Clinical trial NCT02195869
Conditions: Graft Versus Host Disease
Keywords: PCYC1129 PCYC1129CA 1129 Ibrutinib PCI32765 IMBRUVICA Pharmacyclics PCYC GVHD Steroid dependent refractory chronic graft versus host disease chronic graft versus host disease immunology
Sponsor: Pharmacyclics LLC.
Start date: 2014-07-14; Completion date: 2017-09-15
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and clinical efficacy of ibrutinib in subjects with steroid dependent or refractory Chronic Graft Versus Host Disease.

Detailed description:

Arms: arm 1: Subjects receive daily dose of 420 mg of Ibrutinib capsules arm 2: Subjects receive daily dose of 280 mg of Ibrutinib capsules arm 3: Subjects receive daily dose of 140 mg of Ibrutinib capsules arm 4: Subjects receive daily dose of recommended phase 2 dose
Interventions: intervention 1: Ibrutinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Ibrutinib (PCI-32765) 
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PROTOCOL 
 
 
TITLE: 
A Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid 
Dependent or Refractory Chronic Graft Versus Host Disease 
PROTOCOL NUMBER: 
PCYC-1129-CA 
STUDY DRUG: 
Ibrutinib (PCI-32765) 
IND NUMBER: 
102,688 
SPONSOR MEDICAL 
MONITOR: 
Lori Styles MD 
Pharmacyclics, LLC 
Phone: +1 (408) 215-3770 
Email: lstyles@pcyc.com 
SPONSOR: 
Pharmacyclics LLC  
995 East Arques Avenue  
Sunnyvale, CA 94085-4521 
United States of America 
 
Pharmacyclics' protocol developed in collaboration with:  
 
David B. Miklos, MD PhD 
Stanford University 
Stanford, CA 94305-5623 
Samantha Jaglowski, MD MPH 
Ohio State University 
Columbus, OH 43210 
DATE FINAL: 
Original: 
Amendment 1: 
Amendment 2: 
 
10 April 2014 
24 June 2015 
21 October 2015 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics LLC that must not be disclosed to 
anyone other than the recipient study staff and members of the institutional review board/ethics 
committee. This information cannot be used for any other purpose other than the evaluation or 
conduct of the clinical study without the prior written consent of Pharmacyclics LLC 
 
 




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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF IN-TEXT TABLES .......................................................................................................7 
LIST OF APPENDICES ...............................................................................................................7 
SYNOPSIS ......................................................................................................................................8 
ABBREVIATIONS ......................................................................................................................15 
1. 
BACKGROUND .........................................................................................................17 
1.1. 
Chronic Graft Versus Host Disease ..............................................................................17 
1.2. 
Pathogenesis of Chronic Graft Versus Host Disease ....................................................18 
1.3. 
B Cells and the Development of cGVHD .....................................................................18 
1.4. 
Other Lymphocytes and the Development of cGVHD .................................................19 
1.5. 
Current Therapies for cGVHD ......................................................................................19 
1.6. 
Ibrutinib Overview ........................................................................................................20 
1.7. 
Summary of Nonclinical Data .......................................................................................21 
1.7.1. 
Pharmacology ................................................................................................................21 
1.7.2. 
Toxicology ....................................................................................................................21 
1.7.2.1. 
Carcinogenesis, Mutagenesis, Impairment of Fertility .................................................22 
1.8. 
Summary of Clinical Data .............................................................................................22 
1.8.1. 
Pharmacokinetics and Product Metabolism ..................................................................22 
1.8.2. 
Summary of Clinical Safety ..........................................................................................23 
1.8.2.1. 
Monotherapy Studies ....................................................................................................23 
1.8.3. 
Risks ..............................................................................................................................24 
1.8.3.1. 
Bleeding Related Events ...............................................................................................24 
1.8.3.2. 
Cytopenia ......................................................................................................................24 
1.8.3.3. 
Atrial Fibrillation ..........................................................................................................24 
1.8.3.4. 
Diarrhea .........................................................................................................................24 
1.8.3.5. 
Infections .......................................................................................................................24 
1.8.3.6. 
Second primary Malignancies .......................................................................................24 
1.8.3.7. 
Rash ...............................................................................................................................25 
1.9. 
Study Rationale .............................................................................................................25 
1.9.1. 
Ibrutinib (Btk Inhibitor) Targets of Interest in cGVHD ................................................25 
1.9.2. 
Ibrutinib in Murine cGVHD Models.............................................................................25 
1.9.3. 
Justification of Study Design and Dose Rationale ........................................................26 
2. 
STUDY OBJECTIVE .................................................................................................26 
2.1. 
Primary Objective .........................................................................................................26 
2.2. 
Secondary Objectives ....................................................................................................27 
2.3. 
Exploratory Objective(s) ...............................................................................................27 
3. 
STUDY DESIGN .........................................................................................................28 
3.1. 
Overview of Study Design ............................................................................................28 
3.2. 
Study Schema ................................................................................................................29 
3.3. 
Phase 1b Safety/DLT Assessment ................................................................................30 
3.3.1. 
Phase 1b DLT Schema ..................................................................................................30 
4. 
SUBJECT SELECTION ............................................................................................30 


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4.1. 
Inclusion Criteria ...........................................................................................................30 
4.2. 
Exclusion Criteria..........................................................................................................32 
5. 
TREATMENT OF SUBJECTS .................................................................................34 
5.1. 
Treatment Allocation and Blinding ...............................................................................34 
5.2. 
Study Treatment ............................................................................................................34 
5.2.1. 
Phase 1b Dose Selection and Stopping Rules ...............................................................34 
5.2.2. 
Definition of Dose Limiting Toxicities .........................................................................35 
5.2.3. 
Phase 2 ..........................................................................................................................35 
5.3. 
Study Medication ..........................................................................................................35 
5.3.1. 
Ibrutinib .........................................................................................................................35 
5.3.1.1. 
Formulation/Packaging/Storage ....................................................................................35 
5.3.1.2. 
Dose and Administration ..............................................................................................36 
5.3.1.3. 
Overdose .......................................................................................................................36 
5.3.1.4. 
Dose Modification for Adverse Reactions ....................................................................36 
5.3.1.5. 
Dose Modification for Hepatic Impaired Subjects........................................................37 
5.3.2. 
Management of Immunosuppression ............................................................................38 
5.3.3. 
Management of Steroids ...............................................................................................38 
5.3.4. 
Prophylaxis for Infections .............................................................................................38 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES .............................................38 
6.1. 
Concomitant Medications .............................................................................................38 
6.1.1. 
Permitted Concomitant Medications .............................................................................38 
6.2. 
Medications to be Used with Caution ...........................................................................39 
6.2.1. 
CYP3A Inhibitors/Inducers ...........................................................................................39 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib ..................39 
6.2.3. 
QT Prolonging Agents ..................................................................................................39 
6.2.4. 
Antiplatelet Agents and Anticoagulants ........................................................................40 
6.3. 
Prohibited Concomitant Medications ............................................................................40 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures ............................40 
6.4.1. 
Minor Surgical Procedures ............................................................................................40 
6.4.2. 
Major Surgical Procedures ............................................................................................40 
6.4.3. 
Emergency Procedures ..................................................................................................41 
7. 
STUDY EVALUATIONS ...........................................................................................41 
7.1. 
Description of Procedures .............................................................................................41 
7.1.1. 
Screening/Administrative ..............................................................................................41 
7.1.2. 
Informed Consent ..........................................................................................................41 
7.1.3. 
Confirm Eligibility ........................................................................................................41 
7.1.4. 
Medical History and Demographics..............................................................................41 
7.1.5. 
Prior and Concomitant Medications .............................................................................42 
7.1.6. 
Adverse Events .............................................................................................................42 
7.1.7. 
Physical Examination ....................................................................................................42 
7.1.8. 
Imaging .........................................................................................................................42 
7.1.9. 
Karnosky Performance Status .......................................................................................42 
7.1.10. 
Vital Signs .....................................................................................................................42 
7.1.11. 
Laboratory .....................................................................................................................43 
7.1.11.1.  Hematology ...................................................................................................................43 
7.1.11.2.  Chemistry (Serum) ........................................................................................................43 


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7.1.11.3.  Coagulation Studies ......................................................................................................43 
7.1.11.4.  Hepatitis Serologies ......................................................................................................43 
7.1.11.5.  Donor/Host Chimerism .................................................................................................43 
7.1.11.6.  Immunosuppressant Level ............................................................................................43 
7.1.11.7.  Pregnancy Test ..............................................................................................................43 
7.1.11.8.  Quantitative Serum Immunoglobulins ..........................................................................44 
7.1.12. 
Diagnostics/Procedures .................................................................................................44 
7.1.12.1.  ECG ...............................................................................................................................44 
7.1.12.2.  Oxygen Saturation/Pulmonary Function Tests (PFTs) .................................................44 
7.1.13. 
Pharmacokinetics/Biomarkers ......................................................................................44 
7.1.13.1.  Pharmacokinetics ..........................................................................................................44 
7.1.13.2.  Biomarkers and Pharmacodynamic (PD) Studies .........................................................45 
7.1.13.3.  T/B/NK Counts .............................................................................................................46 
7.2. 
Efficacy Evaluations .....................................................................................................47 
7.2.1. 
NIH Response Criteria (see Appendix F and Appendix G) ..........................................47 
7.2.2. 
Lee cGVHD Symptom Scale ........................................................................................47 
7.2.3. 
Failure Free Survival .....................................................................................................47 
7.3. 
Sample Collection and Handling ..................................................................................47 
8. 
STUDY PROCEDURES .............................................................................................48 
8.1. 
Screening Phase ............................................................................................................48 
8.1.1. 
Screening Visit ..............................................................................................................48 
8.2. 
Treatment Phase ............................................................................................................49 
8.2.1. 
Progressive Disease Visit ..............................................................................................52 
8.2.2. 
End-of-Treatment Visit .................................................................................................52 
8.3. 
Follow-up Phase ............................................................................................................53 
8.3.1. 
Response Follow-up ......................................................................................................53 
8.3.2. 
Long-Term Follow-up ...................................................................................................53 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ................................................54 
9.1. 
Completion ....................................................................................................................54 
9.2. 
Withdrawal from Study Treatment ...............................................................................54 
9.3. 
Withdrawal from Study .................................................................................................54 
10. 
STATISTICAL METHODS AND ANALYSIS .......................................................55 
10.1. 
Subject Information .......................................................................................................55 
10.2. 
Endpoints ......................................................................................................................55 
10.2.1. 
Primary Endpoints .........................................................................................................55 
10.2.2. 
Secondary Efficacy Endpoints ......................................................................................56 
10.2.2.1.  Rate of Sustained Response for at Least 5 Months .......................................................56 
10.2.2.2.  Duration of Response (DOR) ........................................................................................56 
10.2.2.3.  Corticosteroid Requirement Changes Over Time .........................................................56 
10.2.2.4.  Change in cGVHD Symptom Scale ..............................................................................56 
10.2.3. 
Safety Endpoints ...........................................................................................................56 
10.2.4. 
Exploratory Endpoints ..................................................................................................56 
10.2.4.1.  Photographic Changes in Skin and Mucocutaneous Manifestations. ...........................56 
10.2.4.2.  Pharmacokinetic Analysis .............................................................................................57 
10.2.4.3.  Biomarker and Pharmacodynamic Studies ...................................................................57 
10.2.4.4.  Failure Free Survival .....................................................................................................57 


