3.1.1
General definitions
Investigational drug and study treatment
Investigational drug/study treatment, will refer to the ruxolitinib in this single arm study. 
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 study treatment was administered as per the DAR eCRF. The date of first administration 
of study treatment will also be referred as start of investigational drug.
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 study treatment was administered as per DAR eCRF. The date of last administration of 
study treatment will also be referred as end of investigational drug.
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,
, 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.


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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.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event and observation periods 
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 date of first administration of study treatment to 30 days after 
date of last actual administration of ruxolitinib (including start and stop date)
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.
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.
The following time windows are defined for descriptive summaries on aGvHD assessment, 
biomarkers and safety (Table 2-1) by visit. The end of treatment assessment will be mapped 
into the time points as approperate.  
Table 2-1
Time windows for aGvHD assessment, 
and safety 
assessment (lab, vital sign, growth, etc.)
Time Window
Planned Visit Timing 
Time Window Definition


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On treatment
Baseline (Day 1)
On or before Study Day 1
≤ Study Day 1 
Week 1
Study Day 7
Study Days 4 – 10
Week 2
Study Day 14
Study Days 11 – 17
Week 3  
Study Day 21
Study Days 18 – 24
Week 4
Study Day 28
Study Days 25 – 31
Week 5 
Study Day 35
Study Days 32 – 38
Week 6  
Study Day 42
Study Days 39 – 45
Week 7
Study Day 49
Study Days 46 – 52
Week 8 
Study Day 56
Study Days 53 – 59
Week 12
Study Day 84
Study Days 71 – 98 
Week 16
Study Day 112
Study Days 99 – 126 
Week 20
Study Day 140
Study Days 127 – 154 
Week 24
Study Day 168
Study Days 155 – 182 
Week 28
Study Day 196
Study Days 183 – 210
Week 32
Study Day 224
Study Days 211 – 238
Week 36
Study Day 252
Study Days 239 – 266
Week 40
Study Day 280
Study Days 267 – 294
Week 44
Study Day 308
Study Days 295 – 322
Week 48
Study Day 336
Study Days 323 – 350
Month 12*
Study Day 365
Study Days 351 – 455
Month 18*
Study Day 546
Study Days 456 - 636
Month 24*
Study Day 730
Study Days 637 - 820
Study Day 1 = start date of study treatment;
EOT assessments are mapped to the time points as appropriate;
 
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cutoff 
using the last complete date among the following:
Table 3-2
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 aGvHD treatment since 
discontinuation from study treatment
Non-missing medication/procedure term.
Start/End dates from drug 
administration/concomitant medication record 
Non-missing dose. Doses of 0 are allowed.
Disposition event date from the dispostion log 
page
No condition.


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Source data
Conditions
- aGvHD assessment date
- any specific efficacy assessment date if 
available (e.g., cGvHD assessment, graft failure 
assessment, second primary malignacy 
assessement, hematologic disease 
relapse/progression assessment)
Non-missing assessment
Laboratory/PK collection dates/
 
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
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 cutoff date . The cutoff date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cutoff 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 coming from ‘Survival information’ eCRF. 
3.2
Analysis sets
If the starting dose is different from the assigned dose level due to co-administration of 
ruxolitinib with strong CYP3A4 or dual CYP3A4/CYP2C9 inhibitors, these patients will be 
included under the assigned dose level and considered that they have received the full assigned 
dose. This applies to all analysis sets described below.
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received at least one dose of study treatment. Patients will be analyzed according to 
the treatment they have been assigned to.
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the assigned dose level of ruxolitinib if the patient 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 patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to:

Take the dose of ruxolitinib prior to PK sample.

For pre-dose samples, do not vomit within 2 hours after the previous dosing of ruxolitinib 
prior to sampling; for post-dose samples, do not vomit within 2 hours after the dosing of 
ruxolitinib.


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The PAS will be used for Non-compartmental analysis (NCA) for patients where extensive PK 
sampling is obtained. This analysis set will also be used for any exposure-response analysis 
.
The Efficacy Evaluable Set (EES) comprises all patients to whom study treatment has been 
assigned at the Recommended Phase 2 dose (RP2D) of ruxolitinib and who received at least 
one dose of study treatment at that dose level. If the starting dose is different from the RP2D 
due to co-administration of ruxolitinib with strong CYP3A4 or dual CYP3A4/CYP2C9 
inhibitors, these patients will be included in the EES.
All statisticial analysis and data presentation for all analysis sets will exclude any data collected 
but not required as per study protocol. Data with a Protocol Deviation Code OTH11 (Other 
GCP deviation- Additional samples or Data collected not required as per protocol) will not be 
part of the analysis data or any output presentation. 
Any patients who withdrew Informed Consent or from whom written Informed Consent was 
not obtained (Protocol Deviation INCL01) will be excluded from all analyses sets.
Any data collected in the clinical database (other than acute GvHD biopsy, medical 
history, prior and concomitant medication, donor information, prior or concomitant non-drug 
therapies/procedures and viral load, serology from lab data, 
 and blood 
component transfusion) before signed of informed consent will not be included in the analysis. 
If a patient withdraws informed consent from all further participation in the trial no data will be 
included in the analysis after withdrawal of informed consent date. The informed consent date 
and the date on which a patient withdraws full consent are recorded in the eCRF. 
3.2.1
Subgroup of interest
Efficacy
The primary efficacy endpoint will be summarized by the following subgroups to examine the 
homogeneity of treatment effect using EES:

