Conditions: Chronic Graft Versus Host Disease
Keywords: chronic graft versus host disease PCYC1140 PCYC1140IM 1140 Ibrutinib GVHD Steroid dependent refractory chronic PCI32765 IMBRUVICA Pharmacyclics PCYC graft versus host disease immunology new onset graft versus host disease INTEGRATE Corticosteroids prednisone
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 193
Healthy volunteers: no

Brief summary:
To evaluate the safety and efficacy of ibrutinib in combination with prednisone in subjects with newly diagnosed moderate to severe cGVHD.

Detailed description:

Arms:
arm 1: Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 \[CYP\] inhibitors or hepatic dysfunction as applicable.

Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses. arm 2: Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity.

Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.

Interventions: intervention 1: ibrutinib intervention 2: Placebo intervention 3: Prednisone
Intervention descriptions: intervention 1: Ibrutinib capsules administered orally daily intervention 2: Placebo capsules administered orally daily intervention 3: Prednisone administered daily

Protocol document:
Prot_000.pdf: 
NCT02959944




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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF APPENDICES ...............................................................................................................7 
LIST OF IN-TEXT TABLES .......................................................................................................7 
SYNOPSIS ......................................................................................................................................8 
ABBREVIATIONS ......................................................................................................................14 
1. 
BACKGROUND .........................................................................................................16 
1.1. 
Disease/Histology .........................................................................................................16 
1.1.1. 
Disease Background ......................................................................................................16 
1.1.2. 
Current Treatment Options ...........................................................................................17 
1.2. 
Ibrutinib Overview ........................................................................................................18 
1.2.1. 
Summary of Nonclinical Data .......................................................................................18 
1.2.1.1. 
Pharmacology ................................................................................................................18 
1.2.1.2. 
Safety Pharmacology and Toxicology ..........................................................................19 
1.2.2. 
Summary of Clinical Data .............................................................................................19 
1.2.2.1. 
Pharmacokinetics and Product Metabolism ..................................................................19 
1.2.3. 
Summary of Clinical Safety ..........................................................................................20 
1.2.3.1. 
Monotherapy Studies ....................................................................................................20 
1.2.3.2. 
Combination Studies .....................................................................................................21 
1.2.3.3. 
Chronic GVHD Study ...................................................................................................21 
1.2.4. 
Risks ..............................................................................................................................22 
1.2.4.1. 
Atrial Fibrillation ..........................................................................................................22 
1.2.4.2. 
Bleeding-related Events ................................................................................................22 
1.2.4.3. 
Cytopenias .....................................................................................................................22 
1.2.4.4. 
Diarrhea .........................................................................................................................22 
1.2.4.5. 
Infections .......................................................................................................................22 
1.2.4.6. 
Interstitial Lung Disease (ILD) .....................................................................................23 
1.2.4.7. 
Non-melanoma Skin Cancer .........................................................................................23 
1.2.4.8. 
Rash ...............................................................................................................................23 
1.2.4.9. 
Hypertension .................................................................................................................23 
1.2.5. 
Summary of Clinical Data in Chronic GVHD ..............................................................23 
1.3. 
Prednisone .....................................................................................................................24 
1.3.1. 
Summary of Clinical Data .............................................................................................24 
1.3.2. 
Summary of Clinical Safety ..........................................................................................24 
1.3.3. 
Summary of Clinical Data in Chronic Graft versus Host Disease ................................28 
1.4. 
Study Rationale .............................................................................................................28 
2. 
STUDY OBJECTIVES ...............................................................................................29 
2.1. 
Primary Objective .........................................................................................................29 
2.2. 
Secondary Objective(s) .................................................................................................29 
2.3. 
Exploratory Objective(s) ...............................................................................................29 
3. 
STUDY DESIGN .........................................................................................................30 
3.1. 
Overview of Study Design ............................................................................................30 
3.1.1. 
Study Schema ................................................................................................................31 


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4. 
SUBJECT SELECTION ............................................................................................32 
4.1. 
Inclusion Criteria ...........................................................................................................32 
4.2. 
Exclusion Criteria..........................................................................................................33 
5. 
TREATMENT OF SUBJECTS .................................................................................35 
5.1. 
Treatment Allocation and Blinding ...............................................................................35 
5.1.1. 
Randomized Double-blind Phase ..................................................................................35 
5.1.1.1. 
Blinding .........................................................................................................................35 
5.2. 
Study Treatment ............................................................................................................36 
5.3. 
Study Medication ..........................................................................................................36 
5.3.1. 
Ibrutinib/Placebo ...........................................................................................................36 
5.3.1.1. 
Formulation/Packaging/Storage ....................................................................................36 
5.3.1.2. 
Dose and Administration...............................................................................................37 
5.3.1.3. 
Overdose .......................................................................................................................37 
5.3.1.4. 
Dose Modification for Adverse Reactions ....................................................................37 
5.3.1.5. 
Dose Modification for Subjects with Hepatic Impairment ...........................................39 
5.3.1.6. 
Ibrutinib/Placebo Hold after Withdrawal of All Immunosuppressants.........................39 
5.3.2. 
Prednisone .....................................................................................................................40 
5.3.2.1. 
Formulation/Packaging/Storage ....................................................................................40 
5.3.2.2. 
Dose and Administration...............................................................................................40 
5.3.2.3. 
Overdose .......................................................................................................................41 
5.3.2.4. 
Dose Modification for Adverse Reactions ....................................................................42 
5.4. 
Criteria for Permanent Discontinuation of Ibrutinib/Placebo .......................................42 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES .............................................42 
6.1. 
Permitted Concomitant Medications .............................................................................42 
6.1.1. 
Ancillary Therapy and Supportive Care .......................................................................42 
6.1.2. 
Systemic Immunosuppressant Therapy.........................................................................43 
6.2. 
Medications to be Used with Caution ...........................................................................43 
6.2.1. 
CYP3A Enzyme Inhibitors/Inducers.............................................................................43 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib ..................44 
6.2.3. 
Antiplatelet Agents and Anticoagulants........................................................................44 
6.3. 
Other Systemic Immunosuppressant Therapy for cGVHD ..........................................45 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures............................45 
6.4.1. 
Minor Surgical Procedures ............................................................................................45 
6.4.2. 
Major Surgical Procedures ............................................................................................45 
7. 
STUDY EVALUATIONS ...........................................................................................46 
7.1. 
Description of Procedures .............................................................................................46 
7.1.1. 
Assessments ..................................................................................................................46 
7.1.1.1. 
Informed Consent Form (ICF) ......................................................................................46 
7.1.1.2. 
Confirm Eligibility ........................................................................................................46 
7.1.1.3. 
Medical History and Demographics .............................................................................46 
7.1.1.4. 
Prior and Concomitant Medications..............................................................................46 
7.1.1.5. 
Adverse Events..............................................................................................................47 
7.1.1.6. 
Physical Examination ....................................................................................................47 
7.1.1.7. 
Karnofsky/Lansky Performance Scale ..........................................................................47 
7.1.1.8. 
Vital Signs .....................................................................................................................47 
7.1.2. 
Laboratory .....................................................................................................................47 


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7.1.2.1. 
Hematology ...................................................................................................................47 
7.1.2.2. 
Chemistry (Serum) ........................................................................................................47 
7.1.2.3. 
Infection Surveillance ...................................................................................................48 
7.1.2.4. 
Coagulation Studies ......................................................................................................48 
7.1.2.5. 
Hepatitis Serologies ......................................................................................................48 
7.1.2.6. 
Serum Immunoglobulins ...............................................................................................48 
7.1.2.7. 
Pregnancy Test ..............................................................................................................48 
7.1.3. 
Diagnostics/Procedures .................................................................................................48 
7.1.3.1. 
Electrocardiograms (ECG) ............................................................................................48 
7.1.3.2. 
Forced Expiratory Volume in 1 Second (FEV1)...........................................................49 
7.1.4. 
Pharmacokinetics/Biomarkers.......................................................................................49 
7.1.4.1. 
Pharmacokinetics ..........................................................................................................49 
7.1.4.2. 
Biomarkers and Pharmacodynamic Studies ..................................................................49 
7.1.4.3. 
Biomarker DNA and RNA Sequencing ........................................................................50 
7.2. 
Sample Collection and Handling ..................................................................................50 
7.3. 
Efficacy Evaluations .....................................................................................................50 
7.3.1. 
NIH Consensus Panel Response Criteria ......................................................................50 
7.3.2. 
Lee cGVHD Symptom Scale and SF-36 Questionnaire ...............................................51 
7.3.3. 
Late effects surveillance for adolescents (<22 years at randomization) .......................51 
8. 
STUDY PROCEDURES .............................................................................................51 
8.1. 
Screening Phase ............................................................................................................51 
8.1.1. 
Screening/Consenting Visit ...........................................................................................51 
8.2. 
Treatment Phase ............................................................................................................52 
8.2.1. 
Treatment Visits ............................................................................................................52 
8.2.1.1. 
Week 1 Day 1 ................................................................................................................52 
8.2.1.2. 
Week 2 ..........................................................................................................................53 
8.2.1.3. 
Week 5, 9, 13, 17, 21, 25 ..............................................................................................54 
8.2.1.4. 
Week 37, 49, and every 12 weeks thereafter (± 7 days) ...............................................55 
8.2.2. 
Progressive Disease Visit ..............................................................................................55 
8.2.3. 
End-of-Treatment Visit .................................................................................................56 
8.3. 
Follow-up Phase ............................................................................................................57 
8.3.1. 
Response Follow-up ......................................................................................................57 
8.3.2. 
Long-Term Follow-up ...................................................................................................57 
8.3.3. 
Expected length of participation on study .....................................................................57 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ................................................58 
9.1. 
Completion ....................................................................................................................58 
9.2. 
Discontinuation from Ibrutinib/Placebo ........................................................................58 
9.3. 
Withdrawal from Study .................................................................................................58 
10. 
STATISTICAL METHODS AND ANALYSIS .......................................................59 
10.1. 
Analysis Sets .................................................................................................................59 
10.1.1. 
Intention-to-Treat Population (ITT) ..............................................................................59 
10.1.2. 
Safety Population (SP) ..................................................................................................59 
10.2. 
Sample Size Determination ...........................................................................................59 
10.3. 
Subject Information .......................................................................................................60 
10.4. 
Efficacy Analyses..........................................................................................................60 
10.4.1. 
Primary Efficacy Endpoint ............................................................................................60 


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10.4.2. 
Secondary Endpoints for Efficacy ................................................................................60 
10.4.3. 
Exploratory Endpoints ..................................................................................................61 
10.5. 
Safety Analysis .............................................................................................................62 
10.6. 
Interim Futility Review .................................................................................................63 
10.7. 
Data Monitoring Committee (DMC) ............................................................................63 
11. 
ADVERSE EVENT REPORTING ............................................................................64 
11.1. 
Definitions .....................................................................................................................64 
11.1.1. 
Adverse Events..............................................................................................................64 
11.1.2. 
Serious Adverse Events.................................................................................................65 
11.1.3. 
Severity Criteria (Grade 1-5) ........................................................................................66 
11.1.4. 
Causality (Attribution) ..................................................................................................66 
11.2. 
Unexpected Adverse Events .........................................................................................67 
11.3. 
Special Reporting Situations .........................................................................................67 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ..................................................................................................................67 
11.4.1. 
Assessment of Adverse Events .....................................................................................67 
11.4.2. 
Adverse Event Reporting Period ...................................................................................68 
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events ................................68 
11.4.4. 
Pregnancy ......................................................................................................................69 
11.4.5. 
Other Malignancies .......................................................................................................70 
11.4.6. 
Eye-Related Adverse Events .........................................................................................70 
11.4.7. 
Adverse Events of Special Interest (AESI) ...................................................................70 
11.4.7.1. Major Hemorrhage ........................................................................................................70 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ............70 
12.1. 
Regulatory and Ethical Compliance .............................................................................70 
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval ................................................................................71 
12.3. 
Informed Consent ..........................................................................................................71 
12.4. 
Quality Control and Quality Assurance ........................................................................71 
12.5. 
Protected Subject Health Information Authorization ....................................................72 
12.6. 
Study Files and Record Retention .................................................................................72 
12.7. 
Case Report Forms and Record Maintenance ...............................................................73 
12.8. 
Investigational Study Drug Accountability ...................................................................73 
12.9. 
Study Monitoring/Audit Requirements .........................................................................74 
12.10. 
Investigator Responsibilities .........................................................................................75 
12.11. 
Sponsor Responsibilities ...............................................................................................75 
12.12. 
Financial Disclosure ......................................................................................................75 
12.13. 
Liability and Clinical Trial Insurance ...........................................................................76 
12.14. 
Protocol Amendments ...................................................................................................76 
12.15. 
Publication of Study Results .........................................................................................76 
12.16. 
Study Discontinuation ...................................................................................................77 
13. 
REFERENCES ............................................................................................................78 
14. 
APPENDICES .............................................................................................................82 
 


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LIST OF APPENDICES 
Appendix A. Schedule of Assessments .......................................................................................83 
Appendix B. Schedule of Assessments for Pharmacokinetics, Pharmacodynamics, 
Biomarker and T/B/NK..........................................................................................87 
Appendix C. Karnofsky/Lansky Performance Status ..................................................................88 
Appendix D. Inhibitors and Inducers of CYP3A ........................................................................89 
Appendix E. Child-Pugh Score for Subjects with Chronic Liver Impairment ...........................90 
Appendix F. Lee cGVHD Symptom Scale .................................................................................91 
Appendix G. SF-36 Questionnaire ..............................................................................................93 
Appendix H. Chronic GVHD Activity Assessment – Clinician .................................................99 
Appendix I. 
Response Determination for Chronic GVHD Clinical Trials based on 
Clinician Assessments .........................................................................................102 
Appendix J. 
Chronic GVHD Activity Assessment  Patient Self Report ...............................104 
Appendix K. Prednisone Equivalents Table ..............................................................................105 
Appendix L. Summary of Ancillary Therapy and Supportive Care Interventions ...................106 
Appendix M. Diagnosis of cGVHD  Signs and Symptoms of cGVHD ..................................110 
Appendix N. Staging of cGVHD ...............................................................................................114 
Appendix O. NIH Global Severity/Staging of cGVHD ............................................................117 
Appendix P. Late Effects Surveillance for Adolescents ...........................................................118 
Appendix Q. Corticosteroid-related toxicities and CTCAE preferred terms ............................121 
 
LIST OF IN-TEXT TABLES  
Table 1. 
Ibrutinib/Placebo Dose Modifications ...................................................................38 
Table 2. 
Ibrutinib/Placebo Dose Reduction Levels .............................................................38 
Table 3. 
Ibrutinib/Placebo Dose Modifications for Subjects with Hepatic Impairment ......39 
Table 4. 
Prednisone Taper Schedule ....................................................................................41 
Table 5. 
Ibrutinib/Placebo Dose Modifications for Concomitant Use of CYP3A 
Inhibitors ................................................................................................................44 
 
 


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SYNOPSIS 
Study Title: 
A Randomized, Double-Blind Phase 3 Study of Ibrutinib in 
Combination With Corticosteroids versus Placebo in Combination 
With Corticosteroids in Subjects with New Onset Chronic Graft 
Versus Host Disease (cGVHD) 
Protocol Number: 
PCYC-1140-IM 
Study Phase: 
3 
Study Duration: 
Estimated to be up to 7 years 
Investigational Product and 
Reference Therapy: 
Ibrutinib (IMBRUVICA®) will be supplied as 70 mg and 140 mg 
hard gelatin capsules for oral (PO) administration.  
Placebo will be supplied as hard gelatin capsules and will look 
identical to ibrutinib capsules.  
Objectives: 
Primary Objective: 
To evaluate the efficacy of ibrutinib in combination with prednisone 
(Arm A) versus placebo in combination with prednisone (Arm B) 
based on the response rate at 48 weeks (the proportion of responders 
[CR or PR]) as determined by NIH Consensus Development Project 
criteria in subjects with new onset moderate to severe cGVHD. 
Secondary Objectives: 
To compare the two treatment arms in terms of the following: 
Efficacy 
x 
Response rate at 24 weeks (the proportion of responders [CR or 
PR]) as defined by the NIH Consensus Development Project 
(2014) 
x 
Duration of response (DOR) 
x 
Proportion of subjects obtaining steroid dose level less than 
0.15 mg/kg/d at 24 weeks 
x 
Time to withdrawal of all immunosuppressants (with the 
exception of ibrutinib/placebo)  
x 
Overall survival (OS) 
x 
Lee cGVHD symptom scale improvement 
Safety 
x 
Safety and tolerability  
x 
Differences in steroid-related morbidities (eg, hyperglycemia, 
hypertension)  
Study Design: 
This is a Phase 3, multicenter, international, randomized, double-blind 
study of oral ibrutinib in combination with prednisone versus placebo 
in combination with prednisone in subjects with new onset chronic 
GVHD. 
Approximately 186 subjects with newly diagnosed moderate or severe 
cGVHD, as defined by the NIH Consensus Development Project 
Criteria, will be randomized in a 1:1 ratio to receive either ibrutinib in 
combination with prednisone (Arm A) or placebo in combination with 
prednisone (Arm B). 
Treatment with ibrutinib/placebo will be administered continuously 


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until unacceptable toxicity, progression of the underlying disease, 
death, or the start of a new systemic treatment for cGVHD. 
Ibrutinib/placebo can be discontinued after response in cGVHD disease 
symptoms and withdrawal of other systemic immunosuppressants 
(Section 5.3.1.6). 
Corticosteroid therapy will be tapered as per a standard taper regimen 
with the goal of reducing exposure to high-moderate dose 
corticosteroids as quickly as possible according to clinical severity of 
cGVHD. A standard steroid taper schedule is provided in the protocol 
as guidance for clinicians (Table 4). 
The primary endpoint is the response rate at 48 weeks. Response will 
be defined by the NIH Consensus Development Project Criteria 
(2014) and must occur: 
x 
In the absence of new therapy for cGVHD 
x 
In the absence of progression of the underlying disease that was 
the indication for transplant, or post-transplant 
lymphoproliferative disease (PTLD), or death 
Secondary endpoints will assess for additional clinical benefit 
including Week-24 response, DOR, corticosteroid dose reduction, 
time to withdrawal of all immunosuppressants, OS, and Lee cGVHD 
symptom scale. 
The randomization between arms will be stratified according to: 
x 
Age group (12 to <22 \HDUVROGYV22 years old) 
x 
NIH Global Severity grade (moderate vs. severe) 
x 
Ongoing use of systemic immunosuppressants that were initiated 
for either treatment of or prophylaxis for acute GVHD (Yes vs. 
No) 
Population: 
x 
Subjects with new onset moderate or severe cGVHD as defined 
by the NIH Consensus Development Project Criteria 
(Jagasia 2015) 
x 
Subjects must be in need of systemic treatment for cGVHD with 
corticosteroids 
Centers: 
Multi-center, International  
Inclusion Criteria:  
Eligible subjects will meet all of the following criteria: 
1. New onset moderate or severe cGVHD as defined by the NIH 
Consensus Development Project Criteria (2014, see Appendix M, 
Appendix N, Appendix O). 
2. History of an allogeneic hematopoietic cell transplant.  
3. Need for systemic treatment with corticosteroids for cGVHD. 
4. No previous systemic treatment for cGVHD (including 
extracorporeal photopheresis [ECP]). 
5. Participants may be receiving other immunosuppressants for the 
prophylaxis or treatment of acute GVHD but if the subject is 
receiving prednisone for prophylaxis or treatment of acute GVHD 
it must be at or below 0.5 mg/kg/d.  
6. Participants may have received pre-transplant BTK inhibitors for 
other reasons besides cGVHD such as for the treatment of 


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leukemia or lymphoma, but must not have received a BTK 
inhibitor since the time of transplant. 
7. Age 12 years old.  
8. Karnofsky or Lansky (subjects <16 years) performance score 60. 
9. Adequate renal function defined as an estimated Creatinine 
&OHDUDQFHP/PLQ&RFNFURIW-Gault formula) 
10. Adequate hepatic function as defined by: 
x 
7RWDOELOLUXELQRI[8/1(unless of non-hepatic origin 
or due to Gilbert’s Syndrome) or 
x 
Total bilirubin of > 1.5 x ULN to 3.0 x ULN if due to GVHD 
11. Adequate hematological function defined as: 
x 
$EVROXWHQHXWURSKLOFRXQW[9/L and off growth factor 
support for 7 days 
x 
3ODWHOHWV[9/L and no transfusion for 7 days 
12. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (unless 
abnormalities are unrelated to coagulopathy or bleeding disorder). 
When treated with warfarin or other vitamin K antagonist, then 
,15 (Section 6.2.3). 
Ethical/Other 
13. Male and female subjects of reproductive potential who agree to 
use both a highly effective methods of birth control (eg, implants, 
injectables, combined oral contraceptives, some intrauterine 
devices [IUDs], complete abstinence1, or sterilized partner) and a 
barrier method (eg, condoms, cervical ring, sponge, etc.) during 
the period of therapy and for 90 days for both females and males 
after the last dose of study drug. 
Exclusion Criteria: 
Subjects are excluded if any of the following criteria are met: 
1. Received any previous systemic treatment for cGVHD with the 
following exception: 
x 
Corticosteroids for cGVHD received within the 72 hours 
prior to signing the informed consent form. 
2. Inability tREHJLQDSUHGQLVRQHGRVH mg/kg/d for the 
treatment of cGVHD. 
3. Presence of single-organ, genito-urinary involvement with 
cGVHD as the only manifestation of cGVHD. 
4. 5HFHLYHGDQ\LQYHVWLJDWLRQDODJHQWGD\VEHIRUH 
randomization. 
5. Received donor lymphocyte infusion (DLI) 56 days before 
randomization. 
6. Currently active, clinically significant cardiovascular disease, 
such as uncontrolled arrhythmia or Class 3 or 4 congestive heart 
                                                          
 
1 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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failure as defined by the New York Heart Association Functional 
Classification; or a history of myocardial infarction, unstable 
angina, or acute coronary syndrome within 6 months prior to 
randomization. 
7. Any uncontrolled active systemic infection or active infection 
requiring systemic treatment that was ongoing GD\VEHIRUH 
randomization. This does not include secondary prophylaxis of 
well controlled fungal infections, ongoing treatment of controlled 
viral reactivations (eg, CMV), or treatment or prophylaxis of 
controlled low-grade central line infections (eg, Staphylococcus 
epidermidis).  
8. Progressive underlying malignant disease or active 
post-transplant lymphoproliferative disease. 
9. History of other malignancy (not including the underlying 
malignancy that was the indication for transplant), with the 
following exceptions: 
x 
Malignancy treated with curative intent and with no evidence 
of active disease present for more than 3 years prior to 
Screening and felt to be at low risk for recurrence by treating 
physician 
x 
Adequately treated nonmelanomatous skin cancer or lentigo 
maligna melanoma without current evidence of disease 
x 
Adequately treated cervical carcinoma in situ without current 
evidence of disease 
10. Subject has a concurrent illness which in the opinion of the 
investigator may interfere with the treatment and evaluation of the 
subject. 
11. Known bleeding disorders (eg, von Willebrand’s disease or 
hemophilia). 
12. History of stroke or intracranial hemorrhage within 6 months 
prior to randomization. 
13. Known history of human immunodeficiency virus (HIV). 
14. Subject with chronic liver disease with hepatic impairment per 
Child-Pugh classification Class C (Appendix E). Please note that 
acute liver dysfunction due to cGVHD is not applicable to the 
evaluation of Child-Pugh classification. 
15. Active hepatitis C virus (HCV) or hepatitis B virus (HBV). 
Subjects who are positive for hepatitis B core antibody or 
hepatitis B surface antigen or hepatitis C antibody must have a 
negative polymerase chain reaction (PCR) result before 
randomization. Those who are PCR positive will be excluded. 
16. Vaccinated with live, attenuated vaccines within 4 weeks of 
randomization. 
17. Major surgery within 4 weeks of randomization. 
18. Any life-threatening illness, medical condition, or organ system 
dysfunction that, in the investigator’s opinion, could compromise 
the subject’s safety or put the study outcomes at undue risk. 
19. Unable to swallow capsules or malabsorption syndrome, disease 


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significantly affecting gastrointestinal function, or resection of the 
stomach or small bowel, symptomatic inflammatory bowel 
disease or ulcerative colitis, or partial or complete bowel 
obstruction. 
20. Subjects requiring treatment with a strong CYP3A inducer are not 
eligible, unless a transition to an agent with less CYP3A 
induction is planned (Appendix D). 
21. Female subject who is pregnant, breastfeeding, or planning to 
become pregnant while enrolled in this study or within 3 months 
of last dose of study drug. Male subject who plans to father a 
child while enrolled in this study or within 3 months after the last 
dose of study drug. 
22. Unwilling or unable to participate in all required study 
evaluations and procedures. 
23. Unable to understand the purpose and risks of the study and to 
provide a signed and dated informed consent form (ICF) and 
authorization to use protected health information (in accordance 
with national and local subject privacy regulations). 
Study Treatment: 
1:1 Randomization between Arm A and Arm B 
Arm A: Oral ibrutinib 420 mg daily (3 capsules) in combination with 
oral prednisone starting at 1 mg/kg/day until unacceptable toxicity, 
progression of underlying disease, death, or the need for a new 
systemic treatment for progressive cGVHD. 
Arm B: Oral matching placebo capsules daily (3 capsules) in 
combination with oral prednisone starting at 1 mg/kg/day until 
unacceptable toxicity, progression of underlying disease, death, or the 
need for a new systemic treatment for progressive cGVHD. 
Concomitant Therapy: 
Refer to Section 6 for information on concomitant therapy. 
Safety Plan:  
The safety of this study will be monitored by an independent data 
monitoring committee (DMC) as outlined in the DMC charter and in 
accordance with the Sponsor’s Pharmacovigilance procedures. 
Statistical Methods: 
All efficacy analyses will be performed using the intent-to-treat (ITT) 
population.  
Primary Efficacy Analysis: 
The primary efficacy endpoint of this study is the response rate at 
48 weeks (ie, the proportion of responders [CR or PR]). Response 
will be defined by the NIH Consensus Development Project Criteria 
(2014) and must occur: 
x 
In the absence of new systemic therapy for cGVHD 
x 
In the absence of progression of the underlying disease that was 
the indication for transplant, or death 
Response rates will be compared between the two treatment arms 
using the chi-square statistical test. 
Secondary Efficacy Analysis: 
x 
Response rate at 24 weeks (the proportion of responders [CR or 
PR]) as defined by the NIH Consensus Development Project 


