Clinical trial NCT03112603
Conditions: Graft-versus-host Disease (GVHD)
Keywords: Graft-versus-host disease (GvHD) Chronic GvHD (cGvHD) steroid-refractory ruxolitinib Janus kinase inhibitor
Sponsor: Incyte Corporation
Start date: 2017-06-29; Completion date: 2022-12-15
Enrollment: 330 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy of ruxolitinib against best available therapy in participants with steroid-refractory chronic graft-versus-host disease (SR cGvHD).

Detailed description:

Arms: arm 1: Ruxolitinib for the treatment period and extension period. arm 2: Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6.
Interventions: intervention 1: Ruxolitinib intervention 2: Extracorporeal photopheresis (ECP) intervention 3: Low-dose methotrexate (MTX) intervention 4: Mycophenolate mofetil (MMF) intervention 5: mechanistic Target of Rapamycin (mTOR) inhibitors (everolimus or sirolimus) intervention 6: Infliximab intervention 7: Rituximab intervention 8: Pentostatin intervention 9: Imatinib intervention 10: Ibrutinib
Intervention descriptions: intervention 1: Ruxolitinib twice daily at the protocol-defined starting dose. intervention 2: Best available therapy (BAT) will be selected by the investigator for each participant. BAT may not include experimental agents (ie, those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements. The BAT in this study will be among the following treatments currently used in this setting (no other types or combinations of BATs are permitted in this study). intervention 3: Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. intervention 4: Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. intervention 5: Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. intervention 6: Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. intervention 7: Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. intervention 8: Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. intervention 9: Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. intervention 10: Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A phase III randomized open-label multi-center study of ruxolitinib vs. best 
available therapy in patients with corticosteroid-refractory chronic graft vs 
host disease after allogeneic stem cell transplantation (REACH 3) 
NCT Number: 
NCT03112603 
 
Document Date: 
 
Clinical Study Protocol: 07 October 2021 
 
 
 
 
 
 
 
 
 




Novartis
Confidential
Page 2 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................14
Amendment 2 (07-Oct-2021) ............................................................................................17
Amendment 1 (20-Dec-2017)............................................................................................18
1
Background........................................................................................................................25
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............25
1.2
Introduction to investigational treatment(s) and other study treatment(s).............26
1.2.1
Overview of ruxolitinib.........................................................................26
2
Rationale............................................................................................................................32
2.1
Study rationale and purpose...................................................................................32
2.2
Rationale for the study design ...............................................................................33
36
2.2.2
Rationale for assessment of changes in cGvHD symptoms..................37
2.3
Rationale for dose and regimen selection..............................................................38
2.4
Rationale for choice of combination drugs............................................................38
2.5
Rationale for choice of comparators drugs............................................................38
2.6
Risks and benefits..................................................................................................39
2.7
Rationale for Public Health Emergency mitigation procedures ............................41
3
Objectives and endpoints...................................................................................................41
4
Study design ......................................................................................................................46
4.1
Description of study design ...................................................................................46
4.1.1
Screening Period (Day -28 to Day -1)...................................................46
4.1.2
Main Treatment Periods (Day 1 to EOT)..............................................47
4.1.3
Primary Efficacy Period (Cycle 1 through end of Cycle 6)..................48
4.1.4
Extension Period (Cycle 7 to Cycle 39)................................................49
4.1.5
Cross-Over for BAT patients only (from Cross-Over up to Cycle 
33) .........................................................................................................49
4.1.6
Long-Term Survival Follow-Up (EOT to 39 cycles on study).............49
4.1.7
Safety Follow-Up (Last Dose + 30 days)..............................................49
4.2
Timing of interim analyses and design adaptations...............................................51
4.3
Definition of end of study......................................................................................51
4.4
Early study termination..........................................................................................52


Novartis
Confidential
Page 3 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
5
Population..........................................................................................................................52
5.1
Patient population..................................................................................................52
5.2
Inclusion criteria ....................................................................................................52
5.3
Exclusion criteria...................................................................................................54
6
Treatment...........................................................................................................................57
6.1
Study treatment......................................................................................................57
6.1.1
Dosing regimen.....................................................................................57
6.1.2
Ancillary treatments..............................................................................58
6.1.3
Rescue medication ................................................................................59
6.1.4
Guidelines for continuation of treatment ..............................................59
6.1.5
Treatment duration................................................................................59
6.2
Dose escalation guidelines.....................................................................................62
6.3
Dose modifications................................................................................................62
6.3.1
Dose modification and dose delay ........................................................62
6.4
Concomitant medications ......................................................................................72
6.4.1
Permitted concomitant therapy .............................................................72
6.4.2
Permitted concomitant therapy requiring caution and/or action...........73
6.4.3
Prohibited concomitant therapy ............................................................74
6.4.4
Follow-up for toxicities.........................................................................74
6.5
Patient numbering, treatment assignment or randomization .................................74
6.5.1
Patient numbering .................................................................................74
6.5.2
Treatment assignment or randomization...............................................75
6.5.3
Treatment blinding................................................................................75
6.6
Study drug preparation and dispensation...............................................................75
6.6.1
Study treatment packaging and labeling ...............................................76
6.6.2
Drug supply and storage........................................................................76
6.6.3
Study drug compliance and accountability ...........................................77
6.6.4
Disposal and destruction .......................................................................77
7
Visit schedule and assessments .........................................................................................77
7.1
Study flow and visit schedule................................................................................77
7.1.1
Molecular pre-screening........................................................................90
7.1.2
Screening...............................................................................................90
7.1.3
Run-in period ........................................................................................91
7.1.4
Treatment period...................................................................................92
7.1.5
Discontinuation of study treatment .......................................................93
7.1.6
Withdrawal of consent ..........................................................................94


Novartis
Confidential
Page 4 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.1.7
Follow up for safety evaluations...........................................................94
7.1.8
Lost to follow-up...................................................................................94
7.2
Assessment types...................................................................................................95
7.2.1
Staging and efficacy assessments..........................................................95
7.2.2
Safety and tolerability assessments.....................................................100
7.2.3
Pharmacokinetics ................................................................................104
106
7.2.5
Resource utilization.............................................................................108
7.2.6
Patient reported outcomes...................................................................109
8
Safety monitoring and reporting......................................................................................111
8.1
Adverse events.....................................................................................................111
8.1.1
Definitions and reporting ....................................................................111
8.1.2
Laboratory test abnormalities..............................................................112
8.1.3
Adverse events of special interest.......................................................113
8.2
Serious adverse events.........................................................................................113
8.2.1
Definitions...........................................................................................113
8.2.2
Reporting.............................................................................................113
8.3
Emergency unblinding of treatment assignment .................................................114
8.4
Pregnancies..........................................................................................................114
8.5
Warnings and precautions....................................................................................115
8.6
Data Monitoring Committee................................................................................115
8.7
Steering Committee .............................................................................................115
9
Data collection and management.....................................................................................115
9.1
Data confidentiality .............................................................................................115
9.2
Site monitoring ....................................................................................................116
9.3
Data collection.....................................................................................................116
9.4
Database management and quality control..........................................................117
10 Statistical methods and data analysis ..............................................................................117
10.1
Analysis sets ........................................................................................................117
10.1.1
Full Analysis Set .................................................................................117
10.1.2
Safety set .............................................................................................118
10.1.3
Per-Protocol set ...................................................................................118
10.1.4
Dose-determining analysis set.............................................................118
10.1.5
Pharmacokinetic analysis set...............................................................118
10.1.6
Other analysis sets...............................................................................118
10.2
Patient demographics/other baseline characteristics ...........................................119


Novartis
Confidential
Page 5 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................119
10.4
Primary objective.................................................................................................119
10.4.1
Variable...............................................................................................120
10.4.2
Statistical hypothesis, model, and method of analysis........................120
10.4.3
Handling of missing values/censoring/discontinuations.....................120
10.4.4
Supportive and Sensitivity analyses....................................................121
10.5
Secondary objectives ...........................................................................................121
10.5.1
Key secondary objective(s).................................................................121
10.5.2
Other secondary efficacy objectives ...................................................123
10.5.3
Safety objectives .................................................................................124
10.5.4
Pharmacokinetics ................................................................................126
128
10.5.6
Resource utilization.............................................................................129
10.5.7
Patient-reported outcomes...................................................................129
130
10.7
Interim Analysis...................................................................................................130
10.8
Sample size calculation........................................................................................131
10.9
Power for analysis of key secondary variables....................................................132
11 Ethical considerations and administrative procedures ....................................................132
11.1
Regulatory and ethical compliance......................................................................132
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................132
11.3
Informed consent procedures...............................................................................133
11.4
Discontinuation of the study................................................................................133
11.5
Publication of study protocol and results.............................................................133
11.6
Study documentation, record keeping and retention of documents.....................134
11.7
Confidentiality of study documents and patient records .....................................135
11.8
Audits and inspections.........................................................................................135
11.9
Financial disclosures............................................................................................135
12 Protocol adherence ..........................................................................................................135
12.1
Amendments to the protocol................................................................................135
13 References (available upon request)................................................................................136
14 Appendices ......................................................................................................................140
14.1
Appendix 1: Infection Severity Grading..............................................................140
14.2
Appendix 2: Staging of Chronic GvHD (NIH Criteria) ......................................144
14.3
Appendix 3: Chronic GvHD Disease assessments (Lee 2015) ...........................148
14.4
Appendix 4: Guidelines for response assessment in cGvHD ..............................154


Novartis
Confidential
Page 6 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14.4.1
Introduction and scope ........................................................................154
14.4.2
Efficacy Assessments - Organ specific response at one time point....154
14.4.3
Efficacy Assessments - Overall response assessment at one time 
point.....................................................................................................161
14.5
Appendix 5: HCT Specific Comorbidity Index Score.........................................163
14.6
Appendix 6: CIBMTR classification...................................................................165
14.7
Appendix 7: List of CYP3A4 inhibitors and inducers.........................................178
List of tables
Table 3-1
Objectives and related endpoints ..........................................................43
Table 6-1
Dose and treatment schedule.................................................................57
Table 6-2
Criteria for dose reduction / interruption and re-initiation of 
ruxolitinib treatment for adverse drug reactions ...................................65
Table 6-3
Dose reduction steps for ruxolitinib......................................................70
Table 6-4
Dose re-escalation levels for ruxolitinib ...............................................70
Table 6-5
Preparation and dispensing ...................................................................76
Table 6-6
Packaging and labeling .........................................................................76
Table 6-7
Supply and storage of study treatments ................................................76
Table 7-1
Visit evaluation schedule (randomized treatment period) ....................79
Table 7-2
Visit evaluation schedule for Cross-Over Treatment patients ..............86
Table 7-3
Organs included for the post-baseline cGvHD response assessment....98
Table 7-4
Post-baseline overall response evaluation based on all organs.............98
Table 7-5
Local Clinical Laboratory Collection Plan .........................................101
Table 7-6
Local Virology Laboratory Collection Plan........................................101
Table 7-7
Ruxolitinib Pharmacokinetic blood collection log for extensive PK 
(First 8 adult patients first 4 adolescents) ...........................................105
Table 7-8
Ruxolitinib Pharmacokinetic blood collection log for sparse PK (all 
other patients)......................................................................................105
107
Table 10-1
Noncompartmental pharmacokinetic parameters................................126
Table 10-2
Operational characteristics at the interim analysis..............................131
Table 10-3
Sample size for different scenarios .....................................................132
Table 14-1
Severity grading table and recurrence interval definitions .................140
Table 14-2
Four age groups relevant to HCT........................................................143
Table 14-3
Response determination for chronic GvHD by organ at post-
baseline assessment (comparison vs. baseline)...................................155
Table 14-4
Assessment of the skin score based on BSA and sclerotic features....161


Novartis
Confidential
Page 7 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 14-5
Overall response evaluation................................................................162
Table 14-6
HCT-Specific Comorbidity Index Score.............................................163
Table 14-7
CIBMTR disease risk index................................................................165
Table 14-8
List of CYP3A4 inhibitors and inducers.............................................178
List of figures
Figure 4-1
Schematic Study Design .......................................................................47
Figure 4-2
Overall cGvHD Response assessment vs baseline (pre- Cycle 7 
Day 1)....................................................................................................50
Figure 4-3
Overall cGvHD response assessment vs baseline (from Cycle 7 
Day 1)....................................................................................................51
Figure 6-1
Corticosteroid taper guidelines (Flowers 2015)....................................61
Figure 10-1
Hierarchical testing strategy used for all regions except for US.........122
Figure 14-1
Criteria to determine liver response: general rules .............................156
Figure 14-2
Criteria to determine liver response: Example 1 (PR) ........................157
Figure 14-3
Criteria to determine liver response: Example 2 (unchanged)............158


Novartis
Confidential
Page 8 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
List of abbreviations
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/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
APC
Antigen Presenting Cells
APTT
Activated Partial Thromboplastin Time
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Chemical
AUC
Area under the concentration-time curve
AUCinf
Area under the concentration-time curve from zero to infinity
AUClast
Area under the concentration-time curve from zero to the last measurable concentration
AUCtau
Area under the concentration-time curve during a dosing interval
BAT
Best Available Therapy
BCC
Basal Cell Carcinoma
BCR-ABL
Breakpoint Cluster Region Abelson
BCS
Biopharmaceutical Classification System
BID
bis in diem/twice a day
BM
Bone Marrow
BOR
Best Overall Response
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CAS
Cross-over Analysis Set
cGvHD
Chronic Graft vs. Host Disease
CIBMTR
Center for International Blood and Marrow Transplant Research
CL/F
Clearance
Clcr
Creatinine Clearance
Cmax
Maximum concentration
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNI
Calcineurin Inhibitor
CNS
Central Nervous System
CO
Cross-over
COVID-19
coronavirus disease 2019
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSR
Clinical Study Report
CT
Computerized Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DILI
Drug-Induced Liver Injury
DLI
Donor Lymphocyte Infusion
DMC
Data Monitoring Committee


Novartis
Confidential
Page 9 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
DOR
Duration of Response
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ECP
Extracorporeal Photopheresis
eCRF
Electronic Case Report Form
EFS
Event-Free Survival
EoT
End of Treatment
eSAE
Electronic Serious Adverse Event
ET
Essential Thrombocythemia
FACT-BMT
Functional Assessment of Cancer therapy – Bone Marrow Transplantation
FAS
Full Analysis Set
FFS
Failure-Free Survival
G-CSF
Granulocyte colony Stimulating Factor
GGT
Gamma-Glutamyl Transferase
GI
Gastrointestinal
GvHD
Graft vs. Host Disease
GvL
Graft vs. Leukemia
HBC
Hepatitis C Virus
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCT
Hematopoietic Cell Transplantation
HDL
High Density Lipoprotein
HHV-6
Human Herpes Virus
HIV
Human Immunodeficiency Virus
HLA
Human Leukocyte Antigen
Hr
hour
IA
Interim Analysis
IB
Investigator Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IL
Interleukin
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
ITT
Intention To Treat
IUD
Intra-Uterine Device
IUS
Intra-Uterine system
JAK
Janus Kinase
JAK-STAT
Janus Kinase-Signal Transducer & Activator of Transcription
KPS
Karnofsky Performance Score
Lambda_z
Rate constant
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LPS
Lansky Performance Score


Novartis
Confidential
Page 10 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
LSS
Lee Symptom Scale
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDS
Myelodysplastic Syndromes
MF
Myelofibrosis
mLSS
Modified Lee Symptom Scale
MM
Multiple Myeloma
MMF
Mycophenolate Mofetil
Mo
Month
mPBSC
Mobilized Peripheral Blood Stem Cells
MPNs
Myeloproliferative Neoplasms
MR
Malignancy Relapse
MTX
Methotrexate
NIH
National Institutes of Health
NRM
Non-Relapse Mortality
o.d.
omnia die/once a day
ORR
Overall Response Rate
OS
Overall Survival
PDCO
Paediatric Committee
 
PHI
Protected Health Information
PK
Pharmacokinetics
PLT
Platelet
PML
Progressive Multifocal Leuko-Encephalopathy
PPS
Per-Protocol Set
PR
Partial Response
PRO
Patient Reported Outcome
PT
Prothrombin Time
PTLD
Post-transplant lymphoproliferative disease
PV
Polycythemia Vera
QoL
Quality of Life
R Value
ALT/ALP in x ULN
RA
Rheumatoid Arthritis
RAP
The Report and Analysis Plan is a regulatory document which provides evidence of 
preplanned analyses
REB
Research Ethics Board
SAE
Serious Adverse Event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SC
Steering Committee
SCC
Squamous Cell Carcinoma


Novartis
Confidential
Page 11 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
SR
Steroid Refractory
SR-cGvHD
Steroid Refractory Chronic Graft vs. Host Disease
T1/2
Half-life
TB
Tuberculosis
TBIL
Total Bilirubin
Tmax
Time to reach the peak concentration
TNF
Tumor Necrosis Factor
Tregs
Regulatory T-cells
ULN
Upper Limit of Normal
Vz/F
Apparent volume of distribution
VZV
Varicella Zoster
WBC
White Blood Cells
WHO
World Health Organization


Novartis
Confidential
Page 12 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue,
urine, stool, etc. taken from a study subject
Control drug
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient 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)
Investigational drug
The study treatment whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with “investigational 
new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are tested 
in a fixed combination. Investigational treatment generally does not include other 
study treatments administered as concomitant background therapy required or 
allowed by the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject/healthy volunteer who 
enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium.


Novartis
Confidential
Page 13 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points
Withdrawal of consent
Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not 
want any further study related contact


Novartis
Confidential
Page 14 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Protocol summary
Title
A phase III randomized open-label multi-center study of ruxolitinib vs. best available 
therapy in patients with corticosteroid-refractory chronic graft versus host disease 
after allogeneic stem cell transplantation.
Brief title
Study of efficacy and safety of ruxolitinib vs. best available therapy (BAT) in patients 
with corticosteroid refractory chronic graft versus host disease 
Sponsor and
Clinical Phase
Novartis (all countries except US) and Incyte (US only)
Phase 3
Investigation type
Drug (INC424/ruxolitinib)
Study type
Interventional
Purpose and rationale
The purpose of the study is to assess the efficacy of ruxolitinib when added to 
immunosuppression therapy in patients with moderate to severe corticosteroid 
refractory chronic graft versus host disease (SR-cGvHD).
The rationale of the study is based on current knowledge of chronic graft versus host 
disease pathophysiology and published studies that ruxolitinib impairs human 
dendritic cell activation, modulates cytokine levels in dendritic cells, and deceases T-
cell proliferation in murine models. Further, published data has shown that ruxolitinib 
has evidence of activity when added to immunosuppressive therapy in patients with 
steroid refractory chronic graft versus host disease.
Primary Objective(s) 
and Key Secondary 
Objective
Primary Objective:
To compare the efficacy of ruxolitinib versus Investigator’s choice Best Available 
Therapy (BAT) in patients with moderate or severe SR-cGvHD assessed by Overall 
Response Rate (ORR) at the Cycle 7 Day 1 visit. 
The endpoint for this objective is ORR defined as the proportion of patients in each 
arm demonstrating a complete response (CR) or partial response (PR) without the 
requirement of additional systemic therapies for an earlier progression, mixed 
response or non-response. Scoring of response will be relative to the organ score at 
the time of randomization. 
Key Secondary Objectives: 
To compare the rate of failure free survival (FFS) and the change in the modified 
Lee Symptom Scale score between treatment groups. FFS will be used as the first 
key secondary endpoint for all regions except in the US and the change in modified 
Lee Symptom Scale score will be compared thereafter. In the US, the order will be 
reversed.
The endpoints of this objective are (1) Composite time to event endpoint will 
incorporate the following FFS events: i) relapse or recurrence of underlying disease 
or death due to underlying disease, ii) non-relapse mortality, or iii) addition or 
initiation of another systemic therapy for cGvHD, and (2) rate of patients with 
clinically-meaningful improvement at Cycle 7 Day 1 of the modified Lee Symptom 
Scale relative to baseline
Secondary Objectives
● Best overall response (BOR) 
● Estimate ORR at the end of Cycle 3 
● Duration of response 
● Overall survival
● Non-relapse mortality (NRM)
● Proportion of patients with ≥50% reduction in the daily steroid dose at Cycle 7 
Day 1
● Proportion of patients who successfully tapered off all steroids at Cycle 7 Day 1
● Cumulative incidence of Malignancy Relapse/Recurrence (MR)
● Change in FACT-BMT and EQ-5D
● To assess pharmacokinetics of ruxolitinib
● Safety and tolerability of ruxolitinib and BAT 
● Medical resource utilization


Novartis
Confidential
Page 15 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Study design
This is a randomized open-label multi-center study of ruxolitinib vs. BAT in patients 
with moderate or severe corticosteroid-refractory chronic graft versus host disease 
after allogeneic stem cell transplantation. Patients randomized to the BAT arm are 
allowed to cross over to the ruxolitinib arm after the Cycle 7 Day 1 visit. 
Population
The study will enroll approximately 324 adults and adolescents ≥12 years old who 
have undergone allogeneic stem cell transplantation and have developed moderate 
or severe steroid refractory chronic graft versus host disease
Inclusion criteria
For a full list of inclusion criteria, refer to Section 5.2. Key inclusion criteria include:
● Male or female patients ≥12 years old at the time of signing the ICF
● 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 non-myeloablative, myeloablative, and reduced intensity 
conditioning are eligible
● Evident myeloid and platelet engraftment: Absolute neutrophil count (ANC) > 
1000/mm3 and platelet count > 25,000/ mm3
● Patients with clinically diagnosed moderate to severe cGvHD according to NIH 
Consensus Criteria (Jagasia 2015) prior to randomization:
● Moderate cGvHD: At least one organ (not lung) with a score of 2, 3 or more 
organs involved with a score of 1 in each organ, or lung score of 1
● Severe cGvHD: at least 1 organ with a score of 3, or lung score of 2 or 3
● Patients currently receiving systemic or topical corticosteroids for the treatment of 
cGvHD for a duration of < 12 months prior to Cycle 1 Day 1 (if applicable), and have 
a confirmed diagnosis of steroid refractory cGvHD defined per 2014 NIH consensus 
criteria (Martin 2015) irrespective of the concomitant use of a calcineurin inhibitor, as 
follows:
● A lack of response or disease progression after administration of minimum 
prednisone 1 mg/kg/day for at least 1 week (or equivalent), OR
● Disease persistence without improvement despite continued treatment with 
prednisone at >0.5 mg/kg/day or 1 mg/kg/every other day for at least 4 weeks (or 
equivalent), OR
● Increase to prednisolone dose to >0.25 mg/kg/day after two unsuccessful attempts 
to taper the dose (or equivalent)
● Patient must accept to be treated with only one of the following BAT options on 
Cycle 1 Day 1. (Additions and changes are allowed during the course of the study, 
but only with BAT from the following BAT options): extracorporeal photopheresis 
(ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR 
inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, 
ibrutinib
Exclusion criteria
For a full list of exclusion criteria, refer to Section 5.3. Key exclusion criteria include:
● Patients who have received two or more systemic treatments for cGvHD in 
addition to corticosteroids ± CNI for cGvHD
● Patients that transition from active aGvHD to cGvHD without tapering off 
corticosteroids ± CNI and any systemic treatment
● Patients who were treated with prior JAK inhibitors for aGvHD; except when the 
patient achieved complete or partial response and has been off JAK inhibitor 
treatment for at least 8 weeks prior to Cycle 1 Day 1
● Failed prior alloSCT within the past 6 months from Cycle 1 Day 1
● Patients with relapsed primary malignancy, or who have been treated for relapse 
after the alloSCT was performed
● SR-cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) 
administered for pre-emptive treatment of malignancy recurrence. Patients who 
have received a scheduled DLI as part of their transplant procedure and not for 
management of malignancy relapse are eligible
● Any corticosteroid therapy for indications other than cGvHD at doses >1 
mg/kg/day methylprednisolone or equivalent within 7 days of Cycle 1 Day 1
Investigational and 
reference therapy
Ruxolitinib (INC424) is the investigational drug administered orally Best Available 
Therapy (BAT) varies depending upon Investigator’s choice identified prior to 
randomization. 




Novartis
Confidential
Page 17 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Amendment 2 (07-Oct-2021)
Study Status
Enrollment has closed and 197 patients are ongoing, as of 07-Oct-2021.
Amendment rationale
The main purpose of the amendment is to restrict the use of live attenuated vaccines
(specifically against SARS-CoV-2) in this population with immunocompromised state while on 
study treatment. Due to feedback from health authorities and based on a risk assessment, 
protocol language was revised for prohibited concomitant medication. These changes do not 
add risk to the patient population.
Furthermore, Novartis standard language, referred to as disruption proofing language, has been 
added to specify trial conduct during public health emergencies. The added language addresses 
study participant safety and trial integrity.
At the time of the amendment finalization enrollment was complete and 329 patients were 
randomized; all patients have surpassed the Cycle 7 Day 1 visit used for the primary endpoint. 
Overall, the changes included in this amendment are not expected to impact subject safety.
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:

Table of contents and List of abbreviations updated to reflect changes in amendment.

Section 1.2: Included updates from Investigator’s Brochure edition 20.

Section 2.6: Updated text and added a statement that no substantial additional risk for 
subject safety due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
and the coronavirus disease 2019 (COVID-19) pandemic has been identified at this time 
and therefore the benefit risk remains unchanged.

Section 2.7: Added section for public health mitigation procedures.

Section 6.4.3: Added statement that use of live attenuated vaccines, (i.e., against SARS-
CoV-2) are prohibited while on study treatment.

Sections 6.5.2 and 6.6.1: Updated Novartis Drug Supply Management to Novartis Global 
Clinical Supply based on organizational change

Section 6.6.3.2: Updated drug accountability text to specify “extra” in addition to unused 
study treatment to be returned. This is consistent with revised standard template text.

Section 7.1: Added statements for public health mitigation procedures.

Section 8.2.2: Included clarification on reporting additional information for SAEs

Section 10.7: Removed statement to clarify scope of the Steering Committee as this was 
revised with the introduction of the Data Monitoring Committee at the time of the last 
amendment.

Section 14.6: Corrected typographical error in abbreviation of CIBMTR.


Novartis
Confidential
Page 18 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Amendment 1 (20-Dec-2017)
Study Status
As of 19-Dec-2017, a total of 15 patients have been screened and 15 patients randomized.
Amendment rationale
The main purpose of the amendment is to extend the available patient population. Due to 
protracted enrollment and feedback from health authorities and investigators, several inclusion 
and exclusion criteria were revised. Additionally, with the recent approval of ibrutinib the 
original protocol-defined list of BAT options would not allow for a complete comparative 
assessment versus ruxolitinib. Therefore, adding ibrutinib to this list was necessary to reflect 
the complete list of treatment options for this patient population. Lastly, a Data Monitoring 
Committee has been added based on health authority feedback to include an independent review 
group.
These changes may add limited heterogeneity to the patient population, yet without expected 
consequences on the trial design and interpretability. As at the time of the amendment 
finalization, 15 patients were randomized, and none of these patients have reached the 6-month 
visit that is used for the primary endpoint. Overall, the changes included in this amendment are 
not expected to lead to a cohort effect.
Inclusion Criteria #7
The window for patients currently receiving systemic or topical corticosteroids for the treatment 
of cGvHD was extended from six months to twelve months prior to Cycle 1 Day 1 to allow for 
a larger population of eligible patients. The original criterion was written to avoid enrolling 
those patients that had permanent fibrotic changes that would not be assessable per the NIH 
criteria. This risk was outlined in the NIH consensus manuscript (Lee 2015). However, the 
growing body of literature on the use of ruxolitinib in patients with GvHD has shown that 
measureable improvement can be seen in very heavily pre-treated patients; even those patients 
with sclerodermatous skin cGvHD (Hurabielle 2017). Therefore, this criterion has been 
extended to allow a broader group of patients that could potentially benefit from this treatment 
option, and would more closely reflect a real-world patient population.
Inclusion Criteria #9
Ibrutinib is added to the protocol list of allowed best available therapies (BAT), as it has 
received regulatory approval in the US and Canada for the treatment of chronic graft versus 
host disease since the original protocol was finalized.
Exclusion Criteria #1
Previously, patients who received any systemic treatment for cGvHD in addition to 
corticosteroids ± CNI for cGvHD were excluded. This has been amended to exclude those 
patients who received two or more systemic therapies, thus patients who have received one 
prior systemic treatment in addition to corticosteroids for cGvHD are potentially eligible. 
Similar to the rationale for the revision of Inclusion #7, this original criterion was intended to 


Novartis
Confidential
Page 19 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
enroll patients that were comparable in disease presentation and chronicity. However, the 
growing body of literature on the use of ruxolitinib in this wider patient population supports the 
inclusion of a more pre-treated patient population (Boiko 2017; Zeiser 2015). Therefore, this 
criterion was extended to allow for 1 additional prior systemic treatment in addition to 
corticosteroids.
Exclusion Criteria #2
Patients with overlap syndrome, defined as presence of simultaneous features of both chronic 
and acute GvHD, were previously excluded. This criterion was too broad and unclear in scope 
which resulted in more patients being excluded from the trial than intended. Therefore the 
criterion was clarified to exclude those patients with active acute progressive disease. The 
question of overlap was then clarified and added to the appropriate organ specific exclusion 
criteria below.
Exclusion Criteria #15
The definition of severely impaired renal function was updated by adding the text “having 
estimated creatinine clearance <30 ml/min measured or calculated by Cockroft Gault equation 
(confirmed within 48 hours prior to study treatment start)”. This criterion was updated to 
provide a more sensitive measure of mild or moderate kidney injury at study entry.
Exclusion Criteria #16
Updated cholestatic criterion to add total bilirubin >2mg/dL attributable to GvHD. This 
criterion was added as a more specific exclusion of patients with ongoing hepatic acute-like 
GvHD, and provides for a more clear definition of the “overlap” population that was removed 
from Exclusion Criteria #2.
Exclusion Criteria #17
Added impairment of GI function example of diarrhea attributed to GvHD. This criterion was 
added as a more specific exclusion of patients with ongoing acute-like GI GvHD, and provides 
for a more clear definition of the “overlap” population that was removed from Exclusion 
Criteria #2.
Secondary Endpoints
The number of patients required for the “extensive PK” sampling schedule was decreased from 
25 adults and all adolescents to 8 adults and 4 adolescents. The sampling schedule was 
simplified to a smaller number of samples as well as a smaller amount of blood per sample. A 
planned PK analysis was performed on data from the first 23 patients randomized in the acute 
GvHD CINC424C2301 trial. Following the review of this data, the assessment schedule in this 
study (CINC242D2301) was reevaluated and thereby reduced. The PK data generated in these 
8 adult patients and 4 adolescent patients with extensive PK sampling (the absolute minimum 
number of patients needed to obtain reliable PK parameter estimates), especially when 
combined with the number of sparse samples that will be collected in all patients enrolled in 
this study and taking ruxolitinib, is considered sufficient to provide information on any 
deviation of the PK characteristics in chronic GvHD compared to other known indications.






Novartis
Confidential
Page 22 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301

Section 5.3: Previously patients who received any systemic treatment for cGvHD in addition 
to corticosteroids ± CNI for cGvHD were excluded. This has been amended to exclude two 
or more systemic therapies, thus patients who have received one prior systemic treatment 
for cGvHD are potentially eligible. Clarified the physiologic replacement dose range that is 
allowed.

Section 5.3: Patients with overlap syndrome defined as presence of simultaneous features 
of both chronic and acute GvHD were previously excluded. This definition has been updated, 
and clarified that patients receiving physiologic replacement doses of corticosteroids are 
allowed.

Section 5.3: Updated impaired renal function exclusion criteria definition.

Section 5.3: Updated impaired GI function exclusion criteria definition.

Section 5.3, Section 6.4.3: Updated exclusion criteria with clarification on allowed dosage 
of aspirin and patient population.

Section 5.3: Added exclusion criteria for patients receiving fluconazole at daily doses higher 
than 200 mg.

Section 5.3: Added exclusion criteria for patients that are receiving and do not agree to stop 
herbal preparations or medications.

Section 5.3: Clarified that contraception guidelines for male and female patients dosed with 
BAT should follow locally approved BAT label or guidance. Specified that contraception 
guidelines in protocol are for patients randomized to ruxolitinib.

Section 6.1.1.2: Clarified that the administration of BAT is also dependent on BAT 
availability for the patient.

Section 6.1.5: Clarified that taper off CNI is allowed only after Cycle 7 Day 1.

Section 6.3.1.4, Section 6.4.2: Clarified dosing recommendations for ruxolitinib when 
combined with CYP450 modulators.

Section 6.4.1, Section 7.2.3: Clarified that patients should be instructed to fast and refrain 
from taking corticosteroids on extensive PK sampling days.

Section 6.4.2: Removed allowance of granulocyte growth factors while on study.

Section 7.1: Clarified that visit windows in Table 7-1 and Table 7-2 do not apply for visits 
with PK assessments.

Table 7-1, Table 7-2: Added clarifying language to cGvHD staging and disease assessment 
descriptions.
.

Table 7-1, Table 7-2, Section 7.2.6: Updated PRO assessment schedule to provide unique 
row per scale, and to reflect revised strategy.

Section 7.1.2: Clarified that screening lab evaluations performed within 10 days of C1D1 
can be used for C1D1.

Section 7.1.2.3, Section 7.2.2.3: Removed height from screening assessments. Clarified that 
height will be measured at C1D1.

Section 7.1.2.3: Clarified that cGvHD disease assessments are to be performed prior to 
randomization on C1D1, and DEXA scans are to be performed prior to first treatment on 
C1D1.




Novartis
Confidential
Page 24 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
IRBs/IECs
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.


Novartis
Confidential
Page 25 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Allogeneic stem cell transplantation (alloSCT) is a curative immunotherapy for patients with 
blood-related malignancies including leukemia, 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 in a bone marrow or stem cell graft recognize 
the transplant recipient as foreign, thereby initiating an adverse immune reaction leading to an 
inflammatory cascade with resultant tissue damage, organ failure, or even death. Chronic GvHD 
(cGvHD) has been historically characterized by autoimmune and alloimmune dysregulation 
occurring after the first 100 days of allo-SCT (Baird 2010). However, the median onset of 
cGvHD is approximately 6 months following alloSCT (Baird 2010). Risk factors for cGvHD 
include prior acute GvHD (aGvHD), grafting with growth factor mobilized blood cells, the use 
of female donor for male recipients and unrelated donors (Flowers 2011).
Approximately 
32,000 
alloSCT 
procedures 
are 
performed 
annually 
world-wide
(Niederweiser 2016) with up to 60% of patients receiving HLA-identical marrow grafts and 70% 
of patients receiving alternative donor marrow grafts who survive beyond 100 days developing 
cGvHD (Lee 2003). Additionally, the prevalence and severity of cGvHD occurring in 30-70% 
of alloSCT patients (Lee 2008), has increased over the past two decades attributable to several 
factors including: i) the increased use of mobilized peripheral blood stem cell (mPBSC) grafts 
(containing higher numbers of donor T-cells than BM), ii) advanced age of transplant recipients 
rising from 55 to 75 years due to development of better tolerated reduced intensity conditioning, 
and, iii) improvements in survival during the first months after alloSCT.
Unfortunately cGvHD remains a serious and common complication of alloSCT, and while 
major progress has been achieved in understanding the pathophysiology of aGvHD; cGvHD is 
far less defined (Wolff 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 2009). Additionally, the 
expression of CD134 (OX40) on the surface of CD8+ and CD4+ T-cells has been associated 
with cGvHD onset, and marks an early T-cell activation by inflammatory cytokines 
(Briones 2011). A decline in regulatory T-cells (Tregs) leads to a loss of peripheral tolerance, 
autoimmunity and cGvHD (Zhang 2006). In fact, patients with cGvHD have lower numbers of 
CD4+ Tregs compared to patients without cGvHD (Bruggen 2014). As opposed to aGvHD, 
which involves only the skin, liver and GI tract, cGvHD can involve almost any organ of the 
body. It is a multi-systemic disorder and can present as a syndrome of variable clinical features 
resembling autoimmune and other immunologic disorders with a variety of clinical signs and
symptoms resembling diseases such as scleroderma, Sjogren’s syndrome, bronchiolitis 


Novartis
Confidential
Page 26 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
obliterans, and chronic immunodeficiency (Greinix 2011), it also can include primary biliary 
cirrhosis, wasting syndrome, immune cytopenias, and chronic immunodeficiency 
(Jagasia 2015, Dhir 2014). Importantly, cGvHD leads to significant morbidity, diminished 
quality of life and decreased overall survival (Lee 2003). Although approximately 50% of newly 
diagnosed cGvHD patients are cured within 7 years after starting systemic immunosuppression, 
10% require continued systemic treatment indefinitely, and the remaining 40% relapse or die 
within 7 years during ongoing prolonged immunosuppressive treatment (Vigorito 2009).
cGvHD is classified into mild, moderate, and severe based on degree of organ involvement 
according to established NIH Consensus Criteria for cGvHD (Jagasia 2015), and approximately 
half of affected patients have 3 or more involved organs.
Systemic immunosuppressive treatment in cGvHD is typically required on average for 1 to 3 
years, and standard initial treatment of moderate and severe cGvHD includes systemic 
corticosteroids, generally prednisone 0.5-1 mg/kg/day followed by taper with or without 
concomitant calcineurin inhibitor treatment. Although corticosteroids are standard of care (SOC) 
in initial stages of moderate to severe cGvHD, published reports identify that 50-60% of patients 
become corticosteroid refractory and meet objective criteria per NIH Consensus to be 
determined to require addition of another systemic therapy beyond systemic corticosteroids and 
calcineurin inhibitor within two years after initial therapy (Inamoto 2014). Few prospective 
comparative studies have been carried out to assess the efficacy and safety of currently used 
second-line therapy for cGvHD. As such, no treatment has been proven superior to another, and 
no SOC exists following the development of corticosteroid refractoriness. Physicians in clinical 
practice use various therapies and in various sequence and dosing schedules, mostly driven by 
their own clinical experience. Secondary treatments (all off label) include extra-corporeal 
photopheresis, rituximab, imatinib, pentostatin, mesenchymal stem cells, mycophenolate 
mofetil, ibrutinib, and mTOR-inhibitors including sirolimus and everolimus.
Despite the availability and use of several medicinal products, none of which are approved 
centrally, SR-cGvHD remains a serious medical condition associated with high morbidity and 
long-term mortality, as well as reduced quality of life, hence representing an area of high unmet 
medical need. This unmet medical need, alongside robust preclinical and clinical proof-of-
concept data provide a strong rationale for investigating ruxolitinib as potential treatment for 
SR-cGvHD.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of ruxolitinib
Ruxolitinib
[(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl-
propanenitrile phosphate], (INCB018424, INC424, ruxolitinib phosphate) is a potent, selective, 
orally available inhibitor of Janus kinases (JAKs) JAK1 (inhibition concentration 50%
[IC50]=3.3 ± 1.2 nM) and JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity
against TYK2 (tyrosine kinase 2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM),
respectively. JAKs mediate the signaling of a number of cytokines and growth factors that are 
important for hematopoiesis and immune response.