Age group (range defined in Table 1-1)

Age group and formulation (tablet, capsule, liquid)

Diagnosis (treatment naïve aGvHD and SR-aGvHD)

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 (range defined in Table 1-1)

Age group and formulation (Tablet, capsule, liquid)

Diagnosis (treatment naïve aGvHD and SR-aGvHD)



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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 age group, formulation and 
 
only subgroup:

Overview of adverse events

Adverse events by preferred term

Adverse events with suspected relationship to study treatment by preferred term

Serious AEs, irrespective of causality, by preferred term

Adverse events leading to study treatment discontinuation by preferred term 

Overview of adverse events of special interest 

On-treatment deaths

All study deaths 
The following summaries will be provided by age group and and by treatment-naive vs SR 
aGvHD:

Overview of adverse events

AEs, irrespective of causality, by primary system organ class and preferred term

AEs with suspected relationship to study treatment, by primary system organ class and 
preferred term

Serious AEs, irrespective of causality, by primary system organ class and preferred term

Serious AEs with suspected relationship to study treatment, by primary system organ class 
and preferred termOn-treatment deaths, by primary system organ class and preferred term

Overview of adverse events of special interest
3.3
Patient disposition, demographics and other baseline 
characteristics
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 (defined in Table 
1-1) and for all patients and listings will be reported by age group to assess baseline 
comparability. If more than one dose group are assigned under one age group, summaries and 
listings will be reported by both age group and dose group. 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 and for all patients. 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). 


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Diagnosis and extent of disease 
Summary statistics will be tabulated for diagnosis, overall aGvHD grade at diagnosis/baseline
and stem cell transplant type. 
For underlying disease, the analysis will include the following: primary diagnosis classification, 
details of primary diagnosis, time from diagnosis of underlying disease to start of study 
treatment, CIBMTR risk assessment.
For transplant related disease history, the analysis will include the following: conditioning 
regimen type, total HCT-specific comorbidity index score, time from transplant to the start of 
study treatment, time from diagnosis of underlying disease to transplant, stem cell type, 
cytomegalovirus status, time from engraftment to start of study treatment, time from transplant 
to engraftment, donor information including age, gender, HLA typing method, HLA match 
score, source of grafts, CMV status, T-cell depleted (Y/N), total nucleated cell dose. 
For aGvHD disease history, the analysis will include the following: time from diagnosis of 
aGvHD to start of study treatment, Overall aGvHD grade when diagnosis of aGvHD, steroid 
refractory aGvHD criteria met, prior aGvHD therapy (steroid only, steroid + CNI, missing), 
time from diagnosis of aGvHD to steroid refractory, time from steroid refractory aGvHD to 
start of study treatment, Overall aGvHD grade when diagnosis of SR aGvHD, and aGvHD 
organ involvement.
Medical history
Medical history and ongoing conditions, including underlying disease conditions and symptoms 
entered on eCRF will be summarized and listed by age group and for all patients. The 
summaries will be presented by primary system organ class (SOC), preferred term (PT) and 
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.
3.3.1
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 and the study as well as the reason for discontinuation, 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 listed separately.


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Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
age group.
3.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
3.4.1
Study treatment / compliance
Duration of exposure in days 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. 
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/formulations within the age group.
Duration of exposure to study treatment
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) 
– (date of first administration of study treatment) + 1. 
Summary of duration of exposure of study 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 in patient-years
The duration of exposure in patient-years is a total of the duration of exposure in years from all 
the patients in the agegroup. 
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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Duration of exposure to CNIs
Duration of exposure to CNI treatment (days) = (last date of exposure to CNI) – (date of first 
administration of CNI) + 1. 
Duration of exposure to CNI in patient (years)
The duration of exposure to CNI in patient-years is a total of the duration of exposure to CNI
in years from all the patients in the age group.
Cumulative dose
The planned cumulative dose for ruxolitinib refers to the total planned dose as per protocol 
for each group 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 of dose per 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).
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. Number of patients with dose change due to dose 
tapering (change of dose due to efficacy of treatment) and patients with dose change due to 


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other reasons (potential safety concerns) will be sumarised. 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.
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 change when the actual total daily dose is lower than the previous 
actual total daily dose. Any 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 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.
3.4.2
Prior, concomitant and post therapies
3.4.2.1
Prior aGvHD therapy
The number and percentage of patients who received any prior aGvHD therapy will be 
summarized by lowest ATC class, preferred term and age group. Prior aGvHD procedures will 
be summarized by system organ class, preferred term and age group. The above analyses will 
be performed using the FAS. Data will also be listed.
3.4.2.2
Prior aGvhD prophylaxis
The number and percentage of patients who received any aGvHD prophylaxis 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.
3.4.2.3
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. This analysis 
is done based on Full Analysis Set and will be reported in mg/kg/day (weight adjusted).
3.4.2.4
Systemic corticosteroid during study treatment
Doses of methylprednisolone will be converted to prednisone equivalents by multiplying the 
methylprednisolone dose by 1.25 and will be reported in mg/kg/day
The duration of exposure will be summarized for systemic corticosteriod 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. The actual cumulative dose, dose intensity and 