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(2014) 
x 
Duration of response (DOR)  
x 
Steroid dose reduction to a level of less than 0.15 mg/kg/d at 
24 weeks: the proportion of subjects who have steroid dose 
reduced by 24 weeks will be compared between the two treatment 
arms 
x 
Time to withdrawal of all immunosuppressants (with the 
exception of ibrutinib/placebo) will be compared between the two 
treatment arms 
x 
Overall survival (OS): Overall survival will be compared between 
the two treatment arms using the log rank test 
x 
Improvement in Lee cGVHD symptom scale scores will be 
compared between the two treatment arms 
Safety Analysis: 
Safety data will be generated from the Safety Population (SP) which 
consists of all subjects randomized and receiving at least one dose of 
any study drug (ibrutinib or placebo). 
Detailed tabulations of safety data (adverse events, clinical laboratory 
tests and other safety endpoints) will be summarized by treatment arm 
for all subjects receiving study drug.  
Interim Analysis: 
An interim review for futility will be performed for the first 50 
subjects who complete Week 25 visit or discontinue study drug before 
this time. 
Sample Size Determination: 
The null hypothesis is that the two treatment arms have the same 
response rate at 48 weeks and the alternative hypothesis is that the 
response rates of two arms are different. 
Assuming a response rate of 30% at 48 weeks for Arm B (placebo + 
prednisone), a sample size of 186 randomized subjects provides at 
least an 80% power to detect a 20% difference in the response rates at 
48 weeks between the 2 treatment arms (Arm A – Arm B) at an alpha 
level of 5% (2-sided). 
The randomization between arms will be stratified according to: 
x 
Age group (12 to <22 \HDUVROGYV22 years old) 
x 
NIH Global Severity grade (moderate vs. severe) 
x 
Ongoing use of systemic immunosuppressants that were initiated 
for either treatment of or prophylaxis for acute GVHD (Yes vs. 
No) 


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASBMT 
American Society for Blood and Marrow Transplantation 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BAFF 
B-cell activating factor 
BCR 
B-cell receptor 
BTK 
Bruton’s tyrosine kinase 
CFR 
US Code of Federal Regulations 
cGVHD 
chronic graft versus host disease 
CLL 
chronic lymphocytic leukemia 
CRF 
case report form 
CR 
complete response 
CTCAE v. 4.03 
Common Terminology Criteria for Adverse Events version 4.03 
CYP 
cytochrome P450 
DLI 
donor lymphocyte infusion 
DMC 
data monitoring committee 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECP 
extracorporeal photopheresis 
EDC 
electronic data capture  
EMR 
electronic medical records 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second  
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GVHD 
graft versus host disease 
GVT 
graft versus tumor 
HCT 
hematopoietic cell transplantation 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HPA 
Hypothalamic-pituitary-adrenal 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitor concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
IL 
Interleukin 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITK 
IL-2 inducible T-cell kinase 
ITT 
intention-to-treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
KPS 
Karnofsky Performance Status 


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MCL 
mantle cell lymphoma  
mITT 
modified intention-to-treat 
MZL 
marginal zone lymphoma 
SP 
Safety population 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NRM 
non-relapse mortality 
OS 
overall survival 
PCI-32765 
ibrutinib or Imbruvica® 
PCR 
polymerase chain reaction 
PCYC 
Pharmacyclics LLC 
PD 
progressive disease 
PK 
pharmacokinetic 
PO 
oral 
PR 
partial response 
PTLD 
post-transplant lymphoproliferative disease 
PT 
prothrombin time 
QD 
daily  
QOD 
every other day 
QTc 
corrected QT interval 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SCARs 
severe cutaneous adverse reactions 
SD 
stable disease 
SF-36 
36-Item Short Form Health Survey 
SJS 
Stevens - Johnson syndrome 
t1/2 
half life 
TEAE(s) 
treatment-emergent adverse event(s) 
TCR 
T-cell receptor 
TLS 
tumor lysis syndrome 
Tmax 
median time to maximum plasma concentration 
ULN 
upper limit of normal 
USPI 
United States Product Insert 
VZIG 
varicella zoster immune globulin 
WM 
Waldenström’s macroglobulinemia 
 
 


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1. 
BACKGROUND 
1.1. 
Disease/Histology  
1.1.1. 
Disease Background 
Since its first report in 1957, allogeneic hematopoietic cell transplant (HCT) has become a 
standard therapy for many hematologic malignancies and hematopoietic progenitor cell disorders 
(Thomas 1957). Hematopoietic cell transplant can cure patients with chemotherapy resistant 
malignancies through graft versus tumor (GVT) effects generated by the donor’s immune system 
against the recipient’s tumor (Appelbaum 2001). However, just as the donor’s immune system 
can sense and attack the recipient’s malignant cells, so can it sense and attack the recipient’s 
normal tissues resulting in graft versus host disease (GVHD). In the U.S., approximately 8,000 
allogeneic HCTs are now performed each year (Pasquini 2015). Roughly 35% of patients who 
have undergone HCT will develop cGVHD that requires systemic treatment (Flowers 2011). The 
prevalence of cGVHD is increasing due to both the increased use of allogeneic transplantation in 
older adults and the use of peripheral stem cells as a graft source. Chronic GVHD is a serious 
and life threatening impediment to the otherwise curative potential of HCT (Pidala 2011, 
Arai 2011, Baird 2006 and Lee 2003) and it is a leading cause of non-relapse mortality (NRM) 
(Lee 2008). Risk factors for developing cGVHD include prior acute GVHD, older age, use of 
peripheral blood stem cells, use of unrelated and mismatched donors, and lack of T-cell depletion 
(Lee 2008). 
In the past, timing of manifestations of GVHD were used to classify GVHD into two subsets, 
acute GVHD classified as occurring within 100 days of HCT and chronic GVHD classified as 
manifestations beyond 100 days after HCT (Filipovich 2005). In 2005 the National Institutes of 
Health (NIH) sponsored a consensus development conference that proposed new criteria for 
diagnosis and classification of cGVHD for clinical trials (Filipovich 2005). The consensus met 
again in 2014 and proposed minor changes to the diagnostic criteria (Jagasia 2015). The 
published criteria for diagnosis emphasize the distinction between acute and chronic GVHD as 
different subsets of GVHD that can be distinguished by clinical manifestations and not time after 
transplant. The diagnosis of cGVHD is primarily clinical and requires at least one diagnostic sign 
in a target organ per NIH criteria (ie, a sign found only in cGVHD) or at least one distinctive 
sign (ie, a sign highly suggestive of cGVHD) in combination with some other laboratory, biopsy, 
or other test confirmation in the same or another organ. The diagnostic cGVHD findings include 
collagen-vascular changes involving the skin, mouth, genitalia, gastrointestinal tract, lung, 
muscle fascia, and joints (Jagasia 2015) (Appendix M). Pathologically, cGVHD is characterized 
by fibrosis and inflammation of affected organs (Shulman 2006).  
Pathogenesis of Chronic Graft Versus Host Disease 
The immunopathology underlying development of cGVHD can be quite variable and is not 
entirely characterized. Recent information implicates B cells as well as T cells in the generation 
of cGVHD (Sarantopoulos 2015, Allen 2014, Flynn 2014 and Johnston 2014). T cells have long 


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been known to be critically important in the development of cGVHD. Higher rates of cGVHD 
are seen in recipients of colony-stimulating factor mobilized peripheral blood grafts compared 
with marrow grafts and in patients who receive a higher T cell dose (Anasetti 2011). In vivo 
T cell depletion with anti-thymocyte globulin or alemtuzumab can reduce the incidence of 
cGVHD, but at the cost of higher rates of viral or opportunistic infections and relapse of 
underlying disease (Hale 2012, Perez-Simon 2002). Alloreactive T helper cells, including Th1, 
Th2, Th17, and T follicular helper cells, produce effector cytokines resulting in antibody 
deposition, tissue fibrosis, and autoimmunity. 
More recently, alloreactive B cells have been implicated in the development of cGVHD 
(Sarantopoulos 2015, Allen 2014, Flynn 2014, Johnston 2014, Miklos 2005 and Miklos 2004). 
In addition to the production of alloantibodies, B cells contribute to the immune response via 
antibody-independent processes, such as antigen presentation, cytokine and chemokine 
production, and immunoregulatory function (Sahaf 2013). Following activation via the B-cell 
receptor (BCR) signaling pathways, B cells become potent antigen-presenting cells. Activated 
B cells produce a variety of inflammatory cytokines, and antigen presentation by autoreactive 
B cells is critical in autoimmune disorders (Shimabukuro-Vornhagen 2009). Dysfunctional 
B cells have been identified in cGVHD, where patients have a relatively higher number of 
activated memory B cells, higher levels of B-cell-activating factor (BAFF) of the tumor necrosis 
family, and donor-derived alloantibodies (Sarantopoulos 2009). 
1.1.2. 
Current Treatment Options 
Available therapy for cGVHD is primarily broad-spectrum immunosuppressants which increase 
the risk of infections and tumor relapse by inhibiting GVT immunity (Holler 2007). The initial 
and current standard of care treatment for cGVHD is corticosteroids. However, more than 50% 
of the patients eventually relapse or become refractory, requiring second-line treatment, for 
which there is no standard of care. Recently, ibrutinib received approval in the United States for 
the treatment of adult patients with cGVHD after failure of one or more lines of systemic 
therapy. 
Treatment with immunosuppressants is typically needed for a median duration of 2 to 3 years, 
further contributing to morbidity (Syrjala 2012). During that time patients are likely to 
experience some or all of the side effects of corticosteroids which include more frequent 
infections, hypertension, hyperglycemia, decrease in bone density, avascular necrosis, adrenal 
insufficiency, cataracts and disturbed sleep patterns (Sullivan 1988, Rayos [Prednisone] 
USPI 2013). Because of the frequent morbidity associated with prolonged corticosteroid use, 
many other immunosuppressant agents have been investigated in cGVHD, both in the front line 
and second line setting. Several controlled, phase 3 studies where these agents have been added 
on to corticosteroid therapy were all unsuccessful in providing benefit despite showing efficacy 
in early phase studies (Gilman 2012, Martin 2009, Koc 2002, Arora 2001, Koc 2000, and 
Sullivan 1988). An analysis of clinical trial quality measures in 60 trials in cGVHD primarily 
conducted before the NIH standardized response criteria (Pavletic 2006) were developed, 


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revealed that poor study design (eg, lack of rigorous entry criteria, organ response criteria and 
overall response criteria) likely biased efficacy in the early phase trials (Martin 2011) thereby 
leading to later unsuccessful controlled studies with the same agents. Agents such as 
cyclosporine, tacrolimus, sirolimus, and/or mycophenolate mofetil are often added to 
corticosteroid therapy in both frontline and second line settings despite the lack of efficacy. 
There is a lack of standard of care and high unmet need for new therapeutic options to effectively 
suppress immune and fibrotic cascades while preserving GVT and immunity against infection.  
While limited progress related to prevention or treatment of cGVHD has been made, the 
development of the NIH Consensus Criteria for grading and staging of cGVHD represents a 
significant advancement, providing a clinically useful disease burden measure for use in clinical 
trials (Jagasia 2015). In addition, the NIH Consensus Response Criteria have been shown to 
correlate with clinical outcomes (Olivieri 2013, Jacobsohn 2012). 
1.2. 
Ibrutinib Overview  
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of Bruton’s tyrosine kinase (BTK) co-developed by Pharmacyclics LLC and Janssen 
Research & Development LLC for the treatment of B-cell malignancies and cGVHD. 
Ibrutinib has been approved in many regions, including the US and EU, for indications including 
treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior 
therapy, patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma 
(SLL), including CLL/SLL with a deletion of the short arm of chromosome 17 (del17p), patients 
with Waldenström’s macroglobulinemia (WM), Marginal Zone Lymphoma (MZL) who require 
systemic therapy and have received at least one prior anti-CD20-based therapy, and cGVHD 
after failure of one or more lines of systemic therapy. For the most up to date and comprehensive 
nonclinical and clinical information regarding ibrutinib background, safety, efficacy, in vitro and 
in vivo preclinical activity, and toxicology of ibrutinib, always refer to the latest version of the 
ibrutinib Investigator's Brochure (IB) and/or the applicable regional labeling information.   
1.2.1. 
Summary of Nonclinical Data  
1.2.1.1. 
Pharmacology  
Ibrutinib was designed as a selective and covalent inhibitor of the BTK (Pan 2007). In vitro, 
ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM). The irreversible binding of 
ibrutinib to cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this position. 
When added directly to human whole blood, ibrutinib inhibits signal transduction from the BCR 
and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation followed 
by CD69 expression (Herman 2011). In addition to BTK activity, ibrutinib inhibits ITK activity 
with a biochemical IC50 of 26.9 nM. Ibrutinib also blocks T cell receptor-induced IL-2 secretion 


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by a T cell line (Jurkat cells) with an EC50 of 200 nM. In CLL patients receiving ibrutinib, 
binding to ITK also has been demonstrated (Dubovsky 2013). 
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current IB. 
1.2.1.2. 
Safety Pharmacology and Toxicology 
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested. Further, no treatment-related corrected QT interval (QTc) prolongation 
effect was observed at any tested dose in a cardiovascular study using telemetry-monitored dogs. 
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation). Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog). In studies in pregnant 
rats and rabbits, ibrutinib administration was associated with malformations (teratogenicity) at 
ibrutinib doses that result in approximately 14 and 2 times the exposure (area under the 
concentration-time curve [AUC]) in patients administered the dose of 560 mg daily, respectively. 
Fetal loss and reduced fetal body weights were also seen in treated pregnant animals. 
Carcinogenicity studies have not been conducted with ibrutinib. In vitro and in vivo genetic 
toxicity studies showed that ibrutinib is not genotoxic. No effects on fertility or reproductive 
capacities were observed in a study in male and female rats. 
For the most comprehensive information regarding nonclinical safety pharmacology and 
toxicology, please refer to the current IB. 
1.2.2. 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the IB. 
1.2.2.1. 
Pharmacokinetics and Product Metabolism  
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally to doses increased with substantial intersubject variability. The 
mean half-life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median time to maximum 
plasma concentration (Tmax) of 2 hours. Taking into account the approximate doubling in mean 
systemic exposure when dosed with food and the favorable safety profile, ibrutinib can be dosed 
with or without food. Ibrutinib is extensively metabolized primarily by cytochrome 
P450 (CYP) 3A4 enzymes. The on-target effects of metabolite PCI-45227 are not considered 
clinically relevant. Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of 
single dose exposure. Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not 


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altered in patients with creatinine clearance (CrCl) >30 mL/min. Patients with severe renal 
impairment or patients on dialysis have not been studied. Following single dose administration, 
the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), 
moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to 
subjects with normal liver function. A higher proportion of Grade 3 or higher adverse reactions 
were reported in patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic 
dysfunction compared to patients with normal hepatic function. In the Phase 2 study in subjects 
with cGVHD, there were no differences in ibrutinib exposure between subjects with normal 
(n=29) and mild hepatic impairment based on baseline liver function test per NCI criteria (n=13).  
For the most comprehensive information regarding pharmacokinetics (PK) and product 
metabolism, please refer to the current version of the IB. 
1.2.3. 
Summary of Clinical Safety  
A brief summary of safety data from monotherapy studies, combination therapy studies, and a 
cGVHD study is provided below.  
1.2.3.1. 
Monotherapy Studies  
Pooled safety data from a total of 1318 subjects treated with ibrutinib monotherapy in 13 studies 
that have completed primary analysis or final analysis as of the 31 May 2016 cutoff date for the 
current Investigator’s Brochure update in B-cell malignancies are summarized below.  
The most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1318): 
Most frequently reported 
TEAEs 15% a 
Most frequently reported Grade 
3 or 4 TEAEs 3% b  
Most frequently reported 
Serious TEAEs 2% c 
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Pyrexia 
Hypertension 
 
Anemia 
Diarrhea 
 
Neutropenia  
Atrial Fibrillation 
 
Upper respiratory tract infection   
 
Thrombocytopenia 
 
 
Oedema peripheral  
 
 
a Source is Table 6 of IB (v10), b Source is Table 8 of IB (v10), c Source is Table 9 of IB (v10). 


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1.2.3.2. 
Combination Studies 
Pooled safety data from a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in subjects with B-cell malignancies are briefly summarized 
below. Therapies used in combination with ibrutinib in these studies, included BR (bendamustine 
and rituximab), FCR (fludarabine, cyclophosphamide, and rituximab), ofatumumab, and 
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). 
The most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy 
(N=423): 
Most frequently reported 
TEAEs 0%a 
Most frequently reported Grade 
3 or 4 TEAEs %b  
Most frequently reported 
Serious TEAEs %c  
Neutropenia 
Neutropenia 
Pneumonia 
Diarrhea 
Thrombocytopenia 
Febrile neutropenia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Neutrophil count decreased 
Cellulitis 
Anemia 
Anemia 
 
Pyrexia 
Fatigue 
 
 
Hypertension 
 
 
Diarrhea 
 
a Source is Table 10 of IB (v10), b Source is Table 12 of IB (v10), c Source is Table 13 of IB (v10). 
1.2.3.3. 
Chronic GVHD Study 
Safety data from the 42 subjects enrolled in the PCYC-1129-CA study demonstrated that 100% 
of subjects have experienced a treatment-emergent adverse event (TEAE) with a total of 73.8% 
of subjects reported Grade 3 or higher AEs. Fifty-two percent (52.4%) of subjects reported 
serious adverse events (SAEs). The most frequent TEAEs and SAEs are summarized below.  
Most frequently reported TEAEs in subjects receiving ibrutinib for cGVHD (N=42): 
Most frequently reported 
TEAEs > 20% 
Most frequently reported  
Grade 3 or 4 TEAEs > 10% 
Serious TEAEs occurred 
in > 1 subject 
Fatigue 
Fatigue 
Cellulitis 
Diarrhea 
Pneumonia 
Headache  
Muscle spasms 
 
Pneumonia  
Nausea 
  
 Pyrexia 
Increased tendency to bruise 
 
Septic shock 
Thirty subjects (71.4%) were taking moderate or strong CYP3A inhibitors during the study with 
9.5% of subjects taking posaconazole, 42.9% taking fluconazole, and 14.3% taking voriconazole. 


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Concomitant use of moderate and strong CYP3A inhibitors resulted in higher ibrutinib exposure 
but there was no association between concurrent CYP3A inhibitor use and dose reductions or 
discontinuations or with TEAEs leading to dose reductions or discontinuations. 
1.2.4. 
Risks 
1.2.4.1. 
Atrial Fibrillation 
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, hypertension, acute infections, and a previous 
history of atrial fibrillation. Subjects who develop arrhythmic symptoms (eg, palpitations, 
lightheadedness) or new onset dyspnea should be evaluated clinically, and if indicated, have an 
ECG performed. For atrial fibrillation which persists, consider the risks and benefits of ibrutinib 
treatment and follow the protocol dose modification guidelines (see Section 5.3.1.4). 
1.2.4.2. 
Bleeding-related Events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
subdural intracranial hemorrhage, and hematuria. Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. 
Subjects with congenital bleeding diathesis have not been studied. See Section 6.2.3 for guidance 
on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See Section 6.4 
for guidance on ibrutinib management with surgeries or procedures. In an in vitro platelet 
function study, inhibitory effects of ibrutinib on collagen induced platelet aggregation were 
observed, refer to Section 6.2.3. 
1.2.4.3. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Subjects should be monitored for fever, weakness, or 
easy bruising and/or bleeding. 
1.2.4.4. 
Diarrhea 
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe. Should symptoms be severe or prolonged 
follow the protocol dose modification guidelines (see Section 5.3.1.4).  
1.2.4.5. 
Infections 
Infections (including sepsis, bacterial, viral, aspergillus or other fungal infections) were observed 
in subjects treated with ibrutinib therapy. Some of these reported infections have been associated 


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with hospitalization and death. Consider prophylaxis according to standard of care in subjects 
who are at increased risk for opportunistic infections (see Section 6.1). Although causality has 
not been established, cases of progressive multifocal leukoencephalopathy (PML) have occurred 
in subjects treated with ibrutinib. Subjects should be monitored for symptoms (fever, chills, 
weakness, confusion) and appropriate therapy should be instituted as indicated.  
1.2.4.6. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. Should symptoms develop follow 
the protocol dose modification guidelines (see Section 5.3.1.4). 
1.2.4.7. 
Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer. 
1.2.4.8. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Most rashes were mild to moderate in severity. Isolated cases 
of severe cutaneous adverse reactions (SCARs) including Stevens - Johnson syndrome (SJS) 
have been reported in subjects treated with ibrutinib. Subjects should be closely monitored for 
signs and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate. In addition, hypersensitivity-related events including erythema, urticaria, 
and angioedema have been reported. 
1.2.4.9. 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate. 
1.2.5. 
Summary of Clinical Data in Chronic GVHD 
A Phase 1b/2 study (PCYC-1129-CA) to evaluate the safety and efficacy of ibrutinib treatment 
in subjects with cGVHD who had failed steroid therapy was initiated in June 2014. The NIH 
Consensus Panel Response Assessment 2005 was used to determine overall response. As of 01 
September 2016, 42 subjects have been recruited and received at least one dose of study drug in 
the study. The median age is 56 years (19-74 years) with a median duration of GVHD of 
13.6 months prior to study entry. The median number of prior therapeutic regimens is 2.0. 
Thirty-seven subjects have had a response assessment and 5 subjects discontinued prior to the 
first response assessment. Of the 42 subjects with response assessments or who discontinued 


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ibrutinib prior to response assessment, 28 subjects are responders (ORR=67%) based on NIH 
response criteria. Best responses include 9 CRs, 19 PRs, 7 stable disease (SD), 2 progressive 
disease (PD), and 5 unknown due to the early discontinuation of study drug without post baseline 
efficacy assessment. Twenty of the 28 responders (71%) achieved a sustained response for at 
least 20 weeks. Median corticosteroid dose in responding subjects was 0.29 mg/kg/d at baseline, 
0.24 mg/kg/d at Week 12, 0.19 mg/kg/d at Week 24, 0.18 mg/kg/d at Week 36, and 0.13 mg/kg/d 
at Week 48. Five subjects were able to discontinue steroids. Overall response rate results were 
supported by exploratory analyses of patient-reported symptom bother which showed at least a 
7-point decrease in Lee Symptom Scale overall summary score in 24% (10/42) of patients on at 
least 2 consecutive visits.  
These efficacy results are consistent with a response rate and durability that is considered 
clinically compelling in this high-risk population and with an acceptable safety profile. Based on 
data from the PCYC-1129 study the US FDA approved ibrutinib for the treatment of adult 
patients with cGVHD after failure of one or more lines of systemic therapy. 
1.3. 
Prednisone  
Prednisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids (corticosteroids), both 
naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. The 
chemical name for prednisone is pregna-1,4-diene-3,11,20-trione monohydrate,17,21-dihydroxy. 
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-
retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their 
synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of 
many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, 
they modify the body’s immune responses to diverse stimuli. 
1.3.1. 
Summary of Clinical Data 
Prednisone is a corticosteroid indicated in the following conditions: 
x As an anti-inflammatory or immunosuppressive agent for certain allergic, dermatologic, 
gastrointestinal, hematologic, ophthalmologic, nervous system, renal, respiratory, 
rheumatologic, specific infectious diseases or conditions and organ transplantation 
x For the treatment of certain endocrine conditions 
x For palliating of certain malignant conditions 
1.3.2. 
Summary of Clinical Safety 
Alterations in Endocrine Function  
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, and 
hyperglycemia. Monitor patients for these conditions with chronic use. 


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Corticosteroids can produce reversible HPA axis suppression with the potential for corticosteroid 
insufficiency after withdrawal of treatment. Drug-induced secondary adrenocortical insufficiency 
may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist 
for months after discontinuation of therapy; therefore, in any situation of stress occurring during 
that period, hormone therapy should be reinstituted. If the patient is receiving corticosteroids 
already, dosage may have to be increased. 
Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be 
administered concurrently. Mineralocorticoid supplementation is of particular importance in 
infancy. 
Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in 
hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in 
dosage.  
Increased Risks Related to Infection  
Corticosteroids may increase the risks related to infections with any pathogen, including viral, 
bacterial, fungal, protozoan, or helminthic infections. The degree to which the dose, route and 
duration of corticosteroid administration correlates with the specific risks of infection is not well 
characterized, however, with increasing doses of corticosteroids, the rate of occurrence of 
infectious complications increases.  
Corticosteroids may mask some signs of infection and may reduce resistance to new infections.  
Corticosteroids may exacerbate infections and increase risk of disseminated infections.  
The use of prednisone in active tuberculosis should be restricted to those cases of fulminating or 
disseminated tuberculosis in which the corticosteroid is used for management of the disease in 
conjunction with an appropriate anti-tuberculous regimen.  
Chickenpox and measles can have a more serious or even fatal course in non-immune children or 
adults on corticosteroids. In children or adults who have not had these diseases, particular care 
should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with 
varicella zoster immune globulin (VZIG) may be indicated. If patient is exposed to measles, 
prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. If chickenpox 
develops, treatment with antiviral agents may be considered. 
Corticosteroids should be used with great care in patients with known or suspected Strongyloides 
(threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead 
to Strongyloides hyperinfection and dissemination with widespread larval migration, often 
accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.  