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10.3. 
Sample Size Determination ...........................................................................................57 
10.4. 
Efficacy Analysis ..........................................................................................................57 
10.5. 
Safety Analysis .............................................................................................................58 
11. 
ADVERSE EVENT REPORTING ............................................................................59 
11.1. 
Definitions .....................................................................................................................59 
11.1.1. 
Adverse Events .............................................................................................................59 
11.1.2. 
Serious Adverse Events.................................................................................................60 
11.1.3. 
Severity Criteria (Grade 1-5) ........................................................................................61 
11.1.4. 
Causality (Attribution) ..................................................................................................61 
11.2. 
Unexpected Adverse Events .........................................................................................61 
11.3. 
Special Reporting Situations .........................................................................................62 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ..................................................................................................................62 
11.4.1. 
Assessment of Adverse Events .....................................................................................62 
11.4.2. 
Adverse Event Reporting Period ...................................................................................63 
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events ................................63 
11.4.4. 
Adverse Events of Special Interest (AESI) ...................................................................64 
11.4.4.1.  Major Hemorrhage ........................................................................................................64 
11.4.5. 
Pregnancy ......................................................................................................................64 
11.4.6. 
Other Malignancies .......................................................................................................65 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ............65 
12.1. 
Regulatory and Ethical Compliance..............................................................................65 
12.2. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval ................................................................................65 
12.3. 
Informed Consent ..........................................................................................................66 
12.4. 
Quality Control and Quality Assurance ........................................................................66 
12.5. 
Protected Subject Health Information Authorization ....................................................66 
12.6. 
Study Files and Record Retention .................................................................................67 
12.7. 
Case Report Forms and Record Maintenance ...............................................................68 
12.8. 
Investigational Study Drug Accountability ...................................................................68 
12.9. 
Study Monitoring/Audit Requirements .........................................................................69 
12.10. 
Investigator Responsibilities .........................................................................................70 
12.11. 
Sponsor Responsibilities ...............................................................................................70 
12.12. 
Financial Disclosure ......................................................................................................70 
12.13. 
Liability and Clinical Trial Insurance ...........................................................................70 
12.14. 
Protocol Amendments ...................................................................................................71 
12.15. 
Publication of Study Results .........................................................................................71 
12.16. 
Study Discontinuation ...................................................................................................72 
13. 
REFERENCES ............................................................................................................73 
14. 
APPENDICES .............................................................................................................78 
 
 
 


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LIST OF IN-TEXT TABLES  
Table 1: 
Ibrutinib Dose Modifications .......................................................................................37 
Table 2: 
Pharmacokinetic Sampling Schedule ..........................................................................45 
Table 3: 
PD (BTK and ITK Occupancy) Sampling Schedule (collection for PCYC) ..............46 
Table 4: 
T/B/NK Sampling Schedule (collection for PCYC)....................................................46 
LIST OF APPENDICES 
Appendix A. 
Schedule of Assessments .....................................................................................79 
Appendix B. 
NIH Defined Diagnostic or Distinctive Features of Chronic GVHD ..................81 
Appendix C. 
Karnofsky Performance Status Scores .................................................................83 
Appendix D. 
Non-Investigational Treatments for cGVHD .......................................................84 
Appendix E. 
Lee cGVHD Symptom Scale ...............................................................................85 
Appendix F. 
Chronic GVHD Activity Assessment – Clinician ................................................87 
Appendix G. 
Chronic GVHD Activity Assessment − Patient Self Report ................................92 
Appendix H. 
Response Criteria for Partial Response and Progression in cGVHD ...................93 
Appendix I. 
Guidelines for Chronic GVHD Activity Assessment – Clinician (FORM A) .....95 
Appendix J. 
Inhibitors and Inducers of CYP3A .......................................................................96 
Appendix K. 
Child-Pugh Score .................................................................................................97 
 


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SYNOPSIS 
Study Title: 
A Multicenter Open-label Phase 1b/2 Study of Ibrutinib in Steroid 
Dependent or Refractory Chronic Graft Versus Host Disease 
Protocol Number: 
PCYC-1129-CA 
Study Phase: 
1b/2 
Study Duration: 
Estimated to be 2-3 years 
Investigational Product 
and Reference Therapy: 
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration. 
Objectives: 
Phase 1b: 
Primary Objective: 
• 
To evaluate the safety and tolerability of ibrutinib in steroid 
dependent/refractory chronic graft versus host disease (cGVHD) 
Secondary Objectives: 
• 
To evaluate the clinical efficacy of ibrutinib in steroid 
dependent/refractory cGVHD by measuring: 
o Best overall cGVHD response (NIH-defined complete response 
[CR] and partial response [PR] ) 
o Rate of sustained response for at least 5 months 
o Duration of response (DOR) 
o Corticosteroid requirement changes over time 
o Change in symptom burden measured by the Lee cGVHD 
Symptom Scale 
Phase 2: 
Primary Objective: 
• 
To evaluate the clinical efficacy of ibrutinib in steroid 
dependent/refractory cGVHD by measuring best overall cGVHD 
response (NIH-defined CR and PR) 
Secondary Objectives: 
• 
Rate of sustained response for at least 5 months 
• 
Duration of response (DOR) 
• 
To evaluate the safety and tolerability of ibrutinib in steroid 
dependent/refractory cGVHD 
• 
To evaluate the impact of ibrutinib on corticosteroid requirement 
changes over time 
• 
To evaluate ibrutinib treatment effect on change in symptom burden 
measured by the Lee cGVHD Symptom Scale 
Exploratory Objectives (Phase 1b and Phase 2): 
• 
To evaluate the clinical efficacy of ibrutinib by measuring failure free 
survival (FFS) at 6 and 12 months 
• 
To evaluate photographic changes in skin and mucocutaneous 
manifestations with ibrutinib treatment 
• 
To determine the pharmacokinetics (PK) of ibrutinib in subjects with 
cGVHD 


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• 
To determine the alloreactive B cell depletion, T-helper cell 
composition, and BTK/ITK blockade including: 
o HY antigen-specific allogeneic B cell depletion in males who 
receive allo-HCT from a female donor. 
o Quantification of HY IgG and IgM alloreactive antibodies in 
males who receive allo-HCT from a female donor. 
o BTK and ITK binding site occupation. 
o 
B cell depletion, flow cytometric analysis of T-helper cell 
composition, T and B cell cytokine analysis, and phosphoflow 
analysis of CD4+ T-cell ITK blockade.  
Study Design: 
This is a Phase 1b/2 open-label study designed to evaluate the safety and 
efficacy of ibrutinib in treating subjects with steroid dependent/refractory 
chronic GVHD. 
Phase 1b will begin with the evaluation of the safety of standard dose 
(420 mg) ibrutinib with the potential for subsequent dose reductions if 
dose limiting toxicities (DLTs) are detected. A modified 3+3+3 design 
will be used to determine a safe dose to carry forward to Phase 2 of the 
study (recommended Phase 2 dose [RP2D], see Section 3.3.1). Between 
6-27 subjects will be evaluated in Phase 1b depending on the frequency of 
DLTs and need for dose reductions. 
Phase 2 will evaluate the efficacy of the RP2D of ibrutinib determined in 
Phase 1b. Subjects will be given ibrutinib continuously along with their 
pre-existing immunosuppressants for cGVHD and followed for signs of 
progression/resolution of cGVHD. Approximately 34 subjects will be 
enrolled in Phase 2 to reach approximately 40 subjects (Phase 1b + Phase 
2 subjects) treated at the RP2D.  
Subjects not experiencing a DLT in the Phase 1b portion of the study are 
permitted to continue undergoing Phase 2 procedures and follow up at 
their Phase 1 dose. 
Population: 
Steroid dependent or refractory chronic graft versus host disease.  
Centers: 
Multiple, US  
Key Inclusion Criteria: 
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria. 
1. Steroid dependent/refractory classic chronic GVHD defined at any 
time post-HCT as: 
a) Dependent disease - Persistent cGVHD manifestations requiring a 
glucocorticoid dose ≥ prednisone 0.25 mg/kg/day (0.5 mg/kg 
orally every other day or equivalent) for at least 12 weeks. 
b) Refractory disease - Progressive cGVHD manifestations despite 
treatment with a glucocorticoid dose ≥ prednisone 0.5 mg/kg/day 
(1 mg/kg orally every other day or equivalent) for at least 4 
weeks. 
2. No more than 3 previous treatments for cGVHD. Treatment with 
glucocorticoids is considered a treatment for cGVHD and should be 
included in determining the number of previous treatments. 
Participants may have received pre-transplant ibrutinib for other 
reasons besides cGVHD such as for the treatment of leukemia or 
lymphoma.  


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3. Participants must be receiving baseline systemic glucocorticoid 
therapy for cGVHD at study entry. The dose of steroids must be 
stable for 28 days prior to starting ibrutinib. 
4. At the time of trial enrollment, participants may be receiving other 
immunosuppressive therapies in addition to glucocorticoids. 
Immunosuppressant doses must be stable for 28 days prior to starting 
ibrutinib. Monoclonal T and B cell antibodies must be discontinued at 
least 56 days before starting ibrutinib. 
5. Chronic GVHD manifestations (Appendix B) that can be followed on 
physical or laboratory exam including at least one of the following 
criteria:  
• 
>25% body surface area (BSA) NIH-defined criteria 
“Erythematous rash”  
• 
>4 total mouth score by NIH-defined criteria  
6. Clinically stable or worsening cGVHD between Screening and Day 1 
cGVHD response assessments (see Section 7.1.3) 
7. ≥18 years of age 
8. Life expectancy ≥6 months 
9. Karnofsky performance status ≥60 (see Appendix C) 
10. Adequate hepatic and renal function as defined as: 
a) Serum creatinine ≤1.5 x ULN 
b) AST, ALT and Alkaline phosphatase ≤3 x ULN or of non-hepatic 
origin, such as hemolysis 
c) Total bilirubin ≤2 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome) 
d) Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault 
formula) 
11. Adequate hematological function defined as: 
a) Absolute neutrophil count ≥1.0 x 109/L and off growth factor 
support for 7 days 
b) Platelets ≥30 x 109/L and no transfusion support for 7 days 
c) Hemoglobin ≥8 g/dL and no transfusion or growth support 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). 
13. ≤6 stools per day 
14. Oxygen saturation after exertion maintained at ≥88% on room air. If 
not, FEV1 ≥50% on pulmonary function tests performed within 
6 months of study entry.  
15. Ability to understand and willingness to sign a written informed 
consent form.  
16. Myeloablative or non-myeloablative allogeneic hematopoietic cell 
transplant for underlying hematological disease. 


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Exclusion Criteria: 
Subjects are excluded if any of the following criteria are met: 
1. Known or suspected active acute GVHD. 
2. Received any investigational agents ≤28 days before starting 
ibrutinib. 
3. Current treatment with sirolimus AND either cyclosporine or 
tacrolimus. 
4. History of treatment with a tyrosine kinase inhibitor (eg, imatinib), 
purine analogs or other cancer chemotherapy in the 4 weeks prior to 
starting ibrutinib. 
5. 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. 
6. Any uncontrolled active systemic infection or infection requiring 
systemic treatment that was completed ≤7 days before the first dose 
of ibrutinib. 
7. Progressive underlying malignant disease including post-transplant 
lymphoproliferative disease.  
8. History of other malignancy (not including the underlying 
malignancy that was the indication for transplant), with the following 
exceptions: 
• 
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; 
• 
Adequately treated nonmelanomatous skin cancer or lentigo 
maligna melanoma without current evidence of disease; 
• 
Adequately treated cervical carcinoma in situ without current 
evidence of disease. 
9. Subject is pregnant, breast-feeding, or of childbearing potential 
without a negative serum or urine pregnancy test within 7 days of 
enrollment. Male or female patients of childbearing potential 
unwilling to use effective contraceptive precautions throughout the 
trial. 
10. Subject not willing to comply with treatment or response evaluation. 
11. Moderate or severe hepatic impairment (Child-Pugh classification). 
12. Subject has a concurrent illness which in the opinion of the 
investigator may interfere with the treatment and evaluation of the 
patient. 
13. Concomitant use of warfarin or other Vitamin K antagonists  
14. Subject has a known allergy or hypersensitivity to ibrutinib. 
15. Vaccinated with live, attenuated vaccines within 4 weeks of first dose 
of ibrutinib. 
16. Known bleeding disorders (eg, von Willebrand’s disease or 
hemophilia). 
17. History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment. 