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relative dose intensity (relative to the starting dose of corticosteroids) will be summarized up to 
Day 28, Day 56 and end of on-treatment period.(Section 3.4.1) This analysis will be based on 
Safety Set. The data will be reported on the Study treatment eCRF through the end of treatment
period per EOT Disposition eCRF, and on the Prior and Concomitant Medications eCRF for 
any data prior and after the end of treatment. The list of systemic corticosteroids will be 
documented in Data Quality Plan.
3.4.2.5
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. Data will be analysed similarly to steroids 
and ruxolitinib as described in section 3.4.1. These data are reported on the study treatment 
CRF through the end of treatment per EOT Disposition eCRF, and on the Prior and Concomitant 
Medications eCRF after the end of treatment. The list of CNIs will be documented in the Data 
Quality Plan.
3.4.2.6
Additional systemic aGvHD therapy
New additional systemic aGvHD 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. These medications will 
be derived as per Appendix Section 6.4.3. Procedures are not coded by ATC class and hence 
they will appear under uncoded on the same table. 
3.4.2.7
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments, blood component 
transfusions and procedures) other than the study treatment administered to a patient coinciding 
with the study treatment period. Concomitant therapy include 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. 


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All concomitant CYP3A4 inhibitors and type of blood component transfusions will be 
summarized by ATC class and preferred term based on Full analysis Set.
3.5
Analysis of the primary objective
The primary objective of the Phase I is to assess pharmacokinetic (PK) parameters of ruxolitinib 
for patients with aGvHD and SR-aGvHD and define an age appropriate RP2D for each of the 
groups 2-4. The primary objective of the Phase II is to measure the activity of ruxolitinib in 
patients with aGvHD or SR-aGvHD assessed by Overall Response Rate (ORR) at Day 28.
3.5.1
Primary endpoint
The primary endpoint of the Phase I is the list of following PK parameters (AUC, Cmax, T1/2, 
Ctrough, and other parameters, as appropriate) which will be derived using non-compartmental 
methods in subjects with extensive sampling (Groups 1, 2, and 3). These parameters will then 
be used to define a RP2D for Groups 2, 3, and 4. The observed PK parameters (within group) 
will be summarized and compared to information obtained from adult and adolescent aGvHD 
patients treated with ruxolitinib on study CINC424C2301. Data from patients older than 2 years 
old will be combined and analyzed by PBPK methods to determine the dose to be administered 
in patients younger than 2 years old (Group 4).
The primary endpoint for the Phase II is the investigator-reported overall response rate (ORR) 
at Day 28, defined as the proportion of patients with complete response (CR) or partial response 
(PR) without requirement for additional systemic therapies for an earlier progression, mixed 
response or non-response as per Table 8-3 of the protocol (Harris et al 2016). Note that response 
is relative to the assessment of aGvHD at the start of study treatment.

Complete-response is defined as a score of 0 for the aGvHD grading in all evaluable 
organs that indicates complete resolution of all signs and symptoms of aGvHD in all 
evaluable organs without administration of additional systemic therapies for any earlier 
progression, mixed response or non-response of aGvHD.

Partial response is defined as improvement of 1 stage in 1 or more organs involved with 
aGvHD signs or symptoms without progression in other organs or sites without 
administration of additional systemic therapies for an earlier progression, mixed response 
or non-response of aGvHD.

Lack of response is defined as no response, mixed response, or progression.

No response is defined as absence of improvement in any organ involved by aGvHD, 
without worsening in any involved organ.

Mixed response is defined as improvement of at least 1 stage in the severity of aGvHD in 
at least one organ accompanied by progression in another organ or development of signs 
or symptoms of aGvHD in a new organ.

Progression is defined as worsening in 1 or more organs by 1 or more stages without 
improvement in any involved organ
Patients requiring additional systemic therapy for aGvHD will be classified as non-responders, 
and patients with missing baseline or Day 28 aGvHD response assessment will be considered 
as treatment non-responders.