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Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in 
the presence of such infections unless they are needed to control drug reactions.  
Corticosteroids may increase risk of reactivation or exacerbation of latent infection.  
If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close 
observation is necessary as reactivation of the disease may occur. During prolonged 
corticosteroid therapy, these patients should receive chemoprophylaxis.  
Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis 
or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has 
spent time in the tropics or any patient with unexplained diarrhea.  
Corticosteroids should not be used in cerebral malaria.  
Alterations in Cardiovascular/Renal Function  
Corticosteroids can cause elevation of blood pressure, salt, and water retention, and increased 
excretion of potassium and calcium. These effects are less likely to occur with the synthetic 
derivatives except when used in large doses. Dietary salt restriction and potassium 
supplementation may be necessary. These agents should be used with caution in patients with 
congestive heart failure, hypertension, or renal insufficiency.  
Literature reports suggest an apparent association between use of corticosteroids and left 
ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with 
corticosteroids should be used with great caution in these patients. 
Use in Patients with Gastrointestinal Disorders  
There is an increased risk of gastrointestinal perforation in patients with certain GI disorders. 
Signs of GI perforation, such as peritoneal irritation may be masked in patients receiving 
corticosteroids. 
Corticosteroids should be used with caution if there is a probability of impending perforation, 
abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; and active or 
latent peptic ulcer. 
Behavioral and Mood Disturbances  
Corticosteroids use may be associated with central nervous system effects ranging from 
euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic 
manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated 
by corticosteroids.  


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Decrease in Bone Density  
Corticosteroids decrease bone formation and increase bone resorption both through their effect 
on calcium regulation (ie, decreasing absorption and increasing excretion) and inhibition of 
osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to 
an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of 
bone growth in children and adolescents and the development of osteoporosis at any age. Special 
consideration should be given to patients at increased risk of osteoporosis (ie, postmenopausal 
women) before initiating corticosteroid therapy and bone density should be monitored in patients 
on long term corticosteroid therapy. 
Ophthalmic Effects  
Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with 
possible damage to the optic nerves, and may enhance the establishment of secondary ocular 
infections due to fungi or viruses.  
The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may 
lead to an increase in the risk of new episodes.  
Intraocular pressure may become elevated in some individuals. If corticosteroid therapy is 
continued for more than 6 weeks, intraocular pressure should be monitored.  
Corticosteroids should be used cautiously in patients with ocular herpes simplex because of 
possible corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.  
Vaccination 
Administration of live or live, attenuated vaccines is contraindicated in patients receiving 
immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered; 
however, the response to such vaccines cannot be predicted. Immunization procedures may be 
undertaken in patients who are receiving corticosteroids as replacement therapy, eg, for 
Addison’s disease.  
While on corticosteroid therapy, patients should not be vaccinated against smallpox. Other 
immunization procedures should not be undertaken in patients who are on corticosteroids, 
especially on high dose, because of possible hazards of neurological complications and a lack of 
antibody response.  
Effect on Growth and Development 
Long-term use of corticosteroids can have negative effects on growth and development in 
children. 


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Growth and development of pediatric patients on prolonged corticosteroid therapy should be 
carefully monitored. 
Use in Pregnancy  
Prednisone can cause fetal harm when administered to a pregnant woman. Human and animal 
studies suggest that use of corticosteroids during the first trimester of pregnancy is associated 
with an increased risk of orofacial clefts, intrauterine growth restriction, and decreased birth 
weight. If this drug is used during pregnancy, or if the patient becomes pregnant while using this 
drug, the patient should be apprised of the potential hazard to the fetus. 
Neuromuscular Effects  
Although controlled clinical trials have shown corticosteroids to be effective in speeding the 
resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the 
ultimate outcome or natural history of the disease. The studies do show that relatively high doses 
of corticosteroids are necessary to demonstrate a significant effect. 
An acute myopathy has been observed with the use of high doses of corticosteroids, most often 
occurring in patients with disorders of neuromuscular transmission (eg, myasthenia gravis), or in 
patients receiving concomitant therapy with neuromuscular blocking drugs (eg, pancuronium). 
This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result 
in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after 
stopping corticosteroids may require weeks to years. 
Kaposi’s Sarcoma  
Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most 
often for chronic conditions. Discontinuation of corticosteroids may result in clinical 
improvement. 
1.3.3. 
Summary of Clinical Data in Chronic Graft versus Host Disease 
Corticosteroids have been the backbone of treatment of cGVHD for more than 3 decades despite 
few formal trials to document its efficacy (Flowers 2015, Wolff 2011, Dignan 2012). While 
effective, prolonged administration of systemic corticosteroids results in substantial morbidity 
including hypertension, bone loss, weight gain, diabetes, cataracts, and myopathy as well as 
increasing the risk for underlying malignancy. The administration of alternate day steroids is 
often attempted to mitigate the risk of these toxicities. In addition, rapid corticosteroid taper and 
discontinuation is preferred in cGVHD. 
1.4. 
Study Rationale  
While corticosteroids are effective in some patients, until the approval of ibrutinib in August 
2017 for adult patients with cGHVD after failure of one or more lines of systemic therapy, there 


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had been no approved therapies for cGVHD as no other immunosuppressant therapy has proven 
to be effective either in front-line or steroid refractory cGVHD patients. Pre-clinical results have 
demonstrated a substantial therapeutic benefit of ibrutinib treatment to reduce the prolonged allo-
immune effects of cGVHD in animal models and supported investigation in clinical studies. Data 
supporting the approval of ibrutinib in cGVHD demonstrated that ibrutinib has robust clinical 
activity with high response rate by NIH criteria as well as an overall favorable safety profile. 
These data also support the continued clinical evaluation of ibrutinib in combination with 
prednisone as a treatment option for patients with new onset cGVHD. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
To evaluate the efficacy of ibrutinib in combination with prednisone (Arm A) versus placebo in 
combination with prednisone (Arm B) based on the response rate at 48 weeks (the proportion of 
responders [CR or PR]) as determined by NIH Consensus Development Project Criteria in 
subjects with new onset moderate to severe cGVHD (Lee 2015, Jagasia 2015). 
2.2. 
Secondary Objective(s) 
x To compare the two treatment arms in terms of the following: 
Efficacy 
x Response rate at 24 weeks (the proportion of responders [CR or PR]) as defined by the 
NIH Consensus Development Project (2014) 
x Duration of response (DOR) 
x Proportion of subjects obtaining a steroid dose level less than 0.15 mg/kg/d at 24 weeks 
x Time to withdrawal of all immunosuppressants (with the exception of ibrutinib/placebo) 
x Overall survival (OS) 
x Lee cGVHD symptom scale improvement 
Safety 
x Safety and tolerability  
x Differences in steroid-related morbidities (eg, hyperglycemia, hypertension)  
2.3. 
Exploratory Objective(s)  
x Pharmacokinetics of ibrutinib when administered in combination with prednisone in 
subjects with cGVHD including adolescent subjects 
x Pharmacodynamic characteristics of ibrutinib (including BTK and ITK occupancy) in 
subjects with cGVHD 


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x Evaluation of biomarkers relevant to disease biology and therapy with ibrutinib for 
cGVHD 
x Improvement in SF-36 patients reported outcome 
3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
This is a Phase 3, multicenter, international, randomized, double-blind study of oral ibrutinib in 
combination with prednisone versus placebo in combination with prednisone in subjects with 
new onset chronic GVHD. 
Approximately 186 subjects with newly diagnosed moderate or severe cGVHD, as defined by 
the 2014 NIH Consensus Development Project Criteria, will be randomized in a 1:1 ratio to 
receive either ibrutinib in combination with prednisone (Arm A) or placebo in combination with 
prednisone (Arm B). It is expected that a minimum of 6 subjects in the adolescent group (12 
and < 22 years of age) will be enrolled. 
Treatment with ibrutinib/placebo will be administered continuously until unacceptable toxicity, 
progression of the underlying disease, death, or the start of a new systemic treatment for 
cGVHD. Progression of the underlying disease will be defined using standard consensus criteria 
for the individual malignancy. 
Corticosteroid therapy will be tapered as per a standard taper regimen with the goal of reducing 
exposure to high-moderate dose corticosteroids as quickly as possible according to clinical 
severity of cGVHD. A standard corticosteroid taper schedule is provided in the protocol as 
guidance to clinicians (Table 4). 
The primary endpoint is the response rate at 48 weeks. Response will be defined by the NIH 
Consensus Development Project Criteria (2014) and must occur: 
x In the absence of new therapy for cGVHD 
x In the absence of progression of the underlying disease that was the indication for 
transplant, or PTLD, or death 
Secondary endpoints will assess for additional clinical benefit including Week-24 response, 
duration of response (DOR), corticosteroid dose reduction, time to withdrawal of all 
immunosuppressants, OS, and Lee cGVHD symptom scale. Corticosteroid reduction will be 
determined by a proportion of patients who are on < 0.15 mg/kg of prednisone at week 24, to 
allow for variations in corticosteroid taper that occur in practice, while at the same time reaching 
a dose that minimizes the toxicity associated with steroids. 
The randomization between arms will be stratified according to: 
x Age group (12 to <22 \HDUVROGYV22 years old) 
x NIH Global Severity grade (moderate vs. severe) 
x Ongoing use of systemic immunosuppressants that were initiated for either treatment of 
or prophylaxis for acute GVHD (Yes vs. No) 


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The rationale for the study concept is provided in Section 1.4. 
3.1.1. 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Phase 
(within 28 days before 
Assess Eligibility Criteria 
Randomization  
Subjects must start ibrutinib/placebo within 72 hours (3 days) after randomization 
Treatment Arm A 
  
Prednisone 1 mg/kg/d 
 
Ibrutinib 420 mg oral once daily continuously  
starting on Week 1 Day 1 
until cGVHD progression,  
progression of underlying malignancy,subject begins 
another systemic treatment for cGVHD or unacceptable 
toxicity 
Treatment Arm B 
  
Prednisone 1 mg/kg/d 
 
Placebo oral once daily continuously 
starting on Week 1 Day 1 
until cGVHD progression,  
progression of underlying malignancy,subject begins 
another systemic treatment for cGVHD or unacceptable 
toxicity 
 
Double-Blind Treatment Phase 
Ibrutinib/Placebo Discontinuation 
Complete End-of-Treatment Visit 
Follow-up Phase  
(up to 60 months after randomization) 
Prior to cGVHD Progression (if applicable):  
Continue cGVHD evaluations 
Follow-up for survival status, subsequent therapies for cGVHD 
 
Following Disease Progression:  
Follow-up for survival status, subsequent therapies for cGVHD 


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4. 
SUBJECT SELECTION 
4.1. 
Inclusion Criteria 
Prior to randomization, each potential subject must satisfy all of the following inclusion criteria.  
Disease Related 
1. New onset moderate or severe cGVHD as defined by the NIH Consensus Development 
Project Criteria (2014, see Appendix M, Appendix N, and Appendix O). 
2. History of an allogeneic hematopoietic cell transplant. 
3. Need for systemic treatment with corticosteroids for cGVHD. 
4. No previous systemic treatment for cGVHD (including extracorporeal photopheresis [ECP]). 
5. Participants may be receiving other immunosuppressants for the prophylaxis or treatment of 
acute GVHD but if the subject is receiving prednisone for prophylaxis or treatment of acute 
GVHD it must be at or below 0.5 mg/kg/d.  
6. Participants may have received pre-transplant BTK inhibitors for other reasons besides 
cGVHD such as for the treatment of leukemia or lymphoma, but must not have received a 
BTK inhibitor since the time of transplant. 
Demographic 
7. $JH12 years old. 
8. Karnofsky or Lansky (subjects <1\HDUVSHUIRUPDQFHVWDWXV60. 
Laboratory 
9. Adequate renal function defined as estimated Creatinine Clearance 30 mL/min (Cockcroft-
Gault formula) 
10. Adequate hepatic function as defined by: 
x Total bilirubin of  1.5 x ULN (unless of non-hepatic origin or due to Gilbert's 
Syndrome) or 
x Total bilirubin of > 1.5 x ULN to 3.0 x ULN if due to GVHD 
11. Adequate hematological function defined as: 
x $EVROXWHQHXWURSKLOFRXQW[9/L and off growth factor support for 7 days  
x 3ODWHOHWV[9/L and no transfusion for 7 days 
12. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (unless abnormalities are unrelated to 
coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K 
antagonist, then INR  (Section 6.2.3). 


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Ethical/Other 
13. Male and female subjects of reproductive potential who agree to use both a highly effective 
methods of birth control (eg, implants, injectables, combined oral contraceptives, some 
intrauterine devices [IUDs], complete abstinence2, or sterilized partner) and a barrier method 
(eg, condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days for 
both females and males after the last dose of study drug. 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
Disease-Related 
1. Received any previous systemic treatment for cGVHD with the following exception:  
x Corticosteroids for cGVHD received within the 72 hours prior to signing the informed 
consent form.  
2. ,QDELOLW\WREHJLQDSUHGQLVRQHGRVH mg/kg/d for the treatment of cGVHD.  
3. Presence of single-organ, genito-urinary involvement with cGVHD as the only manifestation 
of cGVHD. 
Concurrent Conditions 
4. Received any investigational agent GD\VEHIRUH randomization. 
5. Received donor lymphocyte infusion (DLI) GD\VEHIRUHUDQGRPL]DWLRQ 
6. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable angina, 
or acute coronary syndrome within 6 months prior to randomization. 
7. Any uncontrolled active systemic infection or active infection requiring systemic treatment 
that was ongoing GD\VEHIRUHrandomization. This does not include secondary prophylaxis 
of well controlled fungal infections, ongoing treatment of controlled viral reactivations 
(eg, CMV), or treatment or prophylaxis of controlled low-grade central line infections 
(eg, Staphylococcus epidermidis).  
8. Progressive underlying malignant disease or active post-transplant lymphoproliferative 
disease. 
9. History of other malignancy (not including the underlying malignancy that was the indication 
for transplant), with the following exceptions: 
                                                          
 
2 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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x Malignancy treated with curative intent and with no evidence of active disease present for 
more than 3 years prior to Screening and felt to be at low risk for recurrence by treating 
physician 
x Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without 
current evidence of disease 
x Adequately treated cervical carcinoma in situ without current evidence of disease 
10. Subject has a concurrent illness which in the opinion of the investigator may interfere with 
the treatment and evaluation of the subject. 
11. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia). 
12. History of stroke or intracranial hemorrhage within 6 months prior to randomization. 
13. Known history of human immunodeficiency virus (HIV). 
14. Subjects with chronic liver disease with hepatic impairment per Child-Pugh classification 
Class C (Appendix E). Please note that acute liver dysfunction due to cGVHD is not 
applicable to the evaluation of Child-Pugh classification. 
15. Active hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for 
hepatitis B core antibody or hepatitis B surface antigen or hepatitis C antibody must have a 
negative polymerase chain reaction (PCR) result before randomization. Those who are PCR 
positive will be excluded. 
16. Vaccinated with live, attenuated vaccines within 4 weeks of randomization. 
17. Major surgery within 4 weeks of randomization. 
18. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk. 
19. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. 
20. Subjects requiring treatment with a strong CYP3A inducer are not eligible, unless a transition 
to an agent with less CYP3A induction is planned (Appendix D). 
21. Female subject who is pregnant, breastfeeding, or planning to become pregnant while 
enrolled in this study or within 3 months of last dose of study drug. Male subject who plans 
to father a child while enrolled in this study or within 3 months after the last dose of study 
drug. 
22. Unwilling or unable to participate in all required study evaluations and procedures. 
23. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information (in 
accordance with national and local subject privacy regulations). 


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5. 
TREATMENT OF SUBJECTS  
5.1. 
Treatment Allocation and Blinding 
5.1.1. 
Randomized Double-blind Phase 
After the subject provides informed consent on study, site personnel will register the subject in 
Interactive Web Response System (IWRS) to assign a screening number. After the subject has 
completed all screening procedures and has met all requirements of the inclusion/exclusion 
criteria, the site personnel will update IWRS and answer key questions to randomize the subject, 
and have drug assigned. The first dose of ibrutinib/placebo must be administered after 
randomization, which should be no more than 72 hours (3 days) after the subject has been 
randomized by IWRS. 
Approximately 186 subjects will be randomized in a 1:1 ratio to each of the 2 treatment arms. 
Treatment Arm A: ibrutinib in combination with prednisone  
Treatment Arm B: placebo in combination with prednisone 
The randomization between arms will be stratified according to: 
x Age group (12 to <22 \HDUVROGYV22 years old) 
x NIH Global Severity grade (moderate vs. severe) 
x Ongoing use of systemic immunosuppressants that were initiated for either treatment of 
or prophylaxis for acute GVHD (yes vs. no) 
5.1.1.1. 
Blinding  
This is a double-blind study; therefore, the subjects, the investigators, and the Sponsor’s study 
team members will be blinded to the treatment assignment. The investigator will not be provided 
with randomization codes. The codes will be maintained within the IWRS, which has the 
functionality to allow the investigator to break the blind for an individual subject if necessary to 
appropriately manage or treat the subject. Data that may potentially unblind the treatment 
assignment (ie, study drug plasma concentrations) will be handled with special care to ensure 
that the integrity of the blind is maintained and the potential for bias is minimized. 
The investigator should contact the Sponsor or its designee to discuss the particular situation 
before breaking the blind whenever possible. Telephone contact with the Sponsor or its designee 
will be available 24 hours per day, 7 days per week. In the event the blind is broken, the Sponsor 
must be informed as soon as possible. The date, time, and reason for the unblinding must be 
documented in IWRS in the appropriate section of the eCRF and in the source document. The 
IWRS confirmation indicating the code break must be retained with the subject's source 
documents in a secure manner. A subject whose treatment assignment has been unblinded may 
continue the study treatment if the subject is expected to continue receiving clinical benefit. The 


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subject should continue to return for scheduled study visits. The single-blind (ie, subject remains 
blinded to treatment assignment) should be maintained provided the subject’s safety is not 
compromised. 
At the time of the futility analyses, the randomization codes and, if required, the translation of 
randomization codes into treatment and control groups will be disclosed to those authorized and 
only for those subjects included in the interim analyses. 
5.2. 
Study Treatment 
Ibrutinib (420 mg) or placebo will be given orally once daily continuously starting on 
Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, subject begins 
another systemic treatment for cGVHD or unacceptable toxicity.  
Prednisone 1 mg/kg/d will be given orally once daily continuously starting on Week 1 Day 1 
until unacceptable toxicity or until subject is successfully tapered from the prednisone (see 
Section 5.3.2.2.1). Starting prednisone dose may be as low as 0.5 mg/kg/d if a subject cannot 
tolerate higher doses.  
During Screening, prednisone to treat cGVHD may be started prior to randomization if the 
clinical condition of the subject necessitates it. If a subject is started on high dose prednisone for 
treatment of cGVHD prior to randomization, the patient must be randomized within 7 days of 
starting high dose prednisone. 
5.3. 
Study Medication 
5.3.1. 
Ibrutinib/Placebo 
5.3.1.1. 
Formulation/Packaging/Storage 
Ibrutinib capsules are provided as a hard gelatin capsule containing 70 mg and 140 mg of 
ibrutinib. All formulation excipients are compendial and are commonly used in oral 
formulations. Refer to the ibrutinib IB for a list of excipients. 70 mg capsules will only be used 
for subjects who have dose reductions that require a dose of 70 mg and will not be used to 
constitute a dose larger than 70 mg (eg, 2 x 70 mg capsules to give 140 mg). 
The ibrutinib (or placebo) capsules will be packaged in opaque high-density polyethylene plastic 
bottles with labels bearing the appropriate label text as required by governing regulatory 
agencies. All study drug will be dispensed in child-resistant packaging.  
Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 


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5.3.1.2. 
Dose and Administration 
Ibrutinib or placebo is administered orally once daily. It is expected that many subjects 
commencing therapy with high dose prednisone will require anti-fungal prophylaxis.  Please see 
Section 6.2.1 for dose modification guidelines with concomitant use of CYP3A inhibitors or 
inducers.  
The capsules are to be taken around the same time each day with 8 ounces (approximately 
240 mL) of water. The capsules should be swallowed intact and subjects should not attempt to 
open capsules or dissolve them in water. If a dose is not taken at the scheduled time, it can be 
taken as soon as possible on the same day with a return to the normal schedule the following day. 
The subject should not take extra capsules to make up the missed dose. 
The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically 
on an outpatient basis. Ibrutinib will be dispensed to subjects in bottles at each visit. Unused 
ibrutinib dispensed during previous visits must be returned to the site and drug accountability 
records (Section 12.8) updated at each visit. Returned capsules must not be redispensed to 
anyone. 
5.3.1.3. 
Overdose 
Any dose of study drug administered in excess of 420 mg is considered to be an overdose. Signs 
and symptoms of an overdose that meet any SAE criterion must be reported as a SAE in the 
appropriate time frame and documented as clinical sequelae to an overdose.  
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up 
to 12.5 mg/kg/day (1400 mg/day). Healthy subjects were exposed up to single dose of 1680 mg. 
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1680 mg. Subjects who ingested more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. 
Refer to Section 11.4 for further information regarding AE reporting.  
5.3.1.4. 
Dose Modification for Adverse Reactions  
The dose of ibrutinib/placebo must be modified according to the dose modification guidance in 
Table 1 and Table 2 if any of the following toxicities occur: 
x Grade 4 neutropenia (ANC <500/μL) for more than 7 days. See Section 6.1 for 
instructions regarding the use of growth factor support 
x Grade 3 thrombocytopenia (platelets <50,000/μL) in the presence of clinically significant 
bleeding events 
x Grade 4 thrombocytopenia (platelets <25,000/μL) 


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x Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy 
x Any other Grade 4 or unmanageable Grade 3 toxicity 
Adverse events that are considered related to concomitant high dose corticosteroids 
(eg, hyperglycemia, insomnia) do not require dose modification or holding of ibrutinib. 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or 
antiplatelet agents may be considered for the thromboprophylaxis of atrial fibrillation 
(Section 6.2.3).   
For other AEs not listed above, including Grade 2 AEs that are deemed per the investigator 
potentially manageable by dose reduction, these can be managed with a one dose level reduction. 
In the event that the investigator feels deviation from the recommendations above is required, 
please consult the medical monitor to discuss for approval. 
If the dose of ibrutinib/placebo is reduced for an adverse event, at the investigator’s discretion, 
the dose of ibrutinib may be re-escalated after 4 weeks of a dose reduction in the absence of a 
recurrence of the toxicity that led to the reduction. Dose changes must be recorded in the Dose 
Administration eCRF.  
Table 1. 
Ibrutinib/Placebo Dose Modifications 
Occurrence Action to be Taken  
First 
:LWKKROGVWXG\GUXJXQWLOUHFRYHU\WR*UDGHRUbaseline; may restart at original dose 
level 
Second 
:LWKKROGVWXG\GUXJXQWLOUHFRYHU\WR*UDGHRUEDVHOLQHPD\UHVWDUWDWGRVHOHYHO
lower (eg, 280 mg/day for 420 mg/day dose) 
Third 
Withhold study GUXJXQWLOUHFRYHU\WR*UDGHRUEDVHOLQHPD\UHVWDUWDWGRVHOHYHO
lower (eg, 140 mg/day for 420 mg/day dose) 
Fourth 
Discontinue study drug 
Table 2. 
Ibrutinib/Placebo Dose Reduction Levels 
Starting Dose Level 
420 mg 
280 mg 
140 mg 
Dose Reduction Level 1 
280 mg 
140 mg 
70 mg 
Dose Reduction Level 2 
140 mg 
70 mg 
Discontinue 
Dose Reduction Level 3 
Discontinue  
Discontinue 
-- 
For required dose modification for hepatic impairment refer to Section 5.3.1.5 and for 
concomitant treatment with CYP3A inhibitors refer to Section 6.2.1.  


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5.3.1.5. 
Dose Modification for Subjects with Hepatic Impairment 
Dose modifications for hepatic impairment will depend on baseline total bilirubin level and 
subsequent changes in bilirubin levels per Table 3 below. If the elevation of bilirubin is due to a 
non-hepatic cause or Gilbert’s Syndrome, then no dose modifications are necessary. 
Table 3. 
Ibrutinib/Placebo Dose Modifications for Subjects with Hepatic Impairment 
Starting Dose Level by 
Bilirubin Levels 
Bili [8/1DWEDVHOLQH: 
 420 mg  
Bili >1.5-3 x ULN at baseline: 
140 mg 
 
On-VWXG\ELOLUXELQOHYHO[
ULN 
Continue 420 mg 
Increase to 420 mg 
On-study bilirubin level >1.5-3 x 
ULN 
Reduce to 140 mg 
Continue 140 mg 
On-study bilirubin level >3 x 
ULN 
x 
Hold* until bili level >1.5-3 
x ULN restart at 140mg 
x 
When bili level [8/1
restart at 420mg 
x 
Hold* until bili level >1.5-3 
x ULN restart at 140mg 
x 
When bili level [8/1
restart at 420mg 
Bili = bilirubin 
* In cases where the investigator wishes to restart ibrutinib/placebo after ibrutinib/placebo has been 
held for more than 28 days for hepatic impairment, please contact the medical monitor for approval. 
In the event a patient has had a dose reduction due to a non-hepatic toxicity and then develops 
elevated bilirubin level (or vice versa) that requires a dose reduction, the lower of the two dose 
reductions should be used. The medical monitor should be consulted for any questions involving 
dose reductions. 
5.3.1.6. 
Ibrutinib/Placebo Hold after Withdrawal of All Immunosuppressants 
At the physician’s discretion, ibrutinib/placebo may be held if ALL of the following conditions 
are met: 
x All systemic immunosuppressants used for the treatment of cGVHD have been 
discontinued. (The continued use of very low doses of corticosteroids used only for 
physiologic adrenal replacement is allowed) 
x cGVHD response has been maintained for 12 weeks after complete withdrawal of all 
immunosuppressants (not including ibrutinib/placebo) 
x The subject has received a minimum of 48 weeks of ibrutinib/placebo 
If cGVHD returns/worsens after ibrutinib/placebo has been held for the above criteria, 
ibrutinib/placebo may be re-started after consulting with the medical monitor. 