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18. Known history of human immunodeficiency virus (HIV) or active 
with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects 
who are positive for hepatitis B core antibody, hepatitis B surface 
antigen, or hepatitis C antibody must have a negative polymerase 
chain reaction (PCR) result before enrollment. Those who are PCR 
positive will be excluded. 
19. Major surgery within 4 weeks of first dose of study drug. 
20. Concurrent use of a strong cytochrome P450(CYP) 3A inhibitor 
(Appendix I) 
21. 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. 
Study Treatment: 
Ibrutinib will be dosed daily and will continue as long as the subject is 
deriving clinical benefit and the subject is not experiencing unacceptable 
toxicity.  
Phase 1b: 
Three dose levels of ibrutinib may be tested: 140 mg/day, 280 mg/day and 
420 mg/day. The starting dose will be 420 mg/day and the dose will be 
modified based on the occurrence of dose limiting toxicities (DLTs). 
Phase 1b will follow a modified 3+3+3 design with 6-9 subjects at each 
dose level. The dose will be selected as the RP2D if the subject incidence 
of DLTs during the first 28 days of study treatment is <33%. Before 
determining the RP2D, 6 subjects in any given cohort must have 
completed the DLT observation period which is defined as 28 days of 
therapy. Using the modified 3+3+3 design, the maximum tolerated dose 
(MTD) is exceeded when ≥3 out of 9 subjects in a dose level experience a 
DLT. If there are 3 DLTs at a dose level, the MTD is exceeded and the 
next lower dose level will be enrolled.  
Enrollment in a dose level cohort will proceed as follows: 
• 
If no DLT is observed during the DLT observation period in the 
initial 3 subjects of a dose level, then a second group of 3 subjects 
will be enrolled at the same dose level for a total of 6 subjects. If 
0-1 DLT occur out of 6 subjects, then this dose will be the RP2D. 
If 2 DLTs occur out of 6, then the dose level cohort will be 
expanded to enroll a total of 9 subjects. If no further DLTs occur 
then this dose will be the RP2D. 
• 
If 1 DLT is observed in the initial 3 subjects, the dose level will 
be expanded to enroll 3 additional subjects at the same dose level 
for a total of at least 6 subjects. If no further DLT(s) are observed, 
then this dose will be the RP2D. If 2 DLTs are observed out of 6 
subjects, then the dose level cohort will be expanded to enroll a 
total of 9 subjects. If no further DLTs are observed in this group 
of subjects then this dose will be the RP2D. 
• 
If 2 DLTs are observed in the initial 3 subjects, then enrollment to 
this dose level will be stopped. A DLT review will occur to 
determine if the dose should be lowered. 


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• 
If 3 DLTs are observed, then the dose level will be stopped and 
the next lower dose will be assessed. 
If a subject experiences a DLT during the DLT observation window, the 
subject will discontinue treatment and not be replaced in that dose level. 
The decision to proceed with a RP2D or to dose reduce will be made in a 
Dose Level Review Meeting by the Sponsor in conjunction with 
representative investigators after consideration of all available safety and 
laboratory information. 
A dose limiting toxicity (DLT) is defined as any drug-related hematologic 
or non-hematologic toxicity Grade 3 or higher, with the following 
exceptions: 
• 
Grade 4 nausea, vomiting, or diarrhea or Grade 3 diarrhea defined 
by ≥7 stools/day persisting for 3 days despite best supportive care 
• 
Grade 4 neutropenia or Grade 3 neutropenia persisting for 
14 days or Grade 3 neutropenia of any duration with fever 
• 
For subjects with Grade 2 rash at entry, DLT will be progression 
to Grade 3 AND a doubling of % BSA involvement 
• 
For subjects with Grade 3 rash at entry, DLT will be progression 
to Grade 4 OR a doubling of % BSA involvement 
Phase 2: 
Following the establishment of the RP2D, the Phase 2 portion of the study 
will begin accruing additional subjects. Approximately 40 subjects 
(cumulative from both Phase 1b and Phase 2) will be treated with the 
RP2D.  
Concomitant Therapy: 
Refer to Section 6 for information on concomitant therapy. 
Safety Plan: 
This study will be monitored in accordance with the Sponsor’s 
Pharmacovigilance Committee procedures. Adverse events (AEs) and 
serious adverse events (SAEs) will be reviewed by the Sponsor on an 
ongoing basis to identify safety concerns per the Medical Monitoring 
Plan.  
Statistical Methods and 
Data Analysis: 
Phase 1: 
Designed to determine the RP2D and toxicity profile of ibrutinib using 
the modified 3+3+3 design. Up to 3 dose levels will be explored. In 
observing ≤2 DLTs in 9 subjects, RP2D is determined.  
The Phase 1b efficacy data for subjects with RP2D will be combined with 
Phase 2 efficacy data. 
Phase 2 
Primary Efficacy Analysis: 
Best overall cGVHD response rate is defined as the proportion of subjects 
who achieve a NIH-defined complete response (CR) or partial response 
(PR) during the study over all subjects who got RP2D from either 
Phase 1b portion or Phase 2 portion. The cGVHD response rate along 
with its 95% exact binomial confidence interval will be presented.  
Secondary Efficacy Analyses: 
Secondary efficacy variables including sustained response rate, DOR, 


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corticosteroid requirement changes over time, and change in symptom 
burden as measured by the Lee cGVHD Symptom Scale will be analyzed 
descriptively. 
Efficacy analyses will be performed on all subjects who are enrolled for 
RP2D from either Phase 1b portion or Phase 2 portion.  
Safety Analysis: 
All subjects are to be monitored for adverse events during the study. 
Other safety measurements include clinical laboratory tests and vital 
signs. Descriptive statistics will be use to summarize safety data (adverse 
events [AEs], clinical laboratory tests and vital signs) for all subjects 
receiving ibrutinib. Summary statistics will include means, standard 
deviations, and medians for continuous variables and proportions for 
categorical variables. 
Interim Analysis 
Not applicable. 


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ABBREVIATIONS 
AE 
adverse event 
aGVHD 
acute GVHD 
Allo-HCT 
alogenic hematopoietic cell transplant 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASBMT 
American Society for Blood and Marrow Transplantation 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BAFF 
B cell activating factor 
BCR 
B-cell receptor 
BSA 
body surface area 
Btk 
Bruton’s tyrosine kinase 
CFR 
US Code of Federal Regulations 
cGVHD 
chronic GVHD 
CLL 
chronic lymphocytic leukemia 
CNS 
central nervous system 
CRF 
case report form 
CR 
complete response 
CTCAE v. 4.03 
Common Terminology Criteria for Adverse Events version 4.03 
CYP 
cytochrome P450 
DLT 
dose limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECP 
extracorporeal photopheresis 
eCRF 
Electronic case report form 
EDC 
electronic data capture  
EMR 
electronic medical records 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second  
FFS 
failure free survival 
GCP 
Good Clinical Practice 
GVHD 
graft versus host disease 
GVT 
graft versus tumor 
HCT 
hematopoietic cell transplantation 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitor concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 


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IEC 
Independent Ethics Committee 
IGH 
immunoglobin heavy chain 
IL 
Interleukin 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITK 
IL-2 Inducible T-cell kinase 
IV 
Intravenous 
KPS 
Karnofsky performance status 
MCL 
mantle cell lymphoma  
mHAs 
minor histocompatibility antigens  
MMF 
mycophenolate mofetil 
MTD 
maximum tolerated dose 
NIH 
National Institutes of Health 
NRM 
non-relapse mortality 
PCI-32765 
ibrutinib or Imbruvica® 
PCR 
polymerase chain reaction 
PCYC 
Pharmacyclics LLC 
PFTs 
pulmonary function tests 
PK 
Pharmacokinetic 
PR 
partial response 
aPTT 
activated partial thromboplastin time 
PT 
prothrombin time 
QoL 
Quality of life 
QTc 
Corrected QT interval 
REB 
Research Ethics Board 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SCT 
stem cell transplant  
SD 
stable disease 
SOP 
standard operating procedures 
t1/2 
half life 
TCR 
T cell receptor 
TFKs 
Tec family kinases 
Tmax 
median time to maximum plasma concentration 
ULN 
upper limit of normal 
 
 


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1. 
BACKGROUND 
1.1. 
Chronic Graft Versus Host Disease 
Since its first report in 1957, allogeneic hematopoietic cell transplant (HCT) has been refined 
from a dismal failure to a standard therapy for hematologic malignancies and hematopoietic 
progenitor cell disorders (Thomas 1957). Allogeneic HCT can cure patients with chemotherapy 
resistant malignancies through graft versus tumor 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). 
Chronic GVHD (cGVHD) is a serious and life threatening impediment to the otherwise curative 
potential of allogeneic hematopoetic stem cell transplantation (allo-HCT) (Baird 2006; Lee 2003; 
Pidala 2011; Arai 2011). It is the most common long-term complication following allo-HCT, 
affecting 30-70% of patients who survive past the first 100 days (Lee 2010), and it is a leading 
cause of non-relapse mortality (NRM) (Lee 2008). Chronic GVHD is an important cause of late 
morbidity and mortality after allogeneic HCT (Socie 1999; Lee 2002). Patients with active 
cGVHD are more likely to report adverse general health, mental health, functional impairments, 
and pain than allo-HCT survivors without cGVHD (Fraser 2006). Chronic GVHD is also 
associated with decreased quality of life (QoL) and the continued need for immunosuppressive 
medications (Fraser 2006; Sutherland 1997; Lee 2003; Lee 2006). Chronic GVHD can appear as 
early as 3 months following stem cell transplant (SCT), although its manifestations may take 
much longer to appear, and any organ system can be affected (Mohty 2008). The distinct 
cGVHD findings are collagen-vascular changes involving the skin, mouth, genitalia, 
gastrointestinal tract, lung, muscle fascia, and joints (Filipovich 2005). Pathologically, cGVHD 
is characterized by fibrosis and inflammation of affected organs (Shulman 2006).  
Risk factors for developing cGVHD include older patient age, use of peripheral blood stem cells 
versus bone marrow, and lack of T-cell depletion (Lee 2008). While limited progress related to 
prevention or treatment of cGVHD has been made, the development of the National Institutes of 
Health (NIH) Consensus Criteria for grading and staging cGVHD represents a significant 
advancement, providing a clinically useful severity measure for use in clinical trials 
(Filipovich 2005). Therapy for cGVHD is limited to broad-spectrum immune inhibitors which, in 
addition to lacking efficacy, increase the risk of tumor relapse by inhibiting graft versus tumor 
(GVT) immunity (Holler 2007). The initial treatment is corticosteroids, but half of patients 
require second-line treatment, for which there is no standard of care. NRM increases from 12% 
to 27% for patients requiring a therapy change within 4 months of the start of treatment 
(Flowers 2008b). The median treatment duration is 2-3 years, contributing further to morbidity 
(Syrjala 2012). There is a direct clinical need for new therapies which suppress the autoimmune 
and fibrotic cascades yet preserve GVT and immunity against infection. 
 