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aGvHD Flare is defined as any increase in signs or symptoms of aGvHD that is sustained 
for >24h after an initial response (CR or PR) and requires re-escalation of immunosuppressive 
therapy (e.g. corticosteroid, CNI and/or ruxolitinib dosing). While all aGvHD flares will be 
captured on study whether occurring during steroid, CNI or ruxolitinib taper. Only flares in 
GvHD that require new additional systemic therapy, will be considered aGvHD flare failure.
Acute GvHD will be assessed as per Table 8-2 of the protocol. Grade will be calculated based 
on the staging of the organs and recorded on the eCRF by the Investigator. The Investigator 
reported grade will be used for all analyses. Grade and response will be calculated by the 
sponsor for the purposes of data review.
3.5.2
Statistical hypothesis, model, and method of analysis
Pharmacokinetic parameters for patients in Groups 1, 2, 3 and 4 (who are part of the PAS) will 
be compared to adult information from study [CINC424C2301] through the use of ANOVA 
methods. The geometric mean ratio with 90% CI will be provided.
The response rates for ORR at Day 28 will be estimated on the Efficacy Evaluable Set (EES). 
Two-sided 90% confidence intervals [Clopper and Pearson 1934] will be calculated based on 
the exact method for binominal distribution. Summary statistics (frequencies and percentages) 
will be provided.
3.5.3
Handling of missing values/censoring/discontinuations
Patients with missing assessments that prevent the evaluation of the ORR will be considered 
non-responders. This includes aGvHD response assessments at baseline and Days 28, 56. 
Patients who discontinue the study treatment prior to the completion of the Day 28 visit will be 
considered non-responders.
The following analysis windows will be applied to the target day for assessments on overall 
response, where target day for Week X is X*7.
Baseline assessment is the last aGvHD assessment prior to or at the start of study treatment 
(Day 1).
Weeks 1, 2, 3, 4, 5, 6, 7, 8: -3 days/+3 days
Weeks 12 to 48: -13 days/+14 days
3.5.4
Supportive analyses
The subgroup analyses to assess the homogeneity of the treatment effect across demographic 
and baseline disease characteristics will be performed on the EES as appropriate. The subgroups 
are described in section 2.2.1.
A sensitivity analysis excluding subjects who had protocol deviations of organ staging or 
aGvHD response assessments not strictly following standard criteria defined in study protocol 
(PDID: OTHER03, OTHER04 per ECS) at Day 28 will be conducted. 
Efficacy analyses in subgroups 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.


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3.6
Analysis of the key secondary objective
3.6.1
Key secondary endpoint
The key secondary objective of the study is durable ORR at Day 56. 
Durable ORR at Day 56 is defined as the proportions of all patients who achieve a complete 
response (CR) or partial response (PR) at Day 28 and maintain a CR or PR at Day 56. If a 
patient is a CR at Day 28 and a PR at Day 56, he/she will be considered as a durable responder. 
A patient will not be considered a durable responder at Day 56 if any of the following events 
occurs:

Not repsonder at Day 28 

Missing aGvHD assessment at Day 56

No CR or PR at Day 56.

additional systemic therapy for aGvHD prior to Day 56
Durable ORR will be calculated based on the FAS using local investigators review of aGvHD 
assessment data. 
3.6.2
Statistical hypothesis, model, and method of analysis
The durable response rates for ORR at Day 56 will be estimated with 90% confidence intervals 
on EES. Summary statistics (frequencies and percentages). The confidence intervals will be 
calculated based on the exact method for binominal distribution.
3.6.3
Handling of missing values/censoring/discontinuations
Refer to Section 2.5.3
3.7
Analysis of secondary efficacy objective(s)
3.7.1
Secondary endpoints

Overall Response Rate at Day 14
Overall Response Rate at Day 14 is defined as the proportion of patients with complete 
response (CR) or partial response (PR) at Day 14 according to standard criteria [Harris 2016].

Duration of response (DOR)
Duration of response will be calculated for patients whose overall response at Day 28 is CR or 
PR according to updated standard criteria (Harris et al 2016). The start date is the date of first 
documented response of CR or PR (i.e., the start date of response), which could be prior to or 
at Day 28. If it’s prior to Day 28,  there should not be progression or addition of systemic 
therapies for aGvHD between the start date of response and Day 28. The end date is defined as 
the date of progression or the date of addition of systemic therapies for aGvHD on or after 
Day28, since this constitutes a non-response. The date of progression will be the earliest date 
of PD recorded in the aGvHD assessment CRF page or the date of death due to aGvHD in the 
death CRF page.


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Death without prior observation of aGvHD progression (i.e. date of death due to non aGVHD 
reason (Other) in the death CRF page) and onset of chronic GvHD are considered to be 
competing risks. 
Duration of response will be censored at the last response assessment prior to or at the analysis 
cut-off date, if no events/competing risk occurred before or at of cut-off date.

Best Overall Response
Best overall response (BOR) is defined as proportion of patients who achieved overall response 
(CR or PR) at any time point up to and including Day 28 and before the start of additional 
systemic therapy for aGvHD.  
An additional analysis will include BOR at any time point up to the data cut-off date and before 
the start of additional systemic therapy for aGvHD. A swimmer plot for overall response by age 
group, SR-aGvHD vs Treatment Naive and formulation will also be provided for all treated 
subjects.

Overall survival (OS)
Overall survival is defined as the time from date of the start of study treatment 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).

Event Free Survival (EFS)
Event-free survival is defined as the time from the study treatment start date to the date of 
hematologic disease relapse/progression, graft failure or death due to any cause. If a patient is 
not known to have any event, then EFS will be censored at the latest date the patient was known 
to be alive (last contact date on or before the cut-off date).