Novartis
Confidential
Page 27 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Dysregulated JAK-STAT signaling, via upregulation of JAK1 and JAK2 or gain of function 
mutations such as JAK2V617F, has been implicated as a driver of BCR-ABL-negative 
myeloproliferative neoplasms (MPNs), namely myelofibrosis (MF), polycythemia vera (PV) 
and essential thrombocythemia (ET). Ruxolitinib specifically binds to and inhibits JAK1, JAK2 
and mutated JAK2V617F, leading to inhibition of growth factor-mediated cell signaling and 
tumor cell proliferation. Given this mechanism of action of ruxolitinib as a JAK inhibitor and 
the role played by dysregulation of the JAK pathway in the pathogenesis of MPNs, the primary 
clinical development plan for ruxolitinib initially focused on studies to support regulatory 
approval in these disorders.
Of importance to GvHD, strong pre-clinical data shows that inhibition of JAK1/2 signaling 
results in reduced proliferation of donor immune cells, suppression of adverse cytokines in 
response to recipient antigens, as well as impairment of antigen presenting cells in vitro and in 
vivo (Socie 2014, Spoerl 2014). In vivo JAK 1/2 inhibition by ruxolitinib has been shown to 
improve survival of mice in an established GvHD model incorporating human immune cells, 
and impairs differentiation of T-cell populations that are linked to GvHD (Spoerl 2014). The 
role for JAK-inhibition in GvHD was further confirmed with data from a retrospective study in 
patients with SR-cGvHD, showing that the majority of these patients responded to ruxolitinib 
treatment with improved clinical cGvHD symptoms (Zeiser 2015). In this retrospective study, 
patients were treated with an empiric regimen of 5 mg BID for 3 days followed with 10 mg BID 
if no side effects were observed.
Novartis selected the 10 mg BID starting dose without the 5 mg BID run-in based on data from 
the retrospective study (Zeiser 2015), safety data from patients with myeloproliferative 
neoplasms, and PK/PD data from patients with polycythemia vera.
Ruxolitinib was originally developed by Incyte Corporation (Wilmington, Delaware, USA). 
Incyte and Novartis entered into a joint agreement for the co-development of ruxolitinib in 
hematology and oncology indications in 2009. More recently on April 7, 2016, Incyte granted 
Novartis the exclusive rights to research, develop and market ruxolitinib for graft-versus-host 
disease indications outside the USA under the terms of an amended collaboration and license 
agreement. Both companies intend to co-develop ruxolitinib for the treatment of corticosteroid 
refractory acute GvHD (SR-aGvHD) and corticosteroid refractory chronic GvHD (SR-cGvHD) 
following allogeneic stem cell transplantation (alloSCT).
Ruxolitinib is currently approved under the trade name of ‘Jakavi’ in over 100 countries for the 
treatment of disease-related splenomegaly or symptoms in adult patients with (primary 
myelofibrosis) PMF, post-polycythemia vera myelofibrosis (PPV-MF) and post-essential 
thrombocythemia myelofibrosis (PET-MF) including in the EU and Switzerland. The use of 
ruxolitinib to treat polycythemia vera (PV) patients who are resistant to or intolerant of 
hydroxyurea is currently under regulatory review in some countries based on the results from 
the Ph III trial CINC424B2301 (the RESPONSE study). To date, approval in this second 
indication was granted in more than 60 countries including the EU and Switzerland. Ruxolitinib 
is also approved in the USA under the trade name of ‘Jakafi’ and is indicated for the treatment 
of patients with intermediate or high risk myelofibrosis, including PMF, PPV-MF and PET-MF 
and for the treatment of PV patients who have had an inadequate response to or are intolerant 
of hydroxyurea, and in May 2019 for the treatment of SR-aGVHD in adult and pediatric patients 
12 years and older. 


Novartis
Confidential
Page 28 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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. 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 [Investigator Brochure].
1.2.1.2
Clinical experience
Ruxolitinib has been administered to approximately 510 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. As of February 22, 2021, 
approximately 12,600 patients have received ruxolitinib treatment in Novartis- and Incyte-
sponsored investigational clinical trials cumulatively since the Development IBD (DIBD). 
(Refer to [Investigator Brochure] for details).
1.2.1.2.1 Clinical Pharmacology
Eighteen Phase I, two Phase I/II, thirteen Phase II and five Phase III clinical studies (two in MF,
two in GvHD, one in PV) provided clinical pharmacology data on ruxolitinib in healthy 
volunteers and in patients with GvHD, MF, ET, PV, as well as in subjects with renal or hepatic 
impairment, prostate cancer, pancreatic cancer, multiple myeloma (MM), thalassemia 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.


Novartis
Confidential
Page 29 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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 
pharmacokinetics (PK).
Plasma protein binding is approximately 97% ex vivo. 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%.
Co- administration of ruxolitinib with fluconazole at daily doses above 200 mg should be
avoided. 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 baseline platelet count should be reduced by 
approximately 50% to be administered twice a day (or as specified in country specific product 
labels). 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. In GvHD patients with hepatic impairment, no starting 
dose modification is recommended.
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.
In a population pharmacokinetic evaluation in myelofibrosis patients, no relationship was 
apparent between oral clearance (CL/F) and patient age or race, and in women, clearance was 
17.7L/h and in men, 22.1 L/h with 39% inter-subject variability.


Novartis
Confidential
Page 30 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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 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.
Please refer to the [Investigational Brochure] for details on pharmacokinetics 
 
1.2.1.2.2 Summary of Clinical Efficacy Data
The results from two phase III registration studies in myelofibrosis (COMFORT-I [INCB 
18424-351]), and COMFORT-II [INCB 18424-352])) 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 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 and manageable with dose modifications.
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.


Novartis
Confidential
Page 31 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Consistent with its activity in myelofibrosis, ruxolitinib demonstrated in the RESPONSE 
pivotal study its efficacy in polycythemia vera (PV) 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: 22.7% vs 0.9%, respectively (p < 0.0001). More patients randomized to ruxolitinib 
achieved hematocrit control 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 
efficacy analyses at Week 80 data cut-off (03-Sept-2014), Week 208 data cut-off (15-Feb-2017) 
and Week 256 data cut-off (09-Feb-2018) of the RESPONSE study confirmed the durability of 
the responses in the patients randomized to the ruxolitinib arm.
A second randomized, open label, active-controlled Phase IIIb Study B2401 (RESPONSE-2) 
was conducted in 149 PV patients who were resistant to or intolerant of hydroxyurea but without 
palpable splenomegaly. 74 patients were randomized to the ruxolitinib arm and 75 patients to 
the BAT arm. The starting dose and dose adjustments of ruxolitinib and investigator-selected 
BAT were similar to the RESPONSE study. Baseline demographics and disease characteristics 
were comparable between the two treatment arms and similar to the patient population of the 
RESPONSE study. The primary endpoint was the proportion of patients achieving it HCT 
control (absence of phlebotomy eligibility) at Week 28. The key secondary endpoint was the 
proportion of patients achieving CHR at Week 28.
Study B2401 (RESPONSE-2) met its primary objective with a higher proportion of patients in 
the ruxolitinib arm (62.2%) compared to the BAT arm (18.7%) achieving the primary endpoint 
(p<0.0001) [Study B2401]. The key secondary endpoint was also met with significantly more 
patients achieving a CHR in the ruxolitinib arm (23.0%) compared to the BAT arm (5.3%; 
p=0.0019). At week 28, the proportion of patients achieving a ≥50% reduction in symptom 
burden as measured by the MPN-SAF total symptom score was 45.3% in the ruxolitinib arm 
and 22.7% in the BAT arm. 
Graft vs Host Disease
Several recently published studies provide evidence of clinical efficacy and safety of ruxolitinib 
when added to immunosuppressive therapy in patients with SR-aGvHD and SR-cGvHD
(Zeiser 2015; Khoury 2015; Spoerl 2014). Spoerl 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. 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 corticosteroid taper requiring additional systemic 
therapy (Spoerl 2014). Further clinical experience with ruxolitinib in patients with GvHD was 
recently reported in a retrospective study that gathered experience in 95 patients with SR-GvHD, 


Novartis
Confidential
Page 32 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
of whom 41 had SR-cGvHD (Zeiser 2015). In this study, 29/41 (70.7%) of SR-cGvHD patients 
had more than one organ system involved. All patients had moderate (n = 6/41, 14.6%) to severe 
(n = 35/41, 85.4%) SR-cGvHD. Most patients were beyond second-line treatment for cGvHD, 
with a median number of 3 prior treatments (range: 1–10) before ruxolitinib was administered. 
The majority of patients were treated with ruxolitinib as an add-on immunosuppression therapy 
at a dose of 5–10 mg orally twice daily. The overall response rate (ORR) was 85.4% (35/41), 
with 78% (32/41) having a partial response (PR defined as the discontinuation or long-lasting 
(4 weeks) reduction of all systemic immunosuppressive therapy by at least 50%) and 7.3% (3/41) 
having a complete response (CR defined as the absence of any symptoms related to cGvHD).
Only 14.6% (6/41) of the patients showed no response. The median time to response was 3 (1–
25) weeks after initiation of ruxolitinib treatment.
The safety profile of ruxolitinib in SR-cGvHD was generally favorable. Although cytopenias 
in the Zeiser 2015 publication were observed in 17% of SR-cGvHD patients, cytopenias 
preceded ruxolitinib administration in 14.6% of these patients. CMV reactivation was observed 
in 14.6% of SR-cGvHD patients treated with ruxolitinib. This incidence rate compares 
favorably with that reported with other second line GvHD agents including MMF, alemtuzumab, 
and others where CMV reactivation ranges from 70 to 80% (Rager 2011). Relapse of the 
underlying malignancy occurred in 2.4% (1/41) of the patients with SR-cGvHD. This frequency 
is comparable to other studies and suggests that ruxolitinib treatment is not linked to a higher 
relapse risk when compared with other currently applied immunosuppressive drugs (Zeiser 
2015).
Additional 24 month follow-up was presented at the 2016 American Society of Hematology 
conference (Zeiser 2016) which demonstrated a 1-year overall survival (OS) of 92.7% (CI: 
84.7-100%), with an estimated median OS not being reached for these patients. Twenty-four 
percent (10/41) of SR-cGvHD patients have an ongoing response and are free of any 
immunosuppression. Any grade cytopenias (17.1%, 7/41) and CMV reactivation (14.6%, 6/41) 
were observed during ruxolitinib-treatment. GvHD relapse or progression after achieved partial 
response/complete response was observed in 13/36 (36%) patients with SR-cGvHD. Response 
to re-treatment with ruxolitinib or any immunosuppressive therapy was seen 11/13 (86%) 
patients with SR-cGvHD. These findings extend the previous report by showing that patients 
with SR-GvHD may benefit long-term from ruxolitinib treatment (Zeiser 2016).
2
Rationale
2.1
Study rationale and purpose
The scientific rationale for this study of ruxolitinib in adults and adolescents with moderate or 
severe SR-cGvHD is based on current knowledge of cGvHD pathophysiology that begins
with activation of host antigen-presenting cells (APC) expressed by damaged tissues and/or 
pathogens (Dhir 2014). Activated host APC then present host antigens to donor immune cells, 
leading to donor T-cell proliferation and inflammatory cytokine production. Cytokine 
dysregulation has also been implicated through observations that high levels of interleukin 
(IL)-1β, IFNγ, and tumor necrosis factor (TNF)-α are associated with more severe cGvHD
(Socie 2014). These inflammatory cytokines then recruit and induce proliferation of additional 
immune effector cells, thereby perpetuating an adverse cycle of allo-reactive tissue injury and 


Novartis
Confidential
Page 33 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
inflammation (Paczesny 2010). Inhibition of JAK1/2 signaling results in reduced proliferation 
of donor effector T-cells, suppression of pro-inflammatory cytokine production in response to 
alloantigen, as well as impairment of antigen presenting cells in vitro and in vivo (Betts 2011).
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
(Heine 2013; Spoerl 2014). Furthermore, ruxolitinib impairs differentiation of CD4 T-cells into 
IFN-gamma and IL17A-producing cells; both T-cell phenotypes are linked to GvHD 
pathophysiology (Heine 2013). Importantly, Graft-vs-Leukemia (GvL) effects have been shown 
to be maintained in mice treated with ruxolitinib in two different MHC-mismatched alloSCT 
models and using two different murine leukemia models (both lymphoid and myeloid)
(Choi 2014).
This, in addition to the recently published data in which ruxolitinib was shown to have
evidence of clinical efficacy when added to immunosuppressive therapy in patients with SR-
aGvHD and SR-cGvHD (Zeiser 2015; Spoerl 2014), provides strong rationale to test the
hypothesis that ruxolitinib added to immunosuppression therapy for SR-cGvHD patients will
provide higher rates of disease response compared with currently used second line systemic
treatment modalities, and further that this response will be sustained during corticosteroid taper.
2.2
Rationale for the study design
This trial is designed as a randomized (1:1) phase III open label design to investigate the 
efficacy and safety of ruxolitinib vs. Investigator choice Best Available Therapy (BAT) added 
to the patient’s immunosuppressive regimen in adults and adolescents ≥12 years old with 
moderate or severe SR-cGvHD.
Very few prospective comparative studies have been carried out to assess the efficacy and safety 
of currently used second-line therapies for cGvHD. Therefore, a randomized study provides the 
best opportunity to assess whether treatment with ruxolitinib in patients with SR-cGvHD 
provides better efficacy when compared to currently used treatments in this setting. A 
randomized study design will also enable a more robust assessment of ruxolitinib safety in a 
comparative manner.
There are no uniformly used, nor centrally approved second-line treatments following 
corticosteroid resistance in cGvHD, and practices vary as to the selection of various systemic 
therapies since to date no improvement in the high mortality rates has been documented 
despite treatment with these agents. BAT currently used in medical practice includes: extra-
corporeal photopheresis, rituximab, imatinib, pentostatin, mesenchymal stem cells, 
mycophenolate mofetil, ibrutinib, and mTOR-inhibitors including everolimus and sirolimus. As 
these treatments vary from administered tablets to cellular therapy and photopheresis, the open-
label design of this study is inevitable to accommodate the variety of treatments that may be 
considered by investigators for these patients. Additionally, the necessity for modifications and 
dose adjustments in these therapies depending on the subject’s response, make utilizing a 
placebo operationally impossible, and would present an undue burden to the patient. Patients
will be randomized 1:1 to receive either ruxolitinib or BAT, stratifying on GvHD severity


Novartis
Confidential
Page 34 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
(moderate vs. severe). The choice of BAT will be decided by the Investigator before
randomization in this study.
The rationale to stratify patients by severity of cGvHD at the time of randomization is
based on the fact that response rates are variable in patients with different cGvHD severity. 
cGvHD is classified into mild, moderate and severe based on degree of organ involvement 
according to established NIH Consensus Criteria for cGvHD (Jagasia 2015). While milder 
forms of cGvHD are often manageable with local or low-dose systemic immunosuppression 
and do not affect long-term survival, more severe forms require intensive medical management 
and adversely affect survival (Lee 2003).
Moderate and severe SR-cGvHD adult and adolescent patients ≥12 years of age are included in 
this study. While the rates of cGvHD are lower in pediatrics as compared to adults (Dhir 2014), 
adolescents ≥12 years comprise approximately 5% of the cGvHD population (CIBMTR data 
on file). Although the long-term prognosis of cGvHD appears to be slightly better in children 
when compared to adults, they suffer from similar complications and also have poor long term 
outcomes (Dhir 2014). In addition, the standard treatment of SR-GvHD does not differ between 
adolescents and adults (Dignan 2012, Jacobsohn 2010). As such, SR-cGvHD represents a 
significant unmet medical need not only for adult patients but also for children. Adolescents 
≥12 years will be enrolled in the proposed pivotal study since the ruxolitinib tablet formulation 
used in the study is acceptable for administration in this age group. Pediatric patients <12 years 
of age will be considered for future studies using a more suitable liquid formulation and 
following discussion and agreement on the pediatric investigational plan with the 
Paediatric Committee (PDCO).
Multiple measures will be used in this study to reduce bias. For patients randomized to 
BAT, change or addition of new immunosuppressive therapy will only be allowed for 
subjects meeting progression, mixed response, or no response criteria, to prevent subjective 
addition or change of new therapy (see objective response definitions in Section 3). At the study 
visit where disease progression or intolerable toxicity is assessed the patient is allowed to 
change or add a new immunosuppressive therapy. However, if mixed response or no response 
is assessed, change or addition of new therapy is allowed. This response must be confirmed 
prior to addition or change of therapy. This confirmation cannot occur prior to 1 week, and 
should not be done later than 4 weeks after the initial assessment.
The primary and key secondary endpoints of the trial will be based on objective measures 
delineated by standard NIH consensus criteria (Lee 2015). In order to minimize the potential 
for differential corticosteroid tapering of BAT and ruxolitinib, equivalent specific guidance for 
dose increases of systemic corticosteroids to manage GvHD flares (see Section 6.1.5.2) as well 
as corticosteroid dose-tapering per standard guidelines is provided (see Section 6.1.5.1).
A 28-day Screening period is planned to allow sufficient time to obtain results of required tests
and ensure that all eligibility criteria are met. It is important to highlight that the primary 
analysis is not performed using best response, but the response assessment after 6 cycles of 
treatment (a cycle consists of 28 days) as compared to Baseline. The 6 cycle timeframe was 
selected as being clinically meaningful for cGvHD patients, and avoids capturing transient 
responses.


Novartis
Confidential
Page 35 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Cross over to ruxolitinib is allowed in patients randomized to BAT who do not achieve a CR or 
PR after 6 cycles of treatment, as well as in those who lose their response (i.e. have disease 
recurrence off treatment) thereafter or those patients who become intolerant to BAT following 
Cycle 7 Day 1. Allowing cross over at or after the start of Cycle 7 will have no impact on the 
primary endpoint as it is only allowed after assessments for the primary endpoint have been 
completed. BAT patients who achieve a CR or PR on Cycle 7 Day 1 are not allowed to cross 
over to ruxolitinib until disease progression, mixed response, or occurrence of a toxicity to BAT, 
which will allow for a sub-group of patients treated continuously with BAT for a longer duration, 
increasing the likelihood of being able to generate comparative long-term outcome data.
Following Cycle 7 Day 1, a second visit is not required to confirm disease progression or mixed 
response prior to allowing cross over.
Fixing specific and clear rules based on NIH consensus criteria for response (Lee 2015-see
Section 3) to allow change of treatment also minimizes the potential influence on failure-free 
survival (FFS) events after Cycle 7 Day 1, and would allow therefore a reliable comparison of 
FFS between treatment arms. The estimation of FFS probabilities at Cycle 7 Day 1 is not 
impacted by cross over.
Cross over for patients failing BAT is deemed ethically necessary as currently available data 
suggest that these patients could benefit from treatment with ruxolitinib. In addition, not 
allowing cross over is likely to negatively impact patient acceptance to participate in the trial 
and they may seek ruxolitinib treatment through other means.
The primary endpoint of the proposed Phase III study is the proportion of patients in each arm 
demonstrating overall response rate (ORR) consisting of either complete (CR) or partial (PR) 
response at Cycle 7 Day 1 as defined by the 2014 NIH response criteria (Lee 2015). The primary 
endpoint of ORR is being proposed in consultation with cGvHD medical experts based on the 
fact that patient response is a clinically relevant measure of treatment efficacy. Response rates 
have been correlated to long-term outcomes in 2 independent trials. The first trial utilized the 
2005 NIH consensus response criteria and enrolled 40 patients with cGvHD. In that trial, 
patients were eligible if they were diagnosed with moderate to severe cGvHD and were 
refractory to at least 2 immunosuppressive lines of therapy. Clinician response assessment was 
performed at baseline and 6 months. ORR at 6 months was strongly correlated with overall 
survival at 36 months (Olivieri 2013). The second trial utilized the revised 2014 NIH response 
criteria and enrolled 575 patients with cGvHD. Clinician assessment was performed at Baseline 
and 6 months. This trial also demonstrated that at 6 months, clinician-reported response 
predicted OS (Palmer 2016). The response assessments for the primary endpoint will be 
performed by the treating clinician at baseline, weekly for 4 weeks, and then every 4 weeks per 
NIH consensus criteria (Lee 2015).
One of the key secondary endpoints is FFS defined as a composite time to event endpoint 
incorporating the following FFS events: i) relapse or recurrence of underlying disease or death 
due to underlying disease, ii) non-relapse mortality, or iii) addition or initiation of another 
systemic therapy for cGvHD. FFS has been shown to correlate with subsequent non-relapse 
mortality and survival (Palmer 2015) and will enable the assessment of the durability of the 
primary response.


Novartis
Confidential
Page 36 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
cGvHD has a negative impact on QoL, although this is not equally detectable in all patients. 
According to the NIH criteria for grading cGvHD severity, patients with mild cGvHD have 
higher QoL than those with moderate cGvHD, and both of these categories have higher QoL 
than patients with severe cGvHD (Fiuza-Luces 2016). Given the significant impact of 
symptoms on patients with cGvHD, the collection of patient reported outcomes with the Lee 
symptom scale has been recommended by the 2005 and 2014 NIH consensus conference
(Merkel 2016).
The Response Criteria Working Group within the NIH Consensus Development Project on 
Criteria for Clinical Trials in cGvHD recommends the Lee Symptom Scale as GVHD-specific 
core measure and the FACT-BMT as cGvHD nonspecific ancillary measure (in adults) for 
quality-of-life assessments
(Pavletic 2006). In a multicenter observational study 
(#NCT00637689) enrolling 575 patients diagnosed with cGvHD per 2005 NIH Consensus 
Criteria from August 2007 to January 2013, improvements in the Lee skin Symptom Score at 6 
months predicted longer subsequent OS and NRM, and the FACT-BMT trial outcome (total 
score) at 6 months predicted longer subsequent OS at 36 months (Palmer 2016). Therefore, a 
second key secondary objective will be to assess the change in a modified Lee symptom score.
Analysis of primary and key secondary endpoints will occur when all subjects will have 
completed the Cycle 7 Day 1 visit or discontinued study treatment. A final study report will be 
written when all patients will have completed 3 years (39 cycles) on study, discontinued from 
the study, or died.
Collection of PK data will be implemented in this study in order to assess exposure data and 
determine how it compares with data from previous studies, and explore its relationship with 
efficacy and safety parameters.
The study design was reviewed and agreed with the FDA, CHMP, and the PMDA.




Novartis
Confidential
Page 38 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
2.3
Rationale for dose and regimen selection
Ruxolitinib will be administered to patients randomized to the study drug treatment arm at a 
starting dose of 10 mg orally BID, without regard to food. The ruxolitinib starting dose of 10 
mg orally BID is based on the published activity and safety data generated in a retrospective 
study in patients with SR-cGvHD (Zeiser 2015 - see Section 1.2.1.2.2 for further details).
The 10 mg BID dose will be the same in adolescent as in adult patients. This is supported by 
safety and PK data of ruxolitinib from a Phase I study in pediatric patients with various 
malignancies (Loh 2015). The mean values (± SD) 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. The population PK model in adult MF patients 
reported the following parameter estimates: CL/F for males was 22.1 L/h and 17.7 L/h for 
females, with an interpatient variability (IIV) of 39.1%; Vc/F was found to be 58.6 L, with an 
IIV of 28.0%. The PK of ruxolitinib was generally similar in pediatric cancer patients (n=42; 
median age 14 years, range 2-21) compared to that in adult patients with MF. This pediatric 
study tested doses of 15 mg/m2 to 50 mg/m2 BID (equivalent to 10 mg BID – 100 mg BID). 
The safety and tolerability across doses was favorable. Additionally, allometric scaling (taking 
into consideration body weight) for adolescents based on adult exposure data from 
myelofibrosis trials indicate that the dose for adolescents required to obtain similar exposure in 
terms of AUC and Cmax is similar to that of adults (20 mg BID in adults would constitute 16-
18 mg BID in adolescents). Similarly, since ruxolitinib shows dose proportionality, a 10 mg 
BID dose in adolescents is expected to provide a similar exposure as 10 mg BID dosing in 
adults.
Patients may have dose reductions or modifications of ruxolitinib during the course of treatment 
based on adverse events, clinical evaluation, and laboratory assessments. No dose increases 
above 10 mg BID will be allowed in the study due to the very limited clinical experience with 
such doses in patients with GvHD. See Section 6.3 for ruxolitinib dose modifications.
2.4
Rationale for choice of combination drugs
Not applicable.
2.5
Rationale for choice of comparators drugs
This will be an open-label study of ruxolitinib versus Best Available Therapy (BAT) as selected 
by the Investigator. BAT is chosen as comparator as there is currently no broadly approved, or 
uniformly used standard second line therapy in SR-cGvHD. A BAT control arm is required to 
ensure an adequately controlled duration to assess the primary endpoint of the study as well as 
ruxolitinib comparative safety. The BAT in this study will be selected by the Investigator prior 
to subject randomization among the following standard systemic treatments: extracorporeal 
photopheresis (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR 
inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, or ibrutinib. 
Investigational agents only available via clinical trials including JAK inhibitors or combination 
of different treatment are not permitted on the BAT arm. No other BAT will be allowed.


Novartis
Confidential
Page 39 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Following randomization, change or addition of a new systemic therapy in the BAT arm due to 
documented lack of response or toxicity will be allowed in the first 6 cycles, but will be 
considered a treatment failure. At Cycle 7 Day 1 or later after randomization, patients 
randomized to BAT that do not achieve or maintain a CR or PR, or who develop toxicity to 
BAT are allowed to cross over from BAT to ruxolitinib.
2.6
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 6.3 and Section 6.4. The risk to 
patients in this trial may be minimized by compliance with the eligibility criteria and study 
procedures, as well as, close clinical monitoring, and, protocol-defined ruxolitinib dose 
modifications guidelines and treatment discontinuation criteria. There may be unforeseen risks 
with ruxolitinib which could be serious. Refer to the most recent [Investigator Brochure].
As outlined previously, the potential benefit of ruxolitinib for alloSCT patients with SR-cGvHD 
is based on published pre-clinical and clinical data.
Important risks of treatment with ruxolitinib based on the MPN clinical development and post-
authorization experience to date include: i) myelosuppression (thrombocytopenia, anemia and 
leukopenia), ii) infections (including opportunistic infections), iii) tuberculosis, iv) use in 
patients with hepatic impairment, v) use in patients with moderate or severe renal failure or end 
stage renal failure requiring hemodialysis, vi) elevated transaminases, vii.) bleeding, viii) 
progressive multifocal leukoencephalopathy, ix.) Increased systolic blood pressure, x.) non-
melanoma skin cancer, xi) hepatitis B reactivation, xii) developmental toxicity, xiii.) 
Overexposure with concomitant strong CYP3A4 inhibitors or fluconazole, xiv) use with 
CYP3A4 inducers such as rifampicin, and xv) pharmacodynamic interaction between 
ruxolitinib and hematopoietic growth factors or combination with cytoreductive therapies.
These identified and potential risks will be monitored closely and mitigated throughout this 
study in patients randomized to receive ruxolitinib vs. BAT as these risks are also common in 
the alloSCT setting particularly patients with SR-cGvHD.
No substantial additional risk for subject safety due to the SARS-CoV-2 virus and the 
COVID-19 pandemic has been identified at this time and therefore the benefit risk remains 
unchanged. In case of active COVID-19 infection, a careful benefit risk evaluation should be 
performed by the investigator to determine whether a subject can remain on study treatment.
Myelosuppression
Myelosuppression is a common occurrence in alloSCT patients, is commonly experienced with 
the majority of BAT used to treat cGvHD, and is also a commonly experienced effect from 
cGvHD. 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 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.
Administration of hematopoietic growth factors will be allowed per Investigator judgement.


Novartis
Confidential
Page 40 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Bleeding
Hemostatic disturbances are common in patients undergoing alloSCT and have a significant 
impact on morbidity and mortality. Ruxolitinib dose adjustment or dose holding will be based 
on platelet count (see Table 6-2), and platelet transfusions may be given as clinically indicated.
Use in patients with hepatic impairment
As the liver is a target organ in cGvHD pathophysiology, elevated liver function tests including 
bilirubin and AST/ALT cannot be used as a parameter to exclude SR-cGvHD patients or 
determine starting dose. Diagnostic evaluation and management of hepatic impairment in 
SR-cGvHD patients treated on this study will follow institutional guidelines. Guidelines for the 
required diagnostic tests for ruxolitinib induced liver injury are outlined in Section 6.3.1.3.
Use in patients with renal impairment
Renal impairment is a common occurrence in patients with SR-cGvHD due to episodes of mild 
dehydration attributable to GI involvement in the outpatient setting causing decreased oral 
intake as well as concurrent administration of CNI. AlloSCT patients with severely impaired 
renal function are excluded from enrollment. Diagnostic evaluation and management of renal 
impairment in SR-cGvHD patients will follow institutional guidelines.
Infections
Serious bacterial, mycobacterial, fungal, viral and other infections have occurred in MPN 
patients treated with ruxolitinib. Actions to minimize the risk of serious infections in SR-
cGvHD patients will follow standard alloSCT guidelines including close monitoring of clinical 
signs and symptoms of infection, their prompt recognition and treatment. Patients with positive 
serologies pre-transplant for CMV, EBV, HHV-6, HBV, HCV require peripheral blood viral 
load (viral copies/ml) to rule out presence of active viral infection as eligibility requirement. As 
CMV reactivation with ruxolitinib therapy has been observed in SR-aGvHD patients 
(Zeiser 2015), this will be monitored closely in this trial.
Tuberculosis
SR-cGvHD patients in both the ruxolitinib and BAT arms 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.
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-6, HSV, EBV, CMV, 
HBV, HCV and VZV, have been reported with a median time to symptom onset post-HCT of 
between 3 and 8 months, respectively. The incidence of PML in the HCT population is 
significantly less than in patients with HIV, with comparative incidence rates of 35.4 vs. 130 
per one-hundred thousand person years, respectively (Kaufman 2013). Actions to minimize the 


Novartis
Confidential
Page 41 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
risk of PML in SR-cGvHD patients will follow standard alloSCT guidelines including close 
monitoring of any clinical signs of progressive focal neurological symptoms, with prompt 
diagnostic work up and treatment.
Long-Term Follow Up: Non-melanoma skin cancers
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell 
carcinoma have been reported in MPN patients treated with ruxolitinib. Skin cancer incidence 
is increased in alloSCT patients vs. the general population, including increased risk of basal cell 
carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma (MM) occurring 
late, generally 10-15 years after transplant (Omland 2016). Any occurrence of skin cancers will 
be monitored throughout this study.
Safety in pediatric patients
In a Phase I study, ruxolitinib with BID continuous oral dosing in children aged 2.4–21.4 
(median 14.4) years with refractory/recurrent solid tumors (ST) and hematologic malignancies 
was well tolerated and showed similar pharmacokinetics to those in adults. No maximum 
tolerated dose was reached and the recommended dose for continuous BID oral administration 
was 50 mg/m2/dose (Loh 2015).
2.7
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 participant safety and trial integrity 
are listed in relevant sections of this protocol. 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.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Efficacy assessments
Global and organ-specific cGvHD clinician assessments are performed at baseline, Cycle 1 Day 
15, Cycle 2 Day 1, and then every 28 days until Cycle 7 Day 1 according to the NIH Consensus 
Criteria (Lee 2015) (see Appendix 3). Following Cycle 7 Day 1, response will be assessed on 
Cycle 9 Day 1 and every 12 weeks thereafter.

Complete response is defined as complete resolution of all signs and symptoms of cGvHD 
in all evaluable organs without additional therapies.

Partial response is defined as an improvement in at least one organ (e.g. improvement of 
1 or more points on a 4 to 7 point scale, or an improvement of 2 or more points on a 10 to 
12 point scale) without progression in other organs or sites, or addition/initiation of new
systemic treatment.

Lack of response is defined as unchanged, mixed response, or progression.


Novartis
Confidential
Page 42 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301

Progression is defined as worsening of at least one organ and no improvement (CR or 
PR) in any other organ

Mixed response is a CR or PR in at least 1 organ accompanied by progression in 
another organ

Unchanged response is defined as stable disease or absence of improvement in any 
organ involved by cGvHD
cGvHD Flare is defined as any increase in symptoms during taper of any immunosuppressive
therapy for cGvHD, after an initial response (CR or PR). A cGvHD flare is not considered a 
treatment failure unless severity requires addition and/or change of another systemic 
immunosuppressive treatment. See Section 6.1.5.2 for details.
cGvHD Recurrence is defined as the return of cGvHD symptoms after tapering off study 
treatment due to response. Following completion of a taper of systemic therapy, if worsening 
of cGvHD symptoms occur, the patient is allowed to resume treatment for cGvHD as per local 
institutional practice. However, this must be documented as a recurrence of cGvHD.


Novartis
Confidential
Page 43 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary endpoint
Refer to Section 10.4
To compare the efficacy of ruxolitinib vs. Investigator’s 
choice Best Available Therapy (BAT) in patients with 
moderate or severe SR-cGvHD assessed by Overall 
Response Rate (ORR) at the Cycle 7 Day 1 visit
Overall response rate (ORR) on Cycle 7 Day 1 after
randomization, defined as the proportion of patients in 
each arm demonstrating a complete response (CR) or 
partial response (PR) without the requirement of 
additional 
systemic 
therapies 
for 
an 
earlier 
progression, 
mixed 
response or 
non-response. 
Scoring of response will be relative to the organ score 
at randomization.
CMH test, stratified by cGvHD severity (moderate vs. 
severe)
Key secondary endpoints
Refer to Section 10.5.1
To compare the rate of failure free survival (FFS)
To compare change in modified Lee Symptom Score
FFS will be used as the first key secondary endpoint 
for all regions except the US (ROW). The modified Lee 
symptom score will be used as the first key secondary 
endpoint for the US
Composite time to event endpoint incorporating the 
following FFS events: i) relapse or recurrence of 
underlying disease or death due to underlying disease, 
ii) non-relapse mortality, or iii) addition or initiation of 
another 
systemic 
therapy 
for 
cGvHD.
Rate of patients with clinically relevant improvement of 
the modified Lee symptoms score at Cycle 7 Day 1
A fixed sequence hierarchical testing strategy will be 
applied for the primary and the two key secondary 
endpoints. For ROW FFS will be tested first followed 
by the modified Lee symptom score. For US, modified
Lee symptom score will be tested first followed by 
FFS.
FFS: Logrank-test, stratified by cGvHD severity 
(moderate vs. severe)
Modified Lee symptom score: CMH test comparing 
rates of responders, stratified by cGvHD severity 
(moderate vs. severe)
Other secondary endpoints
Refer to Section 10.5.2
Best overall response (BOR)
Proportion of patients who achieved OR (CR+PR) at 
any time point (up Cycle 7 day 1 or the start of 
additional systemic therapy for cGvHD) 
To estimate ORR at end of Cycle 3
Proportion of patients who achieved OR (CR+PR) at 
Cycle 4 Day 1.
Duration of Response
Duration of response (DOR) is assessed for 
responders only. DOR is defined as the time from first 
response until cGvHD progression, death, or the date 
of change/addition of systemic therapies for cGvHD. 