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5.3.2. 
Prednisone  
5.3.2.1. 
Formulation/Packaging/Storage 
Prednisone tablets for oral administration are available in multiple strengths. Commercially 
available prednisone will be supplied by the Sponsor where applicable. The commercial material 
will be relabeled for clinical trial use.  
For situations where a subject who must receive an IV or alternate formulation of corticosteroid 
(eg, hospitalization for AE), the dose should be equivalent to the subject’s prednisone dose using 
the prednisone equivalency table (Appendix K) unless the subjects clinical condition warrants a 
different dose (eg, stress doses of steroids for sepsis). All doses of corticosteroids must be 
entered into the eCRF. 
Refer to the Pharmacy Manual for additional guidance on prednisone storage, preparation and 
handling. 
5.3.2.2. 
Dose and Administration 
Prednisone will be given orally at 1.0 mg/kg/d with rounding to multiples of 5 mg (eg, 15, 20, 
25, etc.). 
If a prednisone dose of 1.0 mg/kg/d is contraindicated (eg, poorly controlled diabetes, major 
mood disturbances) then the starting dose of prednisone may be reduced to 0.5-1.0 mg/kg/d. 
Subjects unable to receive a starting dose of prednisone of at least 0.5 mg/kg/d are ineligible for 
the study. 
If, during Screening, the clinical condition of the subject requires immediate initiation of 
treatment with prednisone, prednisone may be started prior to randomization. If the subject 
begins prednisone during Screening and prior to randomization the eligible subject must be 
randomized within 7 days of starting prednisone. 
If a subject has started corticosteroids within the 72 hours prior to consent, then the subject is 
eligible and can continue corticosteroids after signing consent but must be randomized within 
7 days of signing consent.   
5.3.2.2.1. Prednisone Taper 
Prednisone taper should be attempted by the schedule outlined in Table 4: 


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Table 4. 
Prednisone Taper Schedule 
Study Week # 
Dose (mg/kg, body weight) 
0 
1.0 qd 
2 
0.75 qd 
4 
0.65 qd 
6 
0.50 qd 
8 
0.70 qod* 
10 
0.55 qod 
12 
0.45 qod 
14 
0.35 qod 
16 
0.25 qod 
18 
0.20 qod 
20 
0.15 qod 
22 
0.10 qod 
24 
0.0 
*qod=every other day. #Timing of steroid taper is defined by when the first dose of prednisone is given. 
The prednisone taper should commence by week 2, but it is understood that considerable 
variation in prednisone taper will occur depending on the subjects’ response and other 
intercurrent illnesses. More rapid tapering of prednisone doses is allowed if clinically 
appropriate. Rounding of corticosteroid doses is acceptable. Decisions about the use of qod or 
alternative dosing schedules (eg, Mon/Wed/Fri) may follow institutional practice. Prednisone 
taper should be completed prior to tapering of other immunosuppressants unless the clinical 
condition of the subject dictates tapering/discontinuing other medications sooner (eg, toxicity 
associated with the use of the medication).  
5.3.2.2.2. Flares in cGVHD 
Exacerbation of cGVHD symptoms may occur during prednisone taper or with intercurrent 
illnesses. Temporary re-escalation of prednisone dose is allowed at the physician’s discretion. 
Tapering of increased prednisone dose for a flare should begin within 4 weeks. 
5.3.2.3. 
Overdose 
The effects of accidental ingestion of large quantities of prednisone over a very short period of 
time have not been reported, but prolonged use of the drug can produce mental symptoms, moon 
face, abnormal fat deposits, fluid retention, excessive appetite, weight gain, hypertrichosis, acne, 
striae, ecchymosis, increased sweating, pigmentation, dry scaly skin, thinning scalp hair, 
increased blood pressure, tachycardia, thrombophlebitis, decreased resistance to infection, 
negative nitrogen balance with delayed bone and wound healing, headache, weakness, menstrual 
disorders, accentuated menopausal symptoms, neuropathy, fractures, osteoporosis, peptic ulcer, 


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decreased glucose tolerance, hypokalemia, and adrenal insufficiency. Hepatomegaly and 
abdominal distention have been observed in children.  
Treatment of acute overdosage is by immediate gastric lavage or emesis followed by supportive 
and symptomatic therapy. For chronic overdosage in the face of severe disease requiring 
continuous steroid therapy the dosage of prednisone may be reduced only temporarily, or 
alternate day treatment may be introduced. 
5.3.2.4. 
Dose Modification for Adverse Reactions 
Prednisone will be tapered by study design according to clinical response in cGVHD (Table 4). 
Prednisone suppresses the hypothalamic-pituitary-adrenal (HPA) axis and, therefore, doses must 
be tapered slowly after long-term use. The occurrence of unmanageable adverse reactions from 
prednisone (eg, poorly controlled hypertension) may require a more rapid reduction in 
prednisone dosing, but may not necessitate a change in dose of study drug (ibrutinib/placebo). 
Dose modifications will be at the discretion of the physician and should reflect a balance of 
appropriately treating cGVHD and minimizing adverse effects. 
5.4. 
Criteria for Permanent Discontinuation of Ibrutinib/Placebo 
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk. For a complete list of criteria for permanent discontinuation of 
ibrutinib/placebo, refer to Section 9.2. 
An End-of-Treatment visit (Section 8.2.3) is required for all subjects except for those subjects 
who have withdrawn full consent. 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
Concomitant therapies must be recorded from 30 days prior to signing of the ICF through 
30 days after the last dose of study treatment (ibrutinib/placebo or corticosteroids), start of 
another therapy for cGVHD, or start of a new therapy for progression for the underlying 
malignancy. 
6.1. 
Permitted Concomitant Medications 
6.1.1. 
Ancillary Therapy and Supportive Care 
Ancillary therapy and supportive care for cGVHD is permitted as outlined in the NIH Consensus 
Development Project 2014 Ancillary Therapy and Supportive Care Working Group Report 
(Carpenter 2015, Appendix L). In particular, the use of regimen to specifically treat or prevent 
bronchiolitis obliterans are allowed (eg, inhaled steroids/azithromycin/montelukast) and will not 
be considered systemic treatment for cGVHD. 


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Other supportive medications in accordance with standard clinical practice (such as for emesis, 
diarrhea, etc.) are permitted. Use of neutrophil growth factors (filgrastim and pegfilgrastim) or 
red blood cell growth factors (erythropoietin) is permitted per institutional policy. Transfusions 
may be given in accordance with institutional policy. Anti-fungal prophylaxis should be given as 
outlined in Appendix L. 
After consultation with the medical monitor the following may be considered; localized 
hormonal or bone sparing treatment for malignancies, and localized radiotherapy for medical 
conditions other than the underlying disease. 
6.1.2. 
Systemic Immunosuppressant Therapy 
During the Screening period, the physician will have the discretion to start prednisone while 
eligibility for the study is being confirmed, however, the subject must be randomized within 7 
days of initiating treatment with prednisone. 
Addition of any other new systemic immunosuppressant therapy (including ECP) to treat 
cGVHD is prohibited during Screening and subsequent enrollment into the study. Addition of a 
new systemic immunosuppressant for cGVHD will be considered a treatment failure and 
ibrutinib/placebo will be discontinued. 
At enrollment, subjects may be receiving other immunosuppressants for the prophylaxis or 
treatment of acute GVHD. Tapering of these other immunosuppressants upon start of 
ibrutinib/placebo or prednisone is permitted (see Section 5.3.2.2.1). 
Use of immunosuppressants for reasons other than treatment for cGVHD should be discussed 
with the medical monitor. 
6.2. 
Medications to be Used with Caution 
6.2.1. 
CYP3A Enzyme Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A4. The dose of ibrutinib/placebo should be adjusted 
for concomitant use of CYP3A inhibitors per Table 5 below: 


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Table 5. 
Ibrutinib/Placebo Dose Modifications for Concomitant Use of CYP3A 
Inhibitors 
CYP inhibitor class 
Dose modification instructions 
x 
Mild CYP3A inhibitors 
420 mg once daily. No dose adjustment required. 
x 
Moderate CYP3A inhibitors 
420 mg once daily. No dose adjustment required. 
x 
Voriconazole at any dose  
or 
x 
Posaconazole at doses less than or 
equal to suspension 200 mg BID or 
delayed-release tablet 300 mg QD   
280 mg once daily 
x 
Strong CYP3A inhibitors 
or 
x 
Posaconazole at higher doses 
140 mg once daily or consider alternative with less 
CYP3A inhibitory potential 
Avoid concomitant use of strong CYP3A inducers (Appendix D). Consider alternative agents 
with less CYP3A induction and transition to a new agent within 4 weeks of randomization. 
A list of common CYP3A inhibitors and inducers is provided in Appendix D. For further 
information, please refer to the current version of the ibrutinib IB and examples of inhibitors, 
inducers, and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
This website is continually revised and should be checked frequently for updates. 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor. Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. 
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic 
dose. There is no clinical data available. Therefore, to avoid a potential interaction in the GI 
tract, narrow therapeutic range P-gp substrates such as digoxin, should be taken at least 6 hours 
before or after ibrutinib/placebo.  
6.2.3. 
Antiplatelet Agents and Anticoagulants 
Supplements such as fish oil and vitamin E preparations should be avoided. Use 
ibrutinib/placebo with caution in subjects requiring anticoagulants or medications that inhibit 
platelet function. Subjects with congenital bleeding diathesis have not been studied. For guidance 
on ibrutinib/placebo and the use of anticoagulants during procedures/surgeries see Section 6.4.  
Subjects requiring the use of therapeutic anticoagulation therapy (eg, atrial fibrillation), consider 
the risks and benefits of continuing ibrutinib treatment. Subjects treated with warfarin (or other 


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vitamin K antagonists) should maintain an INR  3.0 and if unable to maintain this level another 
anticoagulant agent should be considered. If therapeutic anticoagulation is clinically indicated, 
treatment with ibrutinib/placebo should be held while anticoagulation is being initiated and not 
be restarted until the subject is clinically stable and has no signs of bleeding. Subjects should be 
observed closely for signs and symptoms of bleeding. No dose reduction is required when study 
drug is restarted.  
6.3. 
Other Systemic Immunosuppressant Therapy for cGVHD 
Addition of any other new systemic immunosuppressant therapy (including ECP) to treat 
cGVHD is prohibited during Screening and subsequent enrollment into the study. The addition 
of other systemic immunosuppressant therapy to treat cGHVD will not allow for the appropriate 
assessment of response attributable to ibrutinib/placebo. The Sponsor must be notified in 
advance (or as soon as possible thereafter) of any instances in which prohibited therapies are 
administered. 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures  
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib/placebo in the perioperative period for subjects 
who require surgical intervention or an invasive procedure while receiving ibrutinib/placebo.  
6.4.1. 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, skin or needle biopsy, lumbar puncture 
[other than shunt reservoir access], thoracentesis, or paracentesis) ibrutinib/placebo should be 
held for at least 3 days prior to the procedure and should not be restarted for at least 3 days after 
the procedure. For bone marrow biopsies that are performed while the subject is on 
ibrutinib/placebo, it is not necessary to hold ibrutinib/placebo.  
6.4.2. 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib/placebo 
should be held at least 7 days prior to the intervention (except for emergency procedures) and 
should be held at least 7 days after the procedure and restarted at the discretion of the 
investigator when the surgical site is reasonably healed without serosanguineous drainage or the 
need for drainage tubes.  


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7. 
STUDY EVALUATIONS 
7.1. 
Description of Procedures 
7.1.1. 
Assessments  
7.1.1.1. 
Informed Consent Form (ICF) 
Adult subjects must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved ICF confirming his or her 
willingness to participate in this study before any study-specific screening procedures are 
performed. Consent of minors consists of signed parental permission form and minor’s assent. 
Subjects must also grant permission to use protected health information per the Health Insurance 
Portability and Accountability Act (HIPAA). In addition, subjects must sign all approved ICF 
amendments per the site IRB/REB/IEC guidelines during the course of the study.  
7.1.1.2. 
Confirm Eligibility 
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria prior to first dose on Day 1 
(Section 4). Details of establishing diagnosis of moderate or severe cGVHD are listed in 
Appendix M, Appendix N, and Appendix O. Please refer to NIH Staging and Response 
Assessment Manual for further details. 
All subjects with prior malignancy as the indication for transplantation must be assessed prior to 
randomization to rule out progression of underlying malignancy. Assessments are to be 
performed and collected as deemed appropriate for the follow-up and management for routine 
standard of care of the underlying malignancy. The results of these assessments do not have to be 
known prior to randomization. 
An enrollment eligibility form must be completed prior to enrollment into the trial. 
7.1.1.3. 
Medical History and Demographics 
The subject’s relevant medical history through review of medical records and by interview will 
be collected and recorded. Concurrent medical signs and symptoms must be documented to 
establish baseline severities. A disease history, including the date of initial diagnosis will be 
recorded. For subjects <22 years of age at the time of enrollment, medical history will include 
surveillance for potential late effects (Appendix P). 
7.1.1.4. 
Prior and Concomitant Medications 
All medications from 30 days prior to signing of ICF through 30 days after the last dose of 
ibrutinib/placebo or prednisone, start of another therapy for cGVHD, or start of a new therapy 
for progression of underlying malignancy will be documented.  


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7.1.1.5. 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 11.1. The occurrence of an 
AE from the time the ICF is signed until first dose should be recorded under medical history in 
the eCRF form. All medical occurrences after the first dose of ibrutinib/placebo or prednisone 
until 30 days after the last dose of ibrutinib/placebo or prednisone, start of new medication for 
cGVHD or start of a new therapy for progression of the underlying malignancy that meet the AE 
definition must be recorded as AEs in the eCRF. If the subject rolls over into a follow-up study, 
AE collection will stop after the last dose is given as part of that study. Laboratory abnormalities 
designated clinically significant by the investigator will also be documented as AEs. Assessment 
for corticosteroid-related AEs, in particular (Appendix Q), should be performed. Additional 
important requirements for AE and SAE reporting are explained in Section 11.4.  
7.1.1.6. 
Physical Examination 
The physical examination will include height (at Screening for adults, and at Screening and 
annually for subjects <22 years at the time of enrollment), weight, and examination per clinical 
practice.  
7.1.1.7. 
Karnofsky/Lansky Performance Scale 
The Karnofsky/Lansky Performance Scale is provided in Appendix C. The Lansky scale is to be 
used for all subjects less than 16 years of age. 
7.1.1.8. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature.  
7.1.2. 
Laboratory 
7.1.2.1. 
Hematology 
Hematology will be evaluated by a central laboratory and parameters will include a complete 
blood count: white blood cells, red blood cells, hemoglobin, hematocrit, platelets, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils. 
7.1.2.2. 
Chemistry (Serum) 
Serum chemistry will be evaluated by a central laboratory and parameters will include sodium, 
potassium, chloride, blood urea nitrogen (BUN)/Urea, creatinine, glucose, calcium, total protein, 
albumin, AST, ALT, alkaline phosphatase, total bilirubin, lactate dehydrogenase (LDH), 
phosphate, uric acid, magnesium and bicarbonate.  


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7.1.2.3. 
Infection Surveillance 
Subjects should be monitored closely for signs or symptoms of aspergillus infection and other 
opportunistic infections. Screening for infectious agents, including fungal (eg, aspergillus) and 
viral (eg, CMV) infections as appropriate for the subjects’ clinical course and medical history, 
should be performed.  
7.1.2.4. 
Coagulation Studies 
Measurement of PT/INR and aPTT will be performed at Screening using a local laboratory. 
7.1.2.5. 
Hepatitis Serologies 
Hepatitis serologies will be evaluated by a local laboratory and include hepatitis C antibody, 
hepatitis B surface antigen, and hepatitis B core antibody. If hepatitis B core antibody, 
hepatitis B surface antigen, or hepatitis C antibody is positive, then PCR to quantitate hepatitis B 
DNA or hepatitis C RNA must be performed and must be negative prior to randomization. 
Hepatitis serologies and/or PCR obtained as part of standard of care within 28 days prior to 
randomization are acceptable for use in establishing eligibility. 
7.1.2.6. 
Serum Immunoglobulins 
Serum immunoglobulins will be evaluated by a central laboratory and include IgA, IgG and IgM 
levels. 
7.1.2.7. 
Pregnancy Test 
Serum pregnancy test will be required at Screening by local laboratory only for women of 
childbearing potential. A urine pregnancy test will also be performed on Day 1 prior to first dose. 
If positive, pregnancy must be ruled out by ultrasound to be eligible. This test may be performed 
more frequently if required by local regulatory authorities. 
7.1.3. 
Diagnostics/Procedures 
7.1.3.1. 
Electrocardiograms (ECG) 
Electrocardiograms should be performed at the investigator’s discretion, particularly in subjects 
with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea.  
During visits in which both ECGs and blood draws are performed, ECGs should be performed 
first. 
At Screening, a 12-lead ECG is required. 


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Abnormalities noted at Screening should be included in the medical history. Subjects <22 years 
of age at enrollment will have a second ECG on Week 2 Day 1 during PK testing. This ECG 
should be done 2-4 hours after ibrutinib/placebo has been taken. 
7.1.3.2. 
Forced Expiratory Volume in 1 Second (FEV1) 
Forced expiratory volume in 1 second (FEV1) should be measured using spirometry and FEV1 
measurement should be obtained prior to randomization.  FEV1 values obtained as standard of 
care within 56 days prior to randomization can be used to fulfill the requirement for a baseline 
FEV1 measurement. If FEV1 results are abnormal at baseline, then subsequent FEV1 
measurements should be obtained every 12 weeks. If the FEV1 result is normal at baseline, then 
subsequent FEV1 measurements should be obtained every 24 weeks. The NIH Lung score 
should be ascertained with every cGVHD activity assessment regardless of whether a FEV1 is 
performed. 
7.1.4. 
Pharmacokinetics/Biomarkers  
7.1.4.1. 
Pharmacokinetics 
Plasma concentrations of ibrutinib and metabolite PCI-45227 after repeated dosing will be 
determined using a validated analytical method. Other potential metabolites of ibrutinib may be 
explored. Refer to Appendix B for PK sample collection schedule. 
If ibrutinib/placebo is on hold or missed at the Week 2 or Week 25 PK evaluation, PK testing 
should be obtained on the next scheduled visit after ibrutinib dose has been stable for a minimum 
of 7 days. 
7.1.4.2. 
Biomarkers and Pharmacodynamic Studies 
Biological specimens collected at specified timepoints during the study may be used for 
pharmacodynamic and biomarker assessments as indicated as well as sequencing expression 
analysis, immunophenotyping and secreted protein analyses. Refer to Appendix B for 
pharmacodynamic, biomarker and T/B/NK sample collection schedule. 
Samples collected in this study may be stored at a biorepository for up to 10 years (or according 
to local regulations) for additional research as new assays are developed for ibrutinib and 
cGVHD. Samples will be used to better understand the effects of ibrutinib, cGVHD, sensitivity 
and/or resistance to the investigational treatment regimen in this study. The research may begin 
at any time during the study or the post-study storage period. Stored samples will be coded 
throughout the sample storage and analysis process and will not be labeled with personal 
identifiers. 
Specific analysis and platforms may include, but are not limited to, soluble protein isolation 
including chemokine and cytokine, protein identification and quantification, viable cell 
manipulation, stimulation and co-culture, kinase drug occupancy studies, flow cytometric or 


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CyTOF based cell identification, and phospho-protein analyses. New analysis platforms and 
assays directed at protein specific outputs may be considered as technologies develop and 
improve or as new relevant disease or therapy markers are recognized. 
7.1.4.3. 
Biomarker DNA and RNA Sequencing 
T-cell and B-cell genetic functional diversity will be determined using a combination of TCR 
and BCR sequencing platform data alongside functional and immunophenotyping assays. The 
goal of these studies will be to establish study drug related changes to the systemic immune 
environment of the subjects. 
RNA and DNA species analysis and or RNA/DNA sequencing may be performed on cells 
obtained from biomarkers specimens in an effort to quantify the expression or mutation of 
specific genes implicated in cGVHD disease pathogenesis and or therapy response. 
7.2. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or central laboratory requisition form. Refer to the Schedule of 
Assessments (Appendix A and Appendix B) for the timing and frequency of all sample 
collections. 
Instructions for the collection, handling, and shipment of samples are found in the Central 
Laboratory Manual. 
7.3. 
Efficacy Evaluations  
7.3.1. 
NIH Consensus Panel Response Criteria 
Response will be defined using the NIH Consensus Panel Chronic GVHD Activity Assessment 
(Appendix H and Appendix I).  
Overall Response: 
Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or 
sites considered in evaluating overall response.  
x Complete Response (CR) is defined as resolution of all manifestations in each organ or 
site.  
x Partial Response (PR) is defined as improvement in at least 1 organ or site without 
progression in any other organ or site.  
x Disease Progression is defined as clinically meaningful worsening in one or more organs 
regardless of improvement in other organs. Note that mixed response (ie, improvement in 
at least 1 organ accompanied by progression in another organ) is considered disease 
progression. 


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x Stable disease (SD): response that does not meet the criteria for CR, PR, or disease 
progression.  
Please refer to NIH Staging and Response Assessment Manual and Appendix I for further 
details. 
7.3.2. 
Lee cGVHD Symptom Scale and SF-36 Questionnaire 
All subjects in the study will complete the Lee cGVHD Symptom Scale (Appendix F) and SF-36 
questionnaire (Appendix G) at all cGVHD activity assessment visits. These questionnaires 
should be administered before other study procedures. 
7.3.3. 
Late effects surveillance for adolescents (<22 years at randomization) 
Late effects surveillance for adolescents will consist of the collection of data on growth and 
development (height, weight, and Tanner Stage) and medical records review for late effects of 
transplantation. This assessment will be performed at Screening and annually up to 5 years post 
randomization (Appendix P). 
8. 
STUDY PROCEDURES 
8.1. 
Screening Phase 
8.1.1. 
Screening/Consenting Visit 
The following procedures will be performed at the Screening Visit within 28 days prior to 
randomization unless otherwise noted: 
x Obtain signed, written informed consent and if applicable, child assent, and parental 
permission 
x Medical history including demographic information 
x Record history related to late effect surveillance for subjects <22 years of age at the time 
of enrollment using the Late-Effects surveillance form (Appendix P) 
x Collection of transplant history, including indication 
x cGVHD Diagnosis and staging (NIH) (Appendix M, Appendix N, and Appendix O) 
x Assessment for relapse/progressive disease for subjects receiving transplant for malignant 
disorders 
x Infection surveillance 
x Evaluation of Karnofsky/Lansky performance status (Appendix C) 
x Physical examination including, height and weight. Document Tanner stage for subjects 
<22 years of age (subjects 22 years may use prior height measurement if available in 
source documents) (Appendix P) 
x Record AEs since signing the ICF 


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x Record concomitant medication history including corticosteroids requirement, 
over-the-counter drugs, vitamins and herbs since 30 days prior to signing ICF 
x cGVHD activity assessment (eg, NIH assessments [Appendix H and Appendix J]). For 
subjects who begin prednisone prior to randomization, cGVHD activity assessment 
should be completed prior to start of prednisone. If prednisone is started at the time that 
ibrutinib/placebo is started (Day 1) then activity assessment can be completed any time 
during Screening up until the day of first dose of ibrutinib/placebo (Day 1).  
x Lee cGVHD Symptom Scale (Appendix F)/SF-36 questionnaire (Appendix G). Perform 
at the same time as cGVHD assessment. 
x FEV1 (see Section 7.1.3.2) 
x Obtain vital signs (including blood pressure, heart rate, respiratory rate, and body 
WHPSHUDWXUHDIWHUWKHVXEMHFWKDVUHVWHGLQWKHVLWWLQJSRVLWLRQIRUPLQXWHV 
x Obtain blood specimens for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Coagulation studies: PT/INR, aPTT 
o Hepatitis serologies/PCR 
x T/B/NK sampling (Appendix B) 
x Biomarker sampling (Appendix B) 
x Obtain 12-lead ECG after the subject has been in a supine position and resting for at least 
10 minutes 
x Obtain serum pregnancy test for women of childbearing potential only 
x Complete eligibility form prior to randomization in Treatment Phase  
x Obtain subject number in the IWRS system 
At any time from consent throughout the treatment period, the subject may be called to discuss 
potential prednisone dosing changes. The phone call will be documented in the source 
documentation and will be entered in the CRF. 
8.2. 
Treatment Phase 
8.2.1. 
Treatment Visits 
8.2.1.1. 
Week 1 Day 1 
Following completion of the Screening Visit and once eligibility has been confirmed, subjects 
are randomized. Randomization should occur as close to the time of the expected first dose as 
possible, ie, not more than 3 days prior to expected first dose with study drug. 