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1.2. 
Pathogenesis of Chronic Graft Versus Host Disease 
The immunopathology underlying development of cGVHD is poorly understood. Mouse models 
typically involve three main mechanisms: autoantibody production, pro-fibrotic pathways, and 
defective thymic function (Schroeder 2011). Thymic damage results in dysfunctional negative 
selection of autoreactive T cells. Recipient B cells are activated by minor antigens and Th2 
cytokines, and present processed antigens to donor CD4+ T cells, which co-stimulate B cells to 
produce autoantibodies and additional stimulatory cytokines (Morris 1990; Shimabukuro- 
Vornhagen 2009). T and B cells then clonally expand, forming memory and effector cells which 
traffic to target organ sites, mediating damage through cytokine-mediated fibrosis. Activated T 
and B cells release inflammatory and fibrosing cytokines, such as IL-13, IL-10, and IL-3. In 
addition, activated macrophages produce transforming growth factor-β (TGF-β), stimulating 
collagen production from fibroblasts which leads to a scleroderma-like syndrome (Schroeder 
2011). T cells are 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 
(Hale 2012; Perez-Simon 2002). More recently, alloreactive B cell have been implicated in the 
development of cGVHD (Miklos 2005; Miklos 2004). 
1.3. 
B Cells and the Development of cGVHD 
Alloreactive B cells are associated with cGVHD and, in particular, antibodies against minor 
histocompatibility antigens (mHAs) correlate with cGVHD incidence (Miklos 2005; 
Miklos 2004). HY antibodies develop in male patients who receive their HCT from a female 
donor. HY IgG positive patients have a cGVHD incidence of 89% and 0% relapse at 5-years 
post-transplant while those without HY IgG have a 31% incidence of cGVHD and 48% relapse 
at 5 years (Miklos 2005; Miklos 2004). HY antigens are mHAs found on the Y chromosome 
with homologous proteins on the X chromosome (Ofran 2010) and by looking at the HY 
antigens in sex-mismatched transplants an allo-immune response representing cGVHD was 
studied. The rationale is that lymphocytes from the female donor graft, which lack a Y 
chromosome, recognize the HY mHAs as foreign, thus producing HY specific antibodies. This 
coordinated HY antibody response in the context of cGVHD suggests that specific anti-B cell 
therapy may be effective in treating cGVHD. In support of this hypothesis, rituximab infused 
2-3 months after allo-HCT in male patients with female donors, prevents development of HY 
antigen-specific alloreactive B cells and IgM antibody (Arai 2012).  
B-cell depletion therapy using rituximab in newly diagnosed cGVHD is steroid sparing, but 
cGVHD frequently recurs as alloreactive B cells recur 9−12 months after rituximab treatment. 
The Miklos group reported at the American Society for Blood and Marrow Transplantation 
(ASBMT) 2013 Meeting a Phase 2 study testing the efficacy of rituximab and corticosteroids in 
35 patients with new onset cGVHD (Sahaf 2013). The clinically significant primary endpoint of 


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achieving NIH partial and complete responses and prednisone taper <0.25 mg/kg/day were seen 
in 15/35 patients (43%, 13 complete response [CR]; 2 partial response [PR]) at 6 months and 
remained 15/35 (43%, 11 CR, 4 PR) through 1 year. However, in contrast to prophylactic 
rituximab treatment 2-3 months post allogeneic HCT, the new onset cGVHD study showed that 
allogeneic HY-specific B cells and antibodies were depleted but uniformly recurred 9−12 months 
after rituximab (Sahaf 2013). 
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 of the tumor necrosis family (BAFF), 
and donor-derived alloantibodies (Sarantopoulos 2009). Immunoglobin heavy chain (IGH) 
diversity, as evaluated by high-throughput sequencing, is decreased at 30 and 90 days following 
SCT among patients who subsequently develop GVHD, suggesting impaired B cell clonotype 
diversification (Logan 2013).  
1.4. 
Other Lymphocytes and the Development of cGVHD 
The Ohio State group recently evaluated the influence of lymphocyte reconstitution at days 30 
and 100 following allogeneic SCT on subsequent development of cGVHD through use of an 
extensive immune reconstitution flow cytometric “immunome” assay. Patients who developed 
cGVHD had a larger increase in CD4+ T cells and a smaller increase in CD8+ T cells over time 
compared with patients who did not, suggesting a selective expansion of CD4+ T cells. Further, 
an increase in percentages of activated B cells was noted. An increase in CD4+ cells is associated 
with an inflammatory phenotype, and a Th2-skewed proinflammatory response may contribute to 
B cell activation. The presence of increased CD4+/CD193+ cells among patients with cGVHD 
supports the notion of a Th2-skewed phenotype, as CCR3 is preferentially expressed on Th2 
cells. While a Th2-skewed phenotype has been demonstrated in mouse models of cGVHD, this 
has not been definitively established in humans (Jaglowski, 2012).  
1.5. 
Current Therapies for cGVHD 
Corticosteroids are the primary therapy for cGVHD. An early double-blind, randomized trial 
compared prednisone and placebo with prednisone and azathioprine as early treatment for 
standard risk cGVHD (Sullivan 1988). Non-relapse mortality was significantly lower (21% vs. 
40%, p=0.003) and overall survival significantly higher (61% vs. 47%, p=.03) in the prednisone 
and placebo arm, establishing prednisone as the primary therapy for cGVHD. Corticosteroid 
treatment may require several months before the full benefits are seen. During this time, patients 
may experience the side effects of corticosteroids: more frequent infections, avascular necrosis, 


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adrenal insufficiency, cataracts, altered mental states, and disturbed sleep patterns 
(Sullivan 1988). Koc et al. tested the addition of cyclosporine to prednisone as a steroid-sparing 
agent and observed fewer complications such as avascular necrosis from steroid use (Koc 2002). 
However, the relapse rate was increased resulting in no overall survival benefit compared to the 
prednisone only arm.  
Second line therapy for cGVHD patients who fail corticosteroids is not well established. The 
addition of mycophenolate mofetil (MMF) was compared to standard therapy in a double blind 
randomized trial (Martin 2009). This trial was stopped early because of decreased survival in the 
MMF arm, leading the investigators to recommend against adding MMF to cGVHD therapy. A 
randomized trial comparing the addition of extracorporeal photopheresis (ECP) to standard 
therapy demonstrated a small but significant benefit (improvement in 4/48 vs. 0/47 patients, 
p=0.04) (Flowers 2008a). However, ECP requires a motivated patient to endure 3-4 hours 
vascularly connected to a pheresis pump on a weekly to monthly basis and may not be feasible 
for all patients. Other therapeutic options include thalidomide (Parker 1995; Kulkarni 2003), 
hydroxychloroquine (Gilman 2000), sirolimus (Couriel 2005; Johnston 2005), and rituximab 
(Ratanatharathorn 2003; Cutler 2006; Canninga-van Dijk 2004). These have complete response 
rates ranging from 10-35% and none has been shown to be clearly superior. 
A recently published single institution study developed a new approach for evaluating clinical 
trial endpoints for testing therapies for second-line treatment of cGVHD (Inamoto 2013). The 
primary study endpoint was failure free survival (FFS) defined as the absence of a third line 
therapy, NRM, and recurrent malignancy. This was a retrospective study of 312 patients at the 
Fred Hutchinson Cancer Research Center who had received systemic steroids for the treatment 
of cGVHD at a dose of at least 0.5 mg/kg/day before second line treatment, were on systemic 
immunosuppressive therapy when the second line therapy was initiated, and had received second 
line therapy due to cGVHD progression after at least one week of initial therapy or due to lack of 
improvement after at least two weeks of initial therapy. FFS was reported at 56% at 6 months 
and at 45% at 12 months from the start of second line therapy (Inamoto 2013). With 48 months 
of follow-up, only 15% of patients were able to successfully withdraw from all immuno-
suppressive therapy. The major cause of FFS was treatment change (ie, need for third line 
therapy) and the study results have set a benchmark for second line cGVHD therapy 
(Inamoto 2013).  
1.6. 
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 (collectively referred to as the Sponsor) for the treatment of B-
cell malignancies.   


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Ibrutinib has been approved in many regions including the US and EUfor indications covering 
the treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia 
(CLL) who have received at least one prior therapy, first-line treatment of patients with CLL 
with a deletion of the short arm of chromosome 17 (del17p) or a TP53 mutation, and patients 
with Waldenström’s macroglobulinemia. Ibrutinib is currently under investigation in various 
indications as a single agent and in combinations.  
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release. B-cells express cell surface 
immunoglobulins comprising the B-cell receptor (BCR), which is activated by binding to 
antigen. Antigen binding induces receptor aggregation and the clustering and activation of 
multiple tyrosine kinases, which in turn activate further downstream signaling pathways 
(Bishop 2003).  
For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib Investigator's Brochure. 
1.7. 
Summary of Nonclinical Data 
For the most comprehensive nonclinical and clinical information regarding ibrutinib, please refer 
to the current version of the Investigator's Brochure. 
1.7.1. 
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 B-cell 
receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation 
followed by CD69 expression (Herman 2011).  
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current Investigator’s Brochure. 
1.7.2. 
Toxicology 
In safety pharmacology assessments, no treatment-related effects were observed in the central 
nervous system (CNS) 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.  


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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 vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic. In a rat 
embryo-fetal toxicity study ibrutinib administration was associated with fetal loss and 
malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 
14 times the exposure (AUC) in patients administered the dose of 560 mg daily, respectively.  
1.7.2.1. 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity studies have not been conducted with ibrutinib. 
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a 
chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo 
bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. 
Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology 
studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects 
on reproductive organs. 
1.8. 
Summary of Clinical Data 
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the Investigator's Brochure.  
1.8.1. 
Pharmacokinetics and Product Metabolism 
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day as well 
as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib increased as doses 
increased with substantial intersubject variability. The mean half life (t1/2) of ibrutinib across 
3 clinical studies ranged from 4 to 9 hours, with a median time to maximum plasma 
concentration (Tmax) of 2 hours. Administration of 420 mg ibrutinib with a high-fat breakfast in 
subjects with CLL approximately doubled the mean systemic exposure compared to intake after 
overnight fasting with median time to Tmax delayed from 2 to 4 hours. Ibrutinib was extensively 
metabolized to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of Btk, with 
approximately 15 times lower inhibitory potency compared to ibrutinib. The metabolite-to-parent 
AUC ratio ranged from 0.7 to 3.4. Steady-state exposure of ibrutinib and PCI-45227 was less 
than 2-fold of first dose exposure. 