Novartis
Confidential
Page 44 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Objective
Endpoint
Analysis
To assess Overall Survival (OS)
Overall survival, defined as the time from the date of 
randomization to the date of death due to any cause. 
To assess Non Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time from 
date of randomization to date of death not preceded by 
underlying disease relapse/recurrence. 
To assess proportion of patients with ≥50% reduction 
in daily corticosteroid dose at Cycle 7 Day1
To assess proportion of patients successfully tapered 
off all corticosteroids at Cycle 7 Day 1
To
assess cumulative incidence of Malignancy 
Relapse/Recurrence (MR)
Malignancy Relapse/Recurrence (MR) is defined as 
the time from date of randomization to hematologic 
malignancy
relapse/recurrence. 
Calculated 
for 
patients with underlying hematologic malignant 
disease.
To evaluate changes in FACT-BMT and EQ-5D
Change in FACT-BMT from baseline to each visit 
where measured.
Change in EQ-5D from baseline to each visit where 
measured.
To assess Pharmacokinetics (PK) of ruxolitinib in SR-
cGvHD patients
Pharmacokinetic parameters of ruxolitinib after a 
single dose and at steady state. Cmax, AUClast, and 
AUCinf. Other PK parameters are CL/F, Vz/F, Tmax 
and T1/2.
To evaluate the safety of ruxolitinib and Best Available 
Therapy
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 medical resource utilization
Resources including duration and frequency of 
hospitalization, emergency room visits, additional 
outpatient 
office 
visits 
to 
general 
practitioner, 
specialist, and urgent care visits.
Frequency of 
concomitant treatments will also be captured.


Novartis
Confidential
Page 45 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301


Novartis
Confidential
Page 46 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
4
Study design
4.1
Description of study design
This randomized, Phase III, open-label, multi-center study will investigate the efficacy and 
safety of ruxolitinib vs. Best Available Therapy (BAT),
added to the subject’s 
immunosuppressive regimen of corticosteroids ± calcineurin inhibitor (CNI) in adults and 
adolescents (≥12 years old) with corticosteroid-refractory chronic Graft vs Host Disease (SR-
cGvHD).
This is an open-label study. Investigators, patients, and Sponsor will have full knowledge of the 
treatment allocation. Approximately 324 patients will be randomized in this study. Each patient 
will be treated and/or followed for a total of 3 years (39 cycles/156 weeks). The study design is
outlined below, with each cycle comprised of 4 weeks (28 days):
4.1.1
Screening Period (Day -28 to Day -1)
Screening activities and assessment of inclusion and exclusion criteria are performed after the 
patient and / or the parents or legal guardian has signed the required Informed Consent Form(s).
Patients will continue to receive their systemic immunosuppressive regimen of corticosteroids 
+/- CNI for SR-cGvHD per standard of care by the Investigator during the Screening and 
Treatment periods.
The Investigator must identify the Investigator’s choice BAT prior to randomization. The 
Investigator’s choice BAT must be entered in the database and IRT at screening. The dose and 
administration schedule of initial BAT may be changed only after initiation of the treatment 
based on the judgment of the Investigator and in accordance with accepted medical practices.
Patients meeting all inclusion and none of the exclusion criteria will be randomized 1:1 to 
receive either ruxolitinib or BAT, and stratified based on cGvHD severity per 2014 NIH 
consensus criteria (Jagasia 2015) at the time of randomization (moderate vs. severe).




Novartis
Confidential
Page 48 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
assessments, and will be monitored for cGvHD recurrence which must be reported in the 
database (See Section 3 for definition of recurrence).
Regardless of the assigned randomized treatment, patients experiencing cGvHD recurrence 
after tapering off study treatment will be treated per Investigator discretion. Patients that were 
originally randomized to the BAT arm experiencing cGvHD recurrence may re-start a single 
agent BAT (±corticosteroids ± CNI), or cross over to the ruxolitinib treatment arm. If a second 
recurrence occurs, the patient must cross over to the ruxolitinib treatment arm, or discontinue 
study treatment and enter the Long-Term Survival Follow-Up. For treatment of a recurrence, 
addition or initiation of a second BAT systemic treatment is not allowed.
Adolescent patients will continue to follow the assessments for “adolescents only” in the Visit 
Evaluation Schedule even if they become 18 years of age and older during the course of the 
study.
4.1.3
Primary Efficacy Period (Cycle 1 through end of Cycle 6)
Cycle 1 Day 1 is defined as the day study treatment begins. This must occur after randomization. 
Typically this is the same day as randomization, but if not logistically possible (i.e., based on 
BAT access) should not be more than 72 hours after randomization. Study visits will occur per 
the following schedule to monitor tolerability and efficacy of the study treatments during the 
Primary Efficacy Period:

Cycle 1: Day 1, 8, 15, 22

Cycle 2 to 6: Day 1 of each cycle
Patients will be treated for a minimum of 6 cycles, until Cycle 7 Day 1, unless they experience 
intolerable toxicity, cGvHD progression, or withdraw from the study (see Section 6 for Study 
Treatment details and permitted/prohibited concomitant therapies).
Addition or initiation of a new systemic therapy in the BAT arm is allowed only after 
documented lack of response (as defined in Section 3), intolerable toxicity, or cGvHD flare and
will be considered a treatment failure for both the primary and key secondary objectives. At the 
study visit in which the patient meets the criteria for disease progression, intolerable toxicity, 
or cGvHD flare treatment failure, addition or initiation of a new systemic BAT treatment is 
allowed. However, if mixed response or no response is assessed, change or addition of a new 
systemic BAT treatment is allowed. This response must be confirmed prior to the addition or 
change of therapy. This confirmation cannot occur prior to 1 week, and should not be done later 
than 4 weeks after the initial assessment (See Figure 4-2). If the confirmation is assessed prior 
to the next scheduled visit at an unscheduled visit, the original visit schedule based on the 
subject’s enrollment date should be resumed.
Primary efficacy assessments will be performed on Cycle 7 Day 1, after completion of 6 cycles 
of treatment.


Novartis
Confidential
Page 49 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
4.1.4
Extension Period (Cycle 7 to Cycle 39)
After the Cycle 7 Day 1 primary efficacy assessment visit, study visits will occur every 3 cycles
(every 12 weeks +/- 14 days) starting with Cycle 9 Day 1 and up to Cycle 39, or EOT, whichever 
occurs first (i.e. C9D1, C12D1, C15D1, etc).
Patients in the Extension Period will either continue treatment with ruxolitinib, the current BAT 
treatment, cross over to the Ruxolitinib treatment arm, or permanently discontinue study 
treatment and enter the Long-Term Survival Follow-Up. Addition or initiation of another 
systemic BAT treatment is not allowed in the Extension Period (See Figure 4-3).
4.1.5
Cross-Over for BAT patients only (from Cross-Over up to Cycle 33)
On Cycle 7 Day 1 and thereafter, patients randomized to BAT may cross over to ruxolitinib 
treatment due to disease progression, mixed response, or unchanged response, due to toxicity 
to BAT, or due to cGvHD flare.
Cross-Over patients will switch to and follow the visit evaluation schedule (starting on Cross-
Over Cycle 1 Day 1) as specified in Table 7-2. Cross-Over patients will be treated and/or 
followed on-study for a total of 39 cycles, inclusive of the initial randomized treatment, Cross-
Over treatment, and long-term survival follow up (i.e. if patients cross over on randomized 
treatment at Cycle 7, they will complete up to cycle 33 in the Cross Over treatment period).
Patients who meet Cross-Over criteria to receive ruxolitinib are allowed to continue their 
systemic immunosuppressive regimen of corticosteroids +/- CNI for SR-cGvHD treatment as 
per standard of care, with cessation required of the BAT treatment before starting treatment 
with ruxolitinib.
Patients undergoing dose tapering should be monitored for cGvHD flare occurrences, which 
must be reported in the database.
4.1.6
Long-Term Survival Follow-Up (EOT to 39 cycles on study)
Patients who permanently discontinue the study treatment prior to completion of 39 cycles on 
study for reasons other than achieving a CR or PR will enter the Long-Term Survival Follow-
Up (LTSFU), and may be treated per Institutional practice. They will be followed 
approximately every 3 months by telephone call for survival and reporting of new cGvHD 
therapies until 39 cycles are completed.
New cGvHD therapies will be entered in the New cGvHD Treatment Since Discontinuation of 
Study Treatment eCRF.
See Section 7.1.5 for permanent treatment discontinuation details.
4.1.7
Safety Follow-Up (Last Dose + 30 days)
A 30-day safety follow-up assessment will be performed after the last dose of ruxolitinib or 
BAT, for patients that permanently discontinue study treatment for reasons other than CR or 
PR.






Novartis
Confidential
Page 52 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
The final analysis will occur at the end of the study. All available data from all patients up to 
this date will be analyzed and summarized in a final CSR.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 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 will be responsible for 
informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The patient population includes male or female patients age ≥12 years or older, who have 
undergone alloSCT, have evidence of myeloid and platelet engraftment (ANC >1,000/mm3
AND platelet count >25,000/mm3 untransfused), and have been diagnosed with moderate or 
severe cGvHD as defined by NIH Consensus Criteria (Jagasia 2015, see Appendix 2), and 
which is determined to be corticosteroid-refractory per NIH Consensus Criteria (Martin 2015).
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are randomized and begin treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria at Screening:
1. Written informed consent, according to local guidelines, signed by the patients and / or by 
the parents or legal guardian prior to any study related screening procedures are performed.
2. Male or female patients ≥12 years old at the time of informed consent
3. Able to swallow tablets
4. 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 non-
myeloablative, myeloablative, and reduced intensity conditioning are eligible
5. Evident myeloid and platelet engraftment:

Absolute neutrophil count (ANC) > 1000/mm3
AND

platelet count > 25,000/ mm3
Note: Use of growth factor supplementation and transfusion support is allowed during the 
trial, however, transfusion to reach a minimum platelet count for inclusion is not 
allowed during screening and at baseline.
6. Patients with clinically diagnosed cGvHD staging of moderate to severe according to NIH 
Consensus Criteria (Jagasia 2015 –see Appendix 2) prior to Cycle 1 Day 1


Novartis
Confidential
Page 53 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301

Moderate cGvHD: At least one organ (not lung) with a score of 2, 3 or more organs 
involved with a score of 1 in each organ, or lung score of 1

Severe cGvHD: at least 1 organ with a score of 3, or lung score of 2 or 3
7. Patients currently receiving systemic or topical corticosteroids for the treatment of cGvHD 
for a duration of < 12 months prior to Cycle 1 Day 1, and have a confirmed diagnosis of 
corticosteroid refractory cGvHD defined per 2014 NIH consensus criteria (Martin 2015)
irrespective of the concomitant use of a calcineurin inhibitor, as follows:

A lack of response or disease progression after administration of minimum prednisone 
1 mg/kg/day for at least 1 week (or equivalent)
OR

Disease persistence without improvement despite continued treatment with prednisone 
at >0.5 mg/kg/day or 1 mg/kg/every other day for at least 4 weeks (or equivalent)
OR

Increase to prednisone dose to >0.25 mg/kg/day after two unsuccessful attempts to taper 
the dose (or equivalent)
8. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 OR
Karnofsky Performance Score (KPS) OR Lansky Performance Score (LPS) of 60-100%.
9. Patient must accept to be treated with only one of the following BAT options on Cycle 1 
Day 1 (Additions and changes are allowed during the course of the study, but only with 
BAT from the following BAT options):

extracorporeal photopheresis (ECP)

low-dose methotrexate (MTX)

mycophenolate mofetil (MMF)

mTOR inhibitors (everolimus or sirolimus)

infliximab

rituximab

pentostatin

imatinib

ibrutinib
Note: Concomitant use of CNI and steroids is allowed. If any medication included in the BAT 
list is used as prophylaxis for underlying malignancy relapse, it must be discontinued prior to 
randomization and entered into the eCRF. For patients randomized to either the ruxolitinib or 
BAT treatment arm, rituximab can be administered post-randomization for the treatment of 
EBV. This EBV infection must be captured either into the Medical History or Adverse Event 
eCRF. If any medication included in the BAT list is used as prophylaxis for cGvHD before 
entering this study, it is allowed to be continued post-randomization, however it must be 
captured on the Concomitant Medication eCRF.


Novartis
Confidential
Page 54 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria at Screening:
1. Patients who have received two or more systemic treatments (BAT) for cGvHD in addition 
to corticosteroids ± CNI for cGvHD
2. Patients that transition from active aGvHD to cGvHD without tapering off corticosteroids 
± CNI and any systemic treatment

Patients receiving up to 30 mg by mouth once a day of hydrocortisone (i.e., physiologic 
replacement dose) of corticosteroids are allowed.
3. Patients who were treated with prior JAK inhibitors for aGvHD; except when the patient 
achieved complete or partial response and has been off JAK inhibitor treatment for at least 
8 weeks prior to Cycle 1 Day 1
4. Failed prior alloSCT within the past 6 months from Cycle 1 Day 1
5. Patients with relapsed primary malignancy, or who have been treated for relapse after the 
alloSCT was performed
6. SR-cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered 
for pre-emptive treatment of malignancy recurrence. Patients who have received a 
scheduled DLI as part of their transplant procedure and not for management of malignancy 
relapse are eligible
7. History of progressive multifocal leuko-encephalopathy (PML)
8. Active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered 
controlled if appropriate therapy has been instituted and, at the time of screening, no signs 
of infection 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
9. Known human immunodeficiency virus (HIV) infection
10. Active tuberculosis infection that developed after alloSCT
11. Evidence of active viral disease including CMV, EBV, HHV-6, HBV, HCV, or BK virus.

Patients with pre-transplant positive serology results must have negative viral load 
results for HBV and HCV within 28 days prior to randomization. Patients with 
unknown viral testing results prior to transplant must have viral load results confirming 
no evidence of active viral disease within 28 days prior to randomization.
12. Patients on mechanical ventilation or have a resting O2 saturation <90% by pulse oximetry
13. History or current diagnosis of cardiac disease indicating significant risk of safety for 
patients participating in the study such as uncontrolled or significant cardiac disease, 
including any of the following:

recent myocardial infarction (within last 6 months from randomization)

New York Heart Association Class III or IV congestive heart failure

unstable angina (within last 6 months prior to randomization)

clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker)


Novartis
Confidential
Page 55 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301

uncontrolled hypertension
14. Any concurrent severe and/or uncontrolled medical conditions which, in the opinion of the 
investigator, could compromise participation in the study, pose a significant risk to the 
subject, or interfere with study results
15. Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL (> 
176.8μmol/L), renal dialysis requirement, or have estimated creatinine clearance <30
ml/min measured or calculated by Cockroft Gault equation (confirmed within 48 hours prior 
to study treatment start).
16. Cholestatic disorders, or unresolved sinusoidal obstructive syndrome/veno-occlusive 
disease of the liver (defined as persistent bilirubin abnormalities not attributable to cGvHD 
and ongoing organ dysfunction)
OR

Total bilirubin >2mg/dL attributable to GvHD. 
17. Impairment of gastrointestinal (GI) function (unrelated to GvHD) or GI disease (unrelated 
to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative 
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection)
OR

Diarrhea attributable to GvHD.
18. Any corticosteroid therapy for indications other than cGvHD at doses >1 mg/kg/day 
methylprednisolone or equivalent within 7 days of Cycle 1 Day 1.
19. Patient is receiving treatment with medications that interfere with coagulation or platelet 
function including, but not limited to, heparin or warfarin sodium (Coumadin®). Use of low 
molecular weight heparin is allowed. In patients in whom aspirin is indicated for secondary 
cardiovascular disease prevention, aspirin daily dose must not exceed 150 mg/day.
20. Patient is receiving fluconazole at daily doses higher than 200 mg.
21. Patient is receiving and does not agree to stop herbal preparations/medications. These herbal 
medications include, but are not limited to, St. John’s Wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrsterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Patients must stop using herbal medications at least 7 days prior to first dose of study 
treatment.
22. Known allergies, hypersensitivity, or intolerance to ruxolitinib or any of its excipients
23. Investigational treatment within 30 days prior to randomization, or within 5 half-lives of the 
investigational product, whichever is longer
24. Pregnant or nursing (lactating) women
25. Female patients randomized to ruxolitinib, ≥ 12 and < 18 years of age and of childbearing 
potential (e.g. are menstruating) who do not agree to abstinence or, if sexually active, do 
not agree to the use of highly effective contraception as defined below, throughout the study 
and for up to 90 days after stopping treatment.


Novartis
Confidential
Page 56 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
OR

Women of child-bearing potential randomized to ruxolitinib, defined as all women 
physiologically capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing and for 90 days after stopping study medication.

Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement 
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception.

In case of use of oral contraception women should have been stable on the same pill for 
a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential.
OR

Female patients randomized to BAT who do not agree to follow locally approved BAT 
label or guidance for contraception requirements.
26. Male patients randomized to BAT who do not agree to follow locally approved BAT label 
or guidance for contraception requirements.
27. Subjects who are not able to understand and to comply with study instructions and 
requirements


Novartis
Confidential
Page 57 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
6
Treatment 
6.1
Study treatment
The study treatment will consist of ruxolitinib or Investigator choice BAT administered in an 
open label manner following randomization of the patient on study Day 1. Patients will be 
randomized 1:1 to receive the assigned study treatment (either ruxolitinib or BAT) and are 
stratified based on cGvHD severity (moderate or severe). Further study treatment duration and 
management are described for ruxolitinib and BAT, respectively, in Section 6.1.1.1,
Section 6.1.1.2, and Section 6.1.5.
In addition to the assigned ruxolitinib or BAT study treatment, patients may receive standard 
alloSCT supportive care including anti-infective medications and transfusion support. Standard 
cGvHD prophylaxis and treatment medications initiated before randomization including 
systemic corticosteroids, calcineurin inhibitors (CNI) (cyclosporine or tacrolimus), and 
topical/inhaled corticosteroid therapy may be continued, per institutional guidelines.
Concomitant use of CNI and steroids is allowed. If any medication included in the BAT list is 
used as prophylaxis for underlying malignancy relapse, it must be discontinued prior to 
randomization and entered into the eCRF. For patients randomized to either the ruxolitinib or 
BAT treatment arm, rituximab can be administered post-randomization for the treatment of 
EBV. This EBV infection must be captured either into the Medical History or Adverse Event 
eCRF. If any medication included in the BAT list is used as prophylaxis for cGvHD, it is 
allowed to be continued post-randomization, however it must be captured on the Concomitant 
Medication eCRF.
Permitted concomitant therapies are described in Section 6.4.1.
6.1.1
Dosing regimen
The Investigator will instruct the subject to take the study treatment as per protocol.
All dosages prescribed and dispensed to the subject and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Ruxolitinib 
(INC424)
5 mg tablet for oral use
10 mg
BID
BAT
Will vary depending upon Investigator’s choice identified prior to randomization. Dose and 
frequency will depend on label (where approved) and institutional guidelines for various 
BAT
6.1.1.1
Ruxolitinib
Ruxolitinib will be administered to all patients randomized to the ruxolitinib arm, orally twice 
per day at a dose of 10 mg BID, given as two 5-mg tablets. Ruxolitinib should be taken orally, 
at the same time each day, approximately 12 hours apart (morning and night) without regards 
to food. Tablets should be swallowed whole, and not crushed or chewed. Ruxolitinib will be 


Novartis
Confidential
Page 58 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
self-administered by the subject in an outpatient setting, and each investigator should instruct 
the patient to take the study drug as per protocol.
Patients should be instructed not to make up missed doses. A missed dose is defined as a case 
when a dose is not taken within 8 hours after the approximate time of the usually daily dosing. 
The missed dose should be omitted and the patient should continue treatment with the next 
scheduled dose. If vomiting occurs during the course of treatment, patients should not take the 
study drug again before the next scheduled dose.
On PK sampling days, ruxolitinib will be administered during the clinical visit after the pre-
dose PK samples and prior to the post-dose PK samples, when instructed by study personnel. 
Patients should be instructed not to take the morning dose of ruxolitinib study treatment on PK 
sampling days (see Table 7-7 & Table 7-8).
All dosages prescribed and dispensed to the subject and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
Tapering of ruxolitinib is not allowed prior to Cycle 7 Day 1 of ruxolitinib treatment, including 
patients who cross over from BAT. Tapering of ruxolitinib and of immunosuppression 
(corticosteroids and CNI) is described in Section 6.1.5.1.
6.1.1.2
Best Available Therapy
Patients will receive Best Available Therapy based on the Investigator’s opinion, taking into 
account the manufacturer’s instructions, labeling, subject’s medical condition, and institutional 
guidelines for any dose adjustment. The BAT in this study will be identified by the Investigator 
prior to subject randomization among the following treatments currently used in this setting:

extracorporeal photopheresis (ECP)

low-dose methotrexate (MTX)

mycophenolate mofetil (MMF)

mTOR inhibitors (everolimus or sirolimus)

infliximab

rituximab

pentostatin

imatinib

ibrutinib
No other types or combinations of BATs are permitted in this study.
The initial BAT determined by the investigator must be entered in the database and IRT at 
screening. The dose and administration schedule of initial BAT may be changed only after 
initiation of the treatment based on the judgment of the Investigator and in accordance with 
accepted medical practices, unless the BAT selected becomes unavailable or unobtainable for 
the patient.
6.1.2
Ancillary treatments
Not applicable


Novartis
Confidential
Page 59 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
6.1.3
Rescue medication
Not applicable
6.1.4
Guidelines for continuation of treatment
The patient may continue study treatment until one of the discontinuation criteria is met. See
Section 7.1.5 for details on discontinuation of study treatment. Dose modifications and follow-
up guidelines for continuation of treatment are described in Section 6.3.
6.1.5
Treatment duration
The treatment period will begin for each patient on Cycle 1 Day 1. Patients will be randomized
to an assigned study treatment arm (ruxolitinib or BAT) and continue study treatment and/or
assessments until discontinuation criteria are met (see Section 7.1.5 for Discontinuation of 
Study Treatment criteria). Patients permanently discontinued from study treatment (ruxolitinib 
or BAT), except for patients who are tapered off study treatment due to response, will enter the 
Long-Term Survival Follow-Up, and may be treated per Institutional practice.
An individual patient will be treated and/or followed on study for 39 cycles (156 weeks/3 years), 
inclusive of randomized treatment, Cross-Over treatment (BAT patients only), and long-term 
survival follow up.
During the treatment period, the patients’ treatment will be managed according to their response 
as follows:

Patients that achieved CR or PR

Ruxolitinib Arm: On Cycle 7 Day 1, patients randomized to ruxolitinib that achieved a 
CR or PR, may continue ruxolitinib and will follow the Visit Evaluation Schedule per
Table 7-1. A taper of ruxolitinib is allowed only on or after Cycle 7 Day 1.

BAT Arm: Patients responding to BAT with a CR or PR will continue on the current 
BAT treatment and assessments per Table 7-1. On or after Cycle 7 Day 1, if the patient 
develops toxicity to BAT treatment, has worsening of cGvHD symptoms, or 
experiences cGvHD flare, the patient may cross over to the ruxolitinib treatment arm 
and follow the Visit Evaluation Schedule per Table 7-2 for Cross-Over treatment, or 
discontinue study treatment.

Both treatment arms: A taper of CNI is allowed after Cycle 7 Day 1. A taper of 
corticosteroids is allowed at any point following documented CR or PR. See 
Section 6.1.5.1 for details.

Patients without CR or PR

Ruxolitinib Arm: On Cycle 7 Day 1, patients randomized to ruxolitinib and still 
receiving benefit from ruxolitinib per investigator decision may continue on study
treatment. However, if the patient is not receiving benefit from ruxolitinib therapy per 
investigator decision, the patient must discontinue study treatment and be treated per 
institutional practice. These patients will enter the Long-Term Survival Follow-Up until 
the completion of 39 cycles.

BAT Arm: Prior to Cycle 7 Day 1, addition or initiation of a new systemic therapy in 
the BAT arm is allowed only after documented lack of response (as defined in 


Novartis
Confidential
Page 60 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Section 3), intolerable toxicity, or cGvHD flare but will be considered a treatment 
failure for both the primary and key secondary objectives. At the study visit in which 
the patient meets the criteria for disease progression, intolerable toxicity, or cGvHD 
flare, addition or initiation of a new systemic treatment is allowed. However, if mixed 
response or no response is assessed, addition or initiation of a new systemic treatment 
is allowed. This response must be confirmed prior to addition or change of therapy. 
This confirmation cannot occur prior to 1 week, and should not be done later than 4 
weeks after the initial assessment.

On or after Cycle 7 Day 1, patients who are randomized to BAT and not achieving 
partial response or better may cross over to the ruxolitinib treatment arm (see 
Table 7-2 for Cross-Over Visit Evaluation Schedule) and addition or initiation of new 
systemic treatment is not allowed. Corticosteroids and CNI for cGvHD treatment are
allowed to be continued.

Both treatment arms: A taper of CNI is allowed per institutional practice. A taper of 
corticosteroids is allowed at any point following documented CR or PR. See 
Section 6.1.5.1 for details.
Patients who taper off study treatment and all immunosuppressive therapy due to achieving a 
CR or PR will continue to follow the currently assigned Visit Evaluation Schedule (Table 7-1
Randomized Treatment, or Table 7-2 Cross-Over Treatment), including all safety and efficacy 
assessments, and will be monitored for cGvHD recurrence which must be reported in the 
database (See Section 3 for definition of recurrence). Regardless of the assigned randomized 
treatment, patients experiencing cGvHD recurrence after tapering off study treatment will be 
treated per Investigator discretion, which may include crossing over to the ruxolitinib treatment 
arm, and will follow the assigned Visit Evaluation Schedule (Table 7-1 for Randomized 
Treatment VES, or Table 7-2 for Cross-Over Treatment VES). Patients that were originally 
randomized to the BAT arm experiencing cGvHD recurrence may re-start a single agent BAT 
(±corticosteroids ± CNI). If a second recurrence occurs, the patient must cross over to the 
ruxolitinib treatment arm, or discontinue study treatment and enter the Long-Term Survival 
Follow-Up. For treatment of a recurrence: addition or initiation of second BAT systemic 
treatment is not allowed, and a more frequent schedule of safety assessments is recommended 
(i.e. every 2 weeks).
Patients who permanently discontinue the study treatment for reasons other than achieving a 
CR or PR prior to completion of 39 cycles on study will enter the Long-Term Survival Follow-
Up, and may be treated per Institutional practice. They will be followed approximately every 3 
months by telephone call for survival and reporting of new cGvHD therapies until 39 cycles on 
study are completed.
See Section 4.1 for additional details on study design.
6.1.5.1
Tapering guidelines
Tapering of corticosteroids, CNI, and ruxolitinib will follow 2 steps: first taper systemic 
corticosteroids following documented CR or PR, and follow with taper of CNI/ruxolitinib.


Novartis
Confidential
Page 61 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
The taper of corticosteroids, as outlined in Figure 6-1, should be attempted at the time of 
documented CR or PR. However, the taper of ruxolitinib and CNI should not be attempted until 
the patient is off corticosteroids AND the patient has completed the assessments for Cycle 7 
Day 1. Ruxolitinib may not be tapered prior to Cycle 7 Day 1 for patients initially randomized 
to the ruxolitinib arm.
During the Treatment Period in both the ruxolitinib and BAT arms, immunosuppression taper 
guidelines are:

Corticosteroids: Every effort should be made to use the minimum dose of corticosteroid 
that is sufficient to control cGvHD manifestations. It is recommended that a taper of 
corticosteroids should be attempted approximately 2 weeks after achieving a CR. Guidelines 
are included in Figure 6-1. If a flare should occur during the taper, treatment should continue 
for at least 3 months prior to attempting to resume the taper.
Figure 6-1
Corticosteroid taper guidelines (Flowers 2015)
Week (time from achieving a CR)
Dose, mg/kg body weight
0
Current dose of corticosteroid Qday (example 1mg)
2
Current dose of corticosteroid (1 mg)/ decrease 
alternate day dose by 50%* (0.5 mg)
4
Current dose of corticosteroid (1 mg)/decrease 
alternate day dose by 50%* (0.25 mg)
6
Current dose of corticosteroid every other day (QOD):
1 mg every other day
8
Decrease current dose of corticosteroid by 10% every 
2 weeks until off
*Alternate-day administration

CNI (cyclosporine or tacrolimus): Once off systemic corticosteroids, and documented CR 
or PR, starting at Cycle 7 Day 1 a 25% dose reduction per month is allowed, or to be tapered 
per institutional practice.

Ruxolitinib: Once off systemic corticosteroids, and documented CR or PR, starting at Cycle 
7 Day 1 a 50% dose reduction every 2 months (56 days) can be initiated. Initial dose 
reduction is to 5 mg orally BID. If sustained cGvHD response is observed (i.e. no worsening 
of cGvHD signs and symptoms), patient is further tapered by a second 50% dosage 
reduction to 5 mg orally QD for an additional 2 months (56 days), prior to cessation.
6.1.5.2
cGvHD flare
If a cGvHD flare occurs during the taper of any immunosuppressive medications, the dose of 
corticosteroids may be re-escalated at the Investigator's discretion and will not be considered 
treatment failure. If cGvHD flare requires addition or initiation of a new systemic therapy due 
to inability to taper corticosteroids below methylprednisolone 1 mg/kg/day (or equivalent <1.25 
mg/kg/day of prednisone) for a minimum 7 days, OR due to re-escalation of corticosteroids to 
methylprednisolone >2 mg/kg/day (or equivalent >2.5 mg/kg/day of prednisone), the subject 
will be considered to have experienced treatment failure. For BAT patients, if cGvHD flare 
requires the addition/initiation of new systemic therapy before C7D1 they may receive this as 
study treatment in the treatment period. After Cycle 7 Day 1, BAT patients may cross over to 
ruxolitinib or discontinue the treatment period and enter the Long-Term Survival Follow-up.


Novartis
Confidential
Page 62 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
If cGvHD flare occurs during ruxolitinib taper after Cycle 7 Day 1, patients may have their 
ruxolitinib dose increased to the prior dose level (maximum 10 mg BID), 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 subject will be considered to have experienced cGvHD flare-failure, and further 
treatment with ruxolitinib is allowed per Investigator’s judgement.
For any subject who develops severe worsening cytopenias necessitating abrupt interruption of 
ruxolitinib, flare of cGvHD may occur. To avoid significant cGvHD flare during abrupt 
ruxolitinib interruption, the subject’s corticosteroid dose should be maintained or increased to > 
0.4 mg/kg/day methylprednisolone (or equivalent prednisone to > 0.5 mg/kg/day) for a 
minimum 7 days after abrupt cessation of ruxolitinib. See Section 6.3.1.1 for more details.
6.2
Dose escalation guidelines
Not applicable
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment.
These dose modifications are summarized in Table 6-2. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-2 or listed in Section 7.1.5.
The ruxolitinib dose will not exceed 10 mg orally BID and will not be less than 5 mg QD. The 
dose for Best Available Therapy, CNI, and/or corticosteroids can be modified as per 
Investigator discretion, institutional guidelines, or as per product label.
A standardized dosing paradigm in Table 6-3 and Table 6-4 will be used to determine dose 
adjustments for safety and efficacy so that each subject is titrated to their most appropriate dose. 
These dose changes must be recorded on the Dosage Administration Record eCRF.
A more frequent schedule of safety assessments is recommended (i.e. every 2 weeks) after 
restarting study treatment due to a dose hold.
If a patient requires a dose interruption of > 21 days from ruxolitinib or BAT, then the patient 
must be permanently discontinued from the study treatment, and will be entered into the Long-
Term Survival Follow-Up.
6.3.1.1
Dose adjustments for ruxolitinib hematologic safety
Dose reductions or interruptions for worsening cytopenias attributed to ruxolitinib are permitted 
in order to allow the subject to continue on the study treatment. Doses adjustments for different 
ranges of cytopenias are described in Table 6-2. The objective of the dose adjustment rules is 
to optimize treatment response for each individual subject while avoiding significant cytopenias.
Dose adjustment steps for ruxolitinib are listed in Table 6-3 and Table 6-4.


Novartis
Confidential
Page 63 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
For any subject who develops severe worsening cytopenias necessitating abrupt interruption of 
ruxolitinib, flare of cGvHD is expected to occur. To avoid significant cGvHD flare during 
abrupt ruxolitinib interruption, the subject’s corticosteroid dose should be maintained or 
increased to > 0.4 mg/kg/day methylprednisolone (or equivalent prednisone to > 0.5 mg/kg/day) 
for a minimum 7 days after abrupt cessation of ruxolitinib.
Ruxolitinib dosing may be restarted or increased following recovery of the hematologic 
parameter(s) to acceptable levels. The objective for restarting or escalating after a reduction for 
hematologic safety is to find the highest safe dosing regimen of ruxolitinib for each subject that 
is necessary to obtain a clinical response, with increases in dose not more than in increments of 
5 mg BID and not more often than every 2 weeks. See Table 6-4.
Treatment with ruxolitinib may be delayed up to 21 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 subject unsuitable for further participation in the 
study.
6.3.1.2
Dose adjustments for ruxolitinib non-hematologic safety
Dose reductions or interruptions for non-hematologic toxicity are permitted in order to allow 
the subject to continue on the study treatment. Dose adjustments for different ranges of non-
hematologic toxicity are described in Table 6-2 and Table 6-3. The objective of the dose 
adjustment rules is to optimize treatment response for each individual subject while avoiding 
significant non-hematologic toxicities.
As organ toxicities are relatively common in alloSCT patients, any adverse event must be 
assessed to determine whether it is suspected to be related to ruxolitinib treatment. Ruxolitinib 
dose adjustments are only required for adverse events that are suspected to be related to the 
study drug. This has particular relevance in evaluation of elevated serum creatinine, as 
elevations related to CNI administration are often seen. Dose adjustment of CNI will follow 
institutional guidelines and investigator judgement, with CNI dose reductions anticipated if 
rising creatinine occurs, to potentially alleviate the need for ruxolitinib dose reductions.
Treatment with ruxolitinib may be delayed up to 21 days to allow for resolution of toxicity.
Patients may resume treatment if no medical condition or other circumstance exists that, in the 
opinion of the Investigator, would make the subject unsuitable for further participation in the 
study.
Ruxolitinib must be permanently discontinued upon any one of the following adverse events
attributed to study drug that fails to resolve to Grade 2 or better within 14 days or if a lower re-
start dose or administration schedule subsequent to any of the following non-hematologic 
toxicities is either not available or likely to be clinically ineffective:

occurrence of a Grade 4 laboratory or non-laboratory abnormality attributable to ruxolitinib

occurrence of a Grade 3 laboratory or non-laboratory abnormality attributable to ruxolitinib 
that remains at Grade 3 or worse for greater than 14 days


Novartis
Confidential
Page 64 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
If any one or more of the treatment discontinuation criteria are met prior to Cycle 7 Day 1, the 
subject will be considered to be a non-responder in terms of the primary endpoint.
Patients who permanently discontinue the study treatment for reasons other than achieving a 
CR or PR prior to completion of 39 cycles on study will enter the Long-Term Survival Follow-
Up, and may be treated per Institutional practice. They will be followed approximately every 3 
months by telephone call for survival and reporting of new cGvHD therapies until 39 cycles on 
study are completed.
The date the subject discontinued the study treatment and the specific reason for permanent 
study treatment discontinuation will be recorded in the eCRF.


Novartis
Confidential
Page 65 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 6-2
Criteria for dose reduction / interruption and re-initiation of ruxolitinib treatment for adverse drug reactions
Dose modifications for ruxolitinib for adverse events a 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: 1 dose level (see Table 6-3), 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 1 dose level. 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 1 dose level
Thrombocytopenia (transfusions are allowed during study treatment, if needed)
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: 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 1 dose level
Grade 4 (PLT < 15,000/mm3)
Mandatory: Hold dose until resolved to ≥20,000/mm3, then resume at 1 dose level. If resolves to ≤ 
Grade 3, can resume initial dose level. If not resolved in ≤14 days the patient must be discontinued.


Novartis
Confidential
Page 66 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Dose modifications for ruxolitinib for adverse events a suspected to be drug-related
Worst toxicity
Investigations (Renal)
Serum creatinine 
Grade 1 (> ULN - 1.5 x ULN)
Recommendation: maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN)
Mandatory: 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 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 - 5.0 x ULN* 
Mandatory: 1 dose level until resolved to ≤ 3.0. Monitor LFTsb weekly, or more frequently if clinically 
indicated, until resolved to ≤ 3.0 x ULN:
If resolved in ≤ 14 days, then increase by one dose level 
If resolved in > 14 days, then maintain the decreased dose level 
> 5.0 - 10.0 x ULN* 
Mandatory: Hold dose. 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 1 dose level
> 10.0 x ULN*
Mandatory: Hold dose. Monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 
3.0 x ULN:
If resolved in ≤ 14 days, then resume at↓ 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 dose level
> 3.0 - 5.0 x ULN 
For patients with baseline value ≤ 3.0 x ULN
Recommendation: Maintain dose level. Repeat LFTsb as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; if abnormal lab values are confirmed upon the repeat test, 1 
dose level until resolved to ≤ 3.0 x ULN. Monitor LFTsb weekly, or more frequently if clinically indicated, 
until resolved to ≤ 3.0 x ULN:


Novartis
Confidential
Page 67 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Dose modifications for ruxolitinib for adverse events a suspected to be drug-related
Worst toxicity
For patients with baseline value > 3.0 -5.0 x ULN
If resolved in ≤ 14 days, then then increase by one dose level 
If resolved in > 14 days, then continue at the 1 dose level 
Recommendation: Maintain dose level. Monitor LFTsb weekly, or more frequently if clinically indicated, 
until resolved to ≤ baseline
> 5.0 - 10.0 x ULN
Mandatory: Hold dose. 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 ≤ 
5.0 x ULN Then:
If resolved in ≤ 14 days, then resume same dose level
If resolved in > 14 days, then resume at↓ 1 dose level
> 10.0 - 20.0 x ULN 
Mandatory: Hold dose. 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 ≤ 
5.0 x ULN. Then resume at↓ 1 dose level. 
> 20.0 x ULN
For patients deriving clinical benefit upon 
Investigator’s judgement
For all other patients
Mandatory: Hold dose. 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 ≤ 3 
x ULN (or ≤ 5 x ULN for patients with baseline value > 3.0 -5.0 x ULN), then resume treatment at ↓ 1 dose 
level. Only 1 dose reduction is allowed; if reoccurs at > 5 x ULN, discontinue patient from study treatment.
Mandatory: 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.
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↓1 dose level
Grade 4 (> 5.0 x ULN)
Recommendation: Hold dose and discontinue patient from study treatment.