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Predose 
x Physical examination  
x Vital signs  
x Performance status (KPS/Lansky) (Appendix C) 
x cGVHD activity assessment per NIH (Appendix H and Appendix J). Only perform if not 
performed previously during Screening (see Section 8.1.1 above). 
x Lee cGVHD Symptom Scale (Appendix F)/SF-36 Questionnaire (Appendix G). Only 
perform if not performed previously during Screening (see Section 8.1.1 above). 
x FEV1. Only perform if not performed previously during Screening (see Section 7.1.3.2) 
x Hematology 
x Serum chemistry 
x Urine pregnancy test for women of childbearing potential 
x Quantitative serum immunoglobulins (IgA, IgM, IgG) 
x Review of baseline AEs and concomitant medications (including corticosteroid 
requirements) 
x Review of inclusion and exclusion criteria to re-confirm subject eligibility prior to first 
dosing 
x Pharmacodynamic sampling (Appendix B) 
x T/B/NK sampling (Appendix B) 
x Biomarker sampling (Appendix B) 
Postdose 
x Administer ibrutinib/placebo at specified dose level, and then dispense remaining amount 
to subject for at-home dosing  
x Provide drug diary and dosing instructions to subject  
x Review AEs 
8.2.1.2. 
Week 2  
Predose 
x Physical examination 
x Hematology 
x Serum chemistry 
x Vital signs 
x Review AEs and concomitant medications (including corticosteroid requirements) 
x Pharmacokinetic sampling (Appendix B) 


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Postdose 
x Administer ibrutinib/placebo at specified dose level 
x Pharmacokinetic sampling at 1, 2, 4, and 6 hours postdose (Appendix B) 
x For subjects <22 years of age at enrollment: Obtain 12-lead ECG approximately 
2-4 hours post ibrutinib/placebo dose, after the subject has been in a supine position and 
resting for at least 10 minutes 
8.2.1.3. 
Week 5, 9, 13, 17, 21, 25  
Predose 
x Physical examination  
x Vital signs  
x Performance status (KPS/Lansky) (Appendix C) 
x Hematology 
x Serum chemistry 
x cGVHD activity assessment per NIH (Appendix H and Appendix J) (Weeks 5, 13 and 25 
only) 
x cGVHD response assessment (Appendix I) (Weeks 5, 13 and 25 only) 
x Lee cGVHD Symptom Scale (Appendix F)/SF-36 Questionnaire (Appendix G) 
(Weeks 5, 13 and 25 only) 
x FEV1 (Week 13 if abnormal at Screening, Week 25 for all subjects, see Section 7.1.3.2)  
x Quantitative serum immunoglobulins (IgA, IgG, and IgM) (Weeks 13 and 25 only) 
x Pharmacokinetic sampling (Appendix B) (Week 25 only) 
x Pharmacodynamic sampling (Appendix B) 
x T/B/NK sampling (Appendix B)  
x Biomarker sampling  
x Review returned subject dosing diary 
x Drug accountability  
x Review AEs and concomitant medications (including corticosteroid requirements) 
Postdose 
x Administer ibrutinib/placebo at specified dose level, and then dispense remaining amount 
to subject 
x Pharmacokinetic sampling at 1, 2, 4, and 6 hours postdose (Week 25 only)  


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8.2.1.4. 
Week 37, 49, and every 12 weeks thereafter (± 7 days) 
Predose 
x Physical examination 
x Vital signs  
x Performance status (KPS/Lansky) (Appendix C) 
x Hematology 
x Serum chemistry 
x cGVHD activity assessment per NIH (Appendix H and Appendix J)  
x cGVHD response assessment (Appendix I) 
x Lee cGVHD Symptom Scale (Appendix F)/SF-36 Questionnaire (Appendix G) 
x FEV1 every 12 weeks if prior FEV1 was abnormal, every 24 weeks if prior FEV1 was 
normal (see Section 7.1.3.2) 
x Quantitative serum immunoglobulins (IgA, IgG, and IgM) 
x Pharmacodynamic sampling (Appendix B) (Weeks 49, 73, and 97 only) 
x T/B/NK sampling (Appendix B) (Weeks 37, 49, 73 and 97 only) 
x Biomarker sampling (Appendix B) (Weeks 37, 49, 73 and 97 only) 
x Review returned subject dosing diary 
x Drug accountability 
x Review AEs and concomitant medications (including corticosteroid requirements) 
Postdose 
x Administer ibrutinib/placebo at specified dose level, and then dispense remaining amount 
to subject 
8.2.2. 
Progressive Disease Visit 
Progressive Disease visit should be performed at any time during the study, if based on clinical 
and/or laboratory evaluation, the Investigator suspects progressive disease. If possible, the visit 
should be performed within 72 hours after the subject’s previous dose.  
x Physical examination 
x Vital signs  
x Performance status (KPS/Lansky) (Appendix C) 
x Hematology 
x Serum chemistry 
x cGVHD activity assessment per NIH (Appendix H and Appendix J)  
x cGVHD response assessment (Appendix I) 
x Lee cGVHD Symptom Scale (Appendix F)/SF-36 Questionnaire (Appendix G) 


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x FEV1 (if not obtained within the previous 12 weeks, see Section 7.1.3.2) 
x Quantitative serum immunoglobulins (IgA, IgG, and IgM) 
x Review AEs and concomitant medications (including corticosteroid requirements) 
x Review returned subject dosing diary 
x Final drug accountability 
x Pharmacodynamic sampling (Appendix B) 
x T/B/NK sampling (Appendix B) 
x Biomarker sampling (Appendix B) 
8.2.3. 
End-of-Treatment Visit 
An End-of-Treatment visit should occur 30 days (±7 days) from the last dose of study drug or 
prior to the start of a new cGVHD treatment. If the subject starts a new cGVHD treatment less 
than 7 days after the Progressive Disease visit, only those procedures not conducted at the 
Progressive Disease visit should be performed at the End-of-Treatment visit. If ibrutinib/placebo 
is held after Week 48 due to response (see Section 5.3.1.6), the End-of-Treatment visit should 
occur 30 days after ibrutinib/placebo was put on hold. 
The following procedures will be performed at the End-of-Treatment visit: 
x Physical examination 
x Vital signs  
x Performance status (KPS/Lansky) (Appendix C) 
x Hematology 
x Serum chemistry 
x cGVHD activity assessment per NIH (Appendix H and Appendix J) (if not performed 
within previous 30 days) 
x cGVHD response assessment (Appendix I) (if not performed within previous 30 days) 
x Lee cGVHD Symptom Scale (Appendix F)/SF-36 Questionnaire (Appendix G) (if not 
performed within previous 30 days) 
x FEV1 (if not obtained within previous 12 weeks) 
x Quantitative serum immunoglobulins (IgA, IgG, and IgM) 
x Review AEs and concomitant medications (including corticosteroid requirements and any 
new cGVHD treatment if applicable) 
x Review returned subject dosing diary 
x Final drug accountability 


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8.3. 
Follow-up Phase 
Once a subject has completed the End-of-Treatment visit they will enter the Follow-up Phase. 
Subjects that withdraw from treatment for reasons other than progressive cGVHD or progression 
of their underlying malignancy will participate in ongoing response follow-up.  
8.3.1. 
Response Follow-up 
Subjects who discontinue ibrutinib/placebo for reasons other than progressive cGVHD or 
progression of underlying malignancy will be followed at pre-specified response assessment time 
points (Weeks 5, 13, 25 and every 12 weeks thereafter) by clinic visit until progressive disease or 
progression of underlying malignancy. During this period, the following procedures will be 
performed: 
x Physical examination 
x Vital signs  
x Performance status (KPS/Lansky) (Appendix C) 
x Hematology 
x Serum chemistry 
x cGVHD activity assessment per NIH (Appendix H and Appendix J)  
x cGVHD response assessment (Appendix I) 
x Lee cGVHD Symptom Scale (Appendix F)/SF-36 Questionnaire (Appendix G) 
x FEV1 every 12 weeks if prior FEV1 abnormal, every 24 weeks if prior FEV1 normal  
x Review corticosteroid requirements and any new cGVHD treatment if applicable 
8.3.2. 
Long-Term Follow-up 
Once subjects have cGVHD progression, or have progression of their underlying malignancy 
(for subjects who have not withdrawn consent), they will be contacted approximately every 
12 weeks (±14 days) by clinic visit or telephone to assess survival and the use of alternative 
cGVHD therapy. In addition, subjects who have progressive cGVHD will continue to have the 
Lee Symptom Scale and SF-36 assessments until the week 60 visit. Subjects will be contacted 
until death, subject withdrawal, lost to follow-up, or study termination by the Sponsor, 
whichever occurs first.  
8.3.3. 
Expected length of participation on study 
The Sponsor will continue to follow adult subjects up to approximately 3 years after the first 
subject was randomized. Adolescents (<22 years of age at the time of randomization) will be 
followed for up to 5 years after randomization; however, the study may close after the last 
patient below 18 years of age has exited the study if all other participating subjects have 
completed a minimum of 1 year of follow-up. Subjects may be rolled over to a long-term 
extension study for long-term follow-up.  


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9. 
SUBJECT COMPLETION AND WITHDRAWAL  
9.1. 
Completion 
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of study.  
9.2. 
Discontinuation from Ibrutinib/Placebo 
Ibrutinib/placebo will be discontinued in the event of any of the following events: 
x Subject begins treatment with another systemic therapy (including ECP) for cGVHD 
x cGVHD progression 
x Progression or relapse of the malignancy that was the indication for transplantation or 
development of PTLD  
x Unacceptable toxicity: an intercurrent illness or AE that prevents further 
ibrutinib/placebo administration despite dose adjustment 
x Noncompliance with study medication 
x Investigator’s decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject) 
x Withdrawal of consent for treatment by subject 
x Unblinding at primary efficacy analysis 
x Study termination by Sponsor 
x Subject becomes pregnant 
x Death 
All subjects, regardless of reason for discontinuation of ibrutinib/placebo will undergo an 
End-of-Treatment visit and be followed as outlined under Section 8.3.  
The investigator should notify the Sponsor within 24 hours if a subject discontinues 
ibrutinib/placebo treatment due to cGVHD progression and should provide documentation of 
cGVHD progression for review by the Sponsor’s medical monitor.  
9.3. 
Withdrawal from Study 
Withdrawal from study (including all follow-up) will occur under the following circumstances: 
x Withdrawal of consent for follow-up observation by the subject 
x Lost to follow-up 
x Study completion / termination 
x Death 


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If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject. The measures taken to follow up should be documented. 
When a subject withdraws before completing the study, the following information should be 
documented in the source documents: 
x Reason for withdrawal; 
x Whether the subject withdraws full consent (ie, withdraws consent to treatment and all 
further contact) or partial consent (ie, withdraws consent to treatment but agrees to 
participate in follow-up visits); and/or, withdraws consent from future biomarker 
research. 
10. 
STATISTICAL METHODS AND ANALYSIS  
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.  
10.1. 
Analysis Sets 
10.1.1. 
Intention-to-Treat Population (ITT) 
The ITT Population is defined as all subjects who are randomized in the study. The ITT 
population will be used for all efficacy analyses. 
The mITT Population is defined as all subjects who are randomized in the study (ITT) and who 
do not have evidence of progression of underlying malignancy from measurements made at or 
before the time of randomization. If indicated, the mITT population may be used for additional 
efficacy analyses. 
10.1.2. 
Safety Population (SP) 
The Safety Population will consist of all randomized subjects who received at least one dose of 
any study drug.  
10.2. 
Sample Size Determination 
The null hypothesis is that the two treatment arms have the same response rate at 48 weeks and 
the alternative hypothesis is that the response rates of two arms are different. 
Assuming a response rate of 30% at 48 weeks for Arm B (placebo + prednisone), a sample size 
of 186 randomized subjects provides at least 80% power to detect a 20% difference in the 
response rates at 48 weeks between the 2 treatment arms (Arm A – Arm B) at an alpha level of 
5% (2-sided). 


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No replacement of subjects will be implemented.  
10.3. 
Subject Information 
The distribution of subjects by treatment arm for each of the analysis populations will be 
provided. The number of subjects randomized, dosed, and discontinued will be summarized. 
Treatment discontinuation will be summarized according to the reasons for discontinuation and 
by treatment arm. 
Demographic and baseline variables and baseline disease characteristics will be summarized by 
treatment arm. 
10.4. 
Efficacy Analyses  
10.4.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is the response rate at 48 weeks (ie, the proportion of 
responders [CR or PR]). Response will be defined by the NIH Consensus Development Project 
Criteria (2014). 
A subject will not be considered as a responder at 48 weeks if the response was not CR or PR, or 
if he/she meets any of following criteria:  
x Starts a second-line systemic therapy for cGVHD at or prior to the response assessment at 
48 weeks 
x Has evidence of progression of the underlying malignancy that was the indication for 
transplant at or prior to response assessment at 48 weeks 
Subjects who withdraw from the study prior to, or are missing the response at, 48 weeks will not 
be considered responders. 
The primary efficacy analysis will be performed using the ITT population. The chi-square test 
will be used to compare the proportions between the two treatment arms. 
10.4.2. 
Secondary Endpoints for Efficacy 
The secondary efficacy endpoints are: 
x Response rate at 24 weeks (the proportion of responders [CR or PR]) as defined by the 
NIH Consensus Development Project (2014) 
x Duration of response (DOR) will be defined from the time of initial partial or complete 
response until progression of cGVHD 
x Proportion of subjects with steroid dose reduction to a level of less than 0.15 mg/kg/d at 
24 weeks 
x Time to withdrawal of all immunosuppressants (with the exception of ibrutinib/placebo)  


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x Overall survival (OS) is defined as the time from randomization until death due to any 
cause  
x Improvement in Lee cGVHD Symptom Scale scores will be compared between the two 
treatment arms 
Proportion of subjects with improvement in overall score on the Lee cGVHD Symptom Scale 
and the proportion of subjects with steroid dose reduction will be analyzed using the same 
method for the primary efficacy endpoint. The Kaplan Meier methodology will be used to 
estimate the distribution of OS for each treatment group. The log-rank test will be used to 
compare the OS between the 2 treatment arms. Time to withdrawal of all immunosuppressants 
will be analyzed using the same method used for OS. 
Duration of response is defined as the interval between the date of initial documentation of a 
response (PR or better), and the date of first documented evidence of progressive cGVHD or 
death for responders only. Responders will include subjects who achieve response (PR or better) 
based on NIH 2014 cGVHD criteria. Non-responders will be excluded from the analysis for 
DOR. Median duration of response will be estimated using Kaplan Meier methodology. 
10.4.3. 
Exploratory Endpoints 
x Pharmacokinetics (PK) parameters of ibrutinib when administered in combination with 
prednisone in subjects with cGVHD including adolescent subjects 
x Pharmacodynamic characteristics (including BTK and ITK occupancy) of ibrutinib in 
subjects with cGVHD 
x Biomarkers relevant to disease biology and therapy with ibrutinib for cGVHD 
x Summary scales of SF-36 patient reported outcome 
Pharmacokinetic 
Ibrutinib and PCI-45227 bioanalytical data will be used in non-compartmental PK analysis. 
Plasma concentrations below the lowest quantifiable concentration will be treated as zero in the 
summary statistics. All subjects and samples excluded from the analysis will be clearly 
documented in the PK report. 
Descriptive statistics will be used to summarize ibrutinib and PCI-45227 concentrations at each 
sampling time point and PK parameters of ibrutinib and PCI-45227 (including, but not limited 
to: Cmax, tmax, AUClast, and t1/2). 
Individual and mean plasma ibrutinib and PCI-45227 concentration time profiles will be plotted. 
Ibrutinib data from this study may also be combined with data from other studies performed with 
ibrutinib in subjects with hematologic malignancies as part of a population-PK analysis using 
nonlinear mixed effects models. For the population-PK analysis, covariates that could potentially 


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correlate with plasma PK parameters will be evaluated. The results of the population-PK 
analyses (if performed) will be presented in a separate report. 
Biomarker and Pharmacodynamics 
The following biomarker assessments will be undertaken:  
1. Sequence-directed Immune Function Assessment 
2. Cytokine, Chemokine, and Soluble Biomarker Assessment 
3. Co-culture Immunologic Function Tests 
4. CyTOF-based Phospho-immunophenotyping 
PK/PD and biomarkers will be evaluated separately and will not be covered in the statistical 
analysis plan (SAP). 
Patient Reported Outcomes 
SF-36 summary scores will be evaluated; detailed analyses will be covered in the statistical 
analysis plan (SAP).   
10.5. 
Safety Analysis 
Analysis of safety data will be conducted on the safety population, which includes randomized 
subjects who receive at least 1 dose of ibrutinib/placebo. The baseline value is defined as the last 
value collected on or prior to the first dose date of ibrutinib/placebo, whichever comes first. 
The safety variables to be summarized include exposure to ibrutinib/placebo and prednisone, 
AEs, clinical laboratory test results (hematology and chemistry), Karnofsky/Lansky performance 
status, and vital sign measurements. In general, safety data will be tabulated or listed. No formal 
statistical testing is planned.  
Growth and development and late effects will be summarized in adolescent subjects. 
Adverse Events 
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  
Treatment-emergent period is defined as the period of time from the first dose of study treatment, 
until the earlier of:  
x Thirty days following the last dose of ibrutinib/placebo or prednisone whichever occurs 
later 
OR 


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x The start date of a new therapy for cGVHD or for the progression of the underlying 
malignancy. 
The TEAEs are those events that: 
x Are not present prior to the treatment-emergent period and occur during the treatment-
emergent period, 
x Are considered related to study drug by the investigator regardless of the start dates of the 
events, or 
x Are present prior to the treatment-emergent period but worsen in severity during the 
treatment-emergent period or are subsequently considered related to study drug by the 
investigator.  
All treatment-emergent AEs will be summarized. For each AE, the number and percentage of 
subjects who experience at least one occurrence of the given event will be summarized. The 
number and percent of subjects with TEAEs will be summarized according to intensity 
(CTCAE, v4.03) and drug relationship, as well as categorized by system organ class and 
preferred term. Summaries and listings may be provided, as appropriate, for those subjects who 
die, who discontinue treatment due to an AE, or who experience a severe or a SAE. 
Clinical Laboratory Tests 
Laboratory tests will be summarized separately for hematology and serum chemistry. All 
laboratory values will be graded using the NCI CTCAE v4.03. The worst toxicity grade during 
the study will be tabulated. 
Steroid-related Toxicities 
Treatment-emergent steroid-related AEs will be summarized by the two study arms (Appendix 
Q). The number and percent of subjects with steroids related TEAEs will be summarized 
according to intensity (CTCAE, v4.03) and will be categorized by system organ class and 
preferred term.  
10.6. 
Interim Futility Review  
An interim analysis (for futility only) will be performed for the first 50 subjects who complete 
the Week 25 visit or discontinue study drug before this time. The independent DMC will review 
the interim futility analysis results and make a recommendation accordingly. Details regarding 
the interim futility review will be described in the DMC charter.  
10.7. 
Data Monitoring Committee (DMC) 
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study and to meet efficacy objectives. The 
committee will meet periodically to review interim data. After the review, the DMC will make 


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recommendations regarding the continuation of the study. The DMC will also oversee the 
interim futility review. This review will be performed for the first 50 subjects who complete the 
Week 25 visit or discontinue study drug before this time. Available pharmacokinetics data will 
be provided to the DMC for the interim futility review. 
The DMC will consist of at least one medical expert in the relevant therapeutic area and at least 
one statistician. The DMC responsibilities, authorities, and procedures will be documented in a 
separate charter. 
11. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. The Sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures. 
11.1. 
Definitions  
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A 1995). 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an AE term. As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 
Adverse events may include, but are not limited to: 
x Subjective or objective symptoms provided by the subject and/or observed by the 
investigator or study staff including laboratory abnormalities of clinical significance. 
x Any AEs experienced by the subject through the completion of final study procedures. 
x AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
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x Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 
The following are NOT considered AEs: 
x Pre-existing Condition: A pre-existing condition (documented on the medical history 
CRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
x Pre-planned or Elective Hospitalization: A hospitalization planned before signing the 
ICF is not considered an SAE, but rather a therapeutic intervention. However, if during 
the pre-planned hospitalization an event occurs, which prolongs the hospitalization or 
meets any other SAE criteria, the event will be considered an SAE. Surgeries or 
interventions that were under consideration, but not performed before enrollment in the 
study, will not be considered serious if they are performed after enrollment in the study 
for a condition that has not changed from its baseline level. Elective hospitalizations for 
social reasons, solely for the administration of chemotherapy, or due to long travel 
distances are also not SAEs. 
x Diagnostic Testing and Procedures: Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
11.1.2. 
Serious Adverse Events 
A SAE based on International Conference on Harmonisation (ICH) and EU Guidelines on 
Pharmacovigilance for Medicinal Products for Human Use is any untoward medical occurrence 
that at any dose: 
x Results in death (ie, the AE actually causes or leads to death). 
x Is life-threatening. Life-threatening is defined as an AE in which the subject was at risk 
of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it were more severe. If either the investigator or the Sponsor believes 
that an AE meets the definition of life-threatening, it will be considered life-threatening. 
x Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
x Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
x Is a congenital anomaly/birth defect. 
x Is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered an SAE when, 
based upon appropriate medical judgment, the event may jeopardize the subject or 
subject may require intervention to prevent one of the other outcomes listed in this 
definition. Examples of such events are intensive treatment in an emergency department 
or at home for allergic bronchospasm, blood dyscrasias, or convulsion that does not result 
in hospitalization; or development of drug dependency or drug abuse. 
Given that the investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 


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evaluation of the significance of the event, if either the Sponsor or the investigator believes that 
the event is serious, the event will be considered serious. 
11.1.3. 
Severity Criteria (Grade 1-5) 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 
(CTCAE v4.03) will be used for grading the severity (intensity) of AEs. The CTCAE v4.03 
displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. 
Should a subject experience any AE not listed in the CTCAE v4.03, the following grading 
system should be used to assess severity: 
x Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities 
x Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
x Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
x Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death 
x Grade 5 (Death related to AE) – experiences which result in subject death 
11.1.4. 
Causality (Attribution)  
The investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence 
cannot be established with the onset of the AE and administration of 
the investigational product; or, a causal relationship is considered 
biologically implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the AE 
and administration of the investigational product, but the AE could 
also be attributed to concurrent or underlying disease, or the use of 
other drugs or procedures. Possibly related should be used when the 
investigational product is one of several biologically plausible AE 
causes. 
Related: 
The AE is clearly related to use of the investigational product. 


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11.2. 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the IB/package insert or is not listed at the 
specificity or severity that has been observed. For example, hepatic necrosis would be 
“unexpected” (by virtue of greater severity) if the IB referred only to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be “unexpected” 
(by virtue of greater specificity) if the IB/package insert listed only cerebral vascular accidents. 
"Unexpected" also refers to AEs that are mentioned in the IB as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the study drug under investigation. 
11.3. 
Special Reporting Situations 
Special reporting situation on a Sponsor study may require expedited reporting and/or safety 
evaluation include, but are not limited to: 
x Overdose of any study drug 
x Suspected abuse/misuse of a study drug 
x Inadvertent or accidental exposure to a study drug 
x Medication error involving a product (with or without subject exposure to the study drug, 
eg, name confusion) 
Occurrence of any special reporting situations should be recorded in the eCRF. If any special 
reporting situation meets the criteria of an AE, it should be recorded on the AEs eCRF. If the AE 
is considered serious, it should be recorded on the AEs eCRF as serious and should be reported 
on the Serious Adverse Event Report Form. The Serious Adverse Event Report Form should be 
sent via email or fax to Pharmacyclics Drug Safety or designee within 24 hours of awareness. 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
11.4.1. 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation timepoints 
during the study. All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, detected through physical examination, clinically significant 
laboratory test, or other means, will be recorded in the subject’s medical record and on the AEs 
CRF and, when applicable, on the Serious Adverse Event Report Form. 
Each recorded AE or SAE will be described by its duration (ie, start and end dates), severity, 
regulatory seriousness criteria (if applicable), suspected relationship to the investigational 
product, and any actions taken. 


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11.4.2. 
Adverse Event Reporting Period 
All AEs whether serious or non-serious, will be documented from the time signed and dated ICF 
is obtained until 30 days following the last dose of study drug (ibrutinib/placebo or prednisone) 
or the start date of a new therapy for cGVHD. The occurrence of AE at the time the ICF is 
signed until first dose should be recorded under medical history in the eCRF form. All medical 
occurrences after the first dose of study drug until 30 days after the last dose of study drug that 
meet the AE definition must be recorded as AEs in the eCRF. SAEs will be reported to the 
Sponsor Drug Safety via an SAE reporting form and will be recorded in the eCRF from the time 
of ICF signing. Serious adverse events reported after 30 days following the last dose of study 
drug should also be reported if considered related to study drug. Resolution information after 30 
days should be provided.  
Progression of cGVHD should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported (see Section 11.1.1). 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document. All records will need to capture the 
details of the duration and the severity of each episode, the action taken with respect to the study 
drug, investigator’s evaluation of its relationship to the study drug, and the event outcome. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the AE to study therapy. All measures required for AE management must be 
recorded in the source document and reported according to Sponsor instructions. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. Autopsy and postmortem reports must be 
forwarded to the Sponsor, or designee, as outlined above, if allowed per local regulatory 
guidelines. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a SAE.  
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events 
All SAEs (initial and follow-up information) will be reported on the Serious Adverse Event 
Report Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, within 
24 hours of the discovery of the event or information. Pharmacyclics may request follow-up and 
other additional information from the investigator (eg, hospital admission/discharge notes and 
laboratory results). The contact information (phone, email and fax) for Pharmacyclics Drug 
Safety can be found on the Serious Adverse Event Report Form and instructions. 


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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
x The event resolves 
x The event stabilizes 
x The event returns to baseline, if a baseline value/status is available 
x The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
x It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow up after 
demonstration of due diligence with follow-up efforts) 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations.  
The investigator (or Sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB. 
11.4.4. 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject or female partner of a male subject must immediately inform the investigator if 
she becomes pregnant from the time of consent to 90 days after the last dose of study drug (s). 
Any female subjects receiving study drug (s) who become pregnant must immediately 
discontinue study drug. The investigator should counsel the subject, discussing any risks of 
continuing the pregnancy and any possible effects on the fetus. 
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. 
Any pregnancy occurring in a female subject or female partner of a male subject must be 
reported from the time of first dose up until 90 days after the last dose of study drug (s). Any 
occurrence of pregnancy must be recorded on the Pregnancy Report Form Part I and sent via 
email or fax to Pharmacyclics Drug Safety, or designee, within 24 hours of learning of the event. 
All pregnancies will be followed for outcome, which is defined as elective termination of the 
pregnancy, miscarriage, or delivery of the fetus. For pregnancies with an outcome of live birth, 
the newborn infant will be followed until 30 days old by completing the Pregnancy Report Form 
Part II. Any congenital anomaly/birth defect noted in the infant must be reported as a SAE. 