Failure Free Survival (FFS)
Failure-free survival is defined as the time from the study treatment start date to date of 
hematologic disease relapse/progression, non-relapse mortality (NRM) or addition of new 
systemic aGvHD treatment. Each type of failure as a competing risk for the other two, and onset 
of chronic GvHD is considered as a competing risk for all three types of failure. If a patient is 
not known to have any event or competing risk, then FFS 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 is defined as the time from the study treatment start date to date of death 
not 
preceded 
by 
hematologic 
disease 
relapse/progression. 
Hematologic 
disease 
relapse/progression is considered a competing risk for NRM with the date of hematologic 
disease relapse/progression being the earlier of documented hematologic disease 
relapse/progression or institution of therapy to treat potential hematologic disease 
relapse/progression. If a patient is not known to have died or to have relapsed/progressed, then 
NRM will be censored at the latest date the patient was known to be alive (last contact date on 
or before the cut-off date).

Incidence of Malignancy Relapse/Progression (MR)
Malignancy relapse/progression is defined as the time from the study treatment start date to date 
of hematologic malignancy relapse/progression. Deaths not preceded by hematologic 


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malignancy relapse/progression are competing risks. If a patient is not known to have event or 
competing risks, then MR will be censored at the latest date the patient was known to be alive 
(last contact date on or before the cut-off date).

Cumulative steroid dosing until Day 56
The weekly cumulative steroid dose will be calculated for each patient up to Day 56 and the 
overall cumulative steriod dose will be calculated for each patient at Day 56. In addition, the 
proportion of patients with any dose reduction and  any dose reduction of at least 50% in 
corticosteroids from baseline until EOT will be provided. 

Incidence of cGvHD
cGvHD is defined as the diagnosis of any cGvHD including mild, moderate, severe. Incidence 
of cGvHD is the time from the start of treatment to onset of cGvHD. Cumulative incidence of 
cGvHD will be estimated, accounting for deaths without prior onset of cGvHD and hematologic 
disease relapse/progression as the competing risks. If a patient is not known to have event or 
competing risks, then the incidence of cGvHD will be censored at the latest date the patient was 
known to be alive (last contact date on or before the cut-off date).

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. 
3.7.2
Statistical hypothesis, model, and method of analysis
All secondary efficacy endpoint analyses will be analyzed using the EES.

Overall Response Rate at Day 14
Overall response rate at Day 14 will be calculated based on the local investigators review of 
aGvHD assessment data. They will be summarized using descriptive statistics (N, %) with two-
sided exact binomial 90% CIs [Clopper and Pearson 1934]. 

Best Overall Response (BOR)
BOR up to and including Day 28 will be calculated based on the local investigators review of 
aGvHD assessment data. They will be summarized using descriptive statistics (N, %) with two-
sided exact binomial 90% CIs [Clopper and Pearson 1934].  BOR up to cut-off date will also 
be analysed in the same way.

Duration of response (DOR)
The estimated cumulative incidence rates and 95% confidence intervals at 1, 2, 6, 12, 18 and 
24 months will be presented. The cumulative incidence curve will be plotted. DOR will be 
summarized for all patients in the EES with overall response of CR or PR at Day 28.  

Overall survival (OS) 
The OS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 1, 2, 6, 12, 18 and 24 month survival estimates and 95% confidence intervals 
[Brookmeyer and Crowley 1982] will be presented. 


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
Event Free Survival (EFS)
The EFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 1, 2, 6, 12, 18 and 24 month survival estimates and 95% confidence intervals 
[Brookmeyer and Crowley 1982] will be presented.

Failure Free Survival (FFS)
Cumulative incidence curve for FFS as well as estimates at 1, 2, 6, 12, 18 and 24 months with 
95% confidence intervals will be presented, accounting for onset of chronic GvHD as the 
competing risk. 
In addition, the cumulative incidence of each of the three components considering the other two 
components as a competing risks will be estimated. Onset of chronic GvHD is considered as a 
competing risk for all three types of failure. 

Non-relapse mortality (NRM) 
The cumulative incidence curve for NRM as well as estimates at 1, 2, 6, 12, 18 and 24 months 
with 95% confidence intervals will be presented.  

Incidence of Malignancy Relapse/Progression (MR)
The cumulative incidence curve for MR and estimates at 1, 2, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented for patients with underlying hematologic malignant 
disease, accounting for NRM as the competing risk.

Cumulative steroid dosing until Day 56
Overall and weekly cumulative steroid dose for each patient up to Day 56 or discontinuation of 
study treatment will be tabulated.  In addition, the relative dose intensity (RDI), by week, will 
be calculated relative to the starting dose of corticosteroids and categorized as (1) complete 
reduction where patients are tapered off corticosteroids by D56, (2) ≤50% RDI  and (3) >50% 
RDI. The proportion of patients in each category and corresponding 95% confidence intervals 
will be presented. 