Novartis
Confidential
Page 68 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Dose modifications for ruxolitinib for adverse events a suspected to be drug-related
Worst toxicity
Vascular disorders
Hypertension
CTCAE Grade 3
Recommendation: 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: 1 dose level until resolved to ≤ Grade 2, then increase by one dose level
Grade 4
Mandatory: Hold dose. Discontinue patient from study treatment
Skin and subcutaneous tissue disorders
Rash/photosensitivity
Grade 1
Recommendation: maintain dose level
Grade 2
Recommendation: maintain dose level
Grade 3
Recommendation: 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 dose level
Grade 4
Mandatory: Hold dose. Discontinue patient from study treament
Other adverse events
Grade 1 or 2
Recommendation: maintain dose level
Grade 3
Recommendation: 1 dose level until resolved to ≤ Grade 2
Recommendation: Hold dose for ≥ Grade 3 vomiting or Grade 3 nausea only if the vomiting or nausea 
cannot be controlled with optimal antiemetic (as per local practice)
Grade 4
Recommendation: Hold dose and then discontinue from study treatment
 
 
 


Novartis
Confidential
Page 69 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Dose modifications for ruxolitinib for adverse events a suspected to be drug-related
Worst toxicity
All dose modifications should be based on the worst preceding toxicity.
For dose level refer to Table 6-3 and Table 6-4
a Common 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.)
* 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 ↓ 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
 


Novartis
Confidential
Page 70 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 6-3
Dose reduction steps for ruxolitinib
Dose Reduction*
Starting dose level – 0
Dose level – 1
Dose level – 2
ruxolitinib
10 mg BID
5 mg BID
5 mg QD**
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
**Dose reduction below 5 mg total daily dose is not allowed.
Patients who have had a dose reduction of ruxolitinib in order to manage toxicity may resume 
treatment at the previous dose if hematologic/non-hematologic parameters meet the required 
threshold(s).
Table 6-4
Dose re-escalation levels for ruxolitinib
Dose Re-escalation*
Current dose
First dose escalation
Second dose escalation
ruxolitinib
5 mg QD
5 mg BID
10 mg BID
5 mg BID
10 mg BID
---
* Dose increases may not exceed 10 mg BID, in increments of 5 mg and not more often than every 2 weeks.
6.3.1.3
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with 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).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
 
 
 
 
 
 


Novartis
Confidential
Page 71 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted.
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is performed 
in the study.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist.
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 SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly
documented.
6.3.1.4
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 6.3.1.1 and 
Section 6.3.1.2).
See Appendix 7 for a list of CYP3A4 inhibitors and inducers.
Strong CYP3A4 inhibitors
A dose reduction of ruxolitinib (e.g. by 50%) should be considered when using strong CYP3A4 
inhibitors. No dose adjustment of ruxolitinib is needed for use with topical ketoconazole. See 
Section 6.4.2.
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%) 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 200 mg daily.
CYP3A4 inducers
No dose adjustment is recommended when ruxolitinib is co-administered with CYP3A4 
inducers.


Novartis
Confidential
Page 72 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
6.3.1.5
Optional dose tapering strategy for study discontinuation
When a decision is made to permanently discontinue ruxolitinib therapy for reasons other than
for hematologic/non-hematologic safety (e.g. when cGvHD complete response is observed), a 
dose tapering strategy should be followed, based on evaluation of the condition of the patient, 
current dosing regimen, and the clinical judgment of the Investigator.
Following any abrupt interruption or discontinuation of ruxolitinib, symptoms of cGvHD flare 
are expected. If considered to be medically necessary, the Investigator may use any treatment 
to manage withdrawal from ruxolitinib including a gradual tapering of the study drug dosage or 
use of other medications including corticosteroid as minimum dosage ≥ 0.4 mg/kg/day 
methylprednisolone (or equivalent prednisone ≥ 0.5 mg/kg/day) to manage cGvHD flare 
anticipated after abrupt ruxolitinib discontinuation.
When a decision has been made to discontinue the subject with utilization of a tapering strategy, 
regardless of the use of concomitant medications, safety data will continue to be assessed in 
accordance with the protocol for a period of time at least through the continued administration 
of ruxolitinib and until the safety follow-up visit is completed (30 days from last ruxolitinib 
dose intake) for adverse event monitoring.
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
Supportive treatments per institutional guidelines for management of alloSCT patients with SR-
cGvHD are allowed. The patient must be told to notify the investigational site about any new 
medications he/she takes after randomization and the start of treatment.
All medications (other than ruxolitinib and BAT) including over-the-counter and 
vitamins/herbal/natural medications must be listed on the Concomitant Medications eCRF. 
Significant non-drug therapies (including physical therapy and blood transfusions) administered 
during the study must be listed on the Surgeries and Procedures eCRF. Any prior medication 
received up to 30 days prior to the first dose of ruxolitinib or BAT 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.
In addition to ruxolitinib or BAT, patients may receive other cGvHD medications administered 
either as cGvHD prophylaxis or treatment prior to randomization which can include CNI 
(cyclosporine or tacrolimus), and corticosteroids. In addition, viral prophylaxis and antibiotics 
are allowed as needed for prevention and treatment of any infections.
Corticosteroids may be taken or administered without regard to food except on days when 
extensive PK samples are drawn; on those days, patients should be instructed to fast and refrain 
from taking corticosteroids until after PK samples are collected. See Section 7 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 


Novartis
Confidential
Page 73 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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.
Change of systemic immunosuppressive therapy after randomization and up to completion of 
Cycle 7 Day 1 will be considered a treatment failure. At the study visit in which the patient 
meets the criteria for disease progression, intolerable toxicity, or cGvHD flare, addition or 
initiation of a new systemic treatment is allowed. However, if mixed response or no response 
is assessed, addition or initiation of a new systemic treatment is not allowed until the next 
scheduled study visit where mixed response or no response is confirmed, at least 4 weeks later.
It is recommended that any subject receiving a CNI at study entry will remain on the same CNI 
as needed while being in the study treatment period.
Patients who undergo alloSCT are at risk for a variety of infections based on the degree of 
immunosuppression induced by the conditioning regimen prior to transplant. As such, it is 
considered routine practice to utilize antibiotics, anti-infectives, and immunizations as 
prophylactic therapies (Tomblyn 2009). In cases where post-transplant anti-infective 
prophylaxis measures are necessary, ongoing therapy may continue at Investigator's discretion 
per institutional guidelines. This includes any viral prophylaxis indicated based on pre-alloSCT 
serologies.
Additional supportive care measures (e.g., use of anti-emetics and anti-motility agents for 
diarrhea management) are permitted at Investigator's discretion.
6.4.2
Permitted concomitant therapy requiring caution and/or action
SR-cGvHD patients receiving ruxolitinib with concomitant medications provided per standard 
institutional guidelines for management after alloSCT including: anti-emetics, calcineurin 
inhibitors, azole fungal prophylaxis, broad spectrum antibiotics in the event of fever (either 
semi-synthetic penicillin or third generation cephalosporin with vancomycin, gentamycin or 
equivalent), acyclovir prophylaxis, 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 6.3.1.4).
Upon initiation of a strong CYP3A4 inhibitor or a dual CYP3A4/CYP2C9 inhibitor, including 
fluconazole up to a dose of 200 mg, 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 6-2) and Investigator judgment, with appropriate 
corticosteroid immunosuppression provided to avoid cGvHD flare.


Novartis
Confidential
Page 74 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
6.4.3
Prohibited concomitant therapy
The following therapies are prohibited during the study until treatment discontinuation:

Due to the high risk of bleeding in alloSCT patients with SR-cGvHD, 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. Low molecular weight heparin (LMWH), acetaminophen, and ibuprofen are
allowed. In patients in whom aspirin is indicated for secondary cardiovascular disease 
prevention, aspirin daily dose must not exceed 150 mg/day.

Concomitant use of another JAK inhibitor besides ruxolitinib.

Herbal preparations/medications are not allowed, as a potential drug-drug interaction is 
possible. These herbal medications include, but are not limited to, St. John’s Wort, Kava, 
ephedra (ma huang), gingko biloba, dehydroepiandrsterone (DHEA), yohimbe, saw 
palmetto, and ginseng. Patients must stop using herbal medications at least 7 days prior to 
first dose of study treatment.

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.

Use 
of 
chemotherapeutic agents and/or 
non-scheduled 
DLI 
for 
malignancy 
recurrence/relapse is not permitted. If required for subject management, the subject is 
discontinued from study treatment.

Any pre-emergent intervention related to graft failure or underlying
disease 
relapse/recurrence including but not limited to: stem cell graft boost, additional conditioning 
chemotherapy or anti-T-cell therapy, non-scheduled DLI, and/or abrupt cessation/taper 
immunosuppression is not permitted. If required for subject management, the subject is 
discontinued from study treatment.

Administration of fluconazole at daily doses higher than 200 mg (Section 6.3.1.4).
Considering the underlying population with immunocompromised state, use of live attenuated 
vaccines (i.e., against SARS-CoV-2) are prohibited while on study treatment.
6.4.4
Follow-up for toxicities
See Section 6.3, or as per label for the best available therapy.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient 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 to the investigator through the Oracle Clinical RDC interface.


Novartis
Confidential
Page 75 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
The investigator or designated staff will contact the 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 be randomized or start treatment for any 
reason, the reason will be entered into the Screening Disposition page.
IRT must be notified within 2 days that the patient was not randomized.
6.5.2
Treatment assignment or randomization
Patients will be assigned to one of the “2” treatment arms (Section 4.1 and Section 6.1) in a 
ratio of 1:1 (ruxolitinib or BAT).
Randomization will be stratified by cGvHD severity: moderate vs severe.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the Interactive Response Technology (IRT) provider 
using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication randomization list 
will be produced by or under the responsibility of Novartis Global Clinical Supply using a 
validated system that automates the random assignment of medication numbers to medication 
packs containing each of the study treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
6.5.3
Treatment blinding
This is an open label study.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) 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.


Novartis
Confidential
Page 76 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 6-5
Preparation and dispensing
Study treatments
Dispensing
Preparation
INC424/ruxolitinib
Tablets 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
BAT
Per local guidelines
Refer 
to 
local 
product 
information
6.6.1
Study treatment packaging and labeling
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.
Ruxolitinib in different formulations and strengths can be used once they are approved.
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.
Table 6-6
Packaging and labeling
Study treatments
Packaging
Labeling (and dosing frequency)
INC424/ruxolitinib
Tablets in HDPE bottles
INC424 (BID)
BAT
Refer to local product information
Refer to local product information
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel 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, the study treatment should be stored according to the 
instructions specified on the drug labels and/or in the Investigator’s Brochure.
Table 6-7
Supply and storage of study treatments
Study treatments
Supply
Storage
INC424/ruxolitinib
Centrally supplied by Novartis
Refer to study treatment label
BAT
Locally
Refer to local product information


Novartis
Confidential
Page 77 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug 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.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
extra/unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and extra/unused study treatment, packaging, drug labels, and a copy of the completed 
drug accountability log to the study monitor or to the sponsor address provided in the 
investigator folder at each site.
6.6.3.3
Handling of other study 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:

CNI

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.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Incyte facility (US only), 
drug supply group or third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 and Table 7-2 list 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 patient’s 
source documentation. The table indicates which assessments produce data to be entered into 
the clinical database (D) or remain in source documents only (S) (“Category” column). Visit 
windows include +/- 3 days in Cycle 1 (except D1), +/- 7 days from Cycle 2 to Cycle 7, and +/-


Novartis
Confidential
Page 78 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14 days thereafter, except for the EOT which must be within +/- 7 days and Safety-Follow up 
which must be performed within +3 days.
For patients randomized to ruxolitinib, the visit windows in Table 7-1 and Table 7-2 do not 
apply for visits with PK assessments.
No eCRF will be used as a source document.
As per Section 2.7, 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. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again.


Novartis
Confidential
Page 79 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 7-1
Visit evaluation schedule (randomized treatment period)
Visit Name
Category
Protocol 
Section
Screening
Treatment Period
Safety 
follow-
up 
Long-
Term 
Survival 
follow-
up
Cycle 1
Cycle 2–
6
(q28 
days)
Cycle 7 
(Primary 
efficacy 
assessment)
Cycle 9 –39
(C9D1 then q12 
weeks)
End of 
treatment visit 
(EoT)
Day of Cycle
-28 
to
-1
1
8
15
22
1
1
1
Last 
dose + 
30 days
Visit window
+/- 3 days 
+/- 7 d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Obtain Informed 
Consent/Assent
D
X
Inclusion/Exclusion 
Criteria
D
X
Disease history 
(alloSCT, aGvHD, 
cGvHD, CIBMTR 
risk assessment)
D
X
HCT-specific Co-
Morbidity Index 
Score
D
X
Intended BAT 
D
X
Demography
D
X
Relevant medical 
history/current 
medical conditions
D
X
Prior/concomitant 
medications
D
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 80 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Screening
Treatment Period
Safety 
follow-
up 
Long-
Term 
Survival 
follow-
up
Cycle 1
Cycle 2–
6
(q28 
days)
Cycle 7 
(Primary 
efficacy 
assessment)
Cycle 9 –39
(C9D1 then q12 
weeks)
End of 
treatment visit 
(EoT)
Day of Cycle
-28 
to
-1
1
8
15
22
1
1
1
Last 
dose + 
30 days
Visit window
+/- 3 days 
+/- 7 d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Blood transfusions
D
X
X
X
X
X
X
X
X
X
X
IWRS/IRT entry
D
X
X
X
X
X
X
X
X
X
Physical 
examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
Performance 
status
D
7.2.2.4
X
X
X
X
X
X
X
X
X
Height 
(*adolescents only)
D
7.2.2.3
X
X*
X*
X*
X*
X*
X *
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
Tanner Staging 
(adolescents only 
– if not Tanner 5 at 
Screening)
D
7.2.2.9
X
X (Cycle 
4only)
X
X
X
Laboratory 
assessments
7.2.2.5
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
X
X
Coagulation
D
7.2.2.5.3
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 81 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Screening
Treatment Period
Safety 
follow-
up 
Long-
Term 
Survival 
follow-
up
Cycle 1
Cycle 2–
6
(q28 
days)
Cycle 7 
(Primary 
efficacy 
assessment)
Cycle 9 –39
(C9D1 then q12 
weeks)
End of 
treatment visit 
(EoT)
Day of Cycle
-28 
to
-1
1
8
15
22
1
1
1
Last 
dose + 
30 days
Visit window
+/- 3 days 
+/- 7 d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Hepatitis serology 
markers
(HBV, HCV)
D
7.2.2.7
X
Viral load by PCR: 
Testing for 
Hepatitis B&C, 
CMV, EBV, HHV-
6, BK
D
7.2.2.7
X
X
X
X
X
X
Urinalysis
D
7.2.2.5.5
X
X
X
X
X
X
X
X
X
Pregnancy test 
(serum)
D
7.2.2.5.4
X
X
Pregnancy test 
(urine)
D
7.2.2.5.4
X
X
X
X
X
X
X
cGvHD staging 
(Appendix 2)
D
7.2.1.1
X


Novartis
Confidential
Page 82 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Screening
Treatment Period
Safety 
follow-
up 
Long-
Term 
Survival 
follow-
up
Cycle 1
Cycle 2–
6
(q28 
days)
Cycle 7 
(Primary 
efficacy 
assessment)
Cycle 9 –39
(C9D1 then q12 
weeks)
End of 
treatment visit 
(EoT)
Day of Cycle
-28 
to
-1
1
8
15
22
1
1
1
Last 
dose + 
30 days
Visit window
+/- 3 days 
+/- 7 d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
cGvHD disease 
assessment –
baseline and post 
baseline response 
scoring
(including FEV1, 
optional biopsy, 
and benefit 
assessment)
(Appendix 3, 
Appendix 4)
D
7.2.1.2
X
X
X
X
X
X
Graft failure 
assessment
D
7.2.1.3
X
X
X
X
X
X
X
X
Chimerism
D
7.2.1.4
X
X
X
X
X
X
Underlying disease 
relapse/recurrence 
assessment (*if 
possible to collect 
information)
D
7.2.1.5
X
X
X
X
X
X
X
X
X*


Novartis
Confidential
Page 83 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Screening
Treatment Period
Safety 
follow-
up 
Long-
Term 
Survival 
follow-
up
Cycle 1
Cycle 2–
6
(q28 
days)
Cycle 7 
(Primary 
efficacy 
assessment)
Cycle 9 –39
(C9D1 then q12 
weeks)
End of 
treatment visit 
(EoT)
Day of Cycle
-28 
to
-1
1
8
15
22
1
1
1
Last 
dose + 
30 days
Visit window
+/- 3 days 
+/- 7 d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Imaging
D
Dexascan Bone 
Imaging 
(adolescents only)
D
7.2.2.8
X
X
X (C12, C24, C36 
only)
X (if not 
performed in the 
preceding 6 
months)
Safety
D
Adverse events
D
8.1
X
X
X
X
X
X
X
X
X
X
Infection 
monitoring
D
7.2.2.6
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 84 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Screening
Treatment Period
Safety 
follow-
up 
Long-
Term 
Survival 
follow-
up
Cycle 1
Cycle 2–
6
(q28 
days)
Cycle 7 
(Primary 
efficacy 
assessment)
Cycle 9 –39
(C9D1 then q12 
weeks)
End of 
treatment visit 
(EoT)
Day of Cycle
-28 
to
-1
1
8
15
22
1
1
1
Last 
dose + 
30 days
Visit window
+/- 3 days 
+/- 7 d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Patient Reported 
Outcomes
D
7.2.6
Modified Lee 
Symptom Scale
D
7.2.6
X
X
X
FACT-BMT
D
7.2.6
X
X
X
X
X
EQ-5D-5L
D
7.2.6
X
X
X
X
X
Resource 
Utilization
Assessments
D
7.2.5
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 85 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Screening
Treatment Period
Safety 
follow-
up 
Long-
Term 
Survival 
follow-
up
Cycle 1
Cycle 2–
6
(q28 
days)
Cycle 7 
(Primary 
efficacy 
assessment)
Cycle 9 –39
(C9D1 then q12 
weeks)
End of 
treatment visit 
(EoT)
Day of Cycle
-28 
to
-1
1
8
15
22
1
1
1
Last 
dose + 
30 days
Visit window
+/- 3 days 
+/- 7 d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Study Drug 
administration 
(ruxolitinib or BAT)
D
6.6
X
X
X
X
X
X
X
PK sampling 
(ruxolitinib arm 
only)
D
7.2.3
See Table 7-7 & Table 7-8
End of Phase 
Disposition
D
X
X
Survival 
assessment
D
7.1.7
X
New cGvHD 
therapies
D
7.2.1.6
X


Novartis
Confidential
Page 86 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 7-2
Visit evaluation schedule for Cross-Over Treatment patients
Visit Name
Category
Protocol 
Section
Cross-Over Treatment Period
End of 
treatment visit 
(EoT)
Safety 
follow-up
Long-
Term 
Survival 
follow-up
Cycle 1
Cycle 2 – 6
(q28 days)
Cycle 7
Cycle 9 –33
(C9D1 then q12 
weeks)
Day of Cycle
1
15
1
1
1
Last dose 
+ 30 days
Visit window
+/- 3 d
+/- 7d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Prior/concomitant 
medications
D
X
X
X
X
X
X
X
Blood transfusions
D
X
X
X
X
X
X
X
IWRS/IRT entry
D
X
X
X
X
X
X
Physical examination
S
7.2.2.1
X
X
X
X
X
X
Performance status
D
7.2.2.4
X
X
X
X
X
X
Height (*adolescents 
only)
D
7.2.2.3
X
X*
X*
X*
X*
X
Weight
D
7.2.2.3
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
Tanner Staging 
(adolescents only – if 
not Tanner 5 at time 
of cross over)
D
7.2.2.9
X
X (Cycle 4 only)
X
X
X
Laboratory 
assessments
7.2.2.5
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2
X
X
X
X
X
X
Coagulation
D
7.2.2.5.3
X
X
X
X
X
X


Novartis
Confidential
Page 87 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Cross-Over Treatment Period
End of 
treatment visit 
(EoT)
Safety 
follow-up
Long-
Term 
Survival 
follow-up
Cycle 1
Cycle 2 – 6
(q28 days)
Cycle 7
Cycle 9 –33
(C9D1 then q12 
weeks)
Day of Cycle
1
15
1
1
1
Last dose 
+ 30 days
Visit window
+/- 3 d
+/- 7d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Viral load by PCR: 
Testing for Hepatitis 
B&C, CMV, EBV, 
HHV-6, BK
D
7.2.2.7
X
X
X
X
X
Urinalysis
D
7.2.2.5.5
X
X
X
X
X
X
Pregnancy test 
(serum)
D
7.2.2.5.4
X
Pregnancy test 
(urine)
D
7.2.2.5.4
X
X
X
X
X
cGvHD disease 
assessment –
baseline and post 
baseline response 
scoring
(including FEV1, 
optional biopsy, and 
benefit assessment) 
(Appendix 3, 
Appendix 4)
D
7.2.1.2
X
X
X
X
X
X
Graft failure 
assessment
D
7.2.1.3
X
X
X
X
X
X
Chimerism
7.2.1.4
X
X
X
X
X


Novartis
Confidential
Page 88 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Cross-Over Treatment Period
End of 
treatment visit 
(EoT)
Safety 
follow-up
Long-
Term 
Survival 
follow-up
Cycle 1
Cycle 2 – 6
(q28 days)
Cycle 7
Cycle 9 –33
(C9D1 then q12 
weeks)
Day of Cycle
1
15
1
1
1
Last dose 
+ 30 days
Visit window
+/- 3 d
+/- 7d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Underlying disease 
relapse/recurrence 
assessment (*if 
possible to collect 
information)
D
7.2.1.5
X
X
X
X
X
X
X*
Imaging
Dexascan Bone 
Imaging 
(adolescents only)
D
7.2.2.8
X
X
X (C12 & C24)
X
Safety
D
Adverse events
D
8.1
X
X
X
X
X
X
X
Infection monitoring
D
7.2.2.6
X
X
X
X
X
X
X


Novartis
Confidential
Page 89 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Visit Name
Category
Protocol 
Section
Cross-Over Treatment Period
End of 
treatment visit 
(EoT)
Safety 
follow-up
Long-
Term 
Survival 
follow-up
Cycle 1
Cycle 2 – 6
(q28 days)
Cycle 7
Cycle 9 –33
(C9D1 then q12 
weeks)
Day of Cycle
1
15
1
1
1
Last dose 
+ 30 days
Visit window
+/- 3 d
+/- 7d
+/- 7 d
+/- 14 d
+/- 7 d
+3 d
+/- 14 d
Patient Reported 
Outcomes
D
7.2.6
FACT-BMT
D
7.2.6
X
X
X
X
X
EQ-5D-5L
D
7.2.6
X
X
X
X
X
Resource Utilization
Assessments
D
7.2.5
X
X
X
X
X
X
Study Drug 
administration 
(ruxolitinib)
D
6.6
X
X
X
X
X
End of Phase 
Disposition
D
X
PK sampling 
D
7.2.3
See Table 7-7 & Table 7-8
Survival Assessment
D
7.1.7
X
New cGvHD 
therapies
D
7.2.1.6
X


Novartis
Confidential
Page 90 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.1.1
Molecular pre-screening
Not applicable
7.1.2
Screening
Prospective patients diagnosed with moderate or severe SR-cGvHD and who meet the inclusion 
and exclusion criteria will be consented prior to beginning screening assessments. The 
screening period can last 28 days (Day -28 to Day -1).
During screening, the patient’s disease history will be assessed. These specific screening 
procedures are outlined in the visit evaluation schedule.
For details on the schedule of assessments, see Table 7-1. Screening lab evaluations performed 
≤10 days of Cycle 1 Day 1 can be used for Cycle 1 Day 1.
A patient with a laboratory test result(s) that does not satisfy the eligibility criteria, may have 
the test(s) repeated during the screening period. These tests may be repeated as soon as the 
Investigator believes that the retest result is likely to be within the acceptable range to satisfy 
the entrance criteria during 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.
In the event that the laboratory test(s) cannot be performed within the 28 day screening period, 
or the re-test(s) do not meet the entrance criteria or the patient’s medical condition has changed 
significantly during the screening period so that inclusion/exclusion criteria are no longer met, 
the patient is considered a Screen Failure, and must be discontinued from the study.
If the Investigator chooses to re-screen the patient, the patient must sign a new ICF, a new 
patient ID number will be assigned by the Investigator, and all required Screening activities 
must be performed.
Once the number of patients screened and enrolled in the respective arm is likely to assure target 
enrollment, the Sponsor may, at its discretion, close the study to further screening. In this case, 
patients who screen fail will not be permitted to re-screen.
7.1.2.1
Eligibility screening
Patient eligibility will be confirmed by the investigative staff 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 treatment arm and dose 
level. This information will be made available during planned interim monitoring visits and 
compared against the clinical database for accuracy.
Additionally, investigative site staff will enter patient information into the eCRF.


Novartis
Confidential
Page 91 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.1.2.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be randomized to a treatment for any reason 
will be considered a screen failure. The reason for not being randomized will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. 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 Phase (see Section 8.2 for SAE 
reporting details). If the patient fails to be randomized, the IRT must be notified within 2 days 
of the screen fail that the patient was not randomized.
7.1.2.3
Patient demographics and other baseline characteristics
Patient information to be collected at screening include:

Demography

Complete Medical History and current medical conditions

Prior and concomitant medications and non-therapies (including physical therapy, oxygen 
and blood transfusions)

Disease History – disease treatment history, donor background, stem cell transplant, and 
GvHD disease history
Furthermore the following assessments will be performed to assess the eligibility of the patient:

Physical Examination (Section 7.2.2.1)

Vital signs (Section 7.2.2.2)

Weight (Section 7.2.2.3)

Performance Status (Section 7.2.2.4)

Laboratory 
evaluations 
(e.g., 
hematology, 
coagulation, 
chemistry,
urinalysis) 
(Section 7.2.2.5)

Chimerism (Section 7.2.1.4)

Viral load by PCR (Section 7.2.2.7)

Hepatitis serology markers (Section 7.2.2.7)

Serum pregnancy (Section 7.2.2.5.4)

Infection monitoring (Section 7.2.2.6)

Chronic GvHD Staging (Section 7.2.1.1)
Key assessments to be conducted for patients who will be randomized to a treatment arm 
include, but not limited to:

Prior to randomization on Cycle 1 Day 1: Chronic GvHD Disease Assessment 
(Section 7.2.1.2)

Prior to first treatment on Cycle 1 Day 1: DEXA scan (adolescents only) (Section 7.2.2.8)
For details on the full schedule of assessments, see Table 7-1 or Table 7-2.
7.1.3
Run-in period
Not applicable


Novartis
Confidential
Page 92 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.1.4
Treatment period
Approximately 324 patients, including adolescent patients (ages 12-17), will be randomized in 
this study.
The treatment period will begin after randomization, on Cycle 1 Day 1. Typically this is the 
same day as randomization, but if not logistically possible (i.e., based on BAT access) should 
not be more than 72 hours after randomization. Cycle 1 Day 1 is the baseline disease assessment 
visit. The total duration on study for an individual patient will be 39 Cycles (156 weeks or 3 
years), inclusive of the randomized treatment period, cross over treatment period, and long-
term survival follow-up.
The visits will occur at the following frequency in the randomized treatment period, as specified 
in Table 7-1:

Every week in Cycle 1 (Day 1, 8, 15, 22) (+/- 3 days)

Every 4 weeks from Cycle 2 Day 1 until Cycle 7 Day 1 (+/- 7 days)

Next visit after Cycle 7 Day 1 is Cycle 9 Day 1 (+/- 7 days)

Every 12 weeks from Cycle 9 Day 1 until Cycle 39 (+/- 14 days)
Patients randomized to the BAT arm who experience disease progression, have a mixed 
response, experience cGvHD flare, or experience toxicity to BAT are permitted to cross over
to the ruxolitinib arm following completion of all assessments at Cycle 7 Day 1, or thereafter.
Cross-Over visits will occur at the following frequency, as specified in Table 7-2:

First day of treatment becomes Cycle 1 Day 1

Cycle 1 Day 15

Cycle 2 Day 1 and every 4 weeks until Cycle 7 Day 1

Next visit after Cycle 7 Day 1 is Cycle 9 Day 1 (+/- 7 days)

Every 12 weeks (+/- 14 days) from Cycle 9 Day 1 until:

A maximum of 39 cycles of study treatment and follow-up is completed, inclusive of 
the randomized treatment period, cross over treatment period, and long-term survival 
follow up (i.e. patients who cross over on Cycle 9 will only complete visits until Cross-
Over Cycle 30).
The Primary Efficacy Endpoint assessment will be conducted on Cycle 7 Day 1 of the 
randomized treatment period with a window of +/- 7 days.
The End of Treatment (EoT) visit is to be completed in the event that the patient permanently 
discontinues the study treatment and enters the long-term survival follow-up, or completes the 
randomized treatment period (ruxolitinib arm, or BAT patients not crossing over) or the cross
over period (BAT arm only).
Unscheduled visits may be performed as necessary. A more frequent schedule of assessments, 
is recommended for dose tapering, dose modifications, or as clinically indicated. Additional 
assessments may be performed as per institutional guidelines, as per the investigator’s 
discretion, or as per the label. Chronic GvHD assessments performed at an unscheduled visit 
and leading to a change in the patient’s management, or during the treatment period leading to 


Novartis
Confidential
Page 93 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
a change in the patient’s response, should be recorded in the eCRF, as well as any other relevant 
assessment performed.
For details on the schedule of assessments, see Table 7-1 or Table 7-2.
7.1.5
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  
r e a s o n a b l e  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 eCRF
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.
Study treatment must also be discontinued under the following circumstances:

Lack of efficacy of chronic GvHD treatment (Section 7.2.1.2).

Underlying disease recurrence, or relapse (Section 7.2.1.5).

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 chronic GvHD (Section 7.2.1.3).

The following deviations from the prescribed dose regimen for study treatment:

Dose hold > 21 days for ruxolitinib or BAT (Section 6.3.1).

Adverse events leading to study treatment discontinuation. (Section 6.3).

Pregnancy (Section 7.2.2.5.4)

Protocol deviation that results in a significant risk to the patient’s safety including use of 
prohibited treatment (Section 6.4.3)
Patients who discontinue study treatment should NOT be considered withdrawn from the
study. They should return for the assessments indicated in Section 7.1, and enter the Long-
Term Survival Follow-Up until completion of 39 cycles on study, inclusive of the randomized 
treatment, Cross Over treatment (BAT patients only), and long-term survival follow up
(Section 7.1.7).
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 7.1.8.
The investigator must also contact the IRT to register the patient’s discontinuation from 
study treatment.
7.1.5.1
Replacement policy
Patients who discontinue prematurely will not be replaced on this study.


Novartis
Confidential
Page 94 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.1.6
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact.
The study sponsor will continue to retain and use all research results that have already been
collected for the study evaluation. All biological samples that have already been collected may
be retained and analyzed at a later date (or as required by local regulations).
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 and record this information.
Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
7.1.7
Follow up for safety evaluations
All patients must have safety evaluations at least 30 days (+ 3 days) after the last dose of study 
treatment. During the safety follow up, adverse events, concomitant medications, transfusions, 
and monitoring of infections will be recorded. If an adverse event or a serious adverse event is 
detected, it should be followed until its resolution or until it is judged to be permanent. See 
Table 7-1 or Table 7-2 for a complete list of assessments for the 30 day follow up visit.
Data collected should be added to the Adverse Events eCRF and the Concomitant Medications 
eCRF.
Long-Term Survival Follow-Up
Patients who permanently discontinue the study treatment prior to the completion of 39 cycles 
on study for reasons other than achieving a CR or PR will enter the Long-Term Survival Follow-
Up, and may be treated per Institutional practice. They will be followed approximately every 3 
months by telephone call for survival, reporting of new cGvHD therapies until 39 cycles on 
study is completed, inclusive of randomized treatment, cross over treatment (BAT patients 
only), and long-term survival follow up.
For details on the schedule of assessments, see Table 7-1 or Table 7-2.
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, 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 eCRF.


Novartis
Confidential
Page 95 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.2
Assessment types
7.2.1
Staging and efficacy assessments
7.2.1.1
Chronic GvHD Staging
At screening, cGvHD Staging will be performed and patients will be classified into mild, 
moderate, and severe based on degree of organ involvement according to established NIH 
Consensus Criteria for cGvHD (Jagasia 2015) (see Appendix 2). Patients will be randomized 
1:1 to receive either ruxolitinib or BAT, and stratified based on cGvHD severity at the time of 
randomization (moderate vs. severe).
The chronic GvHD screening staging assessment is a global and organ-specific clinician 
assessment which focuses on symptom activity in chronic GvHD patients. To classify the 
cGvHD severity, the staging assessment collects individual organ symptom scores (mouth, 
gastrointestinal, lungs, eyes, joints and fascia, liver, skin, genital tract). Assessments for all 
organs must be performed at Screening. The list of organ specific assessments and scoring can 
be found in Appendix 2.
Skin
Skin features are to be scored by % body surface area (BSA), presence of skin abnormalities 
(maculopapular rash/erythema, papulosquamous lesion or ichthyosis, lichen planus - like 
features, sclerotic features, keratosis pilaris – like, and sclerotic involvement), and skin feature 
score.
Mouth
Mouth features are to be scored by presence of lichen planus-like features and degree of oral 
intake limitation.
Eyes
The eye score is determined by assessing severity of dry eye symptoms and degree of vision 
impairment.
Gastrointestinal
The GI tract score is determined by assessing presence and degree of various symptoms 
(esophageal web/proximal structure or ring, dysphagia, anorexia, nausea, vomiting, diarrhea, 
weight loss, failure to thrive).
Liver
The liver score is based on ALT, alkaline phosphates, and total bilirubin.
Lungs
The lung organ score is collected from performing a pulmonary function test, scores are derived 
from the %FEV1 (percentage) results.


Novartis
Confidential
Page 96 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Joints and Fascia
The joints and fascia score is determined by assessing range of motion and activity of daily 
living (ADL). Individual joints and fascia ROM scores are collected for symptom severity of 
shoulder, elbow, wrist/finger, and ankle.
Genital Tract
The genital tract score is determined by assessing applicable signs and level of discomfort 
during exam.
If there is any organ-specific abnormality present but explained entirely by non-GvHD 
documented cause, this should be indicated on the cGvHD Disease Staging eCRF, and the 
applicable conditioned reported in the Medical History or Adverse Event eCRF.
7.2.1.2
Chronic GvHD Disease Assessment
The primary efficacy variable endpoint of the study is overall response rate at Cycle 7 Day 1 
per NIH consensus criteria (Lee 2015). Secondary endpoints include the Best Overall Response 
(BOR) and the overall response rate at Cycle 4 Day 1. The assessment will be performed by the 
treating physician according to the detailed schedule found in Table 7-1 or Table 7-2.
7.2.1.2.1 Baseline organ involvement 
The chronic GvHD assessment is a global and organ-specific clinician assessment which 
focuses on symptom activity in chronic GvHD patients. The assessment collects individual 
organ symptoms (eyes, mouth, lungs, gastrointestinal, liver, skin, joints and fascia).
Assessments for all organs must be performed prior to randomization for the Cycle 1 Day 1
visit (baseline). The list of organ specific assessments and scoring can be found in Appendix 3. 
Skin
Skin features are first to be assessed by % body surface area (BSA), presence of skin 
abnormalities (maculopapular rash/erythema, papulosquamous lesion or ichthyosis, lichen 
planus - like features, sclerotic features, keratosis pilaris – like, and sclerotic involvement), skin 
feature score, and skin and/or joint tightening severity. These assessments will populate the 
overall skin organ score in the eCRF.
Eyes
The eye score is determined by assessing severity of dry eye symptoms.
Mouth
Mouth features are first to be scored by %BSA individually for any erythema, lichenoid, and 
ulcers The total score for all mucosal changes will populate the overall mouth organ score in 
the eCRF.