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11.4.5. 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 
protocol-specified follow-up periods including post-progression follow-up for OS. If observed, 
enter data in the corresponding eCRF. Relapse of underlying malignancy will not be considered 
a new malignancy. 
11.4.6. 
Eye-Related Adverse Events 
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose 
findings should be reported on the ophthalmologic eCRF.  
11.4.7. 
Adverse Events of Special Interest (AESI) 
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities 
by the Sponsor. These events (regardless of seriousness) should be reported on the Serious 
Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, or designee, 
within 24 hours of awareness.  
11.4.7.1. Major Hemorrhage 
Major hemorrhage is defined as any of the following: 
x Any treatment-emergent hemorrhagic AEs of Grade 3 or higher*  
x Any treatment-emergent serious adverse events of bleeding of any grade 
x Any treatment-emergent central nervous system hemorrhage/hematoma of any grade 
*All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 or higher 
AE per CTCAE v4.03. 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.4.7 above. 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS  
12.1. 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki.  


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12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval 
The investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation. Amendments to the 
protocol and ICF must also be approved by the IRB/REB/IEC before the implementation of 
changes in this study. 
The investigator is responsible for providing the IRB/REB/IEC with any required information 
before or during the study, such as SAE expedited reports or study progress reports. 
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) as 
well as country-specific national regulations and/or local laws. 
The following documents must be provided to Pharmacyclics or its authorized representative 
before entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal 
approval; and (2) a copy of the IRB/REB/IEC-approved ICF.  
12.3. 
Informed Consent 
The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as country 
specific national regulations and/or local laws. Parental permission will be obtained for subjects 
who are below the age of legal consent and assent procedures for minors will follow country 
specific national regulations. The ICF will document the study-specific information the 
investigator or his/her designee provides to the subject and the subject’s agreement to participate.  
The investigator or designee (designee must be listed on the Delegation of Authority log), must 
explain in terms understandable to the subject the purpose and nature of the study, study 
procedures, anticipated benefits, potential risks, possible AEs, and any discomfort participation 
in the study may entail. This process must be documented in the subject’s source record. Each 
subject must provide a signed and dated ICF before any study-related (nonstandard of care) 
activities are performed. The original and any amended signed and dated consent forms must 
remain in each subject’s study file at the study site and be available for verification by study 
monitors at any time. A copy of each signed consent form must be given to the subject at the 
time that it is signed by the subject. 
12.4. 
Quality Control and Quality Assurance 
Sponsor shall implement and maintain quality control and quality assurance procedures to ensure 
that the study is conducted and data are generated, documented and reported in compliance with 
the protocol, GCP, and applicable regulatory requirements. This study shall be conducted in 
accordance with the provisions of the Declaration of Helsinki (October 2008) and all revisions 
thereof, and in accordance with the Food and Drug Administration (FDA) regulations (21 CFR 


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Parts 11, 50, 54, 56, and 312, Subpart D – Responsibilities of Sponsors and investigators) and 
with the ICH guidelines on GCP (ICH E6).  
12.5. 
Protected Subject Health Information Authorization 
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 7.1.1.1), either as part of the ICF or as a separate signed document 
(for example, in the US, a site-specific HIPAA consent may be used). The investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 
protected health information obtained during the study may be shared with Pharmacyclics and its 
designees, regulatory agencies, and IRBs/REBs/IECs. As the study Sponsor, Pharmacyclics will 
not use the subject’s protected health information or disclose it to a third party without applicable 
subject authorization. It is the investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each subject. If a subject withdraws 
permission to use protected health information, it is the investigator’s responsibility to obtain the 
withdrawal request in writing from the subject and to ensure that no further data will be 
collected from the subject. Any data collected on the subject before withdrawal will be used in 
the analysis of study results. 
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations. 
12.6. 
Study Files and Record Retention 
The investigator must keep a record of all subjects who have consented to enroll in the study. 
For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is to be 
recorded. 
The investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed Form FDA 1572 and Financial Disclosures, 
signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed case report forms (CRFs), and documentation of CRF 
corrections, SAE forms transmitted to Pharmacyclics and notification of SAEs and related 
reports, source documentation, normal laboratory values, decoding procedures for blinded 
studies, curricula vitae for study staff, and all relevant correspondence and other documents 
pertaining to the conduct of the study. 
All essential documentation will be retained by the investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 


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application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug. 
The investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics 
before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at 
any time. Should an investigator wish to assign the study records to another party or move them 
to another location, advance written notice will be given to Pharmacyclics. Pharmacyclics will 
inform the investigator of the date that study records may be destroyed or returned to 
Pharmacyclics. 
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written 
approval of, any change in the maintenance of the foregoing documents if the investigator wishes 
to move study records to another location or assign responsibility for record retention to another 
party. If the investigator cannot guarantee the archiving requirements set forth herein at his or her 
study site for all such documents, special arrangements must be made between the investigator 
and Pharmacyclics to store such documents in sealed containers away from the study site so that 
they can be returned sealed to the investigator for audit purposes. 
12.7. 
Case Report Forms and Record Maintenance 
The case report forms will be used to collect the clinical study data and must be completed for 
each enrolled subject with all required study data accurately recorded such that the information 
matches the data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts 
and other study-specific source documents). Authorized study site personnel (ie, listed on the 
Delegation of Authority log) will complete CRFs designed for this study according to the 
completion guidelines that will be provided. The investigator will ensure that the CRFs are 
accurate, complete, legible, and completed within a reasonable period of time. At all times, the 
investigator has final responsibility for the accuracy and authenticity of all clinical data. 
The CRFs exists within an electronic data capture (EDC) system with controlled access managed 
by Pharmacyclics or its authorized representative for this study. Study staff will be appropriately 
trained in the use of CRFs and application of electronic signatures before the start of the study 
and before being given access to the EDC system. Original data and any changes of data will be 
recorded using the EDC system, with all changes tracked by the system and recorded in an 
electronic audit trail. The investigator attests that the information contained in the CRFs is true 
by providing electronic signature within the EDC system. After database lock, the investigator 
will receive a copy of the subject data (eg, paper, CD, or other appropriate media) for archiving 
at the study site. 
12.8. 
Investigational Study Drug Accountability 
Ibrutinib and any comparator used must be kept in a locked limited access room. The study drug 
must not be used outside the context of the protocol. Under no circumstances should the 
investigator or other site personnel supply ibrutinib or comparator to other investigators, 


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subjects, or clinics or allow supplies to be used other than as directed by this protocol without 
prior authorization from Pharmacyclics. 
Accountability records for ibrutinib and any comparator must be maintained and readily 
available for inspection by representatives of Pharmacyclics and are open to inspections by 
regulatory authorities at any time.  
An Investigational Drug Accountability Log must be used for drug accountability. For accurate 
accountability, the following information must be noted when drug supplies are used during the 
study: 
1. Study identification number (PCYC-1140-IM) 
2. Subject identification number 
3. Lot number(s) of ibrutinib or placebo dispensed for that subject 
4. Date and quantity of drug dispensed 
5. Any unused drug returned by the subject 
At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with Pharmacyclics’ requirements. If the 
site cannot meet Pharmacyclics’ requirements for disposal/destruction, arrangements will be 
made between the site and Pharmacyclics or its representative, for return of unused 
investigational product. Before disposal/destruction, final drug accountability and reconciliation 
must be performed by the monitor. 
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor. 
12.9. 
Study Monitoring/Audit Requirements 
Representatives of Pharmacyclics or its designee will monitor this study until completion. 
Monitoring will be conducted through personal visits with the investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone. 
The purpose of monitoring is to ensure that the study is conducted in compliance with the 
protocol, standard operating procedures (SOPs), and other written instructions and regulatory 
guidelines, and to ensure the quality and integrity of the data. This study is also subject to 
reviews or audits. 
To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice. If access to the EMR cannot be granted to the 
monitor, the site must ensure that all certified copies of documents are available during 
monitoring visits for all screened and enrolled subjects. During the review of source documents, 
every effort will be made to maintain the anonymity and confidentiality of all subjects during 


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this clinical study. However, because of the experimental nature of this treatment, the 
investigator agrees to allow the IRB/REB/IEC, representatives of Pharmacyclics, its designated 
agents and authorized employees of the appropriate Regulatory Authority to inspect the facilities 
used in this study and, for purposes of verification, allow direct access to the hospital or clinic 
records of all subjects enrolled into this study. A statement to this effect will be included in the 
informed consent and permission form authorizing the use of protected health information. 
Pharmacyclics or its authorized representative may perform an audit at any time during or after 
completion of this study. All study-related documentation must be made available to the 
designated auditor. In addition, a representative of the FDA or other Regulatory Agencies may 
choose to inspect a study site at any time before, during, or after completion of the clinical study. 
In the event of such an inspection, Pharmacyclics will be available to assist in the preparation. 
All pertinent study data should be made available as requested to the Regulatory Authority for 
verification, audit, or inspection purposes. 
12.10. 
Investigator Responsibilities 
A complete list of investigator responsibilities are outlined in the clinical trial research 
agreement and the Statement of Investigator Form FDA 1572, both of which are signed by the 
investigator before commencement of the study. In summary, the investigator will conduct the 
study according to the current protocol; will read and understand the IB; will obtain 
IRB/REB/IEC approval to conduct the study; will obtain informed consent from each study 
participant; will maintain and supply to the Sponsor or designee, auditors and regulatory 
agencies adequate and accurate records of study activity and drug accountability for 
study-related monitoring, audits, IRB/REB/IEC reviews and regulatory inspections; will report 
SAEs to the Sponsor or designee and IRB/REB/IEC according to the specifics outlined in this 
protocol; will personally conduct or supervise the study; and will ensure that colleagues 
participating in the study are informed about their obligations in meeting the above 
commitments. 
12.11. 
Sponsor Responsibilities 
A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement 
and in the laws and regulation of the country in which the research is conducted. In summary, the 
Sponsor will select qualified investigators, provide them with the information they need to 
properly conduct the study, ensure adequate monitoring of the study, conduct the study in 
accordance with the general investigational plan and protocols and promptly inform 
investigators, health and regulatory agencies/authorities as appropriate of significant new adverse 
effects or risks with respect to the drug. 
12.12. 
Financial Disclosure 
A separate financial agreement will be made between each principal investigator and 
Pharmacyclics or its authorized representative before the study drug is delivered. 


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For this study, each investigator and sub-investigator (as designated on the Form FDA1572) will 
provide a personally signed Financial Disclosure Form in accordance with § 21 CFR 54. Each 
investigator will notify Pharmacyclics or its authorized representative of any relevant changes in 
financial disclosure information during the conduct of the study and for 1 year after the study has 
been completed. 
12.13. 
Liability and Clinical Trial Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the 
investigator/designee will be provided. 
The ICF will include a description of treatment in the event of a study related injury and 
handling of the costs associated therewith, incorporating country-specific national regulations 
and/or local laws. Financial compensation for lost wages, disability or discomfort due to the 
study is not available. 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating sites 
at the time of study initiation. 
12.14. 
Protocol Amendments 
Pharmacyclics will initiate any change to the protocol in a protocol amendment document. 
The amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised 
model ICF. Written documentation of IRB/REB/IEC and required site approval must be received 
by Pharmacyclics before the amendment may take effect at each site. Additionally, under this 
circumstance, information on any change in risk and/or change in scope must be provided to 
subjects already actively participating in the study, and they must read, understand and sign each 
revised ICF, confirming willingness to remain in the trial. 
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the investigator and 
Pharmacyclics. 
12.15. 
Publication of Study Results 
Pharmacyclics may use the results of this clinical study in registration documents for Regulatory 
Authorities in the US or abroad. The results may also be used for papers, abstracts, posters, or 
other material presented at scientific meetings or published in professional journals or as part of 
an academic thesis by an investigator. In all cases, to avoid disclosures that could jeopardize 
proprietary rights and to ensure accuracy of the data, Pharmacyclics reserves the right to preview 
all manuscripts and abstracts related to this study, allowing Pharmacyclics sufficient time to 
make appropriate comments before submission for publication. 


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In most cases, the investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results. The medical monitor, study 
director and/or lead statistician may also be included in the list of authors. This custom can be 
adjusted upon mutual agreement of the authors and Pharmacyclics and in accordance with 
current standards for authorship as recorded in professional conference and journal submission 
instructions. 
12.16. 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time. Should this be necessary, both 
the Sponsor and the investigator will arrange discontinuation procedures. In terminating the 
study, the Sponsor and the investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests.  
 


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13. 
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and no survival advantage with filgrastim-mobilized peripheral blood stem cells (PBSC) compared to 
bone marrow (BM) transplants from unrelated donors: results of Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN) Protocol 0201, a Phase III, prospective, randomized trial. ASH Annual 
Meeting Abstracts 2011;118: Abstract 1. 
Appelbaum FR, Haematopoietic cell transplantation as immunotherapy. Nature 2001; 411:385-9. 
Arai S, Jagasia M, Storer B, et al. Global and organ-specific chronic graft-versus-host disease severity 
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Arora M, Wagner JE, Davies SM, et al. Randomized clinical trial of thalidomide, cyclosporine, and 
prednisone versus cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease. 
Biol Blood Marrow Transplant. 2001;7:265-73. 
Baird K, Pavletic SZ. Chronic graft versus host disease. Curr Opin Hematol. 2006;13:426-435.  
Brunton LL, Chabner BA, Knollmann BC (Eds). The Pharmacological Basis of Therapeutics, 12th ed. 
McGraw Hill, New York 2011. p.1216. 
Carpenter PA, Kitko CL, Elad S, et al. National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and 
Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2015;21:1167-87. 
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal 
hypertension. Philadelphia:Saunders. 1964. pp. 50-64.  
Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft-versus-host disease. Br 
J Haematol. 2012;158:46-61. 
Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK 
driving a Th1-selective pressure in T lymphocytes. Blood 2013;122:2539–49. 
Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project 
on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group 
report. Biol Blood Marrow Transplant 2005;11:945-956. 
Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125:606-15. 
Review. 
Flowers ME, Inamoto Y, Carpenter PA, et al. 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. 2011;117:3214-9. 
Flynn R, Du J, Veenstra RG, et al. Increased T follicular helper cells and germinal center B cells are 
required for cGVHD and bronchiolitis obliterans. Blood. 2014;123:3988-98. 
Gilman AL, Schultz KR, Goldman FD, et al. Randomized trial of hydroxychloroquine for newly 
diagnosed chronic graft-versus-host disease in children: a Children's Oncology Group study. Biol Blood 
Marrow Transplant. 2012;18:84-91.  
Hale GA, Shrestha S, Le-Rademacher J, et al. Alternate donor hematopoietic cell transplantation (HCT) 
in non-Hodgkin lymphoma using lower intensity conditioning: A Report from the CIBMTR. 
Biol Blood Marrow Transplant 2012;18:1036-1043. 


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Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic 
target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. 
Blood. 2011;117:6287-96. 
Holler E. Risk assessment in haematopoietic stem cell transplantation: GvHD prevention and treatment. 
Best Pract Res Clin Haematol. 2007;20:281-294.  
International Conference on Harmonization (ICH) Guideline for Industry: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting (ICH-E2A). March 1995. 
International Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: ICH Harmonised Tripartite Guideline: Guidance for Good Clinical 
Practice (ICH-E6)(R1). June 1996.   
Inamoto Y, Savani BN, Shaw BE, et al. Secondary solid cancer screening following hematopoietic cell 
transplantation. Bone Marrow Transplant. 2015.[Epub ahead of print]. 
Investigator's Brochure. Ibrutinib. Version 12.0: 11 December 2018. Pharmacyclics LLC; Janssen 
Research & Development, LLC. 
Jacobsohn DA, Kurland BF, Pidala J, et al. Correlation between NIH composite skin score, 
patient-reported skin score, and outcome: results from the Chronic GVHD Consortium. 
Blood. 2012;120:2545-52. 
Jagasia MH, Greinix HT, Arora M, et al. 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. Biol Blood Marrow Transplant. 2015;21:389-401. 
Johnston HF, Xu Y, Racine JJ, et al. Administration of anti-CD20 mAb is highly effective in preventing 
but ineffective in treating chronic graft-versus-host disease while preserving strong graft-versus-leukemia 
effects. Biol Blood Marrow Transplant. 2014;20:1089-103. 
Koc S, Leisenring W, Flowers ME, et al. Thalidomide for treatment of patients with chronic graft-versus-
host disease. Blood. 2000;96:3995-6. 
Koc S, Leisenring W, Flowers ME, et al. Therapy for chronic graft-versus-host disease: a randomized 
trial comparing cyclosporine plus prednisone versus prednisone alone. Blood 2002;100:48-51. 
Lee SJ, Wolff D, Kitko C, et al. Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. 
National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic 
Graft-versus-Host Disease: IV. The 2014 Response CriteriaWorking Group Report. Biol Blood Marrow 
Transplant. 2015;21:984-999. 
Lee JW, Deeg HJ. Prevention of chronic GVHD. Best Pract Res Clin Haematol. 2008;21:259-270.  
Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 
2003;9:215-233.  
Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term 
survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:348–71. 
Martin PJ, Inamoto Y, Carpenter PA, Lee SJ, Flowers ME. Treatment of chronic graft-versus-host 
disease: Past, present and future. Korean J Hematol. 2011;46(3):153-63.  
Martin PJ, Storer BE, Rowley SD, et al. Evaluation of mycophenolate mofetil for initial treatment of 
chronic graft-versus-host disease. Blood 2009;113:5074-82. 
Miklos DB, Kim H, Zorn E, et al. Antibody Response to DBY minor histocompatibility antigen is 
induced after allogenic stem cell transplantation and in normal female donors. Blood 2004;103:353-359. 


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Miklos DB, Kim HT, Miller KH et al. Antibody responses to H-Y minor histocompatibility antigens 
correlate with chronic graft-versus-host disease and disease remission. Blood 2005;105:2973-2978. 
NCI Common Terminology Criteria for Adverse Events. Version 4.03. 2010. 
Olivieri A, Cimminiello M, Corradini P, et al. Long-term outcome and prospective validation of NIH 
response criteria in 39 patients receiving imatinib for steroid-refractory chronic GVHD. Blood. 
2013;122:4111-8.  
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
ChemMedChem 2007;2:58-61. 
Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR 
Summary Slides, 2015 (http://www.cibmtr.org). 
Pavletic SZ, Martin P, Lee SJ, 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. Response criteria working group report. Biol. Blood Marrow Transplant. 
2006;12:252-66. 
Perez-Simon JA, Kottaridis PD, Martino R, et al. Nonmyeloablative transplantation with or without 
alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. 
Blood. 2002;100:3121-3127. 
Pidala J, Kurland B, Chai X, et al. Patient-reported quality of life is associated with severity of chronic 
graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD 
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varices”. The British Journal of Surgery, 1973;60: 646-9. 
RAYOS (prednisone) delayed-release tablets. Prescribing Information. Horizon Pharma USA Inc. 
Deerfield, IL; 2013. 
Sahaf B, Arai S, Otani J, et al. Rituximab Provides Steroid-Sparing Therapy in New-Onset Chronic 
Graft-Versus-Host Disease. ASBMT 2013;19,S140. Abstract 55. 
Sarantopoulos S, Blazar BR, Cutler C, et al. B cells in chronic graft-versus-host disease. Biol Blood 
Marrow Transplant. 2015;21:16-23.  
Sarantopoulos S, Stevenson KE, Kim HT, et al. Altered B-cell homeostasis and excess BAFF in human 
chronic graft-versus-host disease. Blood. 2009;113:3865-3874.  
Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, von Bergwelt-Baildon MS. The role of B cells in the 
pathogenesis of graft-versus-host disease. Blood. 2009;114:4919-4927. 
Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease: 
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Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 
2006;12:31-47. 
Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among 
patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 
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Sullivan KM, Witherspoon RP, Storb R, et al. Prednisone and azathioprine compared with prednisone and 
placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged 
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Syrjala KL, Martin PJ, Lee SJ. Delivering care to long-term adult survivors of hematopoietic cell 
transplantation. J Clin Oncol. 2012;30:3746-51. 
Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients 
receiving radiation and chemotherapy. N Engl J Med. 1957; 257:491-6. 
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Wolff D, Schleuning M, von Harsdorf S, et al. Consensus Conference on Clinical Practice in Chronic 
GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease. Biol Blood Marrow 
Transplant.2011;17:1-17. 
 
 


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14. 
APPENDICES 








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Footnote: 
a  
The physical examination will include, height (at Screening for adults, and at Screening and annually for subjects <22 years of age at the time of enrollment), 
weight, and examination per clinical practice.  
b  
Confirm eligibility and randomize within 3 days prior to first dose. 
c  
ECG’s may be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of 
dyspnea. At Week 2 12-lead ECG (subject in supine position and resting for at least 10 min prior to ibrutinib dose) performed on subjects <22 years of age at 
enrollment. 
d  
Women of childbearing potential only. Serum pregnancy test required at Screening and urine pregnancy test required at Day 1 prior to first dose. If the test result 
is positive, the pregnancy must be ruled out by ultrasound to be eligible. 
e  
Lee cGVHD Symptom Scale and SF-36 should be completed prior to any assessments, and before being clinically evaluated by the study nurse or physician.  
f  
Pharmacokinetic (PK) samples will be drawn for all subjects according to the schedule in Appendix B predose specimen is required. Pharmacodynamic (PD), 
T/B/NK and Biomarker sampling will be performed on selected days. Refer to Appendix B for more details. 
g  
Hematology and Serum Chemistry may be done within 3 days of Day 1. 
h  
The cGVHD Response assessment, Lee cGVHD Symptom Scale, SF-36, and FEV1 may be done from 7 days prior to Week 25/49 to 21 days after Week 25/49. 
If FEV1 results are abnormal at Screening FEV1 should be obtained every 12 weeks, and if normal at Screening repeat every 24 weeks. Lung score should be 
obtained with every cGVHD assessment. 
i  
Drug diary review and drug accountability only. Must be done at End of Treatment Visit if not already done at Progressive Disease visit. 
j  
Tanner stage and late effects are needed annually up to 60 months post enrollment only for subjects <22yrs of age at enrollment. Adolescents (<22 years of age at 
the time of enrollment) will be followed for up to 5 years after enrollment and may be rolled-over to a long-term extension study during late-effects follow-up. 
k  
cGVHD should be evaluated prior to start of prednisone (if initiated during Screening) or prior to Week1 Day 1 start of prednisone and ibrutinib/placebo. 
l  
cGVHD response assessments and PRO measures at EOT visit need not be repeated if performed within the previous 30 days. 
m  
Subjects in Response follow-up should be evaluated at all pre-specified response assessment time points, including week 5, week 13, week 25, and every 12 
weeks afterward. 
 


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Appendix B. Schedule of Assessments for Pharmacokinetics, Pharmacodynamics, 
Biomarker and T/B/NK 
Day 1,  
Week 
Time 
Pharmacokinetics 
Pharmacodynamics 
Biomarkers 
T/B/NK 
Screening 
 
 
 
X ¼Į 
X 
1 
Predose 
 
X 
X ¼Įȃ 
 
 X 
2 
Predosea 
(trough value) 
X 
 
 
 
1h post doseb (± 
15 min) 
X 
 
 
 
2 h post doseb (± 
15 min) 
X 
 
 
 
4 h post doseb (± 
30 min) 
X 
 
 
 
6 h post doseb (± 
1 h)  
X 
 
 
 
5 
Predose 
 
X 
X ¼Į 
X 
9 
Predose 
 
X 
X ¼Įȃ 
X 
13 
Predose 
 
X 
X ¼Į 
X 
17 
Predose 
 
X 
X ¼Įȃ 
X 
21 
Predose 
 
X 
X ¼Į 
X 
25 
Predosea (trough 
value) 
X 
X 
X ¼Įȃ 
X 
1h post doseb (± 
15 min) 
X 
 
 
 
2 h post doseb (± 
15 min) 
X 
 
4 h post doseb (± 
30 min) 
X 
 
 
 
6 h post doseb (± 
1 h)  
X 
 
 
 
37 
Predose 
 
 
X € 
X 
49 
Predose 
 
X 
X ¼Įȃ 
X 
73 
Predose 
 
X 
X € 
X 
97 
Predose 
 
X 
X ¼Į 
X 
Progressive 
Disease Visit 
 
 
X 
X ¼Į 
X 
Sample Collection Tube Type 
 NaHep 
(2mL) 
ACD  
(8.5 mL) 
€=EDTA 
(10 mL), 
Į=ACD 
(8.5 mL) 
N=NaHep 
(10 mL) 
EDTA 
(10 ml) 
a  
Sample collected 24 hours (± 2 hours) after last intake and prior to dosing on that PK day (applies only on days when PK is collected). 
b  
Record actual time of sample collection (applies only on days when PK is collected). 
The same timepoints as Week 2 and Week 25 PK sample collection will be followed. If ibrutinib/placebo is on hold during scheduled Week 2 
and 25 Week PK evaluation, PK testing should be obtained on the next scheduled visit after ibrutinib dose has been stable for 7 days. 
 