Incidence of cGvHD
The cumulative incidence of cGvHD and estimates at 1, 2, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented, accounting for deaths without prior onset of cGvHD and 
hematologic disease relapse/progression as the competing risks. The cumulative incidence 
curve will be plotted.

Graft failure
Summary statistics of graft failure assessment will be presented over time and at any timepoint 
by dose level and for all patients. In case of very few patients with graft failure (e.g. less than 5 
patients), descriptions using only listings will be provided instead.
3.7.3
Handling of missing values/censoring/discontinuations
Patients with missing assessments that prevent the evaluation of the ORR at Day 14 will be 
considered non-responders. This includes missing aGvHD assessments at baseline and/or Day 
14. The time window for the Day 14 visit is defined in Section 2.5.3.


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3.8
Safety analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
group. If the Phase I starting dose is different to RP2D, the safety data will be listed and 
summarized by age group and dose level. 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.
3.8.1
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 all patients. 
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. 
3.8.1.1
Adverse events of special interest / grouping of AEs
 
 
 
 


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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. 
3.8.1.2
Adverse events of clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on adverse 
events which are not serious adverse events with an incidence greater than 5% and on serious 
adverse events and SAE suspected to be related to study treatment will be provided by system 
organ class and preferred term on the safety set population.
If for a 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.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
3.8.2
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 that occured outside of on-treatment period will be flagged. 
A separate listing of deaths prior to starting treatment will be provided for all screened patients.
3.8.3
Laboratory data
Laboratory, data from all sources (central and local laboratories) will be combined. 


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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 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
The results from viral load testing will be listed.
3.8.4
Other safety data
3.8.4.1
ECG and cardiac imaging data
Not applicable
3.8.4.2
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)
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/body length of the subject. Since height/body length might not be measured at each visit, 
the last available height/body length value before that assessment date will be used instead, i.e. 
using LOCF as imputation method.


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Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-4
below.


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Table 3-4
Clinically notable changes in vital signs
Vital Sign
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           > 140
18-≤24 months           > 135
2-≤3 years                  > 128
3-≤4 years                  > 123
4-≤6 years                   > 117
6-≤8 years                   > 111
8-≤12 years            > 103  
12-≤15 years              > 96
≥15 years                  > 92
12-≤18 months                       < 103
18-≤24 months                       < 98
2-≤3 years                               <92
3-≤<4 years                             <86
4-≤6 years                               <81
6-≤8 years                               <74
8- ≤12 years                            <67     
12-≤15 years                           <62
≥15 years                               <58
Weight
increase from baseline3 of
≥2 BMI- for-age percentile
categories3
decrease from baseline3 of ≥2 BMI-
for-age percentile categories3
Height
increase from baseline of ≥ 
2 height-for-age/gender 
percentile categories3
decrease from baseline of ≥ 2 height-
for-age/gender percentile categories3
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;
published
online 
March
15. 
DOI:10.1016/S0140-6736(10)62226-X.
3 Gender percentiles categories (P3, P5, P10, P25, P50, P75, P85, P90, P95, P97) are 
obtainedfrom the CDC Growth Charts
The number and percentage of patients with notable vital sign values (high/low) will be 
presented.  
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. 


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3.8.4.3
Cumulative incidence of grade 3 infection
Cumulative incidence curves for time to grade >=3 infections as well as 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, considering death or discontinuation from study treatment (due to any reason)
without prior infection as competing risks.
3.8.4.4
Acceptability and Palatability assessment
All acceptability and palatability assessment data will be sumarised and listed by age group and 
formulation. 
3.9
Pharmacokinetic endpoints
Pharmacokinetic Analysis Set (PAS) will be used in all pharmacokinetic data analysis and PK 
summary statistics. 
In patients with extensive PK sampling on Day 1 (samples 1 to 8 described in Section 8.6.1.1
of the protocol), PK parameters of ruxolitinib will be calculated by non-compartmental methods 
using Phoenix WinNonlin (Pharsight, Mountain View, CA) software. The following parameters 
will be calculated (Table 2-5). Additional PK parameters may be estimated as needed.
Table 3-5
Non-compartmental pharmacokinetic parameters of ruxolitinib
AUClast
The AUC from time zero to the last measurable concentration sampling time (Tlast)
AUCinf
The AUC from time zero extrapolated to infinity
AUC0-
12
The AUC from time zero extrapolated to 12 hours
Cmax
The maximum (peak) observed plasma drug concentration
Ctrough
The minimum observed plasma concentration at the end of an administration interval 
(corresponding to the pre-dose concentration prior to the following administration)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (Lambda_z ) of a semi 
logarithmic concentration-time curve
CL/F
The total body clearance of drug from the plasma
Vz/F
The apparent volume of distribution during terminal phase (associated with Lambda_z)
All plasma concentrations will be analyzed using a population PK approach.
Statistical methods for pharmacokinetic analyses
All individual plasma ruxolitinib concentrations data will be listed by group. Descriptive 
summary statistics will be provided by group at each scheduled time point. Summary statistics 
will include n (number of patients with non-missing values), mean (arithmetic and geometric), 
SD, CV (arithmetic and geometric), median, minimum and maximum. Individual profiles with 
median by dose level 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 group. Descriptive statistics (n, 
arithmetic mean, standard deviation (SD), coefficient of variation (CV)% for mean, geometric 
mean, geometric CV%, median, minimum and maximum) will be provided for all PK 
parameters by dose level except for Tmax where median, minimum and maximum will be 
presented.
If the Phase I starting dose is different to RP2D, PK data will be listed and summarized by age 
group and dose level.
Population PK approach on pooled Phase I and Phase II data
Nonlinear mixed effects modeling (population PK) or other model-based approaches, as 
appropriate, will be used to analyse the concentration data from all patients. Details of the 
analysis methods will be developed in a 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 FDA guidance will be followed (Guidance for Industry: Population Pharmacokinetics; 
http//www.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 
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.
3.10
PD and PK/PD analyses
Exposure-Response analysis