Novartis
Confidential
Page 97 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Liver
The baseline liver involvement is assessed using ALT, alkaline phosphates, and total bilirubin. 
Please ensure the liver parameters are obtained, and observed values, units and normal ranges 
are documented.
Gastrointestinal
Individual GI scores are to be collected for frequency of esophageal symptoms (dysphagia or 
odynophagia), upper GI symptoms (early satiety, anorexia, or nausea and vomiting), and lower 
GI (diarrhea).
Lungs
The lung baseline status is assessed by a pulmonary function test to determine the %FEV1 
(percentage) results. In addition, a lung score based on clinical symptoms is used.
Joints and Fascia
Individual joints and fascia scores are to be collected for symptom severity of shoulder, elbow, 
wrist/finger, and ankle.
If there is any organ-specific abnormality present but explained entirely by non-GvHD 
documented cause, this should be indicated on the cGvHD Disease Assessment eCRF, and the 
applicable conditioned reported in the Medical History or Adverse Event eCRF.
As part of the chronic GvHD assessment, a biopsy of the organs involved may be performed 
per institutional practices at investigator’s discretion. If performed, the investigator will indicate 
the results in the appropriate eCRF pages.
7.2.1.2.2 Post-baseline organ involvement and cGvHD response assessment
The chronic GvHD assessment will be performed by the treating physician according to the 
detailed schedule found in Table 7-1 or Table 7-2. At each post-baseline assessment, each organ 
must be assessed using the same criteria as for baseline. Additionally, the response evaluation 
of each organ should be made by comparing the current organ assessment versus the baseline 
organ status documented on Cycle 1 Day 1. To assess the response to ruxolitinib in cross-over 
patients, the baseline is defined as the latest cGvHD evaluation before the start of ruxolitinib.
A high level summary of organ-specific response assessment criteria as per NIH consensus 
guideline (Lee 2015) are listed in Table 7-3.
Table 7-4 summarizes the rules for overall response assessment based on organ specific 
evaluations at each scheduled post-baseline visit. These overall response assessments will be 
used to derive response rates for the primary and secondary endpoints.
More detailed instructions on organ-specific response assessment and overall response 
evaluation, including examples, are given in Appendix 4.


Novartis
Confidential
Page 98 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 7-3
Organs included for the post-baseline cGvHD response assessment
Organ
Evaluation by
Criteria for response assessment
Skin
NIH Skin Score, considering %BSA 
involvement and sclerotic features 
Change of skin score 
Eyes 
NIH Eye Score 
Change of Eye score 
Mouth 
NIH Modified OMRS (Sum of scores for 
erythema, lichenoid and ulcers) 
Change of OMRS 
Esophagus
NIH Esophagus Score 
Change of Esophagus score 
Upper GI
NIH Upper GI Score 
Change of Upper GI score 
Lower GI
NIH Lower GI Score 
Change of Lower GI score 
Liver
Lab 
results 
for 
ALT, 
alkaline 
phosphatase, and Total bilirubin 
Change of values for ALT, alkaline phosphatase, 
and Total bilirubin
Lungs
NIH Lung score AND %FEV1 
Change of %FEV1
Joints and fascia 
NIH Joint and Fascia Score 
and P-ROM scores
Change of Joint and Fascia Score 
and P-ROM scores
Table 7-4
Post-baseline overall response evaluation based on all organs
Organ specific response1
Skin
CR / not involved
PR in at least 
one organ 
with baseline 
involvement
AND
no 
progression in 
any other 
organ (i.e. 
CR, PR,
unchanged, or 
no 
involvement)
PR or CR in one 
or more organ(s) 
with baseline 
involvement
AND
progression in 
one or more 
organs
(incl. new 
occurrence in an 
organ with no 
baseline 
involvement)
Progression in
one or more 
organ(s) with 
baseline 
involvement OR 
new occurrence 
in an organ with 
no baseline 
involvement
AND
no CR or PR in 
any other organ
Organ specific 
response 
‘unchanged’ for 
all organs (incl. 
no involvement)
Eyes 
CR / not involved
Mouth 
CR / not involved
Esophagus
CR / not involved
Upper GI
CR / not involved
Lower GI
CR / not involved
Liver
CR / not involved
Lungs
CR / not involved
Joints and 
fascia 
CR / not involved
Overall 
response
CR
PR
Mixed response
Progression
Unchanged 
response
1 at least one organ must be involved at baseline. Organ specific responses versus baseline status
Further assessments
Patients will be also monitored for occurrence of chronic GvHD flares occurring during 
corticosteroid, CNI, or ruxolitinib taper.
The investigator should carefully record any action taken to manage cGvHD including start of 
tapering, initiation of any new systemic therapy, re-escalation of corticosteroids and the re-
escalated corticosteroid dose, and corticosteroid taper failure.
The data should be entered in the appropriate eCRFs. Worsening of cGvHD, including 
occurrence of GvHD flare will be reported on appropriate specific eCRF and, not as an adverse 
event (Section 8.1.1).
Note: Additional assessments may be done as per institutional guidelines at investigator’s 
discretion. Chronic GvHD assessments performed at an unscheduled visit and leading to a 
change in the patient’s management or a change in patient’s response should be recorded in the 
eCRF.


Novartis
Confidential
Page 99 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.2.1.3
Graft failure monitoring
Patients will be monitored for any evidence of graft failure at each visit after Cycle 1 Day 1.
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 (Section 7.2.1.4).
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 8.1.1).
7.2.1.4
Chimerism
Donor chimerism after a hematopoietic stem cell transplant involves identifying the genetic 
profiles of the recipient and of the donor pre-transplant, and then evaluating the ratio of donor 
to recipient cells in the recipient's blood, or bone marrow.
Chimerism testing using peripheral blood mononuclear cells, bone marrow, or other sources
will be performed as outlined in Table 7-1 or Table 7-2.
In general, genomic polymorphisms should be assessed via polymerase chain reaction analysis 
of short tandem repeat loci from isolated lymphocytes or myeloid cells. Fluorescence in situ 
hybridization analysis may also be used in cases with sex-mismatched transplants (Thiede 2004;
Matsuda 2004).
7.2.1.5
Underlying disease relapse/recurrence assessment
Patients will be closely monitored for any evidence of underlying disease relapse or recurrence 
at each visit during the randomized treatment period, the Cross-Over treatment period, and the 
long-term survival follow-up (if possible) as outlined in Table 7-1 or Table 7-2. If the patient 
has underlying disease relapse or recurrence during the long-term survival follow-up, the 
investigator should make every effort to collect the information and enter it into the appropriate 
eCRF.
The investigator will assess relapse and recurrence of the underlying disease and indicate if any 
therapy was instituted to treat persistent, progressive or relapsed underlying disease, including 
the withdrawal of immunosuppressive therapy, chemotherapy administration, and/or donor 
lymphocyte infusion.
Evaluation and/or evidence of underlying disease relapse/recurrence will be conducted 
according to local institutional practices. Available information on the underlying disease 
recurrence/relapse will be documented on the appropriate eCRF and not as an adverse event 
(Section 8.1.1).
7.2.1.6
New cGvHD treatment
The start of new cGvHD treatment during the Long-Term Survival Follow-Up will be collected 
in the New cGvHD treatment eCRF.


Novartis
Confidential
Page 100 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing the following assessments, as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8.
Additional assessments may be performed as per institutional guidelines, investigator discretion, 
or as per the label for patients taking best available therapy.
7.2.2.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
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.
For details on the schedule of assessments, see Table 7-1 or Table 7-2.
7.2.2.2
Vital signs
Vital signs including supine blood pressure, pulse measurement, and body temperature will be 
performed at every visit (see Table 7-1 and Table 7-2).
7.2.2.3
Height and weight
Height will be measured at baseline (Cycle 1 Day 1) and the end of treatment visit. For 
adolescents, height will be measured at every visit.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1 and Table 7-2.
7.2.2.4
Performance status
Performance status will be assessed according to the ECOG performance status scale (graded 
on a six point scale from 0 to 5), the KPS ranked from 0 to 100, or the LPS ranked from 0 to 
100.
For details on the schedule of assessments, see Table 7-1 or Table 7-2.


Novartis
Confidential
Page 101 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.2.2.5
Laboratory evaluations
Table 7-5
Local Clinical Laboratory 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, White blood cells with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils), Absolute neutrophil count (with bands), Absolute Reticulocytes
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Gamma-glutamyl-transferase 
(GGT), Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus,
Sodium, 
Potassium, Creatinine, Creatine kinase, Total Bilirubin (Direct Bilirubin and Indirect Bilirubin 
only if Total Bilirubin out of range), Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (fasting)
Urinalysis*
Macroscopic Panel (Dipstick)* (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Coagulation
Prothrombin time (PT) , International normalized ratio (INR), Activated partial thromboplastin 
time (APTT), D-Dimer, Fibrinogen
Pregnancy Test
Effective contraception is required and pregnancy testing is mandated at screening and/or 
pre-dose and at the end of the trial. A serum pregnancy test must be performed during 
Screening and at the End of Treatment (EOT) Visit. Urinary pregnancy tests are sufficient at 
all other time points.
*Any findings on urine dipstick will be followed up with a microscopic evaluation (Red Blood Cells, White Blood 
Cells, Casts, Crystals, Bacteria, Epithelial cells)
Table 7-6
Local Virology Laboratory Collection Plan
Test Category
Test Name
Hepatitis 
serology 
markers
Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (HBsAb), Hepatitis B 
core antibody (anti-HBc), and HBV-DNA (baseline) in case of positive serology.
Hepatitis C virus antibody and HCV RNA-PCR (baseline) in case positive serology.
Viral load by PCR
Hepatitis B and C, Cytomegalovirus (CMV), Epstein Barr Virus (EBV), BK virus, and 
Human Herpes Virus 6 (HHV-6) viral load by PCR
Note:
● Patients with prior positive serology results or who receive a graft from a donor with positive serology must 
have 
negative 
peripheral 
blood 
viral 
load 
results 
confirmed 
prior 
to 
randomization
● Patients must have viral load results confirming negative HBV and HCV infections prior to randomization.
● For all other viral load results, patients must have no evidence of active viral infection prior to randomization.
A central laboratory will be used for analysis of 
 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.
7.2.2.5.1 Hematology
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular 
Hemoglobin Concentration (MCHC), Mean Corpuscular Volume (MCV), Platelets, Red blood 
cells, White blood cells with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils), Absolute neutrophil count (with bands), Absolute Reticulocytes will be assessed
locally at every visit (see Table 7-1 and Table 7-2).


Novartis
Confidential
Page 102 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.2.2.5.2 Clinical chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Gamma-glutamyl-transferase 
(GGT), Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Sodium, Potassium, 
Creatinine, Creatine kinase, Total Bilirubin (Direct Bilirubin and Indirect Bilirubin only if Total 
Bilirubin out of range), Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea 
Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (fasting) will be assessed locally 
at every visit (see Table 7-1 and Table 7-2).
7.2.2.5.3 Coagulation
Prothrombin time (PT), International normalized ratio (INR), Activated partial thromboplastin 
time (APTT), D-Dimer, Fibrinogen will be assessed locally at every visit (see Table 7-1 and
Table 7-2).
7.2.2.5.4 Pregnancy and assessments of fertility
All female patients of child bearing potential including adult ≥ 18 years of age and patients ≥ 
12 and < 18 years of age and of childbearing potential (e.g. are menstruating), must undergo a 
serum pregnancy test at screening and at the end of treatment visit.
From Cycle 1 Day 1 and at every subsequent visit, a urine pregnancy test will be performed. A 
positive urine pregnancy test requires immediate interruption of study drug until serum hCG is 
performed and found to be negative. If positive, the patient must be discontinued from the study.
For details on the schedule of assessments, see Table 7-1 or Table 7-2.
If local requirements mandate more frequent pregnancy testing, applicable sites must adhere to 
these requirements even if scheduled visits are less frequent. For women of child bearing 
potential, home pregnancy test kits should be provided by the site for the duration of study 
treatment up to the safety follow up period, or as per label. The outcome of the home urinary 
test should be available at the site as part of the source documentation. The site must instruct 
the patient to contact the investigator immediately in case of a positive test.
7.2.2.5.5 Urinalysis
Urinalysis will be performed using the macroscopic panel (Dipstick) (Color, Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) as 
per Table 7-1 and Table 7-2.
Any significant findings on the macroscopic panel will be followed up with a microscopic 
evaluation.
7.2.2.6
Infection Monitoring
Infections (including opportunistic infections) are important risks identified with ruxolitinib and 
BAT cGvHD therapy and will be monitored closely throughout the study (see Table 7-1 and
Table 7-2). Infections will be reported as adverse events and the AE severity grade will be 
assessed according to CTCAE grading as defined in Section 8.1. In addition, the investigator 
will detail the type of infection as well as method of diagnosis and assess the event according 
to the Infection severity grading (Appendix 1).


Novartis
Confidential
Page 103 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
7.2.2.7
Viral reactivation monitoring
Viral serology and viral load testing will be assessed once the patient has signed the informed 
consent form and prior to randomization.
The following hepatitis serology markers will be assessed at screening:

Hepatitis B surface antigen (HBsAg)

Heptatitis B surface antibody (HBsAb)

Hepatitis B core antibody (anti-HBc)

HBV-DNA

Hepatitis C virus antibody

HCV RNA-PCR
Patients must have viral load results confirming negative HBV and HCV infections prior to 
randomization to confirm eligibility. For all other viral load results, patients must have no
evidence of active viral infection prior to randomization.
The following PCR viral load (blood) will be assessed at screening, baseline, and on Day 1 of 
every scheduled cycle visit:

Hepatitis B and C

Cytomegalovirus (CMV)

Epstein Barr Virus (EBV)

BK virus (by blood or urine PCR)

Human Herpes Virus (HHV-6)
Viral load will be monitored throughout the study. Viral serology can be performed throughout 
the study as per local guidelines and entered into the Viral Serology eCRF.
For details on the schedule of assessments, see Table 7-1 or Table 7-2. Additional viral testing 
may be performed as per local regulations.
7.2.2.8
Bone density - DEXA (Dual Energy X-ray Absorptiometry) scan 
(adolescent patients only)
If the patient is an adolescent (<18 years) at baseline, monitoring of bone density must be 
performed using a DEXA scan while on study, including after becoming >18 years of age.
DEXA scans collected ≤ six months prior to the patient’s enrollment into the trial can be 
considered as the baseline (Cycle 1 Day 1) assessment. In the treatment period, DEXA scans 
will be performed at the following visits:

Cycle 1 Day 1 (pre-dose)

Cycle 7, 12, 24, 36

EOT (if not performed in the preceding 6 months)


Novartis
Confidential
Page 104 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
In the cross over period, DEXA scans will be performed at the following visits if not performed 
in the preceding 6 months:

Cycle 1 Day 1 (pre-dose)

Cycle 7, 12, 24

EOT (if not performed in the preceding 6 months)
The images should be assessed by a qualified radiologist with the ability to interpret pediatric 
data.
At each visit, the Z-score, bone mineral density and bone mineral content will be collected for 
lumbar (L1 - L4) and whole body (except head region). Interpretation of the reported results 
will also be collected. Any hardware can be used as long as the software allows calculation of 
the Z-score based on an appropriate population-based control data set.
For details on the schedule of assessments, see Table 7-1 or Table 7-2.
7.2.2.9
Tanner Staging (adolescents only)
If the patient is an adolescent (< 18 years), assessments of reproductive development will be 
performed using the Tanner Staging scale at Screening. Additional Tanner Staging assessments 
will be based on the score at screening and subsequent scores:

Stage 5 = no additional Tanner Staging assessments needed

Stage 4 or less = continue Tanner Staging assessments per Table 7-1 or Table 7-2.
7.2.3
Pharmacokinetics
Blood sampling for PK of ruxolitinib will be performed in all patients enrolled in the study.
Extensive PK sampling schedule
Early enrolling patients randomized to ruxolitinib arm will follow an “extensive PK” sampling 
schedule as outlined in Table 7-7. Approximately the first eight (8) adult patients and four (4) 
adolescent patients enrolled are required to follow the “extensive PK” sampling schedule.
Patients should be instructed to fast and refrain from taking corticosteroids until after PK 
samples are collected on “extensive PK” sampling days.
Sparse PK sampling schedule
Once this requirement for “extensive PK sampling” for Cycle 1 day 1 and Cycle 1 Day 15 is 
fulfilled, the sponsor will notify all sites. Subsequent patients randomized to ruxolitinib, any
randomized patients receiving ruxolitinib after Cycle 6, and any randomized patients receiving 
BAT that cross over to ruxolitinib will follow the “sparse PK” sampling schedule as outlined 
Table 7-8.
Cross over patients from BAT to ruxolitinib follow a different visit schedule according to 
Table 7-2. PK samples for cross over patients will be taken only at the time of a scheduled visit.


Novartis
Confidential
Page 105 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 7-7
Ruxolitinib Pharmacokinetic blood collection log for extensive PK 
(First 8 adult patients first 4 adolescents)
Treatment 
Cycle
Day
Scheduled Time Point
Dose Reference ID
PK Sample 
No
1
1
Pre-dose/0 hr
111
1111a
201
1
1
Post-dose 0.5 hr (±15 min)
111
-
202
1
1
Post-dose 1 hr (±15 min)
111
-
203
1
1
Post-dose 1.5 hr (±15 min)
111
-
204
1
1
Post-dose 4 hr (± 1 hr)
111
-
205
1
1
Post-dose 6 hr (± 1 hr)
111
-
206
1
1
Post-dose 9 hr (± 1 hr)
111
-
207
1
15
Pre-dose/0 hr
211
2111a
208
1
15
Post-dose 0.5 hr (±15 min)
211
-
209
1
15
Post-dose 1 hr (±15 min)
211
-
210
1
15
Post-dose 1.5 hr (±15 min)
211
-
211
1
15
Post-dose 4 hr (±1 hr)
211
-
212
1
15
Post-dose 6 hr (±1 hr)
211
-
213
1
15
Post-dose 9 hr (±1 hr)
211
-
214
2
1
Pre-dose/0h
311
3111a
215
2
1
Post-dose 1.5 hr (±15 min)
311
-
216
7
1
Pre-dose/0 hr
411
4111a
217
7
1
Post-dose 1.5 hr (±15 min)
411
-
218
39
1
Pre-dose/0 hr
511
5111a
219
39
1
Post-dose 1.5 hr (±15 min)
511
-
220
Unscheduled
2001+
a Dose reference IDs to collect previous dose information for PK trough samples. For the PK trough samples 
the actual date and time of administration of the previous dose of study medication must be recorded with 
appropriate Dose reference IDs as indicated in the above table.
Table 7-8
Ruxolitinib Pharmacokinetic blood collection log for sparse PK (all 
other patients)
Treatment 
Cycle
Day
Scheduled Time Point
Dose Reference ID
PK Sample 
No
1
1
Pre-dose/0 hr
611
6111 a
301
1
1
Post-dose 1.5 hr (±15 min)
611
302
1
15
Pre-dose/0 hr
711
7111 a
303
1
15
Post-dose 1.5 hr (±15 min)
711
304
2
1
Pre-dose/0 hr
811
8111 a
305
2
1
Post-dose 1.5 hr (±15 min)
811
306
7
1
Pre-dose/0 hr
911
9111 a
307
7
1
Post-dose 1.5 hr (±15 min)
911
308
39
1
Pre-dose/0 hr
1011
10111a
309
39
1
Post-dose 1.5 hr (±15 min)
1011
-
310
Unscheduled
2001+
a Dose reference IDs to collect previous dose information for PK trough samples. For the PK trough samples, 
the actual date and time of administration of the previous dose of study medication must be recorded with 
appropriate Dose reference IDs as indicated in the above table.


Novartis
Confidential
Page 106 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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.
7.2.3.1
Pharmacokinetic blood collection and handling
Whole blood (approximately 1 mL) per sampling time as outlined in Table 7-7 and Table 7-8
will be obtained by either direct venipuncture or via an indwelling cannula from a peripheral 
vein into a tube containing di-potassium EDTA. Immediately after collection the tube should 
be inverted several times to prevent clotting. Blood samples should be kept in an ice water bath 
at approximately 4°C until centrifugation. The tubes should be centrifuged within 30 minutes 
of collection at approximately 2000 x g at 4°C for 15 minutes to yield plasma. The plasma will 
be decanted and transferred into a 2-mL polypropylene screw- cap tube, the tube capped, and 
then immediately placed in a freezer at ≤ -60°C until shipment to sponsor and/or designated 
central laboratory.
Refer to the [CINC424D2301 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.


Novartis
Confidential
Page 107 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301


Novartis
Confidential
Page 108 of 178
Amended Protocol Version 02 (Clean)
Protocol No  CINC424D2301
7.2.5
Resource utilization
Medical resource utilization (MRU) will be assessed as follows and recorded in the eCRF:

Frequency and duration of hospitalization from Baseline up to End of Study

Frequency of emergency room visits from Baseline up to End of Study

Frequency of additional outpatient office visits, general practitioner, specialist, and urgent 
care visits from Baseline up to End of Study








Novartis
Confidential
Page 112 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
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 
(chronic GvHD) including occurrence of cGvHD flare, relapse or recurrence of underlying 
disease (including fatal outcomes), should not be reported as a serious adverse event and will 
be reported on specific eCRFs other than AE eCRF.
Adverse events separate from the events listed above (example, deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
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 eCRF. 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.


Novartis
Confidential
Page 113 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
8.1.3
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.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event

Note that progression of disease (including fatal outcomes), if documented by use of 
appropriate method (as per 2014 NIH response criteria, Lee 2015), should not be reported 
as a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to the study sponsor within 24 hours of learning of its 
occurrence.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode immediately, 
without undue delay, and under no circumstances later than within 24 hours of the investigator 
receiving the follow-up information. An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.


Novartis
Confidential
Page 114 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to the study sponsor if the investigator suspects a causal relationship to the study 
treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to the study sponsor. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Sponsor study treatment, the study sponsor (either 
an oncology Novartis Chief Medical Office and Patient Safety (CMO&PS) department 
associate or Incyte pharmacovigilance, as outlined in the study reference manual) may urgently 
require further information from the investigator for Health Authority reporting. The sponsor
may need to issue an Investigator Notification (IN), to inform all investigators involved in any 
study with the same drug that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to the study sponsor within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS) and 
Incyte pharmacovigilance (US only). Pregnancy follow-up should be recorded on the same form 
and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form.


Novartis
Confidential
Page 115 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Pregnancy outcomes must be collected for the female partners of any males randomized to BAT 
who took study treatment in this study (if required per label or as per local regulation). Consent 
to report information regarding these pregnancy outcomes should be obtained from the mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
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 responsible to review safety data as 
outlined in the DMC charter. The DMC will also be responsible to review efficacy and safety 
data during the conduct of the interim analyses as defined in the protocol.
It is expected that the DMC will consist at a minimum of two physicians with appropriate 
disease area qualifications and one statistician. There will be a meeting with the DMC 
describing their roles and responsibilities and discussing potential data format and process 
issues prior to the finalization of DMC charter and the interim analysis plan.
8.7
Steering Committee
The Steering Committee (SC) will ensure transparent management of the study according to the 
protocol through recommending and approving modifications as circumstances require. The SC
will review protocol amendments as appropriate. Together with the clinical trial team, the SC 
will also develop recommendations for publications of study results including authorship rules. 
The details of the role of the SC will be defined in a Steering Committee charter.
9
Data collection and management
9.1
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:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.


Novartis
Confidential
Page 116 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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 participant 
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.
9.2
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 Electronic Case Report Forms 
(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, 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.
9.3
Data collection
This study will use 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 
PK samples and/or data, and ePRO data will be processed 
centrally and the results will be sent electronically to Novartis as described in the Data Transfer 
Specification.


Novartis
Confidential
Page 117 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated 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.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis personnel (or designated CRO).
Randomization codes and 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 the treatment codes 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.
10
Statistical methods and data analysis
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure.




Novartis
Confidential
Page 119 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and
summarized descriptively by treatment group for the FAS and the CAS where applicable.
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 treatment group.
Baseline for safety endpoints (except adverse events), 
patient reported 
outcomes is defined as the last assessment prior to or on the treatment start date.
For evaluations after cross over, the baseline is defined as the last assessment prior to or on the 
start date of cross over treatment.
Baseline for other endpoints is defined as the last assessment or procedure conducted prior to 
or on the randomization date.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
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 and BAT will be summarized by means of 
descriptive statistics. The dose intensity for the ruxolitinib arm (computed as the ratio of actual 
cumulative dose received and actual duration of exposure) will be summarized by means of 
descriptive statistics using the safety set.
Patients randomized to Investigator’s choice of BAT will receive various different categories 
of therapy. Since the units for administration will differ depending on the treatment 
administered for BAT, dosage summaries will not be calculated for the BAT arm.
For both treatment arms, corticosteroid exposure and tapering will be summarized.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized for the ruxolitinib arm 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 treatment group.
10.4
Primary objective
The primary objective is to compare the efficacy of ruxolitinib vs. BAT as assessed by overall 
response rate (ORR) Cycle 7 Day 1.


Novartis
Confidential
Page 120 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
10.4.1
Variable
The primary efficacy variable of the study is overall response rate (ORR) at Cycle 7 Day 1, 
defined as the proportion of patients with complete response (CR) or partial response (PR), 
according to the NIH Consensus Criteria (Lee 2015). Note that response is relative to the 
assessment of cGvHD at randomization.

Complete response is defined as complete resolution of all signs and symptoms of cGvHD 
in all evaluable organs without initiation or addition of new systemic therapy.

Partial response is defined as an improvement in at least one organ (e.g. improvement of 
1 or more points on a 4 to 7 point scale, or an improvement of 2 or more points on a 10 to 
12 point scale) without progression in other organs or sites, initiation or addition of new 
systemic therapies.

Lack of response is defined as unchanged, mixed response, or progression.
cGvHD Flare is defined as any increase in symptoms or therapy for cGvHD after an initial 
response (CR or PR). A cGvHD flare is not considered a treatment failure unless a change of 
therapy or addition of another systemic salvage treatment occurs.
cGvHD Recurrence is defined as the return of cGvHD disease after tapering off study 
treatment due to response. Following completion of a taper of systemic therapy, if worsening 
of cGvHD symptoms occur, the patient is allowed to resume treatment for cGvHD as per local 
institutional practice. For the statistical analyses re-start of treatment for cGvHD is handled in 
the same way as addition or initiation of new systemic treatment.
10.4.2
Statistical hypothesis, model, and method of analysis
The following statistical hypotheses will be tested to address the primary efficacy objective:
H0: ORRrux ≤ ORRBAT vs. H1: ORRrux > ORRBAT
where ORRrux and ORRBAT are the overall response rates at Cycle 7 Day 1 in the ruxolitinib 
and BAT groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor (i.e., cGvHD moderate vs severe), will be used to compare 
ORR between the two treatment groups, at the one-sided 2.5% level of significance.
The primary efficacy variable, ORR at Cycle 7 Day 1, will be analyzed at the time when all 
patients have completed their Cycle 7 Day 1 visit or discontinued earlier. The primary analysis 
will be performed on FAS according to ITT principle. ORR and its 95% confidence interval 
will be presented by treatment group. P-value, odds ratio and 95% Wald confidence limits 
calculated from stratified Cochran-Mantel-Haenszel test will also be presented.
10.4.3
Handling of missing values/censoring/discontinuations
Patients with missing assessments that prevent the evaluation of the primary endpoint will be 
considered non-responders on that treatment arm. This includes missing cGvHD assessments 
at baseline and Cycle 7 Day 1.


Novartis
Confidential
Page 121 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
No data imputation will be applied. Patients who discontinue study treatment should return for 
the regular assessments indicated in Section 7.1. Addition or initiation of a new systemic 
therapy before Cycle 7 Day 1 in any arm will be considered a treatment failure, and patients 
will be counted as non-responder in the primary analysis.
10.4.4
Supportive and Sensitivity analyses
Supportive analysis will include:

A detailed description of response rates (CR, PR. Unchanged, mixed response and 
progression) at Cycle 7 Day 1 by treatment group

ORR at Cycle 7 Day 1 evaluated with the same analysis conventions as for the primary 
efficacy analysis using all patients in the PPS.

A detailed description of the organ specific response for all organs at Cycle 7 Day 1.
If the primary analysis is statistically significant, subgroup analyses to assess the homogeneity 
of the treatment effect across demographic and baseline disease characteristics will be 
performed. The subgroups include but are not limited to:

Age group: 12-17 (adolescent) vs. 18-65 (adult) vs. > 65 (elderly)

Gender

Race

Region Europe (including Australia and Canada), US, Asia, Japan

Chronic GvHD severity (moderate vs. severe)

Source of grafts

Criteria for SR-cGvHD (progression after 7 days, failure to achieve a response after 4 weeks, 
increase in corticosteroids after 2 unsuccessful attempts to taper, significant steroid-related 
toxicity)

Prior cGvHD therapy (corticosteroid only vs. corticosteroid ± CNI)
10.5
Secondary objectives
The secondary objectives in this study include the assessment of: Failure free survival (FFS), 
the modified Lee symptoms score, ORR at Cycle 4 Day 1 (end of Cycle 3), duration of response, 
Overall survival (OS), Non Relapse Mortality (NRM), Incidence of Malignancy 
Relapse/Recurrence (MR), reduction and successful tapering of corticosteroid treatment, 
Pharmacokinetics, PROs and safety.
10.5.1
Key secondary objective(s)
The regulatory recommendations for demonstrating additional benefit to patients with SR-
GvHD differ between US and ROW: whereas the CHMP/PMDA agreed that FFS could be a 
meaningful measure of clinical benefit, the FDA recommended improvement in patient reported 
outcomes. Therefore, this study will have two key secondary objectives:




Novartis
Confidential
Page 123 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
The second key secondary objective (all regions except for US) is to assess the improvement of 
symptoms based on the total symptom score (TSS) using the modified Lee Symptom Scale. A 
responder is defined as having achieved a clinically relevant reduction from baseline of the total 
symptom score (TSS). Details will be described in the statistical analysis plan (SAP).
The rate of TSS responders and its 95% confidence interval will be presented by treatment 
group. The Cochrane-Mantel-Haenszel chi-square test, stratified by the randomization 
stratification factors (i.e. cGvHD moderate vs severe), will be used to compare TSS response 
rates between the two treatment groups, at the one-sided 2.5% level of significance.
Supportive analyses
The FFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 3, 6, 12, 18 and 24 month FFS estimates and 95% confidence intervals
(Brookmeyer and Crowley 1982) will be presented for each treatment group. The hazard ratio 
for FFS will be calculated, along with its 95% confidence interval, using a stratified Cox model.
The cumulative incidence curve of each of the three FFS components (considering the other 
two components as a competing risk) as well as estimates at 3, 6, 12, 18 and 24 months will 
also be presented with 95% confidence intervals.
10.5.2
Other secondary efficacy objectives
Best overall response (BOR)
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 Cycle 7 day 1 and before the start of additional 
systemic therapy for cGvHD.
BOR and its 95% confidence interval will be presented by treatment group. P-value, odds ratio 
and 95% Wald confidence limits calculated from stratified Cochran-Mantel-Haenszel test will 
also be presented.
ORR at Cycle 4 Day 1 (end of Cycle 3)
ORR at Cycle 4 Day 1 and its 95% confidence interval will be presented by treatment group. 
P-value, odds ratio and 95% Wald confidence limits calculated from stratified Cochran-Mantel-
Haenszel test will also be presented.
Duration of Response
Duration of response (DOR) is assessed for responders only. DOR is defined as the time from 
first response until cGvHD progression, death, or the date of additional systemic therapies for 
cGvHD. Patients without event will be censored at the last contact date. Kaplan-Meier method 
and the Kaplan-Meier curves, medians, 3, 6, 12, 18 and 24 months survival probabilities with 
95% confidence intervals will be presented.


Novartis
Confidential
Page 124 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Overall survival (OS)
OS will be analyzed according to the randomized treatment group and strata assigned at 
randomization (cGvHD moderate vs severe). The OS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians, 3, 6, 12 and 24 month survival 
probabilities and 95% confidence intervals (Brookmeyer and Crowley 1982) will be presented 
for each treatment group. The hazard ratio for OS will be calculated, along with its 95% 
confidence interval, using a stratified Cox model.
Non Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time from date of randomization to date of death 
not preceded by underlying disease relapse/recurrence. Cumulative incidence of NRM and 
derived probabilities at Months 1, 2, 6, 12, 18 & 24 will be estimated, considering underlying
disease relapse/recurrence as competing events.
Incidence of Malignancy Relapse/Recurrence (MR)
The cumulative incidence curve for MR and estimates at 3, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented 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/recurrence and its 95% confidence interval at 3, 6, 12, 18 
and 24 months will be presented by treatment group for patients with underlying hematologic 
malignant disease. Odds ratio and 95% Wald confidence limits calculated from stratified 
Cochran-Mantel-Haenszel test will be also presented.
Reduction of daily corticosteroid dose and successful tapering of all 
corticosteroids
This will include the assessment of

proportion of patients with ≥50% reduction in daily corticosteroid dose at Cycle 7 Day 1

proportion of patients successfully tapered off all corticosteroids at 6 months
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose of 
study medication
2. On-randomized treatment period: from day of first dose of study medication to 30 days after 
date of last actual administration of randomized treatment (including start and stop date) or 
end of randomized treatment per end of randomized treatment disposition eCRF, whichever 
is later. For those patients who cross over from BAT to ruxolitinib, the period is from day 
of first dose of randomized study medication to earlier of (i) 30 days after last dose of 
randomized study medication, (ii) the day before first dose of cross over treatment


Novartis
Confidential
Page 125 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
3. On-cross over treatment period: from day of first dose of cross over study medication to 30 
days after last dose of cross over study medication
4. Post-treatment period: starting at day 31 after last dose of study medication.
The main comparative safety analyses will be performed for the time period from the day of the 
first dose up to Cycle 7 Day 1 to avoid potential bias due to different exposure durations related 
to possible cross over from BAT to ruxolitinib after Cycle 7 Day 1. Furthermore, separate safety 
summaries will be generated for the no-randomized treatment period and the on-cross over 
treatment period.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period (either randomized or cross-over period), the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI)
during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
10.5.3.3 Laboratory abnormalities
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. Grade 5 
will not be used.
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 generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE v4.03
grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value


Novartis
Confidential
Page 126 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
For laboratory tests where grades are not defined by CTCAE v4.03

Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the analysis plan.
10.5.3.4 Other safety data
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.
Pediatric data
Pediatric data will be tabulated and listed, notable values will be flagged.
10.5.4
Pharmacokinetics
Pharmacokinetic analysis set (PAS) will be used in all pharmacokinetic data analysis and PK 
summary statistics.
For patients with the “extensive PK” sampling scheme, PK parameters of ruxolitinib will be 
calculated using non-compartmental methods using Phoenix WinNonlin (Pharsight, Mountain 
View, CA) software. Additional PK parameters may be estimated as needed.
Table 10-1
Noncompartmental pharmacokinetic parameters
AUClast
The AUC (area under the concentration-time curve) from time zero to the last measurable 
concentration sampling time (Tlast) (mass x time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-
1)
Cmax
The maximum (peak) observed plasma drug concentration after single dose administration (mass 
x volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration after single dose administration 
(time)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for terminal 
elimination rate constant (time-1)
T1/2
The elimination half-life associated with the terminal slope (Lambda_z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL/F
The total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with Lambda_z) (volume)
Pharmacokinetic variables:
The following pharmacokinetic parameters will be determined using non-compartmental 
method(s) for ruxolitinib in patients with “extensive PK” sampling:
AUCinf, AUCtau, Cmax, Tmax, T1/2, CL/F and Vz/F.


Novartis
Confidential
Page 127 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Statistical methods for pharmacokinetic analyses
Ruxolitinib concentrations data will be listed by treatment and dose. Descriptive summary 
statistics will be provided by treatment and dose at each scheduled time point. Summary 
statistics will include n (number of patients with non-missing values), mean (arithmetic and 
geometric), standard deviation (SD), coefficient of variation (CV%) (arithmetic and geometric), 
median, minimum and maximum. Individual profiles with median by treatment 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 treatment and dose. Descriptive 
statistics (n, arithmetic mean, SD, CV% for mean, geometric mean, geometric CV%, median, 
minimum and maximum) will be provided for all PK parameters by treatment and dose except 
for Tmax where median, minimum and maximum will be presented.
The potential impact of occurrence and severity of GI GvHD on ruxolitinib pharmacokinetic 
parameters will be explored.
Population PK approach
The population pharmacokinetics of study treatment is likely to be adequately described by a 2 
compartment structural pharmacokinetic model with either a zero or a first order absorption 
model. While all concentration measurements will be modeled, clearly outlying observations 
that have a strong influence on the estimated parameters will be excluded. The dependence is 
to be explored. The choice of covariates to be tested in the model will be guided by exploratory 
plots of random effects (inter-individual variability parameters). Those that are judged to show 
evidence of a relationship with the random effects will be tested for entry into the model, using 
the likelihood-ratio test with p < 0.05. The final covariate model will be derived using a rigorous 
and acceptable model building procedure. The population PK analysis will be reported 
separately.
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).
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 in terms of concentration-
effect and dose-effect (effect: overall response rate at Month 3 and 6; Overall survival at 3, 
6 and 12 months)

Characterize the exposure-safety relationship of ruxolitinib in terms of concentration-AEs 
and/or dose-AEs (AEs: frequency of AEs, severity of AEs, AEs of interest).