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Appendix C. Karnofsky/Lansky Performance Status 
.DUQRIVN\6FDOHUHFLSLHQWDJH\HDUV 
Lansky Scale (recipient age <16 years)  
Able to carry on normal activity; no special care 
is needed  
Able to carry on normal activity; no special 
care is needed  
100  
Normal, no complaints, no evidence of 
disease 
100  
Fully active 
90  
Able to carry on normal activity 
90  
Minor restriction in physically 
strenuous play 
80  
Normal activity with effort 
80  
Restricted in strenuous play, tires more 
easily, otherwise active 
Unable to work, able to live at home, cares for 
most personal needs, a varying amount of 
assistance is needed  
Mild to moderate restriction 
70  
Cares for self, unable to carry on normal 
activity or to do active work 
70  
Both greater restrictions of, and less 
time spent in active play 
60  
Requires occasional assistance but is able 
to care for most needs 
60  
Ambulatory up to 50% of time, limited 
active play with assistance/supervision 
50  
Requires considerable assistance and 
frequent medical care 
50  
Considerable assistance required for any 
active play, fully able to engage in quiet 
play 
Unable to care for self, requires equivalent of 
institutional or hospital care, disease may be 
progressing rapidly  
Moderate to severe restriction 
40  
Disabled, requires special care and 
assistance 
40  
Able to initiate quiet activities 
30  
Severely disabled, hospitalization 
indicated, although death not imminent 
30  
Needs considerable assistance for quiet 
activity 
20  
Very sick, hospitalization necessary 
20  
Limited to very passive activity initiated 
by others (eg, TV) 
10  
Moribund, fatal process progressing 
rapidly 
10  
Completely disabled, not even passive 
play 
 
 
 


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Appendix D. Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A enzymes are defined as follows. Refer to Section 6.2.1 on instructions 
for concomitant use of CYP3A inhibitors and inducers with ibrutinib. Further information can be found at 
the following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
carbamaze 
indinavir 
nevirapine 
nelfinavir 
barbiturates 
ritonavir 
glucocorticoids 
clarithromycin 
modafinil 
Itraconazole  
oxcarbazepine 
Ketoconazole  
pioglitazone 
nefazodone 
troglitazone 
saquinavir 
pioglitazone 
suboxone 
Strong CYP3A inducers 
telithromycin 
avasimibe 
cobicistat 
carbamazepine 
boceprevir 
phenobarbital 
mibefradil 
phenytoin  
telaprevir 
rifabutine 
troleandomycin 
rifampin 
posaconazole 
St. John’s Wort 
voriconazole 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
isavuconazole 
 
crizotinib 
 
darunavir 
 
dronedarone 
 
erythromycin 
 
diltiazem  
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delavirdine 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
star fruit 
 
a  
 Itraconazole and ketoconazole will be replaced with voriconazole for study subjects 


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Appendix E. Child-Pugh Score for Subjects with Chronic Liver Impairment 
Measure 
1 point 
2 points 
3 points 
7RWDOELOLUXELQȝPRO/PJG/ 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT/INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
 






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Appendix G. SF-36 Questionnaire 


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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
LUNGS 
 No symptoms 
 Mild 
symptoms 
(shortness of 
breath after 
climbing one 
flight of steps) 
 Moderate 
symptoms 
(shortness of 
breath after 
walking on flat 
ground) 
 Severe symptoms 
(shortness of breath 
at rest; requiring 
02) 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_______________________ 
JOINTS AND 
FASCIA 
 No symptoms 
 Mild tightness 
of arms or 
legs, normal or 
mild decreased 
range of 
motion (ROM) 
AND not 
affecting ADL 
 Tightness of arms 
or legs OR joint 
contractures, 
erythema thought 
due to fasciitis, 
moderate decrease 
ROM AND mild 
to moderate 
limitation of ADL 
 Contractures WITH 
significant decrease 
of ROM AND 
significant 
limitation of ADL 
(unable to tie 
shoes, button shirts, 
dress self, etc.) 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_______________________ 
Reference:  
 
Lee SJ, Wolff D, Kitko C, et al. Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of 
Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 
Response CriteriaWorking Group Report. Biol Blood Marrow Transplant. 2015;21:984-999. 


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Appendix I. Response Determination for Chronic GVHD Clinical Trials based on Clinician Assessments 
 


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Overall Response: 
Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall 
response.  
x Complete Response (CR) is defined as resolution of all manifestations in each organ or site  
x Partial Response (PR) is defined as improvement in at least 1 organ or site without progression in any other organ or site. 
x Disease Progression is defined as clinically meaningful worsening in one or more organs regardless of improvement in other 
organs. Mixed Response: CR or PR in at least 1 organ accompanied by progression in another organ is considered disease 
progression. 
x Stable disease (SD): response that does not meet the criteria for CR, PR, or disease progression. 
      If a patient shows overall cGVHD improvement while organ responses indicate progression in one or more organs, cGVHD 
assessment should be repeated at a different time point, to confirm progression, before discontinuing study drug. Response 
assessments coinciding with chronic GVHD flares (transient worsening of organs that were previously involved) will be inevaluable 
and should be repeated as soon as the flare resolves or at the next assessment time point. If progression is confirmed, time to 
progression will be calculated using first date of disease progression. Lack of Response includes categories of disease progression or 
stable disease.  
Lee SJ, Wolff D, Kitko C, et al. Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health Consensus Development 
Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response Criteria Working Group Report. Biol Blood Marrow 
Transplant. 2015;21:984-999.  


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Appendix J. Chronic GVHD Activity Assessment  Patient Self Report 
 
Today’s Date: ________________________  
 
MR#/Name: ________________________ 
 
CHRONIC GVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT 
 
Reference:  
Lee SJ, Wolff D, Kitko C, et al. Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National 
Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host 
Disease: IV. The 2014 Response Criteria Working Group Report. Biol Blood Marrow Transplant. 2015;21:984-999. 
Symptoms 
 
 
 
Not                                                                                                                 As Bad As 
You 
Present                                                                                                            Can 
Imagine 
 
 
  0         1           2           3          4         5          6          7          8          9         
10 
Please rate how severe the 
following symptoms have been in 
the last seven days. Please fill in 
the circle below from 0 (symptom 
has not been present) to 10 (the 
symptom was as bad as you can 
imagine it could be) for each item. 
Your skin itching at its WORST? 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Your skin and/or joint tightening at 
their WORST? 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Your mouth sensitivity at its 
WORST? 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Your genital discomfort at its 
WORST? 
(Women – vagina, vulva, or labia) 
(Men – penis) 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Eyes 
What is your main complaint with regard to your eyes? 
 
 
Please rate how severe this symptom is, from 0 (not 
at all severe) to 10 (most severe): 
0    1     2    3    4    5     6    7    8    9    
10 
 
Patient Global Ratings: 
 
1. Overall, do you think that your chronic graft versus host disease is mild, moderate or severe? 
1= mild 
2=moderate 
3=severe 
 
2. Please circle the number indicating how severe your chronic graft versus host disease symptoms are, where 0 is 
cGvHD symptoms that are not at all severe and 10 is the most severe chronic GvHD symptoms possible. 
 
          0         1           2           3           4           5           6           7           8            9           10 
 
cGvHD symptoms                                                                                                        Most severe cGvHD                                           
not at all severe                                                                                                             symptoms  possible 
 
3. Compared to a month ago, overall would you say that your cGvHD symptoms are: 
 
+3= Very much better 
+2= Moderately better 
+1=A little better 
 0= About the same 
-1=A little worse 
-2=Moderately worse 
-3=Very much worse 
FORM B 


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Appendix K. Prednisone Equivalents Table 
Corticosteroid Doses Equivalent to 20 mg Prednisone 
Corticosteroid 
Equivalent dose  
(mg) 
Prednisone  
20 
Cortisone 
100 
Cortisol 
80 
Hydrocortisone 
80 
Prednisolone 
20 
Methylprednisolone 
16 
Triamcinolone 
16 
Betamethasone 
3 
Dexamethasone 
3 
Source: 
Brunton LL, Chabner BA, Knollmann BC (Eds). The Pharmacological Basis of Therapeutics, 12th ed. McGraw 
Hill, New York 2011. p.1216.  
 
 
 


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Appendix L. Summary of Ancillary Therapy and Supportive Care Interventions 


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Organ System 
Organ-Specific Intervention* 
 
Prevention 
Treatment 
Skin and appendages 
Photoprotection -sun avoidance and 
physical sunblocks (eg, protective 
clothing, UVA, and UVB 
sunscreens). Avoidance of 
photosensitizing agents (eg, 
voriconazole). Surveillance for 
malignancy [Inamoto 2015, 
Majhail 2012]. 
For intact skin topical emollients 
including urea containing products, 
corticosteroids, antipruritic agents, 
and others (eg, PUVA or narrow band 
UVB, calcineurin inhibitors). 
 
For erosions/ulcerations e 
microbiologic cultures, topical 
antimicrobials, protective films or 
other dressings, debridement, 
hyperbaric oxygen, wound care 
specialist consultation. 
Mouth and oral cavity 
Maintain good oral/dental hygiene. 
Routine dental cleaning and 
radiographs. Surveillance for 
infection and malignancy. 
Nutritional counseling, if needed. 
Topical high and ultra-high potency 
corticosteroids and topical calcineurin 
inhibitors. Topical analgesics. 
Therapy for oral dryness (eg, salivary 
stimulants, sialogogues) and for 
prevention of related complications 
(ie, dental decay). 
Eyes 
Photoprotection. Surveillance for 
infection, cataract formation, and 
increased intraocular pressure. 
Artificial tears, ocular ointments, 
topical corticosteroids or 
cyclosporine, punctal occlusion, 
humidified environment, occlusive 
eye wear, moisture chamber 
eyeglasses, cevimeline, pilocarpine, 
gas-permeable scleral contact lens, 
autologous serum, microbiologic 
cultures, topical antimicrobials, 
doxycycline. 
Vulva and vagina 
Surveillance for estrogen deficiency, 
infection (HSV, HPV, yeast, 
bacteria) and malignancy 
[Majhail 2012]. 
Water-based or silicone lubricants, 
topical estrogens, topical 
corticosteroids or calcineurin 
inhibitors, dilators or vibrators, 
surgery for extensive synechiae or 
obliteration, early gynecology 
consultation. Avoid glycerin, paraben, 
fragrance, and other additive products. 
Gastrointestinal tract 
and liver 
Surveillance for infection (viral, 
bacterial, fungal, parasites) 
Rule out other potential etiologies. 
Dietary modification, enzyme 
supplementation for pancreatic 
insufficiency, bile salt resins, 
gastroesophageal reflux management, 
esophageal dilatation, 
ursodeoxycholic acid, topical 
glucocorticoids, limitation of ethanol 
intake, avoidance of hepatotoxins. 


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Organ System 
Organ-Specific Intervention* 
 
Prevention 
Treatment 
Lungs 
Surveillance for infection 
(Pneumocystis jiroveci, viral, 
fungal, bacterial). 
Rule out other potential etiologies (eg, 
infection, gastroesophageal reflux). 
Inhaled corticosteroids, 
bronchodilators, supplementary 
oxygen, pulmonary rehabilitation. 
Consideration of lung transplantation 
in appropriate candidates. 
Hematopoietic 
Surveillance for infection (CMV, 
parvovirus) 
Rule out other potential etiologies (eg, 
drug toxicity, infection). 
Hematopoietic growth factors, 
immunoglobulin for immune 
cytopenias 
Neurologic 
Calcineurin drug level monitoring. 
Seizure prophylaxis as indicated, 
including blood pressure control, 
electrolyte replacement, 
anticonvulsants. EMG monitoring 
and staging in symptomatic patients 
taking medications known to cause 
neuropathy. Close monitoring of 
distal extremities for wounds in 
insensate patients. 
Occupational and physical therapy to 
prevent falls and improve function, 
treatment of neuropathic syndromes 
with tricyclic antidepressants, SSRI, 
or anticonvulsants [Smith 2013]. 
Orthotics and assistive devices (canes 
and walkers). Bracing, splinting or 
surgical release for entrapment 
neuropathies. 
Immunologic and 
infectious diseases 
Immunizations and prophylaxis 
against Pneumocystis jirovecii, 
VZV, and encapsulated bacteria 
based on CDC guidelines. Consider 
immunoglobulin replacement based 
on levels and recurrent infections. 
Surveillance for infection (viral, 
bacterial, fungal, atypical). 
Organism-specific antimicrobial 
agents. Empiric parenteral broad-
spectrum antibacterial coverage for 
fever. 
Musculoskeletal 
Surveillance for decreased ROM, 
bone densitometry, calcium levels 
and 25-OH vitamin D. Physical 
therapy, calcium, vitamin D, and 
bisphosphonates. Flexion-extension 
x-rays to look for instability. 
Physical therapy, bisphosphonates for 
osteopenia, and osteoporosis. Spinal 
orthosis for instability and/or 
intractable pain. Walking program, 
resistance training, core strengthening. 
SSRI indicates selective serotonin reuptake inhibitors; CDC, Centers for Disease Control.  
*In general, close serial monitoring of all organ systems is recommended to promote early detection 
and intervention directed toward reversing or preventing progression of chronic GVHD manifestations 
and treatment-associated toxicities. Ancillary and supportive care therapies are commonly employed in 
addition to systemic GVHD treatment, although in some cases their use may circumvent the need for 
systemic treatment or allow doses of systemic agents to be reduced. 
 
Carpenter PA, Kitko CL, Elad S. National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and 
Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2015;21:1167–87.  


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Inamoto Y, Savani BN, Shaw BE, et al. Secondary solid cancer screening following hematopoietic cell 
transplantation. Bone Marrow Transplant. 2015.[Epub ahead of print]. 
Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term 
survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:348–71.  
Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among 
patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 
2013;309:1359–67. 
 


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Appendix M. Diagnosis of cGVHD  Signs and Symptoms of cGVHD 


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ORGAN OR SITE 
DIAGNOSTIC 
(Sufficient to establish the 
diagnosis of chronic GVHD) 
DISTINCTIVEa  
(Seen in chronic GVHD, but 
insufficient alone to establish a 
diagnosis) 
OTHER FEATURES OR 
UNCLASSIFIED 
ENTITIESb  
COMMONc  
(Seen with both acute and 
chronic GVHD) 
Skin 
x 
Poikiloderma  
x 
Lichen planus-like features  
x 
Sclerotic features  
x 
Morphea-like features 
x 
Lichen sclerosus-like 
features 
x 
Depigmentation 
x 
Papulosquamous lesions 
x 
Sweat impairment 
x 
Ichthyosis 
x 
Keratosis pilaris 
x 
Hypopigmentation 
x 
Hyperpigmentation 
x 
Erythema 
x 
Maculopapular rash 
x 
Pruritus 
Nails 
 
x 
Dystrophy 
x 
Longitudinal ridging, 
splitting or brittle features 
x 
Onycholysis 
x 
Pterygium unguis 
x 
Nail loss (usually 
symmetric, affects most 
nails) 
 
 
Scalp and body hair 
 
x 
New onset of scarring or 
nonscarring scalp alopecia 
(after recovery from 
chemoradiotherapy) 
x 
Loss of body hair 
x 
Scaling 
x 
Thinning scalp hair, 
typically patchy, coarse 
or dull (not explained by 
endocrine or other 
causes) 
x 
Premature gray hair 
 
Mouth  
x 
Lichen planus-like changes 
x 
Xerostomia 
x 
Mucoceles 
x 
Mucosal atrophy 
x 
Ulcers 
x 
Pseudomembranes 
 
x 
Gingivitis 
x 
Mucositis 
x 
Erythema 
x 
Pain 
Eyes 
 
x 
New onset dry, gritty, or 
painful eyes 
x 
Cicatricial conjunctivitis 
x 
Keratoconjunctivitis sicca  
x 
Confluent areas of punctate 
keratopathy 
x 
Photophobia 
x 
Periorbital 
hyperpigmentation 
x 
Blepharitis (erythema of 
the eyelids with edema) 
 


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ORGAN OR SITE 
DIAGNOSTIC 
(Sufficient to establish the 
diagnosis of chronic GVHD) 
DISTINCTIVEa  
(Seen in chronic GVHD, but 
insufficient alone to establish a 
diagnosis) 
OTHER FEATURES OR 
UNCLASSIFIED 
ENTITIESb  
COMMONc  
(Seen with both acute and 
chronic GVHD) 
Genitalia 
x 
Lichen planus-like features 
x 
Lichen sclerosus-like 
features 
x 
Erosions 
x 
Fissures 
 
 
Females 
x 
Vaginal scarring or 
clitoral/labial agglutination 
x 
Ulcers 
 
 
Males 
x 
Phimosis or urethral/meatus 
scarring or stenosis 
 
 
 
GI Tract 
x 
Esophageal web 
x 
Strictures or stenosis in the 
upper to mid third of the 
esophagus 
 
x 
Exocrine pancreatic 
insufficiency 
x 
Anorexia 
x 
Nausea 
x 
Vomiting 
x 
Diarrhea 
x 
Weight loss 
x 
Failure to thrive 
(infants 
x 
and children 
Liver 
 
 
 
x 
Total bilirubin, 
alkaline phosphatase 
>2 x upper limit of 
normal 
x 
ALT >2 x upper limit 
of normal 
Lung 
x 
Bronchiolitis obliterans 
diagnosed with lung biopsy  
x 
Bronchiolitis obliterans 
syndrome (BOS)d 
x 
Air trapping and 
bronchiectasis on chest CT 
x 
Cryptogenic organizing 
pneumonia (COP)e 
x 
Restrictive lung diseasee 
 


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ORGAN OR SITE 
DIAGNOSTIC 
(Sufficient to establish the 
diagnosis of chronic GVHD) 
DISTINCTIVEa  
(Seen in chronic GVHD, but 
insufficient alone to establish a 
diagnosis) 
OTHER FEATURES OR 
UNCLASSIFIED 
ENTITIESb  
COMMONc  
(Seen with both acute and 
chronic GVHD) 
Muscles, fascia, 
joints 
x 
Fasciitis 
x 
Joint stiffness or 
contractures secondary to 
fasciitis or sclerosis 
x 
Myositis or polymyositisf 
x 
Edema 
x 
Muscle cramps 
x 
Arthralgia or arthritis 
 
Hematopoietic and 
Immune 
 
 
x 
Thrombocytopenia 
x 
Eosinophilia 
x 
Lymphopenia 
x 
Hypo- or hyper-
gammaglobulinemia 
x 
Autoantibodies (AIHA, 
ITP) 
x 
Raynaud’s phenomenon 
 
Other 
 
 
x 
Pericardial or pleural 
effusions 
x 
Ascites 
x 
Peripheral neuropathy 
x 
Nephrotic syndrome 
x 
Myasthenia gravis 
x 
Cardiac conduction 
abnormality or 
cardiomyopathy 
 
Abbreviations: ALT indicates alanine aminotransferase; AIHA, autoimmune hemolytic anemia; ITP, idiopathic thrombocytopenic purpura. 
a  
In all cases, infection, drug effect, malignancy, or other causes must be excluded. 
b  
Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed. 
c  
Common refers to shared features by both acute and chronic GVHD. 
d  
BOS can be diagnostic for lung chronic GVHD only if distinctive sign or symptom present in another organ (see text). 
e  
Pulmonary entities under investigation or unclassified. 
f  
Diagnosis of chronic GVHD requires biopsy. 
 
Jagasia HM, Greinix HT, Arora M, et al. Biol Blood Marrow Transplant.2015;21:389–401.


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Appendix N. Staging of cGVHD  
 


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Source: 
Jagasia HM, Greinix HT, Arora M, et al. Biol Blood Marrow Transplant.2015;21:389–401. 


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Appendix O. NIH Global Severity/Staging of cGVHD 
Mild chronic GVHD 
1 or 2 Organs involved with no more than score 1  
plus 
Lung score 0 
 
Moderate chronic GVHD 
3 or More organs involved with no more than score 1 
OR 
At least 1 organ (not lung) with a score of 2 
OR 
Lung score 1 
 
Severe chronic GVHD 
At least 1 organ with a score of 3 
OR 
Lung score of 2 or 3 
 
Key points: 
x 
In skin: higher of the 2 scores to be used for calculating global severity. 
x 
In lung: FEV1 is used instead of clinical score for calculating global severity. 
x 
If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD 
documented cause, that organ is not included for calculation of the global severity. 
x 
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the 
scored organ will be used for calculation of the global severity regardless of the contributing causes 
(no downgrading of organ severity score). 
Reference: 
Jagasia HM, Greinix HT, Arora M, et al. Biol Blood Marrow Transplant.2015;21:389–401. 


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Appendix P. Late Effects Surveillance for Adolescents 
In addition to procedures listed in Appendix A and Appendix B, aGROHVFHQWVWR22 years of 
age at the time of randomization) will be monitored for growth and development, immune 
reconstitution, and late effects up to 5 years post randomization. 
 
Screening 
Week 49±7 days 
At month 24, 36, 
48, 60 ±30 days  
Additional measurements 
 
 
 
Height and Weight 
X 
X 
X 
Tanner Stage 
X 
X 
X 
Immune Reconstitutiona Tests 
 
X 
X 
History of Late Effects (chart review) 
X 
X 
Xb 
a  
Immune reconstitution studies will include the following studies obtained as part of standard of 
care: 
o T and B cell enumeration 
o Quantitative Immunoglobulins 
o Post-vaccination titers 
b  
Are obtained annually. Post vaccination studies may not be performed annually 


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Medical Record Review for Transplant-Related Late Effects 
 
Symptom 
 
 
No 
yes 
Date of 
Diagnosis 
Was therapy 
Given? 
Was therapy still 
given at the time 
this assessment 
Diabetes/hyperglycemia requiring 
chronic treatment 
 
 
 
 
Hyperlipidemia requiring therapy 
 
 
 
 
Hypothyroidism requiring hormone 
replacement 
 
 
 
 
Gonadal dysfunction requiring 
hormone replacement (testosterone or 
estrogen/progesterone)  
 
 
 
 
Growth hormone deficiency/short 
stature 
 
 
 
 
Avascular necrosis 
 
 
 
 
Osteoporosis 
 
 
 
 
Osteoporotic fracture 
 
 
 
 
Depression or anxiety requiring 
therapy 
 
 
 
 
Post-traumatic stress disorder 
requiring therapy 
 
 
 
 
Cataracts 
 
 
 
 
Other impairment or disease 
 
 
 
 
B-cell immune deficiency 
 
 
 
 
vaccines received over the last year  
 
If vaccines administered complete immunization CRF 
Tanner Stage 
Boys – Development of external genitalia 
Stage 1: Prepubertal 
Stage 2: Enlargement of scrotum and testes; scrotum skin reddens and changes in texture 
Stage 3: Enlargement of penis (length at first); further growth of testes 
Stage 4: Increased size of penis with growth in breadth and development of glans; testes and 
scrotum larger, scrotum skin darker 
Stage 5: Adult genitalia 


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Girls – Breast development 
Stage 1: Prepubertal 
Stage 2: Breast bud stage with elevation of breast and papilla; enlargement of areola 
Stage 3: Further enlargement of breast and areola; no separation of their contour 
Stage 4: Areola and papilla form a secondary mound above level of breast 
Stage 5: Mature stage: projection of papilla only, related to recession of areola 
Boys and Girls – Pubic hair 
Stage 1: Prepubertal (can see velus hair similar to abdominal wall) 
Stage 2: Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or 
along labia 
Stage 3: Darker, coarser and more curled hair, spreading sparsely over junction of pubes 
Stage 4: Hair adult in type, but covering smaller area than in adult; no spread to medial surface 
of thighs 
Stage 5: Adult in type and quantity, with horizontal distribution (“feminine”) 


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Appendix Q. Corticosteroid-related toxicities and CTCAE preferred terms 
Corticosteroid symptom 
CTCAE graded AE 
Glucose intolerance related to steroid use 
Glucose intolerance 
Elevated lipids related to steroid use 
Hypertriglyceridemia, Cholesterol high 
Hypertension 
Hypertension 
Steroid myopathy  
Generalized muscle weakness 
Steroid skin toxicity (eg, striae, thinning of skin, 
etc.) 
Skin atrophy 
Neuropsychiatric symptoms including insomnia 
Insomnia, Agitation, Psychosis, or other psychiatric 
symptoms 
Oral/vaginal candidiasis or uncomplicated zoster 
infection 
Mucosal infection (e.g. oral/vaginal candidiasis) 
Any other infection 
Infections  
Diabetic nephropathy-related to steroid use 
Proteinuria 
Posterior reversible encephalopathy 
Encephalopathy, Reversible posterior 
leukoencephalopathy syndrome 
Abnormal bone density (>than - 2 Z score) 
Osteoporosis (Osteopenia with a t-score -1 to -2.5) 
Insufficiency (pathologic) bone fractures 
Fracture 
Adrenal insufficiency  
Adrenal insufficiency 
Gastrointestinal perforation 
Gastric perforation, Esophageal perforation, 
Duodenal perforation, Colonic perforation, Ileal 
perforation 
Peptic ulcer disease 
Duodenal ulcer 
Osteonecrosis of bones (avascular necrosis) 
Periodontal disease, Avascular necrosis 
Tendon rupture 
Musculosceletal and connective disorders, other 
Retinopathy (diabetic or central serous (choroidal) 
retinopathy) 
Retinopathy 
Intraocular pressure elevation 
Glaucoma, papilledema or eye disorder, other 
Posterior subcapsular cataract 
Cataract 
 

SAP_001.pdf: 
 
PCYC-1140-IM 
Statistical Analysis Plan 
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Version 1.0 
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Statistical Analysis Plan 
 
A Randomized, Double-Blind Phase 3 Study of Ibrutinib in Combination With 
Corticosteroids versus Placebo in Combination With Corticosteroids in Subjects with 
New Onset Chronic Graft Versus Host Disease (cGVHD) 
 
Protocol PCYC-1140-IM 
 
 
 
 
Version:  1.0 
Version Date:  28 January 2020 
 
 
 
Confidentiality Statement 
 
 The information in this document is considered privileged and confidential by Pharmacyclics, LLC and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review Board 
approval and informed consent, or as required by Federal and State Laws. Persons to whom this 
information is disclosed must be informed that this information is privileged and confidential and that it 
should not be further disclosed. 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .......................................................................................................5 
1. 
INTRODUCTION ..................................................................................................................6 
1.1. Study Design ..................................................................................................................6 
1.2. Endpoints .......................................................................................................................6 
1.2.1. Primary Endpoint ..............................................................................................7 
1.2.2. Secondary Endpoints ........................................................................................7 
1.2.3. Exploratory Endpoints ......................................................................................7 
1.3. Statistical Hypotheses ....................................................................................................7 
1.4. Sample Size Determination............................................................................................8 
1.5. Planned Analyses ...........................................................................................................8 
1.5.1. Interim Analysis ................................................................................................8 
1.5.2. Primary Analysis ..............................................................................................8 
1.5.3. Final Analysis ...................................................................................................8 
1.6. Testing Procedure and Level of Significance in the primary analysis ...........................9 
1.7. Blinding and Randomization Methods ..........................................................................9 
1.7.1. Blinding Method ...............................................................................................9 
1.7.2. Randomization Method ....................................................................................9 
2. 
GENERAL ANALYSIS CONSIDERATION ....................................................................10 
2.1. Analysis Sets ................................................................................................................10 
2.1.1. Intent-to-Treat Population (ITT) .....................................................................10 
2.1.2. Modified Intent-to-Treat Population (mITT) ..................................................10 
2.1.3. Safety Population ............................................................................................10 
2.1.4. Pediatric Population ........................................................................................10 
2.1.5. Definition of Subgroups .................................................................................10 
3. 
SUBJECT INFORMATION................................................................................................11 
3.1. Subject Disposition ......................................................................................................11 
3.2. Demographics and Baseline Characteristics ................................................................11 
3.3. Prior and Concomitant Medications ............................................................................12 
3.4. Extent of Exposure to Study Treatment .......................................................................12 
4. 
EFFICACY ............................................................................................................................13 
5. 
SAFETY.................................................................................................................................16 
6. 
MODIFICATIONS OF ANALYSIS TO THE PROTOCOL ...........................................17 
7. 
REFERENCES .....................................................................................................................18 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
cGVHD 
chronic graft versus host disease 
CI 
confidence interval 
CIF 
Cumulative incidence function 
CR 
complete response 
CTCAE v. 4.03 
Common Terminology Criteria for Adverse Events version 4.03 
CYP 
cytochrome P450 
DOR 
duration of response 
DMC 
data monitoring committee 
IST 
Immunosuppressant treatment 
ITT 
Intent-to-treat 
mITT 
Modified intent-to-treat 
IWRS 
interactive web response system 
GVHD 
graft versus host disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIH 
National Institutes of Health 
PCYC 
Pharmacyclics, LLC 
OS 
overall survival 
PD 
progressive disease 
PK 
Pharmacokinetics 
PR 
partial response 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SI 
standard international 
TEAE 
treatment emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
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1. INTRODUCTION 
This statistical analysis plan (SAP) is to lay out key elements including definition and statistical 
methods for analysis of data in evaluation of efficacy and safety for the PCYC-1140-IM study.  
The SAP specifications including endpoint definitions, order of testing, and methods to be used 
to analyze the endpoints, supersedes information included in the protocol. 
Analyses of biomarker and pharmacokinetics (PK) data are addressed in separate documents. 
1.1. 
Study Design 
This is a Phase 3, multicenter, international, randomized, double-blind study of oral ibrutinib in 
combination with prednisone versus placebo in combination with prednisone in subjects with 
new onset chronic graft versus host disease (cGVHD). 
Approximately 186 subjects with newly diagnosed moderate or severe cGVHD, as defined by 
the 2014 NIH Consensus Development Project Criteria, were planned to be enrolled. The study 
enrolled 193 subjects who were randomized in a 1:1 ratio to receive either of the study 
treatments ibrutinib in combination with prednisone (Arm A) or placebo in combination with 
prednisone (Arm B).  
The randomization between arms was stratified according to: 
• Age group (12 to <22 years old vs. 22 years old) 
• NIH Global Severity grade (moderate vs. severe) 
• Ongoing use of systemic immunosuppressants that were initiated for either treatment of 
or prophylaxis for acute GVHD (yes vs. no) 
Treatment with the study drug (ibrutinib/placebo) was administered continuously until 
unacceptable toxicity, progression of the underlying disease, death, or the start of a new systemic 
treatment for cGVHD. Corticosteroid therapy was tapered as per a standard taper regimen with 
the goal of reducing exposure to high-moderate dose corticosteroids as quickly as possible 
according to clinical severity of cGVHD. 
Response was assessed according to the NIH Consensus Development Project Criteria (2014). 
 