The following are objectives for exposure-response analysisCharacterize the exposure-
efficacy relationship of ruxolitinib with efficacy response defined as overall response rate 
at Day 28, durable response at Day 56, and Overall survival. Exposure metrics may be 
described in further details in a separate analysis plan.

Characterize the exposure-safety relationship of ruxolitinib with safety response defined as 
1st occurrence AEs, 1st occurrence of G3/4 AEs, 1st occurrence of AEs of interest, and 
appropriate liver function parameters. Exposure metrics may be described in further details 
in a separate analysis SAP.

Exposure-Biomarker –
For overall survival, if sufficient events have accrued (i.e., at analysis time points after the 
primary analysis), a Cox regression model with appropriate patient demographic and prognostic 
factors as covariates and the log-trough concentration level as a time dependent covariate will 
be fitted as appropriate. Goodness of fit of the model will also be examined, and other exposure 
measures (such as dose intensity) may be considered if appropriate. The survival time should 
be calculated from the time of first dose. The hazard ratio and 95% confidence interval for a 


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decrease by half in exposure will be displayed if appropriate. Kaplan-Meier curves may be 
used to summarize the data based on relevant quantiles of PK.
For incidence of specific AEs, Day 28 response  and Day 56 durable response, logistic 
regression models for efficacy may be used including log- time-averaged trough concentration, 
and log-trough concentration (last observed prior to onset of event) for safety, as well as other 
demographic and prognostic covariates in the model as appropriate. The average trough 
concentration included in the model for Day 28 response will be the geometric mean of the Day 
7, Day 14, Day 21 and Day 28 adjusted trough concentration. A similar average trough 
concentration will be calculated for the Day 56 response except the Day 42 and Day 56 will 
also be included Goodness of fit of the model will also be examined, and other exposure 
measures (such as dose intensity) may be considered if appropriate. The odds ratio and its 95% 
confidence interval for a two-fold increase in exposure will be displayed as appropriate.
Expected steady-state exposures and/or other PK parameters for the population may be 
computed by the population PK model accounting for dose modifications or dose interruptions 
up to the day prior to the day of assessments. Population PK derived parameters may be also 
considered for exposure-response analyses by appropriate methods.
3.11
Patient-reported outcomes
Not applicable.


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3.14
Interim analysis
No formal interim analysis is planned for this study. However, summaries of safety and PK data 
will be produced to support the regular safety monitoring conducted by the DMC and the 
confirmation of RP2D. Efficacy data may also be analyzed when all patients (Phase I and Phase 
II) have completed 24 weeks (approximately 6 months) of treatment or discontinued earlier. 
The final analysis will be conducted when all patients have completed Month 24 (i.e., the end 
of the long-term follow-up period), unless the patients discontinue earlier.
In this clinical trial it is not planned to test specific efficacy hypotheses but to provide estimates 
of efficacy endpoints for the pediatric study population and therefore no-alpha adjustment will 
be made for earlier estimates of efficacy endpoints. However, the data for the primary efficacy 
assessment, ORR at Day 28 will already be final once all patients have completed 6 months of 
treatment.
4
Sample size calculation
In Phase I, 5 patients will be enrolled to each age groups 2 and 3. A minimum of 5 patients in 
Group 1 will also undergo extensive PK sampling during Phase II. Should one or more of the 5 
patients not be evaluable for PK analysis, additional patients may be enrolled to ensure a 
minimum of 5 evaluable PK profiles for Groups 1, 2 and 3.
A comparison of PK parameters (Cmax) from 5 pediatric patients (in Groups 2 and 3 separately) 
to ~25 adult patients (from study CINC424C2301) will be performed. With expected similarity 
in the point estimates across groups (geo-mean ratio, GMR = 1), and accounting for expected 
higher variability in the pediatric patients (CV% ~55.7%, (Loh et al 2015, detailed data on file) 
compared to ~40% in adults), the confidence interval for a GMR of 1 would be [0.609;1.641] 
which demonstrates clinically relevant comparability of exposure to adult exposure (within 2-
fold).
Therefore, with a minimum of 5 evaluable profiles in each of Groups 2 and 3, combined with 5 
evaluable profiles from Group 1 and further sparse PK samples in the Phase II of the study, 
there is sufficient precision to support the PK objectives of the study.
Should the exposure in Group 2, 3 or 4 not be confirmed following the PK sampling in at least 
5 patients, additional patients will be enrolled in that specific age group until the dose/exposure 
is confirmed (i.e., selection of the RP2D for those ages based on exposure and safety review by 
the DMC). Once the RP2D is selected for Groups 2 and 3 any further eligible patients between 
the ages of 2 years and 12 years will be enrolled into the Phase II, and Group 4 will begin 
enrolling patients in the Phase I.
Although several studies of treatments for aGvHD and SR-aGvHD have included pediatric 
patients, it is difficult to find recent estimates for steroid response in de novo aGvHD pediatric 