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The results of human mass balance study of [14C]-ibrutinib conducted in six healthy male 
subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is renally excreted, 
whereas approximately 80% is recovered in feces. Subjects with mild and moderate renal 
insufficiency (creatinine clearance >30 mL/min) were eligible to enroll in Study PCYC-1102-CA 
in which pharmacokinetic (PK) assessments were included. No dose adjustment is needed for 
mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). There is no 
data in patients with severe renal impairment or patients on dialysis. In a hepatic impairment 
study, data showed an increase in ibrutinib exposure. 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. The safety of ibrutinib has not been evaluated in patients 
with hepatic impairment. 
1.8.2. 
Summary of Clinical Safety  
A brief summary of safety data from monotherapy and combination therapy studies is provided 
in below. For more comprehensive safety information please refer to the current version of the 
IB. Additional safety information may be available for approved indications in regional 
prescribing labels where the study is conducted (eg, USPI, SmPC).  
1.8.2.1. 
Monotherapy Studies 
Pooled safety data for a total of 1071 subjects treated with ibrutinib monotherapy from 9 studies 
in B-cell malignancies, which includes subjects from 2 randomized-control studies who crossed 
over from comparator treatment or placebo to receive ibrutinib monotherapy, are summarized 
below.  
Most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1071): 
Most frequently reported 
TEAEs >10%   
Most frequently reported 
Grade 3 or 4 TEAEs >2%  
Most frequently reported 
Serious TEAEs >1%  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Febrile neutropenia 
Cough 
Anemia 
Pyrexia 
Anemia 
Hypertension   
 
Pyrexia 
Atrial fibrillation 
 
Neutropenia  
 
 
 


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1.8.3. 
 Risks 
1.8.3.1. 
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 some major hemorrhagic events, some fatal, including gastrointestinal 
bleeding, 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 6.2.4 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.   
1.8.3.2. 
Cytopenia 
Treatment-emergent grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib.  
1.8.3.3. 
Atrial Fibrillation  
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, acute infections, and a previous history of atrial 
fibrillation. 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). 
1.8.3.4. 
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).  
1.8.3.5. 
Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% of subjects with 
MCL and 35% of subjects with CLL had grade 3 or greater infections per NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.03). The most commonly reported 
infections include pneumonia, cellulitis, urinary tract infection and sepsis. Although causality has 
not been established, cases of progressive multifocal leukoencephalopathy (PML) have occurred 
in patients treated with ibrutinib. 
1.8.3.6. 
Second primary Malignancies 
Second primary malignancies, most frequently skin cancers, have occurred in subjects treated 
with ibrutinib. Second primary malignancies including non-skin carcinomas have occurred in 


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patients treated with ibrutinib. The most frequent second primary malignancy was non-
melanoma skin cancer. 
1.8.3.7. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. In a randomized Phase 3 study (PCYC-1112-CA), rash 
occurred at a higher rate in the ibrutinib arm than in the control arm. Most rashes were mild to 
moderate in severity. 
1.9. 
Study Rationale 
1.9.1. 
Ibrutinib (Btk Inhibitor) Targets of Interest in cGVHD 
Ibrutinib is a first-in-class, potent, orally administered covalently-binding inhibitor of Bruton’s 
tyrosine kinase (Btk) and may be a more potent B cell malignancy drug than rituximab 
(Advani 2012; Byrd 2013). Btk is a critical intermediate in BCR signaling (Mohamed 2009). It is 
a non-receptor tyrosine kinase belonging to the Tec family of kinases (TFKs), and critical for B 
cell processes effected by the BCR (Mohamed 2009). Individuals who lack functioning Btk lack 
circulating B cells and are unable to produce immunoglobulins or mount humoral immune 
responses (Satterthwaite 2000). BCR ligation leads to Btk activation which subsequently 
phosphorylates phospholipase Cγ2 (PLCγ2) triggering a series of downstream events including 
transcriptional regulation involving NF-κB and NFAT (Mohamed 2009). Btk appears to regulate 
B cell survival by triggering the classical pathway in response to BAFF under both BCR and 
BAFF-R signaling (Shinners 2007). 
Ibrutinib is also an irreversible inhibitor of interleukin-2 inducible kinase (ITK). ITK is involved 
in proximal T-cell receptor (TCR) signaling which activates the signaling cascade that includes 
NFAT, NFkB, and MAPK pathways resulting in T cell activation. ITK has a dominant role in the 
activation of Th2 cells, but not in Th1 cells. 
This is an exploratory study and other than anecdotal reports there is no clinical data on the use 
of ibrutinib in cGVHD. 
1.9.2. 
Ibrutinib in Murine cGVHD Models 
Investigators at Ohio State University and University of Minnesota have studied cGVHD in 
mouse models (unpublished data; manuscript submitted). In the LP/J→C57BL/6 model of 
sclerodermatous cGVHD, symptoms become apparent between days 20-25 and peak between 
days 37−47 after HCT. Ibrutinib, vehicle, or cyclosporine treatment was initiated on randomized 
cohorts at day 25, after the majority (72%) of mice had clinical signs of cGVHD. By day 39, 
ibrutinib treated mice displayed a profound lack of signs of cGVHD that were observed in both 
the vehicle and cyclosporine treatment groups including hair loss, hunched posture, and dermal 
lesions. Mice were blindly assessed using a scale which quantitatively grades cGVHD on a scale 


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from 0 to 19. Using this scale, it was documented that mice treated with ibrutinib had 
significantly fewer manifestations of cGVHD compared with vehicle treatment (p=0.0184). In 
addition, ibrutinib significantly extended median time to progression by 14 days; 33% (6 of 18) 
of ibrutinib treated mice did not progress as compared to 12% (2 of 18) of mice receiving vehicle 
and 10% (1 of 11) of mice receiving cyclosporine 10mg/kg/day (p<0.02). 
In addition to the sclerodermatous cGVHD model, these investigators also evaluated ibrutinib in 
a murine model of alloantibody driven multi-organ system cGVHD (MHC disparate, 
C57BL/6→B10.BR). This murine model includes evidence of bronchiolar obliterans (BO). 
Ibrutinib treatment in this model restored pulmonary function defects, reduced germinal center 
reactions, and reversed lung and liver fibrosis. 
1.9.3. 
Justification of Study Design and Dose Rationale 
While rituximab has shown efficacy in a prophylactic role against cGHVD, rituximab used with 
corticosteroids has provided only partial efficacy in steroid-refractory or new onset cGVHD. 
Furthermore, rituximab alone does not deplete alloreactive B cells once cGVHD has developed. 
Ibrutinib has the potential to improve upon the efficacy of rituximab due to its unique 
mechanism of action on B cells in combination with its potential to reverse ITK polarization, 
thus causing a skewing away from a Th2 cytokine profile. 
Btk occupancy >95% has been demonstrated in all patients who received Ibrutinib dosed 
2.5 mg/kg/day or higher. Modest toxicity has been reported at 420 and 840 mg daily. Common 
AEs reported were gastrointestinal upset (diarrhea, nausea, vomiting), fatigue, respiratory 
infections, and rash. Because these AEs may overlap with cGVHD manifestations, a 
conservative dose of 420 mg will be used as the starting does for this trial. This dose is currently 
approved for use in relapsed/refractory CLL with an acceptable safety profile. At 420 mg daily, 
Dubovsky et al. (2013) reported 40-80% ITK occupancy (Dubovsky 2013). If the 420 mg dose 
demonstrates unacceptable toxicity in the cGVHD population then the dose will be lowered to 
280 mg/day which is also expected to produce full BTK occupancy. If further dose reduction is 
required due to toxicity, a dose of 140 mg daily will be used and is the lowest dose 
recommended in the FDA package insert for ibrutinib. 
2. 
STUDY OBJECTIVE  
2.1. 
Primary Objective 
Phase 1b: 
To evaluate the safety and tolerability of ibrutinib in steroid dependent/refractory cGVHD.  


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Phase 2: 
To evaluate the clinical efficacy of ibrutinib in steroid dependent/refractory cGVHD by 
measuring best overall cGVHD response (NIH-defined complete [CR] and partial response 
[PR]). 
2.2. 
Secondary Objectives 
Phase 1b: 
• To evaluate the clinical efficacy of ibrutinib in steroid dependent/refractory cGVHD by 
measuring: 
o Best overall cGVHD response (NIH-defined CR and PR) 
o Rate of sustained response for at least 5 months 
o Duration of response (DOR) 
o Corticosteroid requirement changes over time 
o Change in symptom burden measured by the Lee cGVHD Symptom Scale 
Phase 2: 
• Rate of sustained response for at least 5 months 
• Duration of response (DOR) 
• To evaluate the safety and tolerability of ibrutinib in steroid dependent/refractory 
cGVHD  
• To evaluate the impact of ibrutinib on corticosteroid requirement changes over time 
• To evaluate ibrutinib treatment effect on change in symptom burden measured by the Lee 
cGVHD Symptom Scale 
2.3. 
Exploratory Objective(s)  
Phase 1b and Phase 2: 
• To evaluate the clinical efficacy of ibrutinib by measuring failure free survival (FFS) at 
6 and 12 months 
• To evaluate photographic changes in skin and mucocutaneous manifestations with 
ibrutinib treatment 
• To determine the pharmacokinetics (PK) of ibrutinib in subjects with cGVHD 
• To determine the alloreactive B cell depletion, T-helper cell composition, and BTK/ITK 
blockade including: 
o HY antigen-specific allogeneic B cell depletion in males who receive allo-HCT from 
a female donor. 
o Quantification of HY IgG and IgM alloreactive antibodies in males who receive allo-
HCT from a female donor. 
o BTK and ITK binding site occupation. 
o B cell depletion, flow cytometric analysis of T-helper cell composition, T and B cell 
cytokine analysis, and phosphoflow analysis of CD4+ T-cell ITK blockade. 


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3. 
STUDY DESIGN  
3.1. 
Overview of Study Design 
The primary objective of this Phase 1b/2 study is to evaluate the safety and efficacy of ibrutinib 
in treating subjects with steroid dependent/refractory cGVHD.  
The study will be conducted in two phases. 
Phase 1b will be an open-label, safety study to determine the proper dose to take into the Phase 2 
safety and efficacy study. The study will begin with a standard dose of ibrutinib (420 mg) but 
includes potential dose reduction(s) (to 280 mg and 140 mg) if dose limiting toxicities (DLTs) 
are detected (see Section 5.2.2 below). Depending on the incidence of DLTs, between 
6-27 subjects will be enrolled in the Phase 1b portion of the study. Once the recommended Phase 
2 dose (RP2D) is determined, Phase 2 will commence. 
Phase 2 will be an open-label study using the RP2D determined in Phase 1b. Enrollment will 
continue until a total of approximately 40 subjects (from both Phase 1b and Phase 2) receive the 
RP2D dose. 
Subjects will be treated continuously with ibrutinib and efficacy will be evaluated including: 
• Best overall cGVHD response according to NIH-defined CR and PR 
• Rate of sustained response for at least 5 months 
• Duration of response (DOR) 
• Corticosteroid requirement changes over time 
• Change in symptom burden measured by the Lee cGVHD Symptom Scale 
• Photographic changes in skin and mucocutaneous manifestations 
Both Phase 1b and 2 will include a Screening Phase, Treatment Phase and a Follow-Up Phase. 
The Screening Phase assessments will be performed within 42 days prior to study treatment. 
Eligible subjects will have clinically determined cGVHD and are dependent on or been 
refractory to steroids. Subjects may have had no more than 3 previous therapies for cGVHD and 
must have GVHD involvement in at least one of the following categories: 
• >25% body surface area (BSA) NIH-defined criteria “Erythematous rash” 
• >4 total mouth score by NIH-defined criteria 
Study subjects must have a stable or worsening cGVHD assessment for a minimum of 14 days 
before starting ibrutinib. 
The Treatment Phase will extend from first dose of study treatment until DLT in Phase 1b or 
until disease progression, unacceptable toxicity, recurrence of underlying malignancy, or study 