Average steady-state exposures and/or other PK parameters for the population will be 
derived from observed values (e.g. trough concentrations) or computed (e.g. by population 
PK analysis model accounting for dose modifications or dose interruptions up to the day 
prior to the day of assessments). Derived PK parameters will be used for exposure-response 
analysis by logistic regression or other methods.








Novartis
Confidential
Page 131 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 10-2
Operational characteristics at the interim analysis
With 194 patients (60%) patients and final analysis
No. of 
patients 
(percent)
Alpha spent#
(cumulative)
Required 
odds ratio 
for 
significance 
(if design 
assumption 
correct) 
Corresponding 
ORR for Rux (if 
assumed ORR 
for BAT correct)
Simulated rejection rates 
under H1 (cumulative)
Reject H0
Reject H1
assuming ORR for BAT=0.58 (58%), odds ratio=2.35
Interim 
analysis 
194 (59.9)
0.12
2.05
73.88%
66.37%
0%
Final 
analysis
324 (100)
0.25
1.66
69.65%
93.34%
6.66%
assuming ORR for BAT=0.62 (62%), odds ratio=2.35
Interim 
analysis 
194 (59.9)
0.12
2.10
77.39%
62.94%
0%
Final 
analysis
324 (100)
0.25
1.69
73.39%
91.64%
8.36%
assuming ORR for BAT=0.66 (66%), odds ratio=2.35
Interim 
analysis 
194 (59.9)
0.12
2.17
80.79%
59.25%
0%
Final 
analysis
324 (100)
0.25
1.73
77.05%
89.36%
10.64%
Based on sequential CMH test with one-sided cumulative alpha=2.5% (assuming same ORR and 50% of 
patients in each stratum)
#derived from alpha spending function (rho spending function with rho=1.5)
Early PK analysis
The early “extensive PK” data of ruxolitinib from the first 8 patients (adult and any adolescents 
randomized at the time) will be explored. This will allow for comparison of the exposure of 10 
mg BID in the SR cGvHD population to the known exposure in other indications at the same 
dose level. The data will also be explored in the context of concomitant medications. However 
in this study there will be no comparison between the ruxolitinib treatment arm and the BAT 
treatment arm since there is no PK collected for BAT.
10.8
Sample size calculation
The sample size calculation is based on the primary variable ORR on Cycle 7 Day 1. In a meta-
analysis Olivieri et al. (Lancet Hematology 2015) obtained an estimated pooled effect size for 
ORR for systemic treatment of SR-cGvHD of 0·66 (95% CI 0·62–0·70). However, as most 
studies in this analysis did not use objective response criteria it can be expected that application 
of the NIH Consensus to assess ORR on Cycle 7 Day 1 would lead to lower response rates. 
Sample size calculations were performed to achieve 90% power for different scenarios 
(Table 10-3), assuming a targeted odds ratio of 2.35 and 2.5, respectively. A sample size of 324 
patients is considered as reasonable for this study.


Novartis
Confidential
Page 132 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
With sample size 162 patients in each treatment arm and assuming that the assumptions made 
for sample size calculations are correct (e.g. ORR=0.66 on Cycle 7 Day 1 for BAT for each 
stratum) an observed odds ratio greater than or equal to 1.68 would achieve statistical 
significance.
Table 10-3
Sample size for different scenarios
BAT ORR
Ruxolitinib ORR
Odds ratio1 
Total sample size*
0.58
0.775
2.5
N=247
0.62
0.803
2.5
N=265
0.66
0.829
2.5
N=289
0.58
0.764
2.35
N=278
0.62
0.793
2.35
N=298
0.66
0.820
2.35
N=324
*based on stratified CMH test with one-sided alpha=2.5% (assuming same ORR and 50% of patients in each 
stratum)
10.9
Power for analysis of key secondary variables
The 6-month FFS estimate based on published work is expected to be 0.56 (Inamoto 2013). It
is assumed that treatment with ruxolitinib might reduce the risk of FFS with expected hazard
ratio = 0.64 (considering a 6 months FFS rate of 0.69 for ruxolitinib and 0.56 for BAT).
To ensure 90% power for a one-sided log rank test with α=2.5% significance level a total 
numbers of 212 FFS events would be required. Assuming that enrolment will continue for 18 
months with increasing enrolment during the first 6 months and at a uniform rate about 20 
patients per month thereafter, a total of N=312 patients would needed to be randomized to 
observe the targeted 212 FFS events at about 25 months after the randomization date of the first 
patient. Thus the targeted sample size of N=324 patients is considered adequate for the analysis 
of FFS.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. 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
Confidential
Page 133 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after the patient or a parent or legal guardian 
provides written (witnessed, where required by law or regulation), 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 eCRFs.
The study sponsor will provide to investigators, in a separate document, a proposed informed 
consent form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by the study sponsor 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.
Women 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.
Additional consent form
Not applicable
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion.


Novartis
Confidential
Page 134 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 


Novartis
Confidential
Page 135 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to the Sponsor. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
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.
12.1
Amendments to the protocol
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.


Novartis
Confidential
Page 136 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
13
References (available upon request)
Ahmed, S.S., Wang, X.N., Norden, J., et al, (2015) Identification and validation of biomarkers 
associated with acute and chronic graft versus host disease. Bone marrow transplantation. 
Dec;50(12):1563-71
Baird K, Cooke K, Schultz KR. (2010) Chronic graft-versus-host disease (GVHD) in children. 
Pediatr Clin North Am. Feb;57(1):297-322
Betts, B.C., Sagatys, E.M., Veerapathran, A., et al. (2015) CD4+ T cell STAT3 phosphorylation 
precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity 
and therapeutic response. Journal of leukocyte biology, 97(4), pp.807-819.
Betts, B.C., Abdel-Wahab, O., Curran, S.A., et al (2011) Janus kinase-2 inhibition induces 
durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves 
immunity to recall antigen. Blood, 118(19):5330-5339.
Boiko, J., Wahlstrom, J., Dvorak, C., et al. (2017). Ruxolitinib in Pediatric Patients with Severe 
or Refractory Graft-Versus-Host Disease: A Single-Institution Case Series. Pediatric Blood and 
Cancer. 64: S5-S5.
Briones J, Novelli S, Sierra J. (2011) T-cell costimulatory molecules in acute-graft-versus host 
disease: therapeutic implications. Bone Marrow Res;2011:976793
Brookmeyer R, Crowley J. (1982) A K-sample median test for censored data. Journal of the 
American Statistical Association. 77:433–440.
Brüggen MC, Klein I, Greinix H, et al. (2014) Diverse T-cell responses characterize the 
different manifestations of cutaneous graft-versus-host disease. Blood; 123(2):290–299.
Cella, D. F., (1992) Effect of Cancer on Quality of Life. Quality of Life Research 1.5 353-353.
Čokić, V.P., Mitrović-Ajtić, O., Beleslin-Čokić, B.B., et al. (2015) Proinflammatory cytokine 
IL-6 and JAK-STAT signaling pathway in myeloproliferative neoplasms. Mediators of 
inflammation.
Dhir S, Slatter M, and Skinner R. (2014) Recent advances in the management of graft-versus-
host )disease. Arch Dis Child 2014;0:1–8.
Dignan F, Amrolia P, Clark A, et al. (2012) Diagnosis and management of chronic graft-versus-
host disease. Br J Haematol. 2012;158:46–61.
The EuroQol Group. (1990) EuroQol-a new facility for the measurement of health-related 
quality of life. Health Policy 16(3):199-208.
Fiuza-Luces C, Simpson R, Ramirez M et al. (2016) Physical function and quality of life in 
patients with chronic graft-versus-host disease: A summary of preclinical and clinical studies 
and a call for exercise intervention trials in patients. Bone Marrow Transplant. 51(1):13-26
Flowers ME, Inamoto Y, Carpenter PA, et al. (2011) Comparative analysis of risk factors for 
acute graft-versus-host disease and for chronic graft-versus-host disease according to National 
Institutes of Health consensus criteria. Blood. 117(11):3214-9
Flowers M, Martin PJ. (2015) How we treat chronic graft-versus-host disease. Blood. 125:606-
615


Novartis
Confidential
Page 137 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Greinix H, Loddenkemper C, Pavletic S, et al. (2011) Diagnosis and staging of chronic graft-
versus-host disease in the clinical practice. Biol Blood Marrow Transplant.; 17: 167-175
Herdman M, Gudex C, Lloyd A et al (2011).Development and preliminary testing of the new 
five-level version of EQ-5D(EQ-5D-5L).Qual Life Res; 20:1727-1736
Hurabielle, C, Sicre de Fontbrune, F, Moins Teisserenc, H, et al. (2017) Efficacy and tolerance 
of ruxolitinib in refractory sclerodermatous chronic Graft Versus Host Disease. British Journal 
of Dermatology. Accepted Author Manuscript. doi:10.1111/bjd.15593
Inamoto Y, Flowers ME, Sandmaier BM, et al. (2014) Failure-free survival after initial systemic 
treatment of chronic graft-versus-host disease. Blood;124(8):1363-71
Inamoto Y, Chai X, Kurland BF, et al. (2012) Validation of measurement scales in ocular graft-
versus-host disease. Ophthalmology.;119:487-493.
Inamoto Y, Martin PJ, Chai X, et al. (2012) Clinical benefit of response in chronic graft-versus-
host disease. Biol Blood Marrow Transplant.; 18:1517-1524.
Jacobsohn DA, Rademaker A, Kaup M, Vogelsang GB. Skin response using NIH consensus 
criteria vs Hopkins scale in a phase II study for steroid refractory chronic GVHD. Bone Marrow 
Transplant. 2009;44:813-819.
Jacobsohn, D.A., (2010) Optimal management of chronic graft-versus-host disease in children. 
British journal of haematology, 150(3):278-292.
Jagasia, M.H., Greinix, H.T., Arora, M., et al. (2015) National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 
2014 Diagnosis and Staging Working Group report. Biology of Blood and Marrow 
Transplantation, 21(3):389-401.
Kaufman, G.P., Aksamit, A.J., Klein, C.J., et al. (2014) Progressive multifocal 
leukoencephalopathy: a rare infectious complication following allogeneic hematopoietic cell 
transplantation (HCT). European journal of haematology, 92(1):83-87.
Khoury, H.J., Kota, V., Arellano, M., et al. (2015) Ruxolitinib as sparing agent for steroid-
dependent chronic graft-versus-host disease (cGVHD). Blood, 126(23):1938-1938.
Lee J, Choi S, Kim S et al. (2003) Graft-versus-host disease (GVHD)-specific survival and 
duration of systemic immunosuppressive treatment in patients who develop chronic GVHD 
following allogeneic hematopoietic cell transplantation. Br J Haematol.;122(4):637-44
Lee, S.J., Cook, E.F., Soiffer, R. and Antin, J.H., (2002) Development and validation of a scale 
to measure symptoms of chronic graft-versus-host disease. Biology of Blood and Marrow 
Transplantation, 8(8):444-452.
Lee, S.J. and Flowers, M.E., (2008) Recognizing and managing chronic graft-versus-host 
disease. ASH Education Program Book, (1):134-141.
Lee, S.J., Wolff, D., Kitko, C., et al. (2015) Measuring therapeutic response in chronic graft-
versus-host disease. National Institutes of Health consensus development project on criteria for 
clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working 
Group report. Biology of Blood and Marrow Transplantation, 21(6):984-999.
Loh, M.L., Tasian, S.K., Rabin, K.R., et al. (2015) A phase 1 dosing study of ruxolitinib in 
children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: 


Novartis
Confidential
Page 138 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
A Children's Oncology Group phase 1 consortium study (ADVL1011). Pediatric blood & 
cancer, 62(10):1717-1724.
Martin, P.J., Lee, S.J., Przepiorka, D., et al. (2015) National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: VI. The 
2014 Clinical Trial Design Working Group report. Biology of Blood and Marrow 
Transplantation, 21(8):1343-1359.
Matsuda K, Yamauchi K, Tozuka M, et al. (2004) Monitoring of hematopoietic chimerism by 
short tandem repeats, and the effect of CD selection on its sensitivity. Clin Chem; 50(12): 2411-
4.
McQuellon, R.P., Russell, G.B., Cella, D.F., et al. (1997) Quality of life measurement in bone 
marrow transplantation: development of the Functional Assessment of Cancer Therapy-Bone 
Marrow Transplant (FACT-BMT) scale. Bone marrow transplantation, 19(4):357-368.
Merkel, E.C., Mitchell, S.A. and Lee, S.J., (2016) Content validity of the Lee Chronic Graft-
versus-Host Disease Symptom Scale as assessed by cognitive interviews. Biology of Blood and 
Marrow Transplantation, 22(4):752-758.
NICE. (2013) Guide to the Methods of Technology Appraisal 2013. London: National Institute 
for Health and Care Excellence.
Niederwieser, D., Baldomero, H., Szer, J., et al. (2016) Hematopoietic stem cell transplantation 
activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and 
Marrow Transplantation Group including the global survey. Bone marrow transplantation, 
51(6), pp.778-785.
Olivieri, A., Cimminiello, M., Corradini, P., (2013) Long-term outcome and prospective 
validation of NIH response criteria in 39 patients receiving imatinib for steroid-refractory 
chronic GVHD. Blood, 122(25):4111-4118.
Olivieri, J., Manfredi, L., Postacchini, L., Tedesco, S., Leoni, P., Gabrielli, A., Rambaldi, A., 
Bacigalupo, A., Olivieri, A. and Pomponio, G., 2015. Consensus recommendations for 
improvement of unmet clinical needs—the example of chronic graft-versus-host disease: a 
systematic review and meta-analysis. The Lancet Haematology, 2(7), pp.e297-e305.
Omland, S.H., Gniadecki, R., Hædersdal, M., et al (2016) Skin cancer risk in hematopoietic 
stem-cell transplant recipients compared with background population and renal transplant 
recipients: a population-based cohort study. JAMA dermatology, 152(2):177-183.
Palmer J, Pidala J, Inamoto Y, et al. (2016) Predictors of survival, nonrelapse mortality, and 
failure-free survival in patient streated for chronic graft-versus-host disease. Blood. 127(1):160-
6
Pavletic, S. Z., Martin, P., Lee, S. J. et al. (2006) Measuring Therapeutic Response in Chronic 
Graft-versus-Host Disease: National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria 
Working Group Report. Biology of Blood and Marrow Transplantation, 21(6):984-999.
Rabin, R. and Charro, F.D. (2001) EQ-SD: a measure of health status from the EuroQol Group. 
Annals of medicine, 33(5), pp.337-343.
Rabin, R., Oemar, M. and Oppe, M., (2011) EQ-5D-5L user guide: basic information on how 
to use the EQ-5D-5L instrument. EuroQoL Group. Rotterdam, The Netherlands.




Novartis
Confidential
Page 140 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14
Appendices
14.1
Appendix 1: Infection Severity Grading
Table 14-1
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.


Novartis
Confidential
Page 141 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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
Clinically documented 
infection not requiring 
inpatient management
Pneumonia or 
bronchopneumonia not 
requiring mechanical 
ventilation
Any acute pneumonia 
requiring mechanical 
ventilation


Novartis
Confidential
Page 142 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Type of Infection/ 
Severity Grade
Grade 1
Grade 2
Grade 3
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


Novartis
Confidential
Page 143 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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
Renal:

Serum creatinine > 2 x ULN for age or 2-fold increase in baseline creatinine
Hepatic:

Total bilirubin > 4 mg/dL or

ALT >2 x ULN for age
Table 14-2
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.






















Novartis
Confidential
Page 154 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14.4
Appendix 4: Guidelines for response assessment in cGvHD
14.4.1
Introduction and scope
The response assessment described in this appendix is based on the National Institutes of Health 
(NIH) guideline to measure ‘therapeutic response in Chronic Graft-versus-Host Disease’ 
published by Lee et al (2015). These response criteria will be referred to as NIH criteria.
The objective of this appendix is to provide details on the implementation of the NIH criteria 
in study CINC424D2301.
14.4.2
Efficacy Assessments - Organ specific response at one time point
Chronic Graft-versus-Host Disease may impact different organs. The involvement of each 
organ needs to be assessed at baseline and response will be assessed at each pre-specified post-
baseline visit (e.g. at Cycle 7 day 1 for the primary endpoint ORR response at month 6) during 
the study.
Response determination for all organs is defined in Table 4 of the published NIH response 
criteria (Lee 2015). For an overall response assessment it is required to assess the status of all 
organs at each time point, including those organs which are not involved at baseline.
Table 14-3 below displays the NIH response criteria by organ and introduces the response 
category ‘unchanged/no involvement’ which is in line with the published NIH criteria. Further 
details and examples for the assessment of liver, lung, joints and fascia and skin are given in 
the text below.
14.4.2.1 Liver
Liver response assessment is based on the following biochemistry lab parameters: Alanine 
aminotransferase (ALT), alkaline phosphatase (AP) and total bilirubin (BILI).
Observed lab values and corresponding ULN at baseline should be documented. Observed post-
baseline values will be compared to observed baseline values in order to determine the liver 
response for the post-baseline visit. The steps to apply the rules per NIH criteria and some 
examples are displayed in Figure 14-1, Figure 14-2 and Figure 14-3.
Example 1 (Figure 14-2):

At baseline ALT and AP are increased (> ULN) and BILI is within the normal range.

At the post-baseline visit ALT and BILI are within the normal ranges and the value of AP 
decreased from baseline by 56%: Therefore, the liver response for this visit is assessed as 
‘partial response (PR)’
Example 2 (Figure 14-3):

At baseline Alkaline Phosphatase (AP) is increased (> ULN), whereas ALT and BILI are 
within the normal range.

At the post-baseline visit all 3 parameters are increased (> ULN) but the absolute increase 
for each of the parameters is less than the corresponding value of 2 x ULN. Therefore, the 
week 4 liver response is considered as ‘unchanged’ from baseline.


Novartis
Confidential
Page 155 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
Table 14-3
Response determination for chronic GvHD by organ at post-baseline assessment (comparison vs. baseline)
Organ
Complete response1
Partial response1
Progression1
No involvement/unchanged
Baseline
Post-baseline
Skin
NIH Skin Score 0 after previous 
involvement
Decrease in NIH Skin Score by 
1 or more points
Increase in NIH Skin Score by 1 
or more points, except 0 to 1
Score = 0 
Score = 0 or 1
Equal Scores at both time points
Eyes 
NIH Eye Score 0 after previous 
involvement
Decrease in NIH Eye Score by 
1 or more points
Increase in NIH Eye Score by 1 
or more points, except 0 to 1
Score = 0 
Score = 0 or 1
Equal Scores at both time points
Mouth 
NIH Modified OMRS 0 after 
previous involvement
Decrease in NIH Modified 
OMRS of 2 or more points
Increase in NIH Modified OMRS 
of 2 or more points
Equal OMRS at both time points 
(including Score=0) or change of OMRS 
from baseline less than 2 points 
Esophagus
NIH Esophagus Score 0 after 
previous involvement
Decrease in NIH Esophagus 
Score by 1 or more points
Increase in NIH Esophagus Score 
by 1 or more points, except 0 to 1
Score = 0 
Score = 0 or 1
Equal Scores at both time points
Upper GI
NIH Upper GI Score 0 after 
previous involvement
Decrease in NIH Upper GI 
Score by 1 or more points
Increase in NIH Upper GI Score 
by 1 or more points, except 0 to 1
Score = 0 
Score = 0 or 1
Equal Scores at both time points
Lower GI
NIH Lower GI Score 0 after 
previous involvement
Decrease in NIH Lower GI 
Score by 1 or more points
Increase in NIH Lower GI Score 
by 1 or more points, except from 
0 to 1
Score = 0 
Score = 0 or 1
Equal Scores at both time points
Liver
Normal ALT, alkaline 
phosphatase, and Total bilirubin 
after previous elevation of 1 or 
more
Decrease by 50% 
Increase by 2 x ULN
See text
Lungs
Normal %FEV1 after previous 
involvement
Increase by 10% predicted 
absolute value of %FEV1
Decrease by 10% predicted 
absolute value of %FEV1
Change of %FEV1 from baseline < 10% 
(see text for additional rules)
Joints and 
fascia 
Both NIH Joint and Fascia
Score 0 and P-ROM score
25 after previous involvement
by at least 1 measure
Decrease in NIH Joint and 
Fascia Score by 1 or more 
points or increase in P-ROM 
score by 1 point for any site
Increase in NIH Joint and Fascia 
Score by 1 or more points or 
decrease in P-ROM score by 1 
point for any site
J&F Score=0 and 
P-ROM Score=25
J&F Score=0 and 
P-ROM Score=25
Any situation that does not qualify for 
response or progression (see text)
1 response definition as per Table 4 in the published NIH criteria, see Lee et al (2015), ULN indicates upper limit of normal
 
 
 
 
 
 
 








Novartis
Confidential
Page 159 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14.4.2.2 Lung
Response assessment for Lung will be based on %FEV1.

A patient with baseline value %FEV1 ≥ 75% is considered as having no lung involvement

A post-baseline value of %FEV1>80% is defined as ‘Complete Response’ if the baseline 
value was %FEV < 75%, irrespective of the percent increase.

Partial response: Increase of absolute value of %FEV1 of 10% or more from baseline (only 
if %FEV1 < 70% at baseline) and not CR

Progression: Absolute value of %FEV1 < 65% and decrease of 10% or more from baseline

Unchanged: any situation not covered by the three bullet points above
Handling of missing data:

If baseline %FEV1 is missing and the post-baseline %FEV1 ≥ 75% the lung response for 
that post-baseline visit is to be assigned to ‘unchanged/no involvement’.

If baseline %FEV1 is missing and Lung Score = 0 at baseline and the post-baseline %FEV1 
< 65% the lung response for that post-baseline visit should be assigned a ‘progression’.
14.4.2.3 Joints and fascia
NIH Joint and Fascia score as well as P-ROM score are evaluated.
Involvement at baseline is defined as NIH Joint and Fascia score ≥ 1
A decrease (i.e. worsening) of any site in P-ROM is considered as progression (irrespective of 
the change in the NIH Joints and Fascia score). Similarly, an increase (worsening) in the NIH 
Joints and Fascia score is considered as progression (irrespective of the change in any of the 4 
P-ROMs)
Accordingly, a partial response is only possible if:

at least one site in P-ROM increased by 1 or more points

and all other sites remain unchanged compared to baseline

and NIH Joints and Fascia score is equal to or decreased from baseline
OR

Decrease of the NIH Joints and Fascia Score from baseline with NO worsening in P-ROM 
for any site




Novartis
Confidential
Page 161 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14.4.2.4 Skin
The skin score is based on the Body Surface Area (BSA) and the involvement of sclerotic 
features. Table 14-4 list the criteria to be applied to assess the skin score at baseline and at each 
post-baseline visit, response assessment is to be performed according to the criteria defined in 
Table 14-3.
Table 14-4
Assessment of the skin score based on BSA and sclerotic features
Total BSA
involved (%)
Score
%BSA
Sclerotic 
involvement?
Type of slerotic involvemet
Skin 
feature 
score
Skin 
Score1
none
0
no
NA
0
0
1-18%
1
no
NA
0
1
1-18%
1
yes
Superficial only
(able to pinch)
2
2
1-18%
1
yes
Unable to pinch (“Hidebound”)
Deep sclerotic features
Impaired mobility
Ulceration
3
3
19 – 50%
2
No 
NA
0
2
19 – 50%
2
yes
Superficial only
(able to pinch)
2
2
19 – 50%
2
yes
Unable to pinch (“Hidebound”)
Deep sclerotic features
Impaired mobility
Ulceration
3
3
More than 
50%
3
no
NA
0
3
More than 
50%
3
yes
Superficial only
(able to pinch)
2
3
More than 
50%
3
yes
Unable to pinch (“Hidebound”)
Deep sclerotic features
Impaired mobility
Ulceration
3
3
1 Overall skin score to be used for the response assessment taken as worst of Score for %BSA and Skin 
feature score 
14.4.3
Efficacy Assessments - Overall response assessment at one time 
point
Following the NIH working group recommendations the overall response evaluation (at each 
scheduled post-baseline time point/assessment) will be based on the evaluations for skin, eyes, 
mouth, esophagus, upper GI, lower GI, liver, lungs and joints/fascia. For each post-baseline 
assessment comparison will be made to baseline.

Complete response is defined as complete resolution of all signs and symptoms of cGvHD 
in all evaluable organs without addition of new systemic therapy.

Partial response is defined as an improvement in at least one organ (e.g. improvement of 1 
or more points on a 4 to 7 point scale, or an improvement of 2 or more points on a 10 to 12 
point scale) without progression in other organs or sites, or initiation/addition of new 
systemic therapies.


Novartis
Confidential
Page 162 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301

Lack of response is defined as unchanged, mixed response, or progression.

Progression is defined as worsening of at least one organ an no improvement (CR or PR) in 
any other organ

Mixed response is a CR or PR in at least 1 organ accompanied by progression in another
organ

Unchanged response is defined as stable disease or absence of improvement in any organ 
involved by cGvHD
cGvHD Flare: is defined as any increase in symptoms or therapy for cGvHD after an initial 
response (CR or PR). A cGvHD flare is not considered a treatment failure unless a change of 
therapy or addition of another systemic salvage treatment occurs.
cGvHD Recurrence is defined as the return of cGvHD disease after tapering off study treatment 
due to response. Following completion of a taper of systemic therapy, if worsening of cGvHD 
symptoms occur, the patient is allowed to resume treatment for cGvHD as per local institutional 
practice. For the statistical analyses re-start of treatment for cGvHD is handled in the same way 
as addition or initiation of new systemic treatment.
Table 14-5 summarizes the rules for overall response assessment based on organ specific 
evaluations at a scheduled post-baseline visit (e.g. the primary endpoint at Month 6 – Cycle 7 
Day 1).
Table 14-5
Overall response evaluation
Organ specific response1
Skin
CR / not involved
PR in at least 
one organ with 
baseline 
involvement
AND
no 
progression in 
any other 
organ (i.e. CR, 
PR, 
unchanged, 
no 
involvement)
PR or CR in one 
or more 
organ(s) with 
baseline 
involvement
AND
progression in 
one or more 
organs
(incl. new 
occurrence in 
an organ with 
no baseline 
involvement) 
Progression in
one or more 
organ(s) with 
baseline 
involvement 
OR new 
occurrence in 
an organ with 
no baseline 
involvement
AND
no CR or PR 
in any other 
organ
Organ specific 
response 
‘unchanged’ for all 
organs (incl. no 
involvement ) 
Eyes 
CR / not involved
Mouth 
CR / not involved
Esophagus
CR / not involved
Upper GI
CR / not involved
Lower GI
CR / not involved
Liver
CR / not involved
Lungs
CR / not involved
Joints and 
fascia 
CR / not involved
Overall 
response
CR
PR
Mixed 
response
Progression
Unchanged 
response
1 at least one organ must be involved at baseline. Organ specific response versus baseline status
Source: Lee S, Wolff D, Kitko C, et al. Measuring therapeutic response in chronic graft-versus-
host disease. National institutes of health consensus development project on criteria for clinical 
trials in chronic graft-versus-host disease: IV. The 2014 response criteria working group report. 
Biol Blood Marrow Transplant. 2015:984-999


Novartis
Confidential
Page 163 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14.5
Appendix 5: HCT Specific Comorbidity Index Score
Table 14-6
HCT-Specific Comorbidity Index Score
Comorbidities
Definition
Score
Migraine/headache
0
Osteoporosis
0
Osteoarthritis
0
Hypertension
0
Gastrointestinal
Including inflammatory bowel disease
0
Mild pulmonary
DLCO and/or FEV1 > 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.


Novartis
Confidential
Page 164 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
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


Novartis
Confidential
Page 165 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14.6
Appendix 6: CIBMTR classification
Table 14-7
CIBMTR 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.


Novartis
Confidential
Page 166 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
AML and ALL (con‟t)
High risk (not in 
remission):
Never treated
Primary Induction 
Failure (PIF) 
Relapse
Never treated: The recipient was diagnosed with acute leukemia and never treated. 
For example, this disease status may be appropriate if MDS was initially diagnosed and treated, the MDS
then transformed into AML, and a decision was made to proceed immediately to transplant instead of treating
the AML with therapy.
Primary Induction Failure (PIF): The recipient was treated for acute leukemia but
never achieved durable* complete remission with any therapy (*including relapsed <1 mo from CR1 
determination). The term “PIF” is not limited to the number of treatments used unsuccessfully.
Relapse: Recurrence of disease after CR. Relapse is defined as:
≥5% blasts in the marrow
Extramedullary disease
Reappearance of cytogenetic abnormalities and/or molecular markers associated with the diagnosis that, in
the judgement of a physician, are at a level representing relapse.
Although CIBMTR collects information upon the number of the relapse, this information is not needed for the 
ASBMT RFI
CML
Low risk:
Hematologic CR1
CP1
Hematologic CR 1 deriving from first Chronic Phase (never in AP or BP). 
A treatment response where all of the following criteria are met:
White blood count is less than 10 x 109/L, without immature granulocytes and with less than 5% basophils
Platelet count less than 450 x 109/L
Non-palpable spleen
First chronic phase (CP1): Recipient was in chronic phase from diagnosis to the start of the preparative 
regimen, never in AP or BP. Characterized by:
Relatively few blasts (<10%) present in the blood and bone marrow.
Symptoms are often not present.
The chronic phase may last several months to years depending on the individual recipient and the treatment 
received.
Although CIBMTR collects additional information regarding cytogenetic and molecular response, this 
information is not needed to complete the RFI.
CML (con’t)
Intermediate risk:
CP2
Hematologic CR2
Hematologic CR
deriving from AP or BP
AP1
Second chronic phase (CP2): Recipient had one AP or BP (see BP definition in high
risk group) and was treated back into CP or hematologic CR.
Hematologic CR2: A hematologic CR occurring after treatment for progression from a first hematologic CR (eg
hematologic CR, progress to CP/AP or BP, then treated back into hematologic CR).
Hematologic CR deriving from AP or BP: Hematologic CR occurring after treatment for a single previous
episode of AP or BP.
Accelerated phase 1 (AP1): One or more of the following must be present (WHO


Novartis
Confidential
Page 167 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
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
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


Novartis
Confidential
Page 168 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
● Hemoglobin > 11.0 g/dL or 50% improvement over baseline
Never Treated: The recipient was diagnosed with leukemia and never treated.
Relapse (untreated): The re-appearance of disease after complete recovery (previous
CR). Relapse should be determined by one or more diagnostic tests.
CLL (con‟t)
High risk:
NR/SD 
Progression
No Response/Stable disease (NR/SD): No change OR Less than 50% change in
disease. Not complete response, partial response, or progressive disease.
Progression: Increase in disease burden or new sites of disease. Requires one or more of the following:
≥ 50% increase in the sum of the products of ≥ 2 lymph nodes (≥1 node must be ≥ 2 cm) or new nodes
≥ 50% increase in liver or spleen size, or new hepatomegaly or splenomegaly
≥ 50% increase in absolute lymphocyte count to ≥ 5 x 109/L
Transformation to a more aggressive histology, e.g. transform to diffuse large
B-cell lymphoma known as Richter’s transformation.
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†. 


Novartis
Confidential
Page 169 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
The term “unconfirmed” is defined as scan abnormalities of unknown significance that are not biopsied or
otherwise evaluated.
Hodgkin Disease/Hodgkin
Lymphoma† (con’t)
Intermediate risk:
CR2/+ 
CRU2/+
PR without prior CR 
(PR1)
PR with prior CR
(PR2+) (includes any
sensitive relapse)
CR2+ Confirmed: The recipient relapsed, then achieved complete absence of disease for at least one month 
without radiographic evidence of disease†.
CR2+ Unconfirmed (CRU2+): The recipient has achieved a second or subsequent complete response but
has persistent radiographic abnormalities of unknown significance
Partial remission- (PR): Reductions of ≥ 50% in greatest diameter of all sites of known disease and no new
sites.
Partial response may be represented as PR1, PR2, etc. There are differing interpretations of what the number
after “PR” represents. To avoid confusion, distinguish the type of PR with the following: “without prior CR” and
“with prior CR”. This includes any relapse that is sensitive to chemotherapy, which by definition is achievement
of at least a PR to therapy.
Hodgkin Disease/Hodgkin
Lymphoma† (con’t)
High risk:
Never treated
Primary Refractory (PIF 
res)
Relapse untreated (any 
number)
Relapse resistant (any 
number)
Never Treated: The recipient was diagnosed with lymphoma and never treated.
Primary refractory (less than partial response to initial therapy or PR not maintained at time of HSCT). The
response of the lymphoma to treatment is less than in a partial response (PR). This status would also include
recipients who achieved a prior PR (but never CR) but are not currently in PR.
Relapse: The recipient obtained CR/CRU, but relapsed (any sensitivity, includes PR with prior CR).
Recurrence of disease after CR. This may involve an increase in size of known disease or new sites of
disease. Patients who have any relapse AND have resistant or untreated or unknown sensitivity to
chemotherapy.
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)
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.


Novartis
Confidential
Page 170 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
Waldenstrom
macroglobulinemia
(lymphoplasmacytic
lymphoma) should be
reported as ‘Other’
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,
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


Novartis
Confidential
Page 171 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
diffuse large B-cell
lymphoma, Burkitt’s
lymphoma/Burkitt cell
leukemia,
high grade B-cell lymphoma,
Burkitt- like (provisional
entity), adult T-cell 
lymphoma/leukemia
(HTLV1+), aggressive NK-
cell leukemia, extranodal
NK/T-cell lymphoma
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
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 
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


Novartis
Confidential
Page 172 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
(includes any sensitive 
relapse)
Partial remission- (PR): Reductions of ≥ 50% in greatest diameter of all sites of
known disease and no new sites.
Partial response may be represented as PR1, PR2, etc. There are differing interpretations of what the number
after “PR” represents. To avoid confusion, distinguish the type of PR with the following: “without prior CR” and
“with prior CR”. This includes any relapse that is sensitive to chemotherapy, which by definition is achievement
of at least a PR to therapy.
NHL (Aggressive/
Intermediate and High
Grade)
(con’t)
High risk:
Primary refractory
Relapse untreated (any 
number)
Relapse resistant (any 
number)
Never Treated
Primary refractory (less than partial response to initial therapy or PR not maintained at time of HSCT). The
response of the lymphoma to treatment is less than
in a partial response (PR). This status would also include recipients who achieved a prior PR (but never CR)
but are not currently in PR.
Relapse: The recipient obtained CR/CRU, but relapsed (any sensitivity, includes PR
with prior CR). Recurrence of disease after CR. This may involve an increase in size of known disease or new
sites of disease. Patients who have any relapse AND have resistant or untreated or unknown sensitivity to
chemotherapy.
Never Treated: The recipient has never been treated for NHL. No chemotherapy was given within the 6
months prior to the preparative regimen (disease untreated, REL unt).
Multiple Myeloma
(report plasma cell leukemia,
solitary plasmacytoma,
primary amyloidosis or other
plasma cell disorders as 
„other‟)
Low risk:
CR1 (includes first
sCR) VGPR 1 (eg
VGPR without prior CR)
PR1 (eg PR without
prior CR)
CR1, (CR) A treatment response where all of the following criteria are met:
Negative immunofixation on serum and urine samples
Disappearance of any soft tissue plasmacytomas
 < 5% plasma cells in the bone marrow (confirmation with repeat bone marrow biopsy not 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


Novartis
Confidential
Page 173 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
electrophoresis, or >= 90% reduction in serum M-protein and urine M protein level < 100 mg/24h
PR without prior CR (PR1)
Both of the following must be present:
≥ 50% reduction in serum M-protein
 Reduction in 24-hour urinary M-protein by ≥ 90% or to < 200 mg/24 hours.
If the serum and urine M-protein are not measurable (i.e., do not meet any of the following criteria:
 Serum M-protein ≥ 1 g/dL,
 Urine M-protein ≥200 mg/24 hours;
Then a ≥ 50% decrease in the difference between involved and uninvolved free light chain levels is required 
in place of the M-protein criteria (provided the serum-free light chain assay shows involved level ≥ 10 mg/dL 
and the serum-free light chain ratio is abnormal) .
Multiple Myeloma (con’t)
Low risk: (con’t)
CR1 (includes first
sCR) 
VGPR 1 (eg VGPR 
without prior CR)
PR1 (eg PR without
prior CR)
 If serum and urine M-protein and serum-free light chains are not measurable, a ≥50% reduction in plasma 
cells is required in place of M-protein, provided the baseline bone marrow plasma cell percentage was ≥ 
30%.
 In addition to the above listed criteria, a ≥ 50% reduction in the size of soft tissue plasmacytomas is also 
required, if present at baseline.
 VGPR and PR requires two consecutive assessments† made at any time before the institution of any new 
therapy, and no known evidence of progressive or new bone lesions if radiographic studies were performed; 
radiographic studies are not required to satisfy PR requirements.
For recipients otherwise meeting the criteria for CR, but with no documented marrow with <5% plasma cells , 
status must be classified as PR.
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.