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patients or BAT response in SR-aGvHD pediatric patients. A review of 443 patients (including 
175 patients < 20 years, reported a CR/PR rate of 55% at Day 28, no association with ORR rate 
and patient age was found (MacMillan et al 2010). Other papers report response rates in the 
ranges 50-60% for de novo and SR-aGvHD (Martin et al 2012).
The sample size for the Phase II objective of measuring ORR at D28 is 45 patients regardless 
of age. Of these, there must be at least 20% of the patients with treatment naïve aGvHD and 
40% of the patients with SR-aGvHD to ensure the sample is representative of the study 
population. The remaining can be filled with either diagnosis. Any patient receiving the 
confirmed RP2D during the Phase I will be counted towards the 45 patients.
The sample size calculation for the Ph II activity objective is based on the ORR at Day 28.
Assuming the true ORR at Day 28 of the study population is 80%, an overall sample size of 45 
patients would have 90% probability to have a 90% CI for ORR with lower limit ≥ 60%. In 
addition, considering the Saw-Toothed behavior of power waving for single binomial 
proportion using an exact method (Chernick and Liu 2002). A minimum sample size of 45
subjects would provide >85% of the probability to have a 90% CI with lower limit ≥ 60%. Table 
12-2 provides estimates of power, minimum number of responders required to have a 90% CI 
with lower limit of ≥ 60% and two-sided 90% Clopper-Pearson CIs for various sample size. 
Patients treated at the RP2D from the Phase I contribute to this analysis.
Table 4-1
Probability to have a 90% CI with lower limit ≥ 60% and 90% 
confidence intervals for different number of patients
Sample 
size
Minimum No. of 
responders
Response 
Rate
Probability to have a 90% CI 
with lower limit ≥ 60%
90% CI
37
28
0.76
0.809
0.614
0.867
38
29
0.76
0.784
0.623
0.871
39
29
0.74
0.859
0.604
0.854
40
30
0.75
0.839
0.613
0.858
41
31
0.76
0.818
0.621
0.861
42
31
0.74
0.882
0.604
0.846
43
32
0.74
0.864
0.612
0.849
44
33
0.75
0.846
0.620
0.853
45
33
0.73
0.901
0.604
0.838
46
34
0.74
0.886
0.612
0.842
47
35
0.74
0.869
0.619
0.846
48
35
0.73
0.916
0.604
0.832
49
36
0.73
0.903
0.612
0.835
50
37
0.74
0.889
0.619
0.838
5
Change to protocol specified analyses
No change from protocol


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6
Appendix
6.1
Imputation rules
6.1.1
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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6.1.2
AE, ConMeds and safety assessment date imputation
Table 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 5-2
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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6.1.2.1
Other imputations
Incomplete date of initial diagnosis of aGvHD 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
6.2
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). 
6.3
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)
Further derivation of laboratory parameters might be required for CTCAE grading. 


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CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
will be assigned as described above for grading.
6.4
Statistical models
6.4.1
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].
6.4.2
Key secondary analysis
Same instruction for the confidence interval for ORR as in section 5.4.1
6.4.3
Definition of new or additional systemic treatment for aGvHD
The data source to search for the new or additional systemic therapy is the CRF of “Prior and 
Concomitant Medication” (CONMED) or CRF “Prior or Concomitant non-drug 
therapies/procedures” and “Study treatment CNI” .
Systemic therapies are identified using the Route (if CMROUTE is Intramuscular, Intravenous, 
Oral, Subcutaneous, or Parenteral). 
Any of the following therapies represent new or additional systemic therapy for aGvHD:

Any CNI therapy being initiated newly as ‘treatment for aGvHD’ after the baseline (as 
recorded on Study treatment CNI and with indication = “treatment for aGvHD” on 
CONMED page). That means when a subject starts a new systemic therapy during study 
treatment for the indication ‘treatment for aGvHD’, or a subject received the same 
therapy before as prophylaxis and then changed to treatment of aGvHD as indication, 
this will be considered as new or additional systemic treatment. 
CNI therapy given as ‘treatment for aGvHD’ that started after Day 1 will be considered 
as new or additional systemic treatment, even if the same therapy was given as treatment 
for aGvHD already before start of study treatment but the patient was not receiving such 
therapy on Day 1. Whereas a stop of such therapy after 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 aGvHD’ or 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 aGvHD’ 
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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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.


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7
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