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closure in Phase 2. During the Treatment Phase, efficacy and safety evaluations will be 
performed according to the Schedule of Assessments in Appendix A. 
The Post-treatment Follow-up Phase will begin once a subject discontinues ibrutinib treatment:  
• Subjects who discontinue for reasons other than disease progression (ie, for adverse event 
or Investigator decision), will complete an End-of-Treatment Visit (30 ± 3 days from the 
last dose of ibrutinib) and will be followed until death, lost to follow-up, consent 
withdrawal, or study end, whichever occurs first: 
o Continued disease evaluations 
o Follow-up for recurrence of malignancy 
o Follow-up for new cGVHD treatments 
• Subjects who discontinue due to disease progression will complete an End-of-Treatment 
Visit and be followed for survival status.  
3.2. 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Phase 
(within 42 days of first study treatment) 
Assess Eligibility Criteria- obtain Sponsor approval to enroll 
Enrollment 
Subjects must start ibrutinib within 72 hours of enrollment
Treatment Discontinuation 
Complete End-of-Treatment Visit 
Follow-up Phase 
[until death, lost to follow up, consent withdrawal, or 
study end, whichever occurs first] 
 
Prior to Disease Progression (if applicable):  
• 
Continue disease evaluations 
• 
Follow for the reoccurrence of malignancy 
• 
subsequent cGVHD therapies 
 
Following Disease Progression:  
• 
Survival  
Treatment Phase 
Ibrutinib at 420, 280, or 140 mg/day 


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3.3. 
Phase 1b Safety/DLT Assessment 
Phase 1b will be conducted with up to 27 subjects enrolled depending on the occurrence of 
DLTs. The starting dose will be 420 mg and a modified 3+3+3 design will be used (see 
Section 5.2.1 and Section 3.3.1) to assess DLTs. If DLTs are unacceptably high then the dose of 
ibrutinib may be reduced sequentially to 280 mg or 140 mg. After completion of Phase 1b, 
further enrollment into Phase 2 will commence after the RP2D is identified and the initial safety 
and efficacy data are evaluated as favorable by the Sponsor. Subjects who have not experienced 
a DLT in Phase 1b (after 4 weeks of ibrutinib treatment) may continue into Phase 2 without 
interruption at their initial Phase 1b dose.  
The decision to proceed with a RP2D or to dose reduce will be made in a Dose Level Review 
Meeting by the Sponsor in conjunction representative investigators after careful consideration of 
all available safety and laboratory information.  
3.3.1. 
Phase 1b DLT Schema 
 
 
4. 
SUBJECT SELECTION 
4.1. 
Inclusion Criteria 
To be enrolled in the study, each potential subject must satisfy all of the following inclusion 
criteria. 
1. Steroid dependent/refractory classic cGVHD defined at any time post-HCT as: 
a) Dependent disease – Persistent cGVHD manifestations requiring a glucocorticoid dose 
≥ prednisone 0.25 mg/kg/day (0.5 mg/kg orally every other day or equivalent) for at least 
12 weeks. 


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b) Refractory disease - Progressive cGVHD manifestations despite treatment with a 
glucocorticoid dose ≥ prednisone 0.5 mg/kg/day (1 mg/kg orally every other day or 
equivalent) for at least 4 weeks. 
2. No more than 3 previous treatments for cGVHD. Treatment with glucocorticoids is 
considered a treatment for cGVHD and should be included in determining the number of 
previous treatments. Participants may have received ibrutinib pre-transplant for other reasons 
besides cGVHD such as for the treatment of leukemia or lymphoma.  
3. Participants must be receiving baseline systemic glucocorticoid therapy for cGVHD at study 
entry. The dose of steroids must be stable for 28 days prior to starting ibrutinib 
4. At the time of trial enrollment, participants may be receiving other immunosuppressive 
therapies in addition to glucocorticoids. Immunosuppressant doses must be stable for 28 days 
prior to starting ibrutinib. Monoclonal T and B cell antibodies must be discontinued at least 
56 days before starting ibrutinib. 
5. Chronic GVHD manifestations (Appendix B) that can be followed on physical or laboratory 
exam including at least one of the following criteria:  
• >25% BSA NIH-defined criteria “Erythematous rash”  
• >4 total mouth score by NIH-defined criteria  
6. Clinically stable or worsening cGVHD between Screening and Day 1 cGVHD response 
assessment (see Section 7.1.3 for details). 
7. ≥18 years of age 
8. Life expectancy ≥6 months 
9. Karnofsky performance status ≥60 (see Appendix C).  
10. Adequate hepatic and renal function as defined as: 
a) Serum creatinine ≤1.5 x ULN 
b) Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline 
phosphatase ≤3 x ULN or of non-hepatic origin, such as hemolysis 
c) Total bilirubin ≤2 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-
hepatic origin) 
d) Estimated Creatinine Clearance ≥30 mL/min (using Cockcroft-Gault formula) 
11. Adequate hematological function defined as: 
a) Absolute neutrophil count (ANC) ≥1.0 x 109/L and off growth factor support x 7 days 
b) Platelets ≥30 x 109/L and no transfusion support x 7 days 
c) Hemoglobin ≥8 g/dL and no transfusion or growth support x 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). 
13. ≤6 stools per day 


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14. Oxygen saturation after exertion maintained at ≥88% on room air. If not, forced expiratory 
volume in 1 second (FEV1) ≥50% on pulmonary function tests performed within 6 months of 
study entry.  
15. Ability to understand and willingness to sign a written informed consent form (ICF).  
16. Myeloablative or non-myeloablative allogeneic hematopoietic cell transplant for underlying 
hematological disease. 
17. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no 
menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR 
history of bilateral oophorectomy). Female subjects of reproductive potential must have a 
negative serum pregnancy test upon study entry. 
18. Male and female subjects of reproductive potential who agree to use highly effective 
methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, 
some intrauterine devices [IUDs],  complete abstinence1, or sterilized partner) during the 
period of therapy and for 90 days after the last dose of ibrutinib. 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
1. Known or suspected active acute GVHD 
2. Received any investigational agents ≤28 days before starting ibrutinib. 
3. Current treatment with sirolimus AND either cyclosporine or tacrolimus. 
4. History of treatment with a tyrosine kinase inhibitor (eg imatinib) purine analogs, or other 
cancer chemotherapy in the 4 weeks prior to starting ibrutinib. 
5. 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. 
6. Any uncontrolled active systemic infection or infection requiring systemic treatment that was 
completed ≤7 days before the first dose of ibrutinib.  
7. Progressive underlying malignant disease including post-transplant lymphoproliferative 
disease.  
8. History of other malignancy (not including the underlying malignancy that was the indication 
for transplant), with the following exceptions: 
                                                   
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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• 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; 
• Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without 
current evidence of disease; 
• Adequately treated cervical carcinoma in situ without current evidence of disease. 
9. Subject is pregnant, breast-feeding, or of childbearing potential without a negative serum or 
urine pregnancy test within 7 days of enrollment. Male or female patients of childbearing 
potential unwilling to use effective contraceptive precautions throughout the trial. 
10. Subject not willing to comply with treatment or response evaluation. 
11. Moderate or severe hepatic impairment (Child-Pugh classification, see Appendix K). 
12. Subject has a concurrent illness which in the opinion of the investigator may interfere with 
the treatment and evaluation of the patient. 
13. Concomitant use of warfarin or other Vitamin K antagonists  
14. Subject has a known allergy or hypersensitivity to ibrutinib. 
15. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of ibrutinib. 
16. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia). 
17. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
18. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus 
(HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, 
hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain 
reaction (PCR) result before enrollment. Those who are PCR positive will be excluded. 
19. Major surgery within 4 weeks of first dose of ibrutinib. 
20. Concurrent use of a strong cytochrome P450 (CYP) 3A inhibitor (Appendix I). 
21. 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. 
22. 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 
This is an open label study and no randomization will occur. 
5.2. 
Study Treatment 
5.2.1. 
Phase 1b Dose Selection and Stopping Rules 
Three dose levels of ibrutinib may be tested: 140 mg/day, 280 mg/day and 420 mg/day. The 
starting dose will be 420 mg/day and the dose will be modified based on the dose limiting 
toxicities (DLTs). 
Phase 1b will follow a modified 3+3+3 design with 6-9 subjects at each dose level. The dose will 
be selected as the RP2D if the subject incidence of DLTs during the first 28 days of study 
treatment is <33%. Before determining the RP2D, 6 subjects in any given cohort must have 
completed the DLT observation period which is defined as 28 days of therapy. Using the 
modified 3+3+3 design, the maximum tolerated dose (MTD) is exceeded when ≥3 out of 
9 subjects in a dose level experience a DLT. If there are 3 DLTs at a dose level, the MTD is 
exceeded and then the next lower dose level will be enrolled.  
Enrollment in a dose level will proceed as follows: 
• If no DLT is observed during the DLT observation period in the initial 3 subjects of a 
dose level, then a second group of 3 subjects will be enrolled at the same dose level for a 
total of 6 subjects. If 0-1 DLT occur out of 6 subjects, then this dose will be the RP2D. If 
2 DLTs occur out of 6, then the dose level cohort will be expanded to enroll a total of 
9 subjects. If no further DLTs occur then this dose will be the RP2D. 
• If 1 DLT is observed in the initial 3 subjects, the dose level will be expanded to enroll 
3 additional subjects at the same dose level for a total of at least 6 subjects. If no further 
DLT(s) are observed, then this dose will be the RP2D. If 2 DLTs are observed out of 
6 subjects, then the dose level will be expanded to enroll a total of 9 subjects. If no 
further DLTs are observed in this group of subjects then this dose will be the RP2D. 
• If 2 DLTs are observed in the initial 3 subjects, then enrollment to this dose level will be 
stopped. A DLT review will occur to determine if the dose should be lowered. 
• If 3 DLTs are observed, then the dose level will be stopped and the next lower dose will 
be assessed. 
If a subject experiences a DLT during the DLT observation window, the subject will discontinue 
treatment. 
The decision to proceed with a RP2D or to dose reduce will be made in a Dose Level Review 
Meeting by the Sponsor in conjunction with the investigators after careful consideration of all 
available safety and laboratory information. 