Novartis
Confidential
Page 174 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
PR2/+ (with prior CR):
Same criteria as ‘Myeloma low risk PR’, except a relapse must have occurred and treatment back into PR.
Multiple Myeloma (con’t)
High risk (Con’t):
Relapse from CR 
(untreated)
CR2/+
sCR2/+VGPR2/+ 
PR2/+
(with prior CR)
SD Progression Never
treated PR2/+
SD:
Does not meet the criteria for CR, VGPR, PR, or PD.
SD requires two consecutive assessments made at any time before the institution of any new therapy, and 
no known evidence of progressive or new bone lesions if radiographic studies were performed; radiographic 
studies are not required to satisfy SD requirements
Progression: Requires one or more of the following:
Increase of ≥ 25% from the lowest response value achieved:
 Serum M-component (including an absolute increase ≥0.5 g/dL) (for
progressive disease, serum M-component increases of ≥ 1 g/dL are sufficient
to define relapse if the starting M-component is ≥5 g/dL)
 Urine M-component with an absolute increase ≥200 mg/24 hours
 For recipients without measurable serum and urine M-protein levels: the difference between involved and
uninvolved free light chain levels with an absolute increase > 10 mg/dL
 Bone marrow plasma cell percentage with absolute percentage ≥ 10%
 Definite development of new bone lesions or soft tissue plasmacytomas, or definite increase in the size of
any existing bone lesions or soft tissue
plasmacytomas
 Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or
2.65 mmol) that can be attributed solely to the plasma cell proliferative disorder
 PD requires two consecutive assessments made at any time before classification as disease progression,
and/or the institution of any new therapy†.
Solid Tumors:
Adult Includes: breast
cancer, Ewings sarcoma,
germ cell cancers, 
neuroblastoma, ovarian
cancer, rhabdomyosarcoma,
testicular cancer, renal cell
carcinoma and any other 
solid tumors
All clinical status at
HCT


Novartis
Confidential
Page 175 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
Solid Tumors:
Pediatric
Neuroblastoma
Intermediate Risk
CR1
CRU1
VGPR1
PR1 (PR without prior 
CR) 
Adjuvant
Note addition of RECIST criteria. RECIST criteria are based on the sum of the
longest diameter of measured lesions, rather than product of two dimensions of measured lesions.
First Complete remission (CR1): The recipient has achieved complete absence of disease. RECIST adds:
Disappearance of all target lesions for a period of at least one month. Adjuvant treatment is excluded from this
definition
First Complete Response Unconfirmed (CRU1) Disappearance of all signs and symptoms of disease with
normalization of all biochemical and radiologic parameters, but with persistent, unchanging imaging
abnormalities of unknown significance. RECIST: Complete response with persistent imaging abnormalities of
unknown significance (CRU)
First very good partial response (VGPR): The recipient has obtained a reduction of more than 90% in the 
disease burden after only one line of therapy.
First Partial response: (Note 1st PR would include any first VGPR) No prior CR, reduction of more than 
50% in the disease burden regardless of the number of lines of therapy received. Decrease of ≥ 50% in total 
tumor load of the lesions that have been measured for at least 4 weeks RECIST: Partial response (PR) – At 
least 30% decrease in the sum of the longest diameter of measured lesions (target lesions) taking as 
reference the baseline sum of longest diameters
Adjuvant: High dose treatment with transplantation delivered in the absence of any known residual disease
with an adjuvant intent. Metastatic recipients (any status) should never be considered as adjuvant. Treatment
given after the primary cancer treatment to increase the chances of a cure. Adjuvant cancer therapy may
include chemotherapy, radiation therapy, hormone therapy, or biological therapy.
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 


Novartis
Confidential
Page 176 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
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


Novartis
Confidential
Page 177 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
ASBMT Diagnosis 
Category
ASBMT RFI 
Classification
CIBMTR Classification^
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)
2014 and 2015 Update:
No substantive changes from the 2011 through 2014 documents.
2011 Update:
No changes from the 2010 document.
2010 Updates:
† Several diseases (eg AML, MM, NHL and HL) require an observation period of response of at least 4 weeks or two independent assessments in order to strictly be
considered to have achieved that level of response. However, in many cases, transplantation is conducted before this time has fully elapsed, or
subsequent assessment can be completed. In these circumstances, the best response determined before the transplantation or based upon the last assessment before
transplantation should be used.
^ CIBMTR has included instructions from the CIBMTR TED manual for reference, along with the CIBMTR “matching” disease classifications in bold
font
2009 and 2010 Updates:
General updates to align ASBMT risk categories with disease status collected on CIBMTR TED forms
Matching disease text to the revised TED Forms per W.H.O. criteria (e.g. precursor B-lymphoblastic lymphoma/leukemia moved to ALL from Lymphoma) Matching
response text to the revised TED Forms
Preparative regimen replaces conditioning
Referring to revised CIBMTR Disease Forms for detailed criteria 
Distinguishing PR1/1st PR to PR without prior CR and PR2/2nd PR to PR with prior CR
Waldenstrom macroglobulinemia moved to “Other‟ from Plasma Cell Disorders, and better description of diseases fitting into “Other” category.
Moved mycosis fungoides/Sezary syndrome to the aggressive/intermediate diagnosis category.
Adding Response Evaluation Criteria in Solid Tumors (RECIST) criteria for solid tumors 
Added details from the CIBMTR TED instruction manual.
Date created: 3/4/03 
Date(s) of Revision: 2/27/04; 12/1/04; 11/17/05; 10/23/06; 11/15/07; 9/26/09; 10/18/10, 11/23/11, 11/4/12, 12/3/13; 1/13/14, 2/16/15, 3/23/16. 
Copyright 2016, American Society for Blood and Marrow Transplantation
 
 


Novartis
Confidential
Page 178 of 178
Amended Protocol Version 02 (Clean)
Protocol No. CINC424D2301
14.7
Appendix 7: List of CYP3A4 inhibitors and inducers
Table 14-8
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 ≥ 200 mg daily; 
If clinically necessary to use doses ≥ 200 mg daily consultation with Sponsor is required. Please 
refer to Section 6.4.2 (Permitted concomitant therapy requiring caution and/or action).

SAP_001.pdf: 
 
Official Title: 
A Phase III Randomized Open-label Multi-center Study of Ruxolitinib vs. Best 
Available Therapy in Patients With Corticosteroid-refractory Chronic Graft 
vs Host Disease After Allogeneic Stem Cell Transplantation (REACH3) 
NCT Number: 
NCT03112603 
 
Document Date: 
 
Statistical Analysis Plan: 06 July 2020 
 
 
 
 
 
 
 
 


Clinical Development
INC424/ruxolitinib/Jakavi®/Jakafi®
CINC424D2301 (INCB 18424-365)
A phase III randomized open-label multi-center study of 
ruxolitinib vs. best available therapy in patients with 
corticosteroid-refractory chronic graft vs host disease after 
allogenic stem cell transplantation (REACH 3)
Statistical Analysis Plan (SAP) – Amendment 2
TEMPLATE VERSION AND DATE: Final 2.0 22-Jul-2016, Effective 22-Jul-2016
Author:
(Trial Statistician)
Document type:
SAP Documentation
Document status:
Final
Release date:
06-Jul-2020
Number of pages:
54
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
 
 


Novartis
Confidential
Page 2
SAP
CINC424D2301 / INCB 18424-365
Table of contents
Table of contents .................................................................................................................2
1
Introduction .........................................................................................................................5
1.1
Study design.............................................................................................................5
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................17
2.2.1
Subgroup of interest ..............................................................................19
2.3
Patient disposition, demographics and other baseline characteristics ...................20
2.3.1
Patient disposition.................................................................................21
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................22
2.4.1
Study treatment / compliance................................................................22
2.4.2
Prior, concomitant and post therapies...................................................25
2.5
Analysis of the primary objective..........................................................................27
2.5.1
Primary endpoint...................................................................................27
2.5.2
Statistical hypothesis, model, and method of analysis..........................28
2.5.3
Handling of missing values/censoring/discontinuations.......................28
2.5.4
Supportive analyses...............................................................................28
2.5.5
ORR at Crossover Cycle 7 Day 1 .........................................................29
2.6
Analysis of the key secondary objective ...............................................................29
2.6.1
Key secondary endpoints ......................................................................31
2.6.2
Statistical hypothesis, model, and method of analysis..........................31
2.6.3
Handling of missing values/censoring/discontinuations.......................32
2.7
Analysis of secondary efficacy objective(s)..........................................................32
2.7.1
Statistical hypothesis, model, and method of analysis..........................34
2.7.2
Handling of missing values/censoring/discontinuations.......................34
2.8
Safety analyses.......................................................................................................35
2.8.1
Adverse events (AEs)............................................................................35
2.8.2
Deaths....................................................................................................37
2.8.3
Laboratory data .....................................................................................37
2.8.4
Other safety data ...................................................................................37
2.9
Pharmacokinetic endpoints....................................................................................39
40


Novartis
Confidential
Page 3
SAP
CINC424D2301 / INCB 18424-365
2.11
Patient-reported outcomes .....................................................................................40
40
41
2.14
Interim analysis......................................................................................................41
3
Sample size calculation. ....................................................................................................42
3.1
Primary analysis.....................................................................................................42
3.2
Power for analysis of key secondary variables......................................................43
4
Change to protocol specified analyses ..............................................................................43
44
44
44
44
46
46
47
47
48
53
6
Reference...........................................................................................................................54


Novartis
Confidential
Page 4
SAP
CINC424D2301 / INCB 18424-365
List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
aGvHD
Acute Graft vs. Host Disease
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BAT
Best Available Therapy
bid
bis in diem/twice a day
cGvHD
chronic Graft vs. Host Disease
CIBMTR
Center for International Blood and Marrow Transplant Research
CMH
Cochran–Mantel–Haenszel
CMV
Cytomegalovirus
CR
Complete Response
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
eCRF
Electronic Case Report Form
FACT-BMT
Functional Assessment of Cancer Therapy - Bone Marrow Transplantation
FAS
Full Analysis Set
FFS
Failure-Free Survival
GvHD
Graft vs. Host Disease
HCT
Hematopoietic Cell Transplantation
IRT
Interactive Response Technology that includes Interactive Voice Response
System and Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NRM
Non Relapse Mortality
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic analysis set
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial response 
PRO
Patient-reported Outcomes
QoL
Quality of Life
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
WBC
White Blood Cells
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


Novartis
Confidential
Page 5
SAP
CINC424D2301 / INCB 18424-365
1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study 
Report (CSR) of study CINC424D2301, a phase III, randomized, open-label, multi-center 
study of ruxolitinib versus best available therapy in patients with corticosteroid-refractory 
chronic graft vs. host disease after allogeneic stem cell transplantation.
This SAP is an amendment of SAP amendment 1. The main purpose of this amended SAP is 
to provide details on the overall hierarchical testing procedure for the primary and the two key 
secondary endpoints that was specified for the second interim analysis and documented in the 
DMC SAP. Furthermore, the definition of the Per-Protocol set was modified by adding further 
criteria to exclude patients for a sensitivity analysis. Finally, a few minor modifications and 
formal corrections were made. 
1.1
Study design
This randomized, Phase III, open-label, multi-center study will investigate the efficacy and 
safety of ruxolitinib vs. Best Available Therapy (BAT), added to the subject’s 
immunosuppressive regimen of corticosteroids ± calcineurin inhibitor (CNI) in adults and 
adolescents (≥12 years old) with corticosteroid-refractory chronic Graft vs Host Disease (SR-
cGvHD).
This is an open-label study. Investigators, patients, and Sponsor will have full knowledge of 
the treatment allocation.  Approximately 324 patients will be randomized in this study.  Each 
patient will be treated and followed for a total of 3 years (39 cycles/156 weeks). The study 
design is illustrated in Figure 1-1 below, with each cycle comprised of 4 weeks (28 days).
Patients will be randomized in a ratio of 1:1 (ruxolitinib or BAT), randomization will be 
stratified by cGvHD severity: moderate vs severe (see Protocol Appendix 2).
The following periods were defined:

Primary Efficacy Period (Cycle 1 through end of Cycle 6)
Study treatment will begin on Cycle 1 Day 1 following randomization.  
Study visits will occur per the following schedule to monitor tolerability and efficacy of 
the study treatments during the Primary Efficacy Period:

Cycle 1: Day 1, 8, 15, 22 

Cycle 2 to 6: Day 1 of each cycle
Patients will be treated for a minimum of 6 cycles, until Cycle 7 Day 1, unless they 
experience intolerable toxicity, cGvHD progression, or withdraw from the study (see 
Protocol Section 6 for Study Treatment details and permitted/prohibited concomitant 
therapies). 
Addition or initiation of a new systemic therapy is allowed only after documented lack of 
response (as defined in Protocol Section 3), intolerable toxicity, or cGvHD flare and will 
be considered a treatment failure for both the primary and key secondary objectives.  At 
the study visit in which the patient meets the criteria for disease progression, intolerable 
toxicity, or cGvHD flare treatment failure, addition or initiation of a new systemic 


Novartis
Confidential
Page 6
SAP
CINC424D2301 / INCB 18424-365
treatment is allowed.  However, if mixed response or no response is assessed, addition or 
initiation of a new systemic treatment is allowed after confirmation at the next scheduled 
study visit, at least 4 weeks later (See Protocol Figure 4-2).  
Primary efficacy assessments will be performed on Cycle 7 Day 1, after completion of 6 
cycles of treatment.  

Extension Period (Cycle 7 to Cycle 39)
After the Cycle 7 Day 1 primary efficacy assessment visit, study visits will occur every 3 
cycles (every 12 weeks +/- 7 days) starting with Cycle 9 Day 1 and up to Cycle 39, or 
EOT, whichever occurs first (i.e. C9D1, C12D1, C15D1, etc.). 
Patients in the Extension Period will either continue the current BAT treatment or 
ruxolitinib treatment, cross over to the ruxolitinib treatment arm, or permanently 
discontinue study treatment and enter the Long-Term Survival Follow-Up. Addition or 
initiation of another BAT is not allowed in the Extension Period (See Protocol Figure 4-
3).

Cross-Over for BAT patients only (from Cross-Over up to Cycle 33)
On Cycle 7 Day 1 and thereafter, patients randomized to BAT may cross over to 
ruxolitinib treatment due to disease progression, mixed response, or unchanged response, 
due to toxicity to BAT, or due to cGvHD flare. Cross-Over patients will switch to and 
follow the visit evaluation schedule as specified in Protocol Table 7-2.  Patients crossing 
over from BAT will be treated and/or followed on study for a total of 39 cycles, inclusive 
of randomized treatment, Cross-Over treatment (BAT patients only), and long-term 
survival follow up (i.e. if patients cross over on randomized treatment Cycle 7, they will 
only complete up to cycle 33 in the cross over treatment period).
Patients who meet Cross-Over criteria to receive ruxolitinib are allowed to continue their 
systemic immunosuppressive regimen of corticosteroids +/- CNI for SR-cGvHD 
treatment as per standard of care, with cessation required of the BAT treatment before 
starting treatment with ruxolitinib. 
Patients undergoing dose tapering following response should be monitored for cGvHD 
flare occurrences, which must be reported in the database.  

Long-Term Survival Follow-Up (EOT to 39 cycles on study)
Patients who permanently discontinue the study treatment prior to completion of 39 
cycles on study for reasons other than achieving a CR or PR will enter the Long-Term 
Survival Follow-Up (LTSFU), and may be treated per Institutional practice. They will be 
followed approximately every 3 months by telephone call for survival and reporting of 
new cGvHD therapies until 39 cycles are completed.
New cGvHD therapies will be entered in the New cGvHD Treatment Since 
Discontinuation of Study Treatment eCRF.
See Protocol Section 7.1.5 for permanent treatment discontinuation details.

Safety Follow-Up (Last Dose + 30 days)
A 30-day safety follow-up assessment will be performed after the last dose of ruxolitinib 
or BAT, for patients that permanently discontinue study treatment for reasons other than 
CR or PR.


Novartis
Confidential
Page 7
SAP
CINC424D2301 / INCB 18424-365
The primary efficacy variable, ORR at Cycle 7 Day 1, will be analyzed at the time when all 
patients have completed the Cycle 7 Day 1 visit or discontinued earlier. At this time, the 
primary clinical study report (CSR) will be produced. Following the cut-off date for the 
analysis reported in the primary CSR, the study will remain open. Ongoing patients will 
continue to receive study treatment and be followed as per the Visit Evaluation Schedule, as 
long as patients derive benefit from ruxolitinib or BAT, until completion of 39 cycles (156 
weeks/3 years) of study treatment and/or follow up, inclusive of randomized treatment, cross 
over treatment (BAT patients only), and long-term survival follow up. The end of study is 
defined as the earliest occurrence of one of the following:

All patients have completed 39 cycles OR discontinued from the study OR died
Figure 1-1
Schematic study design 
  
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


Novartis
Confidential
Page 8
SAP 
CINC424D2301 / INCB 18424-365
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary endpoint
  
Refer to Section 2.5 
To 
compare 
the 
efficacy 
of 
ruxolitinib 
vs. 
Investigator’s choice Best Available Therapy (BAT) 
in patients with moderate or severe SR-cGvHD 
assessed by Overall Response Rate (ORR) at the 
Cycle 7 Day 1 visit
Overall response rate (ORR) on Cycle 7 Day 1 after 
randomization, defined as the proportion of patients in 
each arm demonstrating a complete response (CR) or 
partial response (PR) without the requirement of 
additional 
systemic 
therapies 
for 
an 
earlier 
progression, mixed response or non-response. Scoring 
of response will be relative to the organ score at 
randomization.
CMH test, stratified by cGvHD severity (moderate vs. 
severe)
Key secondary endpoints
Refer to Section 2.6
To compare the rate of failure free survival (FFS)
To compare change in modified Lee Symptom Score
FFS will be used as the first key secondary endpoint 
for all regions except the US (ROW). The modified 
Lee symptom score will be used as the first key 
secondary endpoint for the US
Composite time to event endpoint incorporating the 
following FFS events: i) relapse or  recurrence of 
underlying disease or death due to underlying disease, 
ii) non-relapse mortality, or iii)  addition or initiation 
of 
another 
systemic 
therapy 
for 
cGvHD.
Rate of patients with clinically relevant improvement 
of the modified Lee symptoms score at Cycle 7 Day 1
A fixed sequence hierarchical testing strategy will be 
applied for the primary and the two key secondary 
endpoints. For ROW FFS will be tested first followed 
by the modified Lee symptom score.  For US, 
modified Lee symptom score will be tested first 
followed by FFS. 
FFS: Logrank-test, stratified by cGvHD severity 
(moderate vs. severe)
Modified Lee symptom score: CMH test comparing 
rates of responders, stratified by cGvHD severity 
(moderate vs. severe)


Novartis
Confidential
Page 9
SAP 
CINC424D2301 / INCB 18424-365
Objective
Endpoint
Analysis
Other secondary endpoints
Refer to Section 2.7 Analysis of secondary efficacy 
objective(s), 
2.8 
Safety 
analyses
and
2.9 
Pharmacokinetic endpoints
Best overall response (BOR)
Proportion of patients who achieved OR (CR+PR) at 
any time point (up Cycle 7 day 1 or the start of 
additional systemic therapy for cGvHD) 
To estimate ORR at end of Cycle 3
Proportion of patients who achieved OR (CR+PR) at 
Cycle 4 Day 1.
Duration of Response
Duration of response (DOR) is assessed for 
responders only. DOR is defined as the time from first 
response until cGvHD progression, death, or the date 
of change/addition of systemic therapies for cGvHD. 
To assess Overall Survival (OS)
Overall survival, defined as the time from the date of 
randomization to the date of death due to any cause. 
To assess Non Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time 
from date of randomization to date of death not 
preceded by underlying disease relapse/recurrence. 
To assess proportion of patients with ≥50% reduction 
in daily corticosteroid dose at Cycle 7 Day1
To assess proportion of patients successfully tapered 
off all corticosteroids at Cycle 7 Day 1
To
assess cumulative incidence of Malignancy 
Relapse/Recurrence (MR)   
Malignancy Relapse/Recurrence (MR) is defined as 
the time from date of randomization to hematologic 
malignancy relapse/recurrence. Calculated for patients 
with underlying hematologic malignant disease.
To evaluate changes in FACT-BMT and EQ-5D
Change in FACT-BMT from baseline to each visit 
where measured.
Change in EQ-5D from baseline to each visit where 


Novartis
Confidential
Page 10
SAP 
CINC424D2301 / INCB 18424-365
Objective
Endpoint
Analysis
measured.
To assess Pharmacokinetics (PK) of ruxolitinib in SR-
cGvHD patients
Pharmacokinetic parameters of ruxolitinib after a 
single dose and at steady state. Cmax, AUClast, and 
AUCinf. Other PK parameters are CL/F, Vz/F, Tmax 
and T1/2.
To evaluate the safety of ruxolitinib and Best 
Available Therapy
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 medical resource utilization
Resources including duration and frequency of 
hospitalization, emergency room visits, additional 
outpatient office visits to general practitioner, 
specialist, and urgent care visits. Frequency of 
concomitant treatments will also be captured.


Novartis
Confidential
Page 11
SAP 
CINC424D2301 / INCB 18424-365
Objective
Endpoint
Analysis


Novartis
Confidential
Page 12
SAP 
CINC424D2301 / INCB 18424-365
2
Statistical methods
2.1
Data analysis general information
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.
Data included in the analysis
The analysis cut-off date for the primary analysis of study data will be established after all 
randomized patients have completed the Cycle 7 Day 1  visit or  have discontinued study. If a 
CSR is written based on data of the second interim analysis the cut-off date of this interim 
analysis will be used. 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 cut-off date
will be included in the analysis. Any data collected beyond the cut-off date will not be
included in the analysis and will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will 
be reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-
off 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.
The analysis cutoff date for the final analysis of study data will be established when all 
patients have completed the study.
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 
by treatment group; 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) by 
treatment group.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug will refer to the ruxolitinib only. Whereas, study treatment will refer to 
ruxolitinib and BAT. 


Novartis
Confidential
Page 13
SAP 
CINC424D2301 / INCB 18424-365
Randomized treatment will refer to the study treatment received during the randomized 
treatment period. Up to the Cycle 7 Day 1 visit, more than one BAT regimen may be initiated 
as study treatment. These regimens reported on the Dosage Administration Record (DAR)
eCRF are considered randomized treatment. Crossover treatment will refer to the study 
treatment received during the crossover treatment period.
Date of first administration of randomized treatment
The date of first administration of randomized treatment is derived as the first date when a 
nonzero dose of randomized treatment was administered as per the DAR eCRF. The date of 
first administration of randomized treatment will also be referred as start of randomized 
treatment.
Date of first administration of crossover treatment 
The date of first administration of crossover treatment is derived as the first date when a 
nonzero dose of crossover treatment was administered as per the DAR eCRF. The date of first 
administration of crossover treatment (ruxolitinib) will also be referred as start of crossover 
treatment.
Date of last administration of randomized treatment 
The date of last administration of randomized treatment is defined as the last date when a 
nonzero dose of randomized treatment was administered as per DAR eCRF. 
Date of last administration of crossover treatment 
The date of last administration of crossover treatment is defined as the last date when a 
nonzero dose of crossover treatment (ruxolitinib) was administered as per DAR eCRF. 
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 safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption, PK etc.) is the start of
study treatment.
The reference start date for all other, non-safety assessments (i.e., GvHD assessment,
survival time, disease progression, response, ECOG performance status, and patient reported 
outcomes (PRO)) is the date of randomization.
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.


Novartis
Confidential
Page 14
SAP 
CINC424D2301 / INCB 18424-365
Crossover study day
The crossover study day, describes the day of the event or assessment date, relative to the start 
of crossover treatment.
Crossover study day = date of event – start of crossover treatment + 1, if event is on or after 
the start of crossover treatment
Crossover study day = date of event – start of crossover treatment, if event precedes the start 
of crossover treatment
The crossover study day will be displayed in the data listings if an event starts on or after the 
start of crossover treatment.
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
Baseline for safety endpoints (except adverse events), 
 is defined as the 
last assessment prior to or on the treatment start date. 
Baseline for patient reported outcomes is defined as the first assessment prior to or on the 
study treatment start date
For evaluations after cross over, the baseline is defined as the last assessment prior to or on 
the start date of crossover treatment.
Baseline for other endpoints is defined as the last assessment or procedure conducted prior to 
or on the randomization date/day1.
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 mutually exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study any study treatment

On-randomized treatment period: from day of first dose of any study treatment to 30 days 
after date of last actual administration of randomized treatment (including start and stop 
date) or end of the randomized treatment period per end of randomized treatment 
disposition eCRF, whichever is later.  For those patients who cross over from BAT to 
ruxolitinib, the period is from day of first dose of randomized study medication to earlier 
of (i) 30 days after last dose of randomized study medication, (ii) the day before first dose 
of cross over treatment. Up to the Cycle 7 Day 1 visit, more than one BAT regimen may 
be initiated as study treatment. In this case, the last actual administration of randomized 
treatment refers to the last actual administration of the last BAT regimen reported on the 
DAR eCRF.   


Novartis
Confidential
Page 15
SAP 
CINC424D2301 / INCB 18424-365

On-cross over treatment period: from day of first dose of cross over study medication to 
30 days after last dose of cross over study medication) or end of the cross-over treatment 
period per end of cross-over disposition eCRF, whichever is later

Post-treatment period: starting at day 31 after last dose of study treatment or the day after 
end of study treatment per end of treatment disposition eCRFs, whichever is later
Safety summaries (tables, figures) include only data from the on-treatment periods 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.
The main comparative safety analyses will use data from the on-randomized treatment period 
and will be performed for the time period from the day of the first dose up to Cycle 7 Day 1 to 
avoid potential bias due to different exposure durations related to possible cross over from 
BAT to ruxolitinib after Cycle 7 Day 1.  Furthermore, separate safety summaries will be 
generated for the entire on-randomized treatment period and the on-cross over treatment 
period.
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 summary on cGvHD assessment, 
 PROs and safety (Table 2-1) by visit. The end of treatment assessment will be 
mapped into the time points as needed.  
Table 2-1
Time windows for cGvHD assessment, 
PROs and safety 
assessment (lab, vital sign, etc.)
Time Window
Planned Visit Timing 
Time Window Definition
On treatment
Baseline1
On or before Study Day 1
≤ Study Day 1 
Cycle 1 Day 8
Study Day 8
Study Days 5 – 11
Cycle 1 Day 15
Study Day 15
Study Days 12 – 18
Cycle 1 Day 22
Study Day 22
Study Days 19 – 25
Cycle 2 Day 1
Study Day 29
Study Days 26 – 39
Cycle 3 Day 1
Study Day 57
Study Days 47 – 67
Cycle 4 Day 1
Study Day 85
Study Days 75 – 95
Cycle 5 Day 1
Study Day 113
Study Days 103 – 123


Novartis
Confidential
Page 16
SAP 
CINC424D2301 / INCB 18424-365
Cycle 6 Day 1
Study Day 141
Study Days 131 – 151
Cycle 7 Day 1
Study Day 169
Study Days 159 – 179   
Cycle 9 Day 1
Study Day 225
Study Days 211 – 239
Cycle 12 Day 1
Study Day 309
Study Days 295 – 323
         every 12 weeks
+ 84 day 
+84 days to lower and upper 
bound
Cycle 39 Day 1
Study Day 1065
Study Days 1051 – 1079
Safety follow-up
30 days after last dose
Last dose date + 30
1 baseline assessment valid if performed prior to or on start date of randomized treatment;
Study Day 1 = reference start date (either randomization date, or start of randomized treatment)
Crossover Study Day 1 = start date of crossover treatment
EOT (randomized treatment or crossover treatment) assessments are mapped to the time points 
as needed.
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-2
Last contact date data sources
Source data
Conditions
Date of Randomization 
No Condition
Last contact date/last date patient was known to 
be alive from Survival Follow-up page 
- Patient status is reported to be alive, lost to 
follow-up or unknown.
Start/End dates from new cGvHD treatment since 
discontinuation from study treatment
Non-missing medication/procedure term.
Start/End* dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
Date of discontinuation from end of treatment 
pages
No condition.
- cGvHD assessment date
- any specific efficacy assessment date if 
available (e.g. graft failure assessment, 
hematologic disease relapse/progression 
assessment)
Non-missing assessment .
Start/End dates of AE 
Non-missing verbatim term
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date
of a dose administration record) will not be used to derive the last contact date. Partial date 


Novartis
Confidential
Page 17
SAP 
CINC424D2301 / INCB 18424-365
imputation is allowed for event (death)/censoring is coming from ‘Survival information’ 
eCRF. 
The last contact date will be used for censoring of patients in the analysis of overall survival.
2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed 
according to the treatment and strata they have been assigned to during the randomization 
procedure.
Per protocol set (PPS) 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the clinical study protocol (CSP).
The following list of protocol deviations will lead to exclusion of the patient from the Per-
Protocol Set:

not corticosteroid refractory cGvHD (i.e. criteria not verified via documented prior 
medication) 

more than one prior systemic therapy for the treatment of cGvHD, in addition to 
corticosteroids and CNI

not moderate or severe cGvHD at randomization

having transitioned from active aGvHD to cGvHD without tapering off corticosteroids +/− 
CNI (potential overlap syndrom)

taking any prohibited medication as specified in this protocol after start of study treatment 
and before the end of study treatment

study treatment received is different from treatment assigned by randomization, or no 
study treatment received at all

study treatment dispensing errors and/or non-compliance (if considered relevant and 
documented as protocol deviation) 

cGVHD  disease assessment on at least one organ  is  missing at baseline 

missed Cycle 6 and/or 7 Day 1 cGvHD assessment due to the Covid-19 pandemic
Safety
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 randomized treatment if the patient took at least one dose of that treatment or 
the first treatment received if the randomized treatment was never received.


Novartis
Confidential
Page 18
SAP 
CINC424D2301 / INCB 18424-365
Pharmacokinetic analysis set (PAS)
The Pharmacokinetic analysis set (PAS) includes all subjects who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, subjects are required to:

take a dose of ruxolitinib

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

for pre-dose samples, have the sample collected before the next dose administration

The PAS will be used for NCA analysis for patients where extensive PK sampling is 
obtained and for population PK where sparse sampling is obtained.  This analysis set will 
also be used for any exposure-response analysis 
 
Cross-over analysis set 
The Cross-over Analysis Set (CAS) comprises all patients randomized to and who receive 
BAT, who then cross over and receive at least one dose of ruxolitinib.  This analysis set will 
be used for all analyses for cross over patients.
Patient Classification: 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific patient classification rules defined in
Table 2-3. 
Table 2-3
Patient classification based on protocol deviations and non-PD 
criteria
Analysis set
Protocol deviations leading 
to exclusion
Non 
protocol 
deviation 
leading to exclusion
FAS 
INCL02
Not applicable
Safety Set
INCL02
No dose of study treatment 
Per-Protocol Set
INCL02, INCL05, 
INCL07,EXCL01,  EXCL02, 
TRT03, TRT04, TRT05, 
TRT06, TRT07, TRT08, 
COMD01, COMD02 and 
OTH01 and OTH07
No dose of study treatment
Crossover Analysis Set
INCL02
No dose of ruxolitinib
PK Analysis Set
INCL02
No dose of ruxolitinib, No 
evaluable PK concentration
Note: Based on CINC424D2301_SSD_Edit_checks_and Protocol Deviation Specifications Version 19
INCL02 - Written Study informed consent /assent not obtained.


Novartis
Confidential
Page 19
SAP 
CINC424D2301 / INCB 18424-365
Withdrawal of Informed Consent
Any data collected in the clinical database after a patient withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a 
patient withdraws full consent is recorded in the eCRF.  
2.2.1
Subgroup of interest
Efficacy
The primary efficacy endpoint will be summarized by the following subgroups to examine the 
homogeneity of treatment effect provided that the primary efficacy analysis based on the FAS 
is statistically significant: 

Age group (12- <18, 18-65, >65 years)

Gender

Race

Region Europe (including Australia and Canada), US, Asia excluding Japan, Japan

Chronic GvHD severity (moderate vs. severe)

Source of grafts 

Criteria for SR-cGvHD (a) a lack of response or disease progression after administration 
of minimum prednisone 1 mg/kg/day for at least 1 week, b) disease persistence without 
improvement despite continued treatment with prednisone at >0.5 mg/kg/day or 1 
mg/kg/every other day for at least 4 weeks OR c) increase to prednisolone dose to >0.25 
mg/kg/day after two unsuccessful attempts to taper the dose)

Prior cGvHD therapy (corticosteroid only vs. corticosteroid ± CNI)
No formal statistical test of hypotheses will be performed for the subgroups, only point 
estimate of the treatment effect and 95% confidence intervals will be provided). The objective 
of the efficacy subgroup analysis is to demonstrate homogeneity of treatment effect in the 
above subgroups. 
Safety
Key safety analyses will be repeated on the Safety Set in the following subgroups:

Age group (12- <18, 18-65, >65 years)

Gender

Race
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to or more commonly observed in a subgroup of patients.  The following 
summaries will be presented by subgroup:

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


Novartis
Confidential
Page 20
SAP 
CINC424D2301 / INCB 18424-365

Serious AEs with suspected relationship to study treatment, by primary system organ class 
and preferred term

On-treatment deaths, by primary system organ class and preferred term
Adolescent patients
In addition to the analyses of the primary efficacy endpoint and the safety summaries 
displayed for the age group < 18 years, PK will be analyzed separately for adolescents. 
Japanese patients
Subgroup analyses will also be performed for the patients treated in Japan. No selection will 
be done on the basis of ethnicity, the purpose being to evaluate the population of patients 
living in Japan, not a specific ethnic set of patients.
2.3
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 treatment arm and for all 
patients and listings will be reported by treatment arm to assess baseline comparability.  No 
inferential statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. gender, age groups: 12- <18 vs. 18-65 vs. >65 years, 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). 
Baseline stratification factors
The number (%) of patients in each stratum (moderate vs. severe cGvHD) based on data 
obtained from the IRT system will be summarized overall and by treatment arm for the FAS. 
Discordances between the stratum recorded in IRT at the time of randomization and the actual 
stratum recorded in the clinical database through the data collected on eCRF will be cross-
tabulated and listed.
Diagnosis and extent of disease
Summary statistics will be tabulated for diagnosis and extent of disease in underlying primary 
disease, stem cell transplant and chronic GvHD. 
For underlying primary disease, the analysis will include the following: diagnosis category 
and subcategory, details of diagnosis, time since diagnosis of underlying disease, CIBMTR 
risk assessment.


Novartis
Confidential
Page 21
SAP 
CINC424D2301 / INCB 18424-365
For transplant related disease history, the analysis will include the following: conditioning 
regimen type, total HCT-specific comorbidity index score, time since transplant, time from 
diagnosis of underlying disease to transplant, stem cell type, cytomegalovirus status, donor
information including age, gender, HLA typing method, HLA match score, source of grafts 
(HLA matched related donor, unrelated UCB (umbilical cord blood), related haploidentical, 
HLA matched/mismatched URD (unrelated donor)),  CMV status, T-cell depleted (Y/N), total 
nucleated cell dose. 
For cGvHD disease history, the analysis will include the following: prior diagnosis of aGvHD, 
time since initial diagnosis of cGvHD, overall severity of initial cGvHD, steroid refractory 
cGvHD criteria met (lack of response or disease progression after administration of minimum 
prednisone 1 mg/kg/day for at least 1 week, disease persistence without improvement despite 
continued treatment with prednisone at >0.5 mg/kg/day or 1 mg/kg/every other day for at least 
4 weeks, Increase to prednisolone dose to >0.25 mg/kg/day after two unsuccessful attempts to 
taper the dose), cGvHD severity at baseline (study entry), time since steroid refractory 
cGvHD, cGvHD organ involvement, steroid dose at randomization.
Medical history
Medical history and ongoing conditions, including underlying disease conditions and 
symptoms entered on eCRF will be summarized and listed by treatment arm..  The summaries 
will be presented by primary system organ class (SOC), preferred term (PT) and treatment 
arm. Medical history and current medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. The MedDRA version used for 
reporting will be specified in the CSR and as a footnote in the applicable tables/listings.
Other
Intended BAT strategy in case of SR-cGvHD  prior to randomization will be summarized by 
treatment arm.
All data collected at baseline including childbearing potential will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also
by treatment arm. The number (%) of randomized patients will be presented overall and by 
treatment group. The number (%) of screened and not-randomized patients and the reasons for 
screening failure will also be displayed. The number (%) of patients who were randomized 
but not treated, primary reason for not being treated and the number (%) of patients who were 
treated will be presented. The number (%) of patients in the FAS who are still on treatment, 
who discontinued the treatment phases (randomized treatment, crossover treatment) as well as 
the reason for discontinuation, and the survival follow-up will be presented overall and by 
treatment group.
Protocol deviations
The number (%) of patients in the FAS with any reportable protocol deviation will be 
tabulated by deviation category (as specified in the study Data Handling Plan) overall and by 
treatment group for the FAS. All protocol deviations will be listed.