An independent data monitoring committee (DMC) was established to monitor and review safety 
and other relevant data on an ongoing basis to ensure the safety of the subjects enrolled in this 
study and to review results from an interim futility analysis based on data from the first 50 
subjects enrolled in the study. 
1.2. 
Endpoints 
The primary and secondary endpoints that will be analyzed are listed in this section. Changes 
from what is outlined in the protocol are described in section 6. 
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1.2.1. 
Primary Endpoint 
x Response rate at 48 weeks  
1.2.2. 
Secondary Endpoints 
x 
Time to withdrawal of all corticosteroids for treatment of cGVHD  
x 
Time to withdrawal of all immunosuppressants, including corticosteroids for treatment of 
cGVHD (with the exception of ibrutinib/placebo)  
x 
Response rate at 24 weeks  
x 
Improvement in Lee cGVHD Symptom Scale  
x 
Proportion of subjects who achieve reduction of corticosteroids dose level less than 
0.15 mg/kg/d at 24 weeks sustained for at least 30 days 
x 
Overall survival (OS) 
x 
Duration of response (DOR) 
 
Safety 
x 
Safety and tolerability of ibrutinib in combination with prednisone compared to prednisone in 
combination with placebo. 
x 
Differences in corticosteroids -related morbidities (e.g., hyperglycemia, hypertension) 
1.2.3. 
Exploratory Endpoints 
x Improvement in SF-36 patient reported outcome 
x Improvement in Karnofsky performance scale score 
1.3. 
Statistical Hypotheses  
The primary hypothesis of this study is that the experimental treatment ibrutinib with prednisone 
compared with placebo with prednisone will significantly improve response rate ʌ at 48 Weeks, 
as determined by NIH Consensus Development Project Criteria, in subjects with new onset 
moderate to severe cGVHD. 
 
The statistical hypotheses are as follows:  
H0: The response rate of the experimental treatment group, ʌI(t), and the control group, ʌC(t), are 
equal at time t = 48 Weeks: 
H0:  ʌI(t) = ʌC(t), for t = 48 Weeks 
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versus 
H1: The response rate of experimental treatment group, ʌI(t), is different from that of the control 
group, ʌC(t), at time t =48 Weeks: 
H1: ʌI(t)  ʌC(t), for t = 48 Weeks 
These hypotheses will be tested using the chi-square test. 
1.4. 
Sample Size Determination 
The study was powered to test the primary endpoint of the study. 
The sample size was computed assuming a response rate of 30% at 48 weeks for Arm B (placebo 
+ prednisone). A sample size of 186 randomized subjects provides at least 80% power to detect a 
20% difference in the response rates at 48 weeks between the 2 treatment arms at an alpha level 
of 5% (2-sided). 
No replacement of subjects was implemented. 
The sample size and power calculations were produced using the software package, East (Cytel 
Software Corp, Cambridge, MA). 
1.5. 
Planned Analyses 
1.5.1. 
Interim Analysis 
No interim efficacy analysis was performed by the sponsor. An interim futility analysis was 
performed by the DMC after the first 50 subjects were enrolled and their response at week 24 
was established. 
1.5.2. 
Primary Analysis 
The primary analysis will be performed approximately one year after enrollment of the last 
subject. 
1.5.3. 
Final Analysis 
After the primary analysis the sponsor will continue to follow the subjects for an additional year 
to further quantify response for subjects on the study treatment and to assess OS. In addition, 
withdrawal of all systemic therapies for cGVHD (including ibrutinib/placebo) will be assessed. 
The final analysis will be performed approximately two years after enrollment of the last subject. 
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1.6. 
Testing Procedure and Level of Significance in the primary analysis 
To preserve the study wise type I error rate of 0.05, the primary and secondary endpoints will be 
tested based on a serial gatekeeping testing procedure at the two-sided significance level of 0.05 
according to the hierarchical order specified below: 
1. Response rate at 48 weeks  
2. Time to withdrawal of all corticosteroids for treatment of cGVHD 
3. Time to withdrawal of all ISTs, including corticosteroids for treatment of cGVHD 
(with the exception of ibrutinib/placebo) 
4. Response rate at 24 weeks 
5. Improvement in Lee cGVHD Symptom Scale at 2 consecutive visits 
6. Proportion of subjects who achieve reduction of corticosteroids dose level to less than 
0.15 mg/kg/d at 24 weeks sustained for at least 30 days 
Since the number of deaths at the primary analysis is expected to be low, formal analysis for OS 
will be performed at the final analysis. However, summary of OS will be provided based on 
available data at the time of the primary analysis. Duration of response will be analyzed to 
support the response endpoints. 
1.7. 
Blinding and Randomization Methods 
1.7.1. 
Blinding Method 
This is a double-blind study; the subjects, the investigators, and the Sponsor are blinded to the 
treatment assignment.  
1.7.2. 
Randomization Method 
Central randomization was implemented in this study. Subjects were randomized based on the 
following stratification factors: 
x Age group (12 to <22 years old vs 22 years old) 
x NIH Global Severity grade (moderate vs. severe) 
x Ongoing use of systemic immunosuppressants that were initiated for either treatment of 
or prophylaxis for acute GVHD (yes vs. no) 
Subjects were randomized in a 1:1 ratio to either Treatment Arm A or Treatment Arm B within 
each randomization stratum. This randomization scheme was implemented within the Interactive 
Web Response System (IWRS). 
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2. GENERAL ANALYSIS CONSIDERATION 
2.1. 
Analysis Sets 
2.1.1. 
Intent-to-Treat Population (ITT) 
The intent-to-treat (ITT) population includes all randomized subjects. Subjects in the ITT 
population will be analyzed according to the treatment to which they were randomized. The ITT 
population will be the primary population for the analyses of efficacy endpoints (except for 
duration of response), all baseline characteristics, and patient reported outcome (PRO) endpoints. 
2.1.2. 
Modified Intent-to-Treat Population (mITT) 
The mITT population will include all ITT subjects who do not have evidence of progression of 
underlying malignancy at or before randomization. The mITT population will be used for 
sensitivity analyses of the primary efficacy endpoints. 
2.1.3. 
Safety Population 
Subjects in the ITT population who received at least one dose of either ibrutinib or placebo will 
be included in the safety population. Subjects in the safety population will be analyzed according 
to the actual treatment received and will be used to summarize the safety (including dosing) data. 
2.1.4. 
Pediatric Population 
The pediatric population includes the subset of the ITT population who were <18 years of age at 
the time of randomization. Summary or listing of the primary endpoint and selected secondary 
endpoints will be produced for the pediatric population as appropriate. 
2.1.5. 
Definition of Subgroups 
Subgroup analyses will be performed for the selected variables to assess the internal consistency 
of the treatment benefit and/or safety. The subgroup variables and the cutoff values are subject to 
change if warranted to better represent the data. 
 
 
 
 
 
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Table 1. Subgroup Definition  
Subgroup 
Definition of Subgroup 
Analysis Type 
Age 
<65 years, 65 years 
D, E, S 
Sex 
Male, Female 
D, E, S 
Race 
White, Non-White 
D, E, S 
Geographic region 
US, Non-US 
D, E, S 
NIH Global cGVHD Severity grade 
Moderate, Severe 
D, E, S 
Ongoing use of systemic 
immunosuppressants at enrollment 
that were initiated for either treatment 
of or prophylaxis for GVHD 
Yes, No 
D, E, S 
Hepatic impairment (Based on NCI 
ODWG liver function classification) 
Yes, No 
D, S 
Renal impairment 
Yes, No 
D, S 
analysis type D= demographic and baseline disease characteristics 
analysis type E= efficacy  
analysis type S= safety  
 
3. SUBJECT INFORMATION   
Subject information will be summarized descriptively with no formal testing performed. 
Summaries will be presented by arm (ibrutinib+ prednisone vs placebo + prednisone). 
3.1. 
Subject Disposition 
Subject randomization will be summarized by region, country, site and by stratification factors. 
Subject disposition for each study treatment (for ibrutinib/placebo and for prednisone) and for 
study participation will be tabulated.  
Time on study is defined in the same way as overall survival with reversed censoring, i.e., 
subjects who died will be censored at death date. The Kaplan-Meier methodology will be used to 
estimate the median time on study.  
3.2. 
Demographics and Baseline Characteristics 
Demographic information and baseline characteristics will be summarized using descriptive 
statistics for ITT population by treatment arm. Demographic information includes age, gender, 
race, ethnicity, and geographic region. Baseline disease characteristics include time from initial 
diagnosis of cGVHD, cGVHD staging (moderate, severe), acute GVHD history, ongoing use of 
immunosuppressants, donor HLA matching, Karnofsky performance score, organs involved, 
primary disease (i.e., the disease that was indication for the transplant) and time from transplant 
to cGVHD diagnosis. 
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3.3. 
Prior and Concomitant Medications 
Medications will be coded to preferred term and Anatomical Therapeutic Chemical (ATC) class 
according to World Health Organization (WHO) Drug dictionary where applicable. 
Prior medications are defined as medications that started prior to the first dose date of study drug 
(ibrutinib/placebo). Concomitant medications are defined as medications that were taken at any 
time on treatment (i.e. from the date of the first dose of study drug through the date of the last 
dose of study drug).  
Concomitant medications will be summarized by therapeutic class and preferred term and by 
treatment arm for all subjects in the safety population. Each subject will be counted once for 
each preferred term, and each therapeutic class.   
The following medications will be summarized separately for the safety population:  
x 
Prior acute GVHD treatment 
x 
Prior GVHD prophylactic treatment 
x 
Concomitant medications  
x 
The following concomitant medications of special interest will be summarized separately: 
x 
Systemic immunosuppressants other than prednisone  
x 
Cyp3A Inhibitors (moderate, strong) 
x 
Cyp3A Inducers  
x 
Anticoagulants and antiplatelets 
x 
Subsequent systemic cGVHD treatment 
3.4. 
Extent of Exposure to Study Treatment 
Exposure to study treatment will be summarized for ibrutinib/placebo and for prednisone by 
treatment arm for the safety population.   
Prednisone daily dosing will be summarized over time. Duration of prednisone treatment and 
total dose received will be summarized 
The following parameters will be summarized for the study drug ibrutinib/placebo: 
x 
Treatment duration  
x 
Relative dose intensity  
x 
Number (%) of subjects with dose reduced due to AE      
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4. EFFICACY 
Analysis of efficacy endpoints will be conducted on the ITT population, unless otherwise 
specified. Table 2 summarizes the efficacy endpoints and analysis methods to be performed. For 
subgroup and exploratory analyses, the analyses will be performed where appropriate. 
An unstratified analysis will be performed for the primary endpoint, because only 8 subjects 
aged 12 to <22 years were enrolled, which may result in half of the strata with only a few or 
possibly no subjects randomized to a particular treatment arm. In addition, errors in the 
assignment of stratification factors into the IWRS for both cGVHD severity and ongoing use of 
immunosuppressants occurred at the site level in the study. 
Table 2. Efficacy Endpoints definition and Analyses 
Endpoint 
Definition 
Analysis Method 
Population 
Primary Endpoint 
Response Rate at 48 
Weeks 
 
Proportion of responders [complete response 
(CR) or partial response (PR)] as assessed by 
investigators at 48 weeks using the NIH 
Consensus Panel Chronic GVHD Activity 
Assessment. 
A subject will NOT be considered as a responder 
at 48 weeks if he/she meets any of following 
criteria:  
x 
Starts a second line systemic therapy for 
cGVHD at or prior to the response 
assessment at 48 weeks 
x 
Has evidence of progression of the 
underlying malignancy that was the 
indication for transplant at or prior to 
response assessment at 48 weeks 
x 
Subjects withdrawing from the study or 
from response assessment prior to 48 weeks.  
Unstratified Chi-
square test  
 
Subgroups (from 
Table 1) 
Comparison of the 
treatment arms 
within each 
subgroup using p-
values from 
unstratified Chi 
square test and 
graph of Odds Ratio 
(95% CI) for each 
subgroup.  
ITT 
 
 
For mITT and 
Pediatric 
population, 
summary or 
listing will be 
provided as 
appropriate  
Secondary Endpoints  
Time to withdrawal of 
all corticosteroids for 
treatment of cGVHD 
Time from randomization until the date of 
complete withdrawal (to 0mg) of corticosteroids 
used to treat GVHD and sustained for 30 days. 
Subjects will be considered having a competing 
risk at the time of death, relapse of the 
underlying disease, progression of cGVHD, or 
start of subsequent cGVHD therapy. Subjects 
with no competing event will be censored at last 
available study visit.  
 
The two Cumulative 
Incidence Functions 
(CIFs) of 
corticosteroid 
withdrawal will be 
compared using 
Gray’s Chi square 
test. 
Graphs of the CIFs 
and landmark 
estimates (95%) 
at 6 months and 
12 months 
ITT  
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Endpoint 
Definition 
Analysis Method 
Population 
obtained from 
the CIFs will be 
provided. 
Time to withdrawal of 
all ISTs, including 
corticosteroids for 
treatment of cGVHD 
(with the exception of 
ibrutinib/placebo) 
Time from randomization until the date of 
complete withdrawal (to 0mg) of all 
corticosteroids used to treat GVHD AND 
discontinuation of all ISTs sustained for 30 days. 
Subjects will be considered having a competing 
risk at the time of death, relapse of the 
underlying disease, progressive disease (PD) of 
cGVHD, or start of subsequent cGVHD therapy. 
Subjects with no competing event will be 
censored at last available study visit  
The two CIFs of 
withdrawal of all 
immunosuppressants 
will be compared 
using Gray’s Chi 
square test. Graphs 
of the CIFs and 
landmark estimates 
(95%) at 6 months 
and 12 months 
obtained from the 
CIFs will be 
provided 
 
ITT  
Response rate at 24 
weeks 
Proportion of responders [complete response 
(CR) or partial response (PR)] as assessed by 
investigators at 24 weeks using the NIH 
Consensus Panel Chronic GVHD Activity 
Assessment. 
A subject will NOT be considered as a responder 
at 24 weeks if he/she meets any of following 
criteria:  
x 
Starts a second line systemic therapy for 
cGVHD at or prior to the response 
assessment at 24 weeks 
x 
Has evidence of progression of the 
underlying malignancy that was the 
indication for transplant at or prior to 
response assessment at 24 weeks 
Subjects withdrawing from the study or from 
response assessment prior to 24 weeks.  
Comparison of the 
proportions between 
the two arms will be 
performed using 
Chi-square test 
 
ITT 
Improvement in overall 
score on Lee cGVHD 
Symptom Scale  
Proportion of subjects who had Lee total score 
decreasing at least 7 points at 2 consecutive 
visits with no PD, relapse of underlying disease 
or start of subsequent cGVHD treatment. 
 
 
Proportion of subjects who had Lee total score 
decreasing at least 7 points at any time during the 
study (not preceded by PD, relapse of underlying 
disease or start of subsequent cGVHD treatment)  
 
 
Comparison of the 
proportions between 
the two arms will be 
performed using chi-
square test. 
 
Supportive: 
Summary of the 
proportions of 
subjects with at least 
7 points 
improvement at any 
ITT 
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Endpoint 
Definition 
Analysis Method 
Population 
 
 
 
Mean Lee scores overtime 
 
time will be 
provided. 
 
Summary of mean 
Lee scores overtime 
and graphs by 
treatment arm will 
be provided  
Proportion of subjects 
who achieve reduction 
of corticosteroids dose 
level to less than 
0.15 mg/kg/d at 
24 weeks sustained for 
at least 30 days 
Proportion of subjects with prednisone 
equivalent dose reduction to a level of less than 
0.15 mg/kg/d for a duration of at least 30 days at 
24 weeks 
 
 
 
Mean daily corticosteroid dosing overtime  
Comparison of the 
proportions between 
the two arms will be 
performed using 
Chi-square test 
 
Supportive: 
Mean (95%CI) of 
daily corticosteroid 
dosing over time 
will be summarized 
and plotted by arm 
 
ITT  
Duration of response 
The interval between the date of initial 
documentation of a response (PR or better), and 
the date of first documented evidence of 
progressive cGVHD, relapse of underlying 
disease, start of subsequent cGVHD treatment, 
or death for responders only. 
DOR will be 
estimated by 
Kaplan-Meier 
methodology: 
median DOR and 
landmark estimates 
with 2-sided 95% 
CIs will be provided 
for each treatment 
arm. K-M plots will 
be provided 
Responders 
include 
subjects 
with 
response at 
any time 
during study 
treatment 
Overall Survival  
Time from the date of randomization until the 
date of death due to any cause. All deaths 
observed at the time of the data extraction date 
will be considered as events. For subjects who 
were not known to have died at the time of the 
analysis, OS data will be censored at date last 
known alive. 
Survival will be 
estimated by 
Kaplan-Meier 
methodology: 
median OS and 
landmark estimates 
with 2-sided 95% 
CIs will be provided 
for each treatment 
arm. Kaplan-Meier 
plots will be 
provided 
ITT 
Exploratory Endpoints 
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Endpoint 
Definition 
Analysis Method 
Population 
Improvement in SF-36 
patient reported 
outcome  
SF-36 subscales over time for each treatment 
arm 
Descriptive 
summary statistics 
mean and 95% CI 
for each timepoint 
ITT 
Improvement in 
Karnofsky performance 
scale score 
Karnofsky scores over time for each treatment 
arm 
Descriptive 
summary statistics 
mean and 95% CI 
for each timepoint 
ITT 
 
5. SAFETY 
Safety data will be summarized by arm for the safety population and where appropriate for the 
pediatric subgroup. Table 3 summarizes the planned safety analyses. Adverse events (AEs) will 
be coded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1. Severity of AEs will be graded by the investigator according to the NCI-CTCAE 
v4.03 for hematologic and non-hematological AEs.  
The primary analysis will use the ibrutinib/placebo treatment-emergent period, which will 
include all reported AEs satisfying any of the following criteria: 
x Those events that occurred or worsened after the first dose of ibrutinib/placebo, through the 
treatment phase, and within 30 days following the last dose of ibrutinib/placebo or initiation 
of subsequent cGVHD systemic therapy, whichever occurred first. 
x Events with a missing onset date with a resolution date during the ibrutinib/placebo 
treatment phase; or  
x Events that were considered study drug-related regardless of the start date of the event. 
 
For completeness, an additional analysis will be performed to assess AEs that occurred while the 
patient was being treated with either component of the study treatment (ibrutinib/placebo and/or 
prednisone; hereinafter referred to as study treatment AEs) and which will include all reported 
AEs satisfying any of the following criteria: 
x Those events that occurred or worsened after the first dose of ibrutinib/placebo or 
prednisone, through the treatment phase, and within 30 days following the last dose of 
ibrutinib/placebo or prednisone, or initiation of subsequent cGVHD systemic therapy, 
whichever occurred first. 
x Events with a missing onset date with a resolution date during the ibrutinib/placebo or 
prednisone treatment phase; or  
x Events that were considered related to either ibrutinib/placebo or prednisone regardless of 
the start date of the event. 
 
Summaries of treatment emergent AEs (TEAEs) and study treatment AEs will be provided, 
unless otherwise specified.  
 
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All laboratory values will be converted to and reported as international standard (SI) units. In 
general, only data from the central laboratory will be summarized and analyzed. All gradable 
laboratory parameters will be graded using the NCI CTCAE v4.03. Unless otherwise specified, 
only baseline and post-baseline values collected during the ibrutinib/placebo treatment-emergent 
period will be included in the safety analysis. Additionally, summary of hematologic toxicity 
will be provided. 
  
 
Table 3: Summary of Safety Analyses  
Assessment Type 
Definition 
Methods 
 
 
Study treatment 
(ibrutinib/placebo 
and/or prednisone) 
adverse events 
Study treatment AEs, serious study treatment AEs, Grade 3 or 
higher study treatment AEs, study treatment AEs related to 
prednisone, study treatment AEs leading to prednisone treatment 
discontinuation. 
Study treatment AEs resulted in death 
Predefined corticosteroid-associated AEs will be summarized 
 Descriptive summary statistics and/or 
listings 
 
 
Ibrutinib/placebo 
TEAEs 
TEAEs, TE SAEs, Grade 3 or worse TEAEs,  
Related TEAEs  
TEAEs leading to treatment discontinuation, TEAEs leading to 
dose reduction.  
TEAEs related to corticosteroids, TEAEs leading to 
corticosteroid treatment discontinuation. 
TEAEs resulting in death 
Protocol-defined events of special interest (major hemorrhage) 
and other safety observations 
Predefined corticosteroid-associated AEs will be summarized 
Descriptive summary statistics and/or 
listings 
Central Laboratory 
results collected 
during the 
ibrutinib/placebo 
TEAE period 
Worst post-baseline toxicity grade for selected CTCAE gradable 
hematology and chemistry laboratory measurements. Liver 
function abnormalities. 
Descriptive summary statistics and/or 
listings 
Vital Signs 
collected during the 
ibrutinib/placebo 
TEAE period  
Blood pressure, heart rate 
Descriptive summary statistics and/or 
listings 
AE: adverse event; TEAE= treatment-emergent adverse events as defined in Section 5; SAE= serious adverse event; 
CTCAE= Common Terminology Criteria for Adverse Events. 
6. MODIFICATIONS OF ANALYSIS TO THE PROTOCOL 
x New secondary endpoint added: “Time to withdrawal of all corticosteroids for treatment 
of cGVHD sustained for at least 30 days”.  For all endpoints that involve corticosteroid or 
IST withdrawal, the period of withdrawal had to be sustained for 30 days.  
x Karnofsky scores will be analyzed as an exploratory efficacy endpoint in this SAP rather 
than as a safety endpoint as stated in the study protocol. 
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7. REFERENCES 
Jagasia MH, Greinix HT, Arora M, et al. 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. Biol Blood Marrow Transplant. 2015;21:389-401.  
Lee SJ, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure 
symptoms of chronic graft-versus-host disease. Biology of Blood and Marrow Transplantation 
2002;8:444-452. 
Lee SJ, Wolff D, Kitko C, et al. Measuring Therapeutic Response in Chronic Graft-versus-Host 
Disease. National Institutes of Health Consensus Development Project on Criteria for Clinical 
Trials in Chronic Graft-versus-Host Disease: IV. The 2014 Response Criteria Working Group 
Report. Biol Blood Marrow Transplant. 2015;21:984-999. 
 
Gray, R. (1988), A Class of K-Sample Tests for Comparing the Cumulative Incidence of a 
Competing Risk. The Annals of Statistics, 16, 1141–1154.  
 
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