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5.2.2. 
Definition of Dose Limiting Toxicities 
The following DLT criteria apply only to Phase 1b of the study. After completing the DLT 
period (28 days), Phase 1b subjects will be evaluated by standard safety reporting.  
A DLT is defined as any drug-related hematologic or non-hematologic toxicity Grade 3 or 
higher, with the following exceptions: 
• Grade 4 nausea, vomiting, or diarrhea or Grade 3 diarrhea defined by ≥7 stools/day 
persisting for greater than 3 days despite best supportive care 
• Grade 4 neutropenia or Grade 3 neutropenia persisting for greater than 14 days or Grade 
3 neutropenia of any duration with fever 
• For subjects with Grade 2 rash at entry, DLT will be progression to Grade 3 AND a 
doubling of % BSA involvement 
• For subjects with Grade 3 rash at entry, DLT will be progression to Grade 4 OR a 
doubling of % BSA involvement 
5.2.3. 
Phase 2 
Following the establishment of the RP2D, the Phase 2 portion of the study will begin accruing 
additional subjects. Approximately 40 subjects (cumulative from both Phase 1b and Phase 2) will 
be treated with the RP2D. Subjects enrolled in the Phase 2 part of the study will have met the 
same inclusion/exclusion criteria as Phase 1b subjects and will be treated with the RP2D. 
Subjects continuing from Phase 1b and subjects enrolled in Phase 2 will continue to be treated 
unless they have intervening unacceptable toxicity or meet other criteria for subject 
discontinuation (see Section 9). 
5.3. 
Study Medication 
5.3.1. 
Ibrutinib 
5.3.1.1. 
Formulation/Packaging/Storage  
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib. All 
formulation excipients are compendial and are commonly used in oral formulations. Refer to the 
ibrutinib Investigator's Brochure for a list of excipients.  
The ibrutinib 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 
ibrutinib capsules drug will be dispensed in child-resistant packaging.  
Refer to the Pharmacy Manual for additional guidance on study drug storage, dispensing 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 is administered orally once daily. 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 patients should not attempt to open capsules or dissolve them in water. The use of 
strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be avoided for the 
duration of the study (Appendix J). 
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 subjects 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 except Week 1 Day 2 and 
Week 2. Unused ibrutinib 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 that specified in this protocol is considered to 
be an overdose. Signs and symptoms of an overdose that meet any Serious Adverse Event 
criterion must be reported as a Serious Adverse Event 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 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 
During Phase 1b, ibrutinib will be stopped according to DLT rules in Section 5.2.1 during the 
28 day DLT window. Thereafter, subjects enrolled in Phase 1b will have ibrutinib modified or 
discontinued according to the guidelines in Table 1. 
For Phase 2, the dose of ibrutinib should be modified according to the dose modification 
guidelines in Table 1 if any of the following toxicities occur: 
• Grade 3 ANC (<1,000/µL) with an associated temperature ≥38.5°C 
• Grade 4 ANC (<500/µL) for more than 7 days. Refer to Section 6.1.1 for instruction 
regarding the use of growth factor support 
• Grade 3 thrombocytopenia (<50,000/µL) in the presence of Grade ≥2 bleeding events 
• Grade 4 thrombocytopenia (<25,000/µL) 


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• Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic 
and/or anti-diarrheal therapy  
• Any other Grade 4 or unmanageable Grade 3 toxicity attributed to ibrutinib 
Table 1: 
Ibrutinib Dose Modifications 
Hematologic Adverse Events 
Occurrence Action to be Taken 
First 
Withhold ibrutinib until recovery to an ANC ≥750 or platelets >25,000 with no evidence 
of Grade ≥2 bleeding; may restart at original dose level 
Second 
Withhold ibrutinib until recovery to an ANC ≥750 or platelets >25,000 with no evidence 
of Grade ≥2 bleeding; may restart at 1 dose level lower  
Third 
Withhold ibrutinib until recovery to an ANC ≥750 or platelets >25,000 with no evidence 
of Grade ≥2 bleeding; may restart at 1 dose level lower  
Fourth 
Discontinue ibrutiniba 
Non-Hematologic Adverse Events 
First 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at original dose level
Second 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower 
Third 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower 
Fourth 
Discontinue ibrutiniba 
a. If ibrutinib is discontinued for toxicity, subject will end the Treatment Phase of the study. 
 
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 6.2.4).  
Dose changes must be recorded in the Dose Administration eCRF. At the Investigator’s 
discretion, the dose of ibrutinib may be re-escalated after 8 weeks of a dose reduction in the 
absence of a recurrence of the toxicity that led to the reduction. 
5.3.1.5. 
Dose Modification for Hepatic Impaired Subjects 
Ibrutinib is metabolized in the liver. For subjects who develop mild liver impairment while on 
study (Child-Pugh class A), the recommended dose reduction for ibrutinib/placebo is to a level 
of 280 mg daily (two capsules). For subjects who develop moderate liver impairment (Child-
Pugh class B), the recommended dose reduction is to a level of 140 mg daily (one capsule). 
Subjects who develop severe hepatic impairment (Child-Pugh class C) must hold study drug 
until resolved to moderate impairment (Child-Pugh class B) or better, and could be re-treated 
according to resolved hepatic conditions (ie, 140 mg or 280 mg for moderate or mild 
impairment, respectively). Monitor subjects for signs of toxicity and follow dose modification 
guidance as needed (refer to Appendix K). 


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5.3.2. 
Management of Immunosuppression 
Participants may be receiving other immunosuppressive therapies (including extra-corporeal 
photopheresis [ECP]) in addition to glucocorticoids. In addition, due to potential drug-drug 
interactions with ibrutinib, drug levels for immunosuppressant agents such as cyclosporine, 
tacrolimus, and/or sirolimus are highly recommended during the clinical trial. The doses for 
these immune-suppressants should be adjusted per institutional practices based on the measured 
drug level. Changes in immunosuppressive medications being used for the treatment of cGVHD 
should not be altered during the DLT window unless levels are documented to be at sub-
therapeutic or toxic levels. Concurrent use of sirolimus and a calcineurin inhibitor (tacrolimus or 
cyclosporine) are prohibited. 
5.3.3. 
Management of Steroids 
Systemic steroids may be decreased at the treating physician’s discretion. The initial taper of 
steroids may begin two weeks following initiation of ibrutinib if a clinical response is seen. The 
recommendation is to not taper below 50 percent of the original dose by the 12-week assessment 
period unless there is a documented medical reason for steroid reduction below 50 percent 
(eg, uncontrolled diabetes, infection). A specific steroid taper schedule will not be mandated.  
Because cGVHD by its nature is a protean disease with clinical manifestations that wax and 
wane over time, closely spaced clinical evaluations will detect temporary exacerbations of 
cGVHD manifestations but may not accurately reflect the long term trajectory of a subject’s 
cGVHD and response to treatment. Therefore, in the event a participant experiences a flare of 
cGVHD, a temporary increase in steroids will be allowed until symptoms return to baseline or 
criteria are met for progressive cGVHD. If criteria are met for progressive cGVHD, the 
participant will be scored as a treatment failure and removed from the study. 
Non-absorbable oral steroids will be allowed and recorded. 
5.3.4. 
Prophylaxis for Infections 
Prophylaxis for infections will be managed according to institutional guidelines. 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
Concomitant therapies must be recorded throughout the study beginning 60 days prior to the start of 
the first dose of ibrutinib until 30 days after the last dose of study drug. 
6.1. 
Concomitant Medications  
6.1.1. 
Permitted Concomitant Medications 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted. Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell 


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growth factors (erythropoietin) is permitted per institutional policy and in accordance with the 
ASCO guidelines (Smith 2006). Transfusions may be given in accordance with institutional 
policy.  
6.2. 
Medications to be Used with Caution 
6.2.1. 
CYP3A Inhibitors/Inducers 
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong CYP3A 
(eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, 
itraconazole, and nefazadone) or moderate CYP3A inhibitors and consider alternative agents 
with less CYP3A inhibition. If a strong CYP3A inhibitor must be used, reduce ibrutinib dose to 
140 mg or withhold treatment temporarily for the duration of the inhibitor use. Subjects should 
be monitored for signs of ibrutinib toxicity. If a moderate CYP3A inhibitor must be used, reduce 
ibrutinib to 140 mg for the duration of the inhibitor use. No dose adjustment is required in 
combination with mild inhibitors. Avoid grapefruit and Seville oranges during ibrutinib 
treatment, as these contain moderate inhibitors of CYP3A (see Section 5.3.1.2).  
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort). Consider alternative agents with less CYP3A induction.  
A list of common CYP3A inhibitors or inducers is provided in Appendix J; a comprehensive list 
of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. This website is continually revised and 
should be checked frequently for updates. 
For the most comprehensive effect of CYP3A inhibitors or inducers on ibrutinib exposure, please 
refer to the current version of the IB. 
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 (with an IC50 of 2.15 μg/mL). 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.  
6.2.3. 
QT Prolonging Agents 
Any medications known to cause QT prolongation should be used with caution; periodic ECG 
and electrolyte monitoring should be considered.  


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6.2.4. 
Antiplatelet Agents and Anticoagulants 
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in subjects requiring anticoagulants or medications that inhibit platelet function. Subjects 
with congenital bleeding diathesis have not been studied. Ibrutinib should be held at least 3 to 
7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding (see 
Section 6.4). 
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
(other than warfarin or a vitamin K antagonist) during the course of the study should have 
treatment with ibrutinib held, and ibrutinib should not be restarted until the subject is clinically 
stable. Subjects should be observed closely for signs and symptoms of bleeding. No dose 
reduction is required when study drug is restarted.  
6.3. 
Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy are 
prohibited while the subject is receiving ibrutinib treatment.  
Localized, hormonal, or bone sparing treatment may be considered with prior approval of the 
Medical Monitor.  
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 in the perioperative period for patients who 
require surgical intervention or an invasive procedure while receiving ibrutinib.  
6.4.1. 
Minor Surgical Procedures 
For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis) ibrutinib 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, it is not necessary to hold ibrutinib for these procedures.  
6.4.2. 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be 
held at least 7 days prior to the intervention 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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6.4.3. 
Emergency Procedures 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site is 
reasonably healed, for at least 7 days after the urgent surgical procedure. 
7. 
STUDY EVALUATIONS  
7.1. 
Description of Procedures 
7.1.1. 
Screening/Administrative 
All screening clinical and laboratory assessments must be performed within 42 days of first dose 
of study drug (some exceptions apply). 
7.1.2. 
Informed Consent 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved informed consent form (ICF) 
confirming his or her willingness to participate in this study before any study-specific screening 
procedures are performed. 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.  
7.1.3. 
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 (Section 4). Each subject must have 
an eligibility checklist completed by the site and reviewed/approved by the Sponsor Medical 
Monitor, prior to enrollment. 
Clinical assessment of cGVHD must be clinically stable or worsening for a minimum of 14 days 
between screening and first dose of ibrutinib. If cGVHD assessment shows clinical improvement 
during this period, subject may be re-assessed at least 14 days later. If cGVHD assessment is 
stable or worsening between the last 2 assessments then the subject may receive first dose of 
ibrutinib. Please contact the medical monitor for any questions concerning eligibility. 
7.1.4. 
Medical History and Demographics 
The subject’s complete 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 and list of 
all prior cGVHD therapies, transplant history, dates administered, and responses and duration of 
response to these treatments, also will be recorded.  


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7.1.5. 
Prior and Concomitant Medications 
All medications from 60 days prior to the first dose through 30 days after the last dose of study 
drug will be documented. If a subject discontinues study treatment without evidence of 
progressive disease, receipt of all subsequent anti-cGVHD therapies will be collected until death, 
subject withdrawal of full consent, loss to follow-up, or study termination by Sponsor, whichever 
comes first. 
7.1.6. 
Adverse Events 
The accepted regulatory definition for an adverse event is provided in Section 11.1. 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 with study drug until 
30 days after the last dose of study drug that meet the adverse event definition must be recorded 
as AEs in the eCRF. Laboratory abnormalities designated clinically significant by the 
Investigator will also be documented as adverse events. Additional important requirements for 
adverse event and serious adverse event reporting are explained in Section 11.4. 
7.1.7. 
Physical Examination 
The complete physical examination will be performed at time points specified in the Schedule of 
Assessments (Appendix A) and will include, at a minimum, the general appearance of the 
subject, height (screening only) and weight, and examination of the skin, eyes and fundi, ears, 
nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and 
lymphatic system. Please refer to Efficacy Evaluations (Section 7.2) for the description of NIH 
cGVHD and Lee Symptom Assessments. 
On Weeks 2, 9, 13, 17, 21, and 25 visits, only a limited symptom-directed physical examination 
is required. Review of symptoms should include inquiry of ocular symptoms; subjects should be 
referred to an ophthalmologist for a formal examination if any grade ≥2 symptoms are reported. 
7.1.8. 
Imaging 
Photographic images of the skin and oral cavities will be captured at time points specified in the 
Schedule of Assessments (Appendix A) and sent to an independent central repository.  
7.1.9. 
Karnosky Performance Status 
The Karnosky Performance Status (KPS) index is provided in Appendix C. The performance 
status will be assessed at time points specified in the Schedule of Assessments (Appendix A).  
7.1.10. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and body temperature and will 
be assessed at time points specified in the Schedule of Assessments (Appendix A). 


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Vital signs should be obtained after the subject has been resting in the sitting position for at least 
3 minutes. Height and weight will also be measured at Screening. 
7.1.11. 
Laboratory 
7.1.11.1. Hematology 
Hematology parameters performed at local laboratory will include a complete blood count: white 
blood cells, red blood cells, hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils and bands (if reported).  
7.1.11.2. Chemistry (Serum) 
Serum chemistry parameters performed at local laboratory will include sodium, potassium, 
chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, lactate dehydrogenase (LDH), phosphate, uric acid, 
magnesium and bicarbonate.  
7.1.11.3. Coagulation Studies 
Measurement of prothrombin time (PT)/INR, and activated partial thromboplastin time (aPTT) 
will be performed at local laboratory at Screening.  
7.1.11.4. Hepatitis Serologies 
Hepatitis serologies include hepatitis C antibody, hepatitis B surface antigen, and hepatitis B 
core antibody and will be evaluated. If hepatitis B core antibody, hepatitis B surface antigen or 
hepatitis C antibody is positive, then PCR to quantitate hepatitis B or C DNA must be performed 
and must be negative prior to randomization /enrollment. 
7.1.11.5. Donor/Host Chimerism 
Donor/host chimerism for the evaluation of engraftment status of the stem cell transplantation 
will be evaluated at local laboratory at time points specified in the Schedule of Assessments 
(Appendix A).  
7.1.11.6. Immunosuppressant Level 
Measurement of immunosupressant levels at local laboratory will be obtained if clinically 
indicated.  
7.1.11.7. Pregnancy Test 
Serum pregnancy tests are required at Screening by local laboratory and only for women of 
childbearing potential. A urine pregnancy test will also be performed on Day 1 prior to first dose. 


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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. 
7.1.11.8. Quantitative Serum Immunoglobulins 
Testing for IgA, IgG and IgM levels will be performed at a local laboratory (time points 
specified in the Schedule of Assessments [Appendix A]).  
7.1.12. 
Diagnostics/Procedures 
7.1.12.1. ECG 
ECGs should be performed at the investigator’s discretion, particularly in subjects with 
arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea. 
Subjects should be in supine position and resting for at least 10 minutes before study-related 
ECGs. During visits in which both ECGs and blood draws are performed, ECGs should be 
performed first. 
At Screening, 12-lead ECGs will be done in triplicate (≥1 minute apart); the calculated QTcF 
average of the 3 ECGs must be <470 msec for eligibility.  
Any clinically significant abnormalities noted at Screening should be included in the medical 
history. 
7.1.12.2. Oxygen Saturation/Pulmonary Function Tests (PFTs) 
Subjects should be evaluated for oxygen saturation or have PFTs at Screening, if not performed 
within 6 months of study entry. 
Evaluation of oxygen saturation by pulse oximeter is acceptable after exertion (eg, brisk walk, 
marching in place, climbing stairs). If oxygen saturation is not done at Screening, then a 
Pulmonary Function Test with a FEV1≥50% performed within 6 months of enrollment is 
acceptable. 
7.1.13. 
Pharmacokinetics/Biomarkers  
7.1.13.1. Pharmacokinetics 
Plasma concentrations of ibrutinib and PCI-45227 will be determined using a validated analytical 
method. Other potential metabolites of ibrutinib may be explored. Refer to the Schedule of 
Assessments (Appendix A) and the Pharmacokinetic Sample Schedule (Table 2). 


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Table 2: 
Pharmacokinetic Sampling Schedule 
Week 
Study Day 
of Study 
Week 
Predose 
Time After Dosinga 
1h ± 15 min 
2 h ± 15 min 
4 h ± 30 min 
6 h (± 1 h) 
1 
1 
x 
x 
x 
x 
x 
1 
2 
xb 
 
 
 
 
2 
1 
x 
x 
x 
x 
x 
a. 
Record actual time of sample collection. 
b. Sample collected 24 hours (± 2 hours) after Day 1 dose and prior to dosing on Day 2. 
 
Pharmacokinetics Sample Collection for Subjects Treated with a Concomitant CYP3A 
Inhibitor While on Ibrutinib Treatment 
For subjects who have a dose reduction due to toxicity or who start a moderate or strong CYP3A 
inhibitor while on treatment with ibrutinib, additional PK blood samples for evaluation of 
ibrutinib exposure is requested at the following scheduled visit after concomitant CYP3A 
inhibitor has started and is still in use. PK samples will be collected at:  
• Pre-dose (If possible, sample should be obtained 22-24 hours post the previous day’s 
dose and before dosing on the day of the scheduled visit)  
• 1 hour ± 15 min 
• 2 hours ± 15 min 
• 4 hours ± 30 min 
• 6 hours ± 1 h 
Refer to the Laboratory Manual for instructions on collecting and processing these samples. On 
the day of the sampling visit, the clinical staff will instruct the subject not to take a dose before 
arrival at the clinic. Study drug intake will be observed by clinic staff. The actual time (versus 
requested time) that each sample is drawn must be recorded using a 24 hour format. The same 
clock should be used for recording the time of dosing. 
7.1.13.2. Biomarkers and Pharmacodynamic (PD) Studies 
Samples collected may be used for pharmacodynamic and biomarker assessments including BTK 
and other kinase activity and signaling, expression analysis, sequencing, flow cytometry and 
secreted protein analyses. Fluids including blood collected during the course of the study may be 
used for, but not limited to, pharmacodynamics and biomarker assessments as noted above. 
Studies will be conducted at specialty laboratories to determine alloreactive B cell depletion, 
T-helper cell composition, and BTK and ITK occupancy. Specifically, the following studies will 
be conducted: 


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a) Biomarker Studya: HY antigen-specific allogeneic B cell depletion in males who 
receive HCT from a female donor. 
b) Biomarker Studya: Quantification of HY IgG and IgM alloreactive antibodies males 
who receive HCT from a female donor . 
c) Pharmacodynamics Study: BTK and ITK binding site occupation (Pharmacyclics, LLC 
[PCYC]) (Table 3). 
d) Other Studiesa: B cell depletion, flow cytometric analysis of T-helper cell composition, 
T and B cell cytokine analysis, and phosphoflow analysis of CD4+ T-cell ITK blockade. 
a. Performed at designated central laboratory, refer to Laboratory Manual. 
Table 3: 
PD (BTK and ITK Occupancy) Sampling Schedule (collection for PCYC) 
Week 
Study Day  
of Study Week 
Predosea 
Time After Dosinga 
4 h ± 30 min 
1 
1 
x 
x 
1 
2 
xb 
 
2 
1 
xb 
x 
9 
1 
xb 
x 
13 
1 
xb 
x 
a. Record actual time of sample collection. 
b. Sample collected 24 hours (± 2 hours) after Day 1 dose and prior to dosing on the study day. 
 
After samples are collected, samples will be processed onsite before shipping to PCYC for final 
storage/analysis. Please refer to Laboratory Manual for instructions. 
7.1.13.3. T/B/NK Counts 
The blood sample(s) for T/B/NK cell count (CD3+, CD4+, CD8+, CD19+, CD16/56+) must be 
collected at the time points specified in the Schedule of Assessments (Appendix A) and the 
T/B/NK Sampling Schedule (Table 4). 
Table 4: 
T/B/NK Sampling Schedule (collection for PCYC)  
Week 
Study Day 
of Study Week 
Predosea 
Time After Dosinga 
4 h ± 30 min 
Screening 
 
X 
 
1 
1 
X 
x 
1 
2 
xb 
 
2 
1 
xb 
x 
9 
1 
xb 
x 
13 
1 
xb 
x 
a. Record actual time of sample collection. 
b. Sample collected 24 hours (± 2 hours) after Day 1 dose and prior to dosing on the study day. 


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After samples are collected, samples will be processed onsite before shipping to PCYC for final 
storage/analysis. Please refer to laboratory manual for instructions.  
7.2. 
Efficacy Evaluations 
7.2.1. 
NIH Response Criteria (see Appendix F and Appendix G) 
All subjects in the study will have their response assessed using the NIH cGVHD Response 
assessment (Pavletic 2006; Measurement of Therapeutic Response, ASBMT Web site) at 
baseline, at week 5, and after every 12 weeks of therapy. Response will be determined by the 
following criteria: 
1. Complete Response – Complete resolution of all reversible manifestations of cGVHD. 
Irreversible manifestations will be defined by NIH consensus criteria (Pavletic 2006) 
(eg, ocular xerosis, esophageal stricture, and bronchiolitis obliterans). 
2. Partial Response – At least a 25% absolute or 50% relative change (whichever is greater) 
when comparing start and end measurements in one cGVHD domain without worsening in 
the other domains (Appendix H). 
3. Stable Disease – No worsening in baseline cGVHD manifestations. 
4. Progressive Disease – Worsening in any one cGVHD domain by at least an absolute change 
of 25% from baseline unless baseline values are within 25% of the scale used to score 
cGVHD. In addition, a new cGVHD manifestation also counts as progression (Appendix H). 
7.2.2. 
Lee cGVHD Symptom Scale  
All subjects in the study will complete the Lee Symptom scale (Appendix E) after every 
12 weeks of study treatment. A change in >7 points on the Lee cGVHD Symptom Scale will be 
considered clinically significant and relates to improvement in quality of life (Lee 2006). 
7.2.3. 
Failure Free Survival 
Failure free survival will be defined as no death, no relapse of underlying malignancy, and no 
new immunosuppressive therapy. FFS will be assessed every 6 months starting with beginning of 
therapy. FFS with corticosteroid requirements at 6 months and 12 months on therapy will be 
assessed as described in Inamato et al. (Inamato 2013). 
7.3. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or laboratory requisition form. Refer to the Schedule of Assessments 
(Appendix A) for the timing and frequency of all sample collections. 
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual. 


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8. 
STUDY PROCEDURES  
Each of the phases (1b or 2) in this study is divided into 3 sub-phases: Screening Phase, a 
Treatment Phase, and a Follow-up Phase. The Schedule of Assessments (Appendix A) 
summarizes the frequency and timing of efficacy, PK, PD, biomarker, and safety measurements 
applicable to this study. All subjects enrolled will undergo the same study procedures throughout 
the study unless otherwise noted. 
Details for each part are presented below and can be found on the Schedule of Assessments 
(Appendix A). 
8.1. 
Screening Phase 
The Screening period can occur up to 42 days prior to the first dose of ibrutinib. All subjects 
must first read, understand, and sign the IRB/REB/IEC approved ICF before any study-specific 
screening procedures are performed. Standard of care follow-up per institutional practices do not 
require prior consent (eg, routine laboratory testing). All study tests and procedures should be 
performed at the study center at which the subject was enrolled and will be receiving treatment. 
After signing the ICF, screening, and being deemed eligible for entry, subjects will be enrolled in 
the study after review and approval of screening inclusion/exclusion records by the Sponsor 
Medical Monitor.  
8.1.1. 
Screening Visit 
The following procedures will be performed at the Screening Visit within 42 days prior to first 
dose of study drug and randomization unless otherwise noted: 
• Obtain signed, written informed consent 
• Medical history including demographic information 
• Collection of transplant history 
• Evaluation of KPS performance status 
• Complete physical exam including height and weight (may use prior height measurement 
if available in source documents). 
• Record adverse events since signing the ICF 
• Record concomitant medication history including over-the-counter drugs, vitamins and 
herbs 
• cGVHD assessment (eg, NIH assessments [Appendix F and Appendix