Novartis
Confidential
Page 22
SAP 
CINC424D2301 / INCB 18424-365
Analysis sets
The number (%) of patients in each analysis set (defined in 2.2 Analysis sets) will be 
summarized by treatment group and stratum.
2.4
Treatments (study treatment, rescue medication, 
concomitant therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, in days, for ruxolitinib and BAT will be summarized 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. Duration of 
exposure to each BAT regimen (extracorporeal photopheresis (ECP), low-dose methotrexate 
(MTX). mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), 
infliximab, rituximab, pentostatin, or imatinib) will be summarized using the same approach.
Actual cumulative dose, dose intensity (DI) and relative dose intensity (RDI) will be 
summarized for the ruxolitinib arm only, since patients randomized to Investigator’s choice of 
BAT will receive various different categories of therapy. 
The number (%) of patients who have dose reductions or interruptions, and the reasons, will 
be summarized for the ruxolitinib group.
Patient level listings of all doses administered on treatment along with dose change reasons 
will be produced for both treatment groups.  
The Safety Set and Crossover Analysis Set will be used for all safety summaries.
Duration of exposure to study treatment
Duration of exposure to randomized treatment (days) = (last date of exposure to 
randomized treatment) – (date of first administration of randomized treatment) + 1. 
Duration of exposure to crossover treatment (days) = (last date of exposure to crossover 
treatment) – (date of first administration of crossover treatment) + 1. 
The last date of exposure to study treatment is the latest of the last dates of exposure to study 
treatment (see Table 2-4).
Table 2-4
Definition of last date of exposure of study treatment
Scenario
Definition of last date of exposure of 
study treatment 
Example
Scenario 1: Study 
treatment with a 
periodical administration 
The planned end date of the last 
period in which the last non-zero 
dose of the study treatment was last 
administered.
Note :  If the patient changed to 
another BAT, died or was lost to 
follow-up before the derived last 
date, the last date of exposure to 
study treatment is the date prior to 
Example 1: In a once-a-week 
administration, the last date of 
exposure is the date of last 
administration + 6 days.
Example 2: In a twice-a-week 
administration, the last date of 
exposure is the date of last 
administration + 3 days.


Novartis
Confidential
Page 23
SAP 
CINC424D2301 / INCB 18424-365
the start of the next BAT, date of 
death or the date of last contact, 
respectively. 
If the derived last date of exposure 
goes beyond the data cutoff date, it
should be truncated to the date of 
data cutoff.
Scenario 2: Study 
treatment with daily/IV 
administration 
Date of last administration of a non -
zero dose of the study treatment.
Example 3: A patient had a 
permanent discontinuation of the 
study treatment 06Jan2017 after 
being put on a temporary 
interruption since 01Jan2017. In 
this case the last date of exposure 
is- 31Dec2016. 
Scenario 3: Study 
treatment as an antibody 
Date of last administration of a non -
zero dose of the study drug + 
number of days antibody persists in 
vivo – 1 day.
Note :  If the patient changed to 
another BAT, died or was lost to 
follow-up before the derived last 
date, the last date of exposure to 
study treatment is the date prior to 
the start of the next BAT, date of 
death or the date of last contact, 
respectively. 
If the derived last date of exposure 
goes beyond the data cutoff date, it 
should be truncated to the date of 
data cutoff.
Example 4: For a study treatment 
which antibody persists in vivo for 
28 days, the last date of exposure 
is the date of last administration + 
28 days – 1 day.
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 a treatment group. It will be calculated for randomized treatment (by 
treatment group) and crossover treatment, respectively.
Duration of treatment period
Duration of randomized treatment period (days) = end date of on-randomized-treatment 
period – date of first administration of randomized treatment + 1
Duration of crossover treatment period (days) = end date of on-crossover-treatment period 
– date of first administration of crossover treatment + 1
The on-randomized-treatment period and on-crossover-treatment period are defined in 2.1.1 
General definitions
The duration of randomized treatment period, in days, for ruxolitinib and BAT will be 
summarized by means of descriptive statistics. It will also be categorized into time intervals; 


Novartis
Confidential
Page 24
SAP 
CINC424D2301 / INCB 18424-365
frequency counts and percentages will be presented for the number (%) of patients in each 
interval. The duration of crossover treatment period will be summarized similarly.
Duration of treatment period in patient-years 
The duration of treatment period (randomized and crossover) in patient-years is a total of the 
duration of treatment period in years from all the patients in a treatment group. It will be 
calculated for randomized treatment (ruxolitinib vs. BAT) and crossover treatment separately. 
Cumulative dose
The planned cumulative dose for ruxolitinib refers to the total planned dose as per the 
protocol (10 mg bid) up to the last dose date. 
The actual cumulative dose of randomized ruxolitinib refers to the total actual dose of 
randomized ruxolitinib as documented in the DAR eCRF. 
The actual cumulative dose of crossover ruxolitinib refers to the total actual dose 
administered, over the duration for which the patient is on the crossover ruxolitinib as 
documented in the DAR 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
Dose intensity (DI) of randomized ruxolitinib for patients with non-zero duration of 
exposure is defined as follows: 
DI (mg / day) = Actual cumulative dose (mg) of randomized ruxolitinib / Duration of 
exposure to randomized ruxolitinib (days).
Dose intensity (DI) of crossover ruxolitinib for patients with non-zero duration of exposure 
is defined as follows: 
DI (mg / day) = Actual cumulative dose (mg) of crossover ruxolitinib / Duration of exposure 
to crossover 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) = Planned Cumulative dose (mg) / Duration of exposure (days). 
The protocol planned starting dose for ruxolitinib is 10 mg BID.
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg / day)  / PDI (mg / day).  
DI and RDI will be summarized for randomized and crossover ruxolitinib treatment, 
separately.


Novartis
Confidential
Page 25
SAP 
CINC424D2301 / INCB 18424-365
The actual cumulative dose, DI and RDI up to Cycle 7 Day 1 and last date of exposure to 
study treatment (randomized or crossover) will be summarized. Graphical display will also be 
generated. 
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose reductions, or interruptions, and the reasons, will be 
summarized for ruxolitinib (randomized and crossover treatment separately). Separate 
summaries will be generated for patients with dose change due to dose tapering (change of 
dose due to efficacy of treatment) and patients with dose change due to other reasons 
(potential safety concerns).The number of patients who have drug permanently discontinued
and the reasons, will be summarized by treatment group.
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for 
permanent discontinuation’ will be used to summarize the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose.
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
2.4.2
Prior, concomitant and post therapies
2.4.2.1
Prior prophylaxis
Prior prophylaxis includes all systemic treatments that started prior to the diagnosis of cGvHD 
and administered as prophylaxis for GvHD. The number and percentage of patients who 
received any prophylaxis (e.g. CNI) prior to randomization will be summarized by lowest 
ATC class, preferred term and treatment arm using FAS. 
Listings will be generated for prophylaxis.
2.4.2.2
Systemic corticosteroid 
As per protocol the steroid doses of methylprednisolone will be converted to prednisone 
equivalents by multiplying the methylprednisolone dose by 1.25. Prednisone doses for each 
subject are converted to mg/kg/day.
The duration of exposure to systemic corticosteroids will be summarized for on-randomized-
treatment period and on-crossover-treatment period separately. 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 relative dose intensity 
(relative to the starting dose of corticosteroids) will be summarized up to the Cycle 7 Day 1


Novartis
Confidential
Page 26
SAP 
CINC424D2301 / INCB 18424-365
visit and end of on-treatment period. Graphical display will also be generated. These analyses 
will be based on Safety Set.
2.4.2.3
Calcineurin inhibitors (CNIs) during study treatment
The duration of exposure will be summarized for systemic CNIs (cyclosporine or tacrolimus) 
during on-randomized-treatment period and on-crossover-treatment period, respectively. 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.
2.4.2.4
Additional systemic cGvHD therapy
New additional systemic cGvHD therapy (medications and procedures) since start of study 
treatment will be listed and summarized by lowest ATC class, preferred term, overall and by 
treatment group by means of frequency counts and percentages using FAS.
As per agreement with the Steering Committee members during the SSC meeting on 13th of 
Nov 2018,  initiation of systemic CNI at the time of or after start of study treatment despite 
absence of lack of efficacy will be counted as new additional systemic treatment. Note: 
Although the protocol does not explicitly prohibit initiation of systemic CNI at time of 
randomization or initiation of study treatment potential impact of CNI on efficacy outcome in 
responders cannot be excluded.
2.4.2.5
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments, supportive care 
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 for randomized 
treatment phase using Safety Set will include:

Medications starting on or after the start of randomized treatment but no later than end of 
on-randomized-treatment period; and

Medications starting prior to start of randomized treatment and continuing after the start of 
randomized treatment.
The summaries for crossover treatment phase using Crossover Analysis Set will include:

Medications starting on or after the start of crossover treatment but no later than end of 
on-crossover-treatment period; and

Medications starting prior to start of crossover treatment and continuing after the start of 
crossover treatment.


Novartis
Confidential
Page 27
SAP 
CINC424D2301 / INCB 18424-365
All concomitant therapies will be listed using Safety Set. Any concomitant therapies starting
and ending prior to the start of randomized treatment or starting beyond end of on-
randomized-treatment period if not crossed over, or starting beyond end of on-crossover-
treatment period if crossed over, will be flagged in the listing. 
The prohibited concomitant medications will be summarized by lowest ATC class and 
preferred term up to the end of on-randomized-treatment and on-crossover-treatment periods, 
respectively. The list of prohibited medications will be provided and updated regularly by 
clinical team according to the clinical database review. 
In addition, a subset of concomitant medications i.e. hemopoietc cytokines and transfusions 
(red blood cells and platelets) will be grouped and summarized by treatment group.  
2.5
Analysis of the primary objective
The primary objective of the study is to compare the overall response rate (ORR) at Cycle 7 
Day 1 between the ruxolitinib arm and BAT arm  in steroid refractory cGvHD  patients.
2.5.1
Primary endpoint
ORR at Cycle 7 Day 1, defined as the proportion of patients with complete response (CR) or 
partial response (PR), according to the NIH Consensus Criteria (Lee 2015). ORR will be 
calculated based on the FAS using local investigators’ overall response assessed at the Cycle 
7 Day 1 visit and taking into account initiation or addition of new systemic therapy before this 
time point.

Complete response is defined as complete resolution of all signs and symptoms of 
cGvHD in all evaluable organs without initiation or addition of new systemic therapy.

Partial response is defined as an improvement in at least one organ (e.g. improvement of 
1 or more points on a 4 to 7 point scale, or an improvement of 2 or more points on a 10 to 
12 point scale) without progression in other organs or sites, initiation or addition of new 
systemic therapies.

Lack of response is defined as unchanged, mixed response, or progression.
A flare of cGvHD is defined as any increase in symptoms or therapy for cGvHD after an 
initial response (CR or PR). However, a flare may not lead to progression or additional 
systemic therapy. Only flares in GvHD that require new additional systemic therapy, will be 
considered cGvHD flare failure. Patients who fail corticosteroid taper fulfilling either one of 
the following criteria should initiate additional systemic therapy:

Re-escalation of the corticosteroid dose to methylprednisolone > 2 mg/kg/day (or 
equivalent  prednisone dose > 2.5 mg/kg/day), OR   

Failure to taper the methylprednisolone dose to <1 mg/kg/day (or equivalent prednisone 
dose <1.25 mg/kg/day) for a minimum 7 days.
cGvHD Recurrence is defined as the return of cGvHD disease after tapering off study 
treatment due to response.  Following completion of a taper of systemic therapy, if worsening 
of cGvHD symptoms occur, the patient is allowed to resume treatment for cGvHD as per local 
institutional practice. For the statistical analyses re-start of treatment for cGvHD is handled in 
the same way as addition or initiation of new systemic treatment.


Novartis
Confidential
Page 28
SAP 
CINC424D2301 / INCB 18424-365
A patient will not be considered a responder at Cycle 7 Day 1 if any of the following events 
occurs prior to the Cycle 7 Day 1 visit:

Missing overall cGvHD response assessment at Cycle 7 Day 1

No CR or PR at Cycle 7 Day 1

Addition of or start of new systemic therapy for cGvHD
2.5.2
Statistical hypothesis, model, and method of analysis
The following statistical hypotheses will be tested to address the primary efficacy objective: 
H0: ORRrux ≤ ORRBAT  vs.  H1: ORRrux > ORRBAT
where ORRrux and ORRBAT are the overall response rates at Cycle 7 Day 1 in the ruxolitinib 
and BAT groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by 
the randomization stratification factor (i.e., cGvHD moderate vs severe), will be used to 
compare ORR between the two treatment groups, at the one-sided 2.5% level of significance.
With protocol amendment 1 an efficacy and safety interim analysis was added and is targeted 
when 194 (60% of the targeted 324 patients) have completed the Cycle 7 Day 1 visit or 
discontinued from the study earlier and data of assessments are available. Following the 
group-sequential methodology defined in amendment 1 the efficacy stopping bound and the 
respective alpha to be spent will be calculated based on actual information fraction (number of 
patients included in FAS at the interim analysis divided by 324) using the pre-specified alpha 
spending function.
ORR will be summarized using descriptive statistics (N, %) by treatment arm along with two-
sided exact binomial 95% CIs [Clopper and Pearson 1934]. P-value, odds ratio and 95% Wald 
confidence limits calculated from stratified Cochran-Mantel-Haenszel test will be also 
presented.
2.5.3
Handling of missing values/censoring/discontinuations
Patients with missing assessments that prevent the evaluation of the primary endpoint will be 
considered non-responders on that treatment arm. This includes missing overall cGvHD
response assessments at baseline and Cycle 7 Day 1. The time window for the Cycle 7 Day 1 
visit is defined in Table 2-1 above.  
No data imputation will be applied. Patients who discontinue study treatment should return for 
the regular assessments indicated in Protocol Section 7.1. Addition or initiation of a new 
systemic therapy before Cycle 7 Day 1 in any arm will be considered a treatment failure, and 
patients will be counted as non-responder in the primary analysis.
2.5.4
Supportive analyses
Supportive analysis will include:

A detailed description of response rates (CR, PR. Unchanged, mixed response and 
progression) at Cycle 7 Day 1 by treatment group 

ORR at Cycle 7 Day 1 evaluated with the same analysis conventions as for the primary 
efficacy analysis using all patients in the PPS (if the PPS differ from the FAS).


Novartis
Confidential
Page 29
SAP 
CINC424D2301 / INCB 18424-365

A detailed description of the organ specific response for all organs at Cycle 7 Day 1.
Subgroup analyses for the primary endpoint 
If the primary analysis is statistically significant, subgroup analyses to assess the homogeneity 
of the treatment effect across demographic and baseline disease characteristics will be 
performed. The subgroups are described in section 2.1.1. 
For each of the subgroups, the following analyses will be performed:

Proportion of patients with ORR using descriptive statistics (N, %) along with two-sided 
exact binomial 95% CIs [Clopper and Pearson 1934]

Odds ratio with 95% CI using a logistic regression model with treatment and stratification 
factors as covariate
Efficacy analyses in subgroups will be purely exploratory and are intended to explore the 
consistency of treatment effect. Forest plot (n, odds ratio, 95% CI) will be produced to 
graphically depict the treatment effect estimates in different subgroups. No inferential 
statistics (p-values) will be produced for the  subgroups.
2.5.5
ORR at Crossover Cycle 7 Day 1 
ORR at Crossover (CO) Cycle 7 Day 1 is defined as the proportion of crossover patients with 
complete response (CR) or partial response (PR) at Crossover Cycle 7 Day 1. ORR will be 
summarized using descriptive statistics (N, %) along with two-sided exact binomial 95% CIs 
[Clopper and Pearson 1934] using local investigators’ overall response assessed at the CO 
Cycle 7 Day 1 visit and taking into account initiation or addition of new systemic therapy 
before this time point. Note that response is relative to the last assessment of cGvHD prior to 
or at the start date of crossover treatment (ruxolitinib).
A patient will not be considered a responder at CO Cycle 7 Day 1 if any of the following 
events occurs prior to CO Cycle 7 Day 1:

Missing overall cGvHD response assessment at crossover or CO Cycle 7 Day 1 

No CR or PR at CO Cycle 7 Day 1 

Addition of or start of new systemic therapy  for cGvHD
2.6
Analysis of the key secondary objective
The regulatory recommendations for demonstrating additional benefit to patients with SR-
GvHD differ between US and ROW: whereas the CHMP/PMDA agreed that Failure free 
survival (FFS) could be a meaningful measure of clinical benefit, the FDA recommended 
improvement in patient reported outcomes.  Therefore, this study will have two key secondary 
objectives: 
Key secondary objectives 

To compare FFS between ruxolitinib and BAT.  FFS is a composite time to event endpoint 
incorporating the following FFS events: i) relapse or recurrence of underlying disease or 
death due of underlying disease, ii.) non-relapse mortality, or iii.) addition or initiation of 
another systemic therapy for cGvHD. 


Novartis
Confidential
Page 30
SAP 
CINC424D2301 / INCB 18424-365

PRO comparison based on the modified Lee symptom score. 
A fixed sequence hierarchical testing strategy will be applied for the primary and the two key 
secondary endpoints. All tests will be one-sided with significance level alpha=2.5%. 
In line with the CHMP/PMDA interactions, FFS is used as the first key secondary endpoint 
for all regions except the US.  The figure below illustrates the sequence that will be used for 
all regions outside the US.  A different testing sequence will be used for the US (FDA), where 
PRO will be tested before testing FFS.
The analysis will be based on the FAS.
The rules how to test key secondary endpoints at the IA were further specified in the DMC 
Statistical Analysis Plan Amendment 1, an overall hierarchical testing procedure (Figure 2-1) 
was implemented to control the familywise error rate (FWER) at the pre-specified overall 
significance level (alpha=0.025) for the primary and the two key secondary endpoints (Glimm 
et al., Statistics in Medicine, 2010).
Unblinded IA results based on cut-off date 9-Jul-2019 were provided to the DMC in Oct 2019 
by the CRO Axio. The efficacy comparison at the IA was based on 196 patients 
corresponding to an information fraction of 196/324 = 0.605 or 60.5% and a significance level 
(as per pre-specified alpha spending function) of 0.011763 for the primary and both key 
secondary endpoints. To avoid any impact on the further conduct of the study the DMC was 
requested to inform Novartis only in case that ‘all three endpoints are positive’ when 
providing their recommendations. The DMC recommended to continue the study as planned.
All randomized patients are included in the primary CSR analysis. Following the overall 
hierarchical testing procedure, the hypotheses that were not rejected at the IA are to be tested 
again in this this CSR analyses spending the remaining alpha, i.e. IA results have to be taken 
into account when interpreting CSR results and are therefore included in this FIR. Assuming 
that N=329 patients will be included in the CSR analsis the significance level for the tests is 
alpha=0.01858. (Note: Sum of required significance levels at the IA and the CSR analysis > 
0.025 because the repeated test for the CSR is correlated to the test at the IA)


Novartis
Confidential
Page 31
SAP 
CINC424D2301 / INCB 18424-365
Figure 2-1
Overall hierarchical testing strategy used for all regions except for US
mLSS: responder analysis based on the total symptom score (TSS)
2.6.1
Key secondary endpoints
FFS is defined as the time from date of randomization to the earliest of i) relapse or 
recurrence of underlying disease or death due to underlying disease, ii.) non-relapse mortality, 
or iii.) addition or initiation of another systemic therapy for cGvHD. If a patient did not 
experience any of these events, FFS will be censored at the latest contact data (on or before 
the cut-off date). 
The second key secondary objective (all regions except for US) is to assess the improvement 
of symptoms based on the total symptom score (TSS) using the modified Lee Symptom Scale.
A conceptual overview and scoring rules are given in Section 5.4.3.  
A responder is defined as having achieved a clinically relevant reduction from baseline of the 
total symptom score (TSS). The proportion of  responders at the Cycle 7 Day 1 visit (as per 
visit window defined in Table 2-1), will be compared between treatment groups
A patient will not be considered a responder at Cycle 7 Day 1 if any of the following events 
occurs prior to the Cycle 7 Day 1 visit:

Missing or insufficient data to calculate TSS at baseline or Cycle 7 Day 1 

No clinical relevant reduction of TSS at Cycle 7 Day 1 

Addition of or start of new systemic therapy for cGvHD 
Multiple data imputation for missing pot-baseline TSS data may be considered to allow 
additional sensitivity analysis.
2.6.2
Statistical hypothesis, model, and method of analysis
Failure free survival (FFS)
Assuming proportional hazards for FFS, the following statistical hypotheses will be tested:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


Novartis
Confidential
Page 32
SAP 
CINC424D2301 / INCB 18424-365
H: θ ≥ 1 vs. H: θ < 1
where θ is the FFS hazard ratio (ruxolitinib  arm versus BAT arm). The analysis to test these 
hypotheses will consist of a stratified log-rank test at an overall one-sided 2.5% level of 
significance. The stratification will be based on the randomization stratification factors ( i.e. 
cGvHD moderate vs severe). 
Modified Lee symptoms score
Using the total symptom score each patient will be classified as either a responder or a non-
responder. A responder definition of 6-7 points has been suggested for the original LSS total 
score (Lee 2002). For the main analysis in this study a reduction of 7 or more points of the 
TSS of the mLSS is considered as response. .
The following statistical hypotheses will be tested to address the primary efficacy objective: 
H0: RRrux ≤ RRBAT  vs.  H1: RRrux > RRBAT
where RRrux and RRBAT are the response rates at Cycle 7 Day 1 in the ruxolitinib and BAT 
groups, respectively. The Cochrane-Mantel-Haenszel chi-square test, stratified by the 
randomization stratification factor (i.e., cGvHD moderate vs severe), will be used to compare 
RR between the two treatment groups, at the one-sided 2.5% level of significance.
Furthermore,  the rate of TSS responders and its 95% confidence interval will be presented by 
treatment group.
Supportive Analyses
The FFS distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians, 3, 6, 12, 18 and 24 month FFS estimates and 95% confidence intervals 
(Brookmeyer and Crowley 1982) will be presented for each treatment group. The hazard ratio 
for FFS will be calculated, along with its 95% confidence interval, using a stratified Cox 
model. 
The cumulative incidence curve of each of the three FFS components (considering the other 
two components as a competing risk) as well as estimates at 3, 6, 12, 18 and 24 months will 
also be presented with 95% confidence intervals. More details on these analyses are given in 
section 5.4.2.
2.6.3 
Handling of missing values/censoring/discontinuations
No data imputation will be performed for key secondary endpoints.
2.7
Analysis of secondary efficacy objective(s)
Best overall response (BOR)
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 Cycle 7 day 1 and before the start 
of additional systemic therapy for cGvHD. ORR will be calculated based on the FAS using 
local investigators’ overall response assessessments.


Novartis
Confidential
Page 33
SAP 
CINC424D2301 / INCB 18424-365
ORR at Cycle 4 Day 1 (end of Cycle 3)
ORR at Cycle 4 Day 1, defined as the proportion of patients with complete response (CR) or 
partial response (PR), according to the NIH Consensus Criteria (Lee 2015). ORR will be 
calculated based on the FAS using local investigators’ overall response assessed at the Cycle 
4 Day 1 visit and taking into account initiation or addition of new systemic therapy before this 
time point.
Duration of Response
Duration of response (DOR) is assessed for responders (i.e. all subjects with BOR=CR or PR)
only. DOR is defined as the time from first response until cGvHD progression, death, or the 
date of additional new systemic therapies for cGvHD. Patients without event will be censored 
at the last contact date.  
Overall survival (OS) 
Overall survival is defined as the time from date of randomization 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). 
Non Relapse Mortality (NRM)
Non-relapse mortality (NRM), defined as the time from date of randomization to date of death 
not preceded by underlying disease relapse/recurrence. Underlying disease relapse/recurrence 
is considered as competing events. If a patient is not known to have died or experienced the 
competing event, then NRM will be censored at the latest date the patient was known to be 
event-free (on or before the cut-off date).
Incidence of Malignancy Relapse/Recurrence (MR)
Incidence of Malignancy Relapse/Recurrence (MR), defined as the time from date of 
randomization to date of relapse/recurrence of the underlying disease. Death not proceeded by 
hematologic relapse/recurrence is considered as competing events. If a patient is not known to 
have relapse/recurrence or died without relapse/recurrence, then incidence of MR will be 
censored at the latest date the patient was known to be event-free (on or before the cut-off 
date).
Reduction of daily corticosteroid dose and successful tapering of all 
corticosteroids 
This will include the assessment of

Systemic steroid treatment per time interval up to Cycle 7 Day 1

proportion of patients successfully tapered off all corticosteroids at 6 months


Novartis
Confidential
Page 34
SAP 
CINC424D2301 / INCB 18424-365
2.7.1
Statistical hypothesis, model, and method of analysis
Best overall response (BOR)
BOR and its 95% confidence interval will be presented by treatment group. P-value, odds 
ratio and 95% Wald confidence limits calculated from stratified Cochran-Mantel-Haenszel 
test will also be presented.
ORR at Cycle 4 Day 1 (end of Cycle 3)
ORR at Cycle 4 Day 1 and its 95% confidence interval will be presented by treatment group. 
P-value, odds ratio and 95% Wald confidence limits calculated from stratified Cochran-
Mantel-Haenszel test will also be presented.
Duration of Response
Duration of response will be calculated for all patients with BOR = CR or PR. Kaplan-Meier 
curves, medians, 6, 12, 18 and 24 months survival probabilities with 95% confidence intervals 
will be presented.
Overall survival (OS) 
OS will be analyzed according to the randomized treatment group and strata assigned at 
randomization (cGvHD moderate vs severe). The OS distribution will be estimated using the 
Kaplan-Meier method, and the Kaplan-Meier curves, medians, 6, 12 and 24 month survival 
probabilities and 95% confidence intervals [Brookmeyer and Crowley 1982] will be presented 
for each treatment group. The hazard ratio for OS will be calculated, along with its 95% 
confidence interval, using a stratified Cox model.
Non Relapse Mortality (NRM)
Cumulative incidence of NRM and derived probabilities at Months 1, 2, 6, 12, 18 & 24 will 
be estimated, considering underlying disease relapse/recurrence as competing events.
Incidence of Malignancy Relapse/Recurrence (MR)
The cumulative incidence curve for MR and estimates at 3, 6, 12, 18 and 24 months with 95% 
confidence intervals will be presented 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/recurrence and its 95% confidence interval at 3, 6, 
12, 18 and 24 months will be presented by treatment group for patients with underlying 
hematologic malignant disease. Odds ratio and 95% Wald confidence limits calculated from 
stratified Cochran-Mantel-Haenszel test will be also presented.
2.7.2
Handling of missing values/censoring/discontinuations
Patients with missing overall response assessments that prevent the evaluation of the ORR at 
Cycle 4 Day 1 and BOR will be considered non-responders on that treatment arm. This 
includes missing cGvHD assessments at Cycle 4 Day 1. The time window for the Cycle 4 Day 
1 visit is defined in Table 2-1 above.  


Novartis
Confidential
Page 35
SAP 
CINC424D2301 / INCB 18424-365
2.8
Safety analyses
All safety analyses will be based on Safety Set, except that the summary of safety data during 
the crossover treatment phase will be based on Crossover Analysis Set.  All listings and tables 
will be presented by treatment group. For safety evaluations (except for AE) during the
randomized treatment period, the last available assessment on or before the date of start of 
randomized treatment is taken as the “baseline” assessment. For safety evaluations (except for 
AE) during crossover treatment phase, the last available assessment on or before the date of 
start of crossover treatment is taken as the “baseline” assessment.  
The main comparative safety analyses will use data from the on-randomized treatment period 
and will be performed for the time period from the day of the first dose up to Cycle 7 Day 1 
(= Day 179, the upper bound of the Cycle 7 Day 1 visit window defined in Table 2-1)  to 
avoid potential bias due to different exposure durations and/or related to possible cross over 
from BAT to ruxolitinib after Cycle 7 Day 1.  Furthermore, separate safety summaries will be 
generated for the entire on-randomized treatment period and the on-cross over treatment 
period.
2.8.1
Adverse events (AEs)
For reporting of AEs the overall observation period will be divided into mutually exclusive 
categories, including pre-treatment, on-treatment (randomized or crossover) and post-
treatment  periods as defined in Section 2.1.1. The 6-month period for the main safety 
comparison will be derived from the on-randomized treatment period as defined above.
AE summaries will include all AEs occurring (new or worsening) during the respective on-
treatment periods. All AEs collected in the AE (e)CRF 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 subjects 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 subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject 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 their frequency in the ruxolitinib arm. 
The following adverse event summaries will be produced by treatment arm; overview of 
adverse events and deaths, AEs by SOC and PT, summarized by relationship (all AEs and 
AEs related to study treatment), seriousness (SAEs and non-SAEs), leading to treatment 
discontinuation, leading to dose interruption/adjustment, and leading to fatal outcome. In 
addition, a summary of serious adverse events with number of occurrences will be produced 
(an occurrence is defined as >1 day between start and prior end date of record of same 
preferred term). 


Novartis
Confidential
Page 36
SAP 
CINC424D2301 / INCB 18424-365
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables of on-
treatment adverse events which are not serious adverse events with an incidence greater than 
5% and  on-treatment serious adverse events and SAEs suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set 
population.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
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.
2.8.1.1
AEs adjusted for subject exposure time 
In order to account for possible differences in exposure of the ruxolitinib arm relative to the 
BAT arm due to crossover from BAT to ruxolitinib after Cycle 7 Day 1, incidence rates of 
adverse events may be presented by adjusting for duration of treatment period in patient-years 
where relevant. 
2.8.1.2
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to the compound ruxolitinib. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, CMQ) may also be used. A CMQ is a customized group of search terms which 
defines a medical concept for which there is no official SMQ available or the available SMQ 
does not completely fit the need. It may include a combination of single terms and/or an 
existing SMQ, narrow or broad. 
For each specified AESI, the number and percentage of patients with at least one event of the 
AESI occurring during the on-treatment period will be summarized. Summaries of these 
AESIs will be provided by treatment arm, (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. 


Novartis
Confidential
Page 37
SAP 
CINC424D2301 / INCB 18424-365
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death)  will be 
produced by treatment arm, system organ class and preferred term. 
All deaths will be listed and post-treatment deaths will be flagged. A separate listing of deaths 
prior to starting treatment will be provided for all screened patients.
2.8.3
Laboratory data
On analyzing laboratory, data from all sources (central and local laboratories) will be 
combined. The summaries will include all assessments available for the lab parameter 
collected no later than end of the on-treatment periods (randomized or crossover).
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 treatment):

Shift tables using CTC grades to compare baseline to the worst on-treatment  value 
The following listings will be produced for the laboratory data:

Listing of all CTC grade 3 or 4 laboratory toxicities
The results from viral load testing will be summarized by visit and treatment.
In addition to the above mentioned tables and listings, other exploratory analyses, for example
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
produced.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Not applicable.
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body mass index (kg/m2), 
body surface area (m2), body temperature (°C), pulse (beats per minute), systolic and diastolic 
blood pressure (mmHg). 
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on 
treatment period will be flagged in the listings. 


Novartis
Confidential
Page 38
SAP 
CINC424D2301 / INCB 18424-365
Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in the 
following table.
Table 2-5
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease  > 10% from Baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
>= 39.1 
-
The number and percentage of patients with notable vital sign values (high/low) will be 
presented  by treatment arm.         
Graphical presentations of vital signs (e.g., body weight, body mass index, systolic blood 
pressure, diastolic blood pressure) over time for change from baseline may be produced via 
boxplots based on time windows and corresponding tables displaying the statistics used for 
the box plots by the selected time points. 
A listing of all vital sign assessments will be produced by treatment arm and notable values 
will be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged. 
2.8.4.3
Pediatric data
Adolescent data will be tabulated and listed, notable values will be flagged.
2.8.4.4
Time to infection
Time to first occurrence of grade 3 infection
Time to first occurrence of infection is defined as time from start of study treatment to the 
date of first occurrence of grade 3 infection severity per protocol Appendix 2, i.e. time in days 
is calculated as (start date of first occurrence of infection ) – (start of study treatment) +1. 
In the absence of an event during the on-treatment period, the censoring date applied will be 
the earliest of the following dates: 

death date

end date of on-treatment period  (randomized or crossover) 


Novartis
Confidential
Page 39
SAP 
CINC424D2301 / INCB 18424-365

data cut-off date

withdrawal of informed consent date
Cumulative incidence curve for time to grade 3 infection as well as estimates at 1, 2 and 6 
months with 95% confidence intervals will be presented for each treatment group considering 
deaths or end of treatment phase (randomized or crossover) without prior infection as 
competing risks.
2.9
Pharmacokinetic endpoints
Pharmacokinetic analysis set (PAS) will be used in all pharmacokinetic data analysis and PK 
summary statistics. 
Plasma samples for PK will be taken at Day 1 (start of treatment), at Day 15 (Cycle 1), to 
characterize the PK after first dose, and at steady state by non-compartmental analysis.  
Additional PK samples will be taken at later visits to characterize exposure-efficacy, 
exposure-safety and population PK modeling as data allows. Concentrations will be expressed 
in mass per volume units.
Pharmacokinetic parameters of ruxolitinib will be calculated using non-compartmental 
methods using Phoenix WinNonlin (Pharsight, Mountain View, CA) software. Additional PK 
parameters may be estimated as needed.
PK parameters
Table 2-6
Non-compartmental PK parameters for ruxolitinib
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for 
terminal elimination rate constant (time-1)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL/F
The total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with z) 
(volume)
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum) will be presented by treatment for 
Pharmacokinetic analysis set for all PK parameters defined in Table 2-6 except Tmax, where 
only n, median, minimum and maximum will be presented.




Novartis
Confidential
Page 41
SAP 
CINC424D2301 / INCB 18424-365
 
2.14
Interim analysis
One early safety interim analysis and an efficacy and safety analysis based on 60% of the 
targeted patients will be performed.
An early safety analysis will be generated when safety data on the first 80 randomized 
patients who have completed Cycle 4 Day 1 are available. No efficacy data will be generated 
for this safety analysis.
An efficacy and safety analysis will be performed when 194 (60% of the targeted 324 patients) 
have completed the Cycle 7 Day 1 visit or discontinued from the study earlier and data of 
assessments are available. Following a 2-look group sequential design a rho-spending 
function with parameter rho=1.5 will be used as alpha spending function, for which 
operational characteristics are given in the Table 2-7. If the number of patients at the IA is not 
exactly 194 at the time of the interim cut-off, the efficacy stopping bound will be recalculated 
based on the pre-specified alpha spending function.


Novartis
Confidential
Page 42
SAP 
CINC424D2301 / INCB 18424-365
Table 2-7
Operational characteristics at the interim analysis
With 194 patients (60%) patients and final analysis
No. of 
patients 
(percent)
Alpha spent#
(cumulative)
Required 
odds ratio for 
significance 
(if design 
assumption 
correct) 
Corresponding 
ORR for Rux (if 
assumed ORR 
for BAT correct)
Simulated rejection rates 
under H1 (cumulative)
Reject H0
Reject H1
assuming ORR for BAT=0.58 (58%), odds ratio=2.35
Interim 
analysis 
194 (59.9)
0.012
2.05
73.88%
66.37%
0%
Final 
analysis
324 (100)
0.025
1.66
69.65%
93.34%
6.66%
assuming ORR for BAT=0.62 (62%), odds ratio=2.35
Interim 
analysis 
194 (59.9)
0.012
2.10
77.39%
62.94%
0%
Final 
analysis
324 (100)
0.025
1.69
73.39%
91.64%
8.36%
assuming ORR for BAT=0.66 (66%), odds ratio=2.35
Interim 
analysis 
194 (59.9)
0.012
2.17
80.79%
59.25%
0%
Final 
analysis
324 (100)
0.025
1.73
77.05%
89.36%
10.64%
Based on sequential CMH test with one-sided cumulative alpha=0.025 (2.5%), assuming same ORR and 50% of 
patients in each stratum)
#derived from alpha spending function (rho spending function with rho=1.5)
Note: derived from Table 10-2 of the amended study protocol, in protocol Table 10-2 one digit for the values in the 
column alpha spent was missing (e.g. 0.25 instead of the correct 0.025), typos were corrected in this table. 
The interim analyses will be performed by an independent statistician and programmer (not 
involved with the conduct of the study). Further details will be described in the DMC charter. 
The results of the interim analyses will be provided to the DMC by the independent 
statistician.
Early PK analysis
To compare the exposure of 10 mg BID in the SR cGvHD population to the known exposure 
in MPN patients, the early extensive ruxolitinib PK data on the first 8 patients (adults and 
any adolescent patients randomized at that time) will be explored once available, also in the 
context of concomitant medications. However, there will be no comparison between the two 
treatment arms because PK data are not collected in BAT patients.
3
Sample size calculation.
3.1
Primary analysis
The sample size calculation is based on the primary variable ORR on Cycle 7 Day 1. In a 
meta-analysis Olivieri et al. (Lancet Hematology, 2015) obtained an estimated pooled effect 
























Novartis
Confidential
Page 54
SAP 
CINC424D2301 / INCB 18424-365
6
Reference
1. Armitage P, McPherson CK and Rowe BC (1969). Repeated significance tests on 
accumulating data. J .R. Statist. Soc. A, 132, 232-244. 
2. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38, 29 - 41. 
3. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
4. Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.
5. Dmitrienko A., Molenberghs G., Chuang-Stein Ch., Offen W. (2005). Analysis of clinical 
trials using SAS. SAS Institute Inc., SAS press.
6. Glimm, E., Maurer, W., and Bretz, F. (2010). Hierarchical Testingof Multiple Endpoints 
in Group Sequential Trials. Statistics in Medicine, 29, 219–228.
7. Mantel, N. and Joseph L Fleisś (1980). Minimum expected cell size requirements for the 
Mantel-Haenszel one degree-of-freedom Chi-Square Test and a related rapid procedure. 
American Journal of Epidemiology, 112, 129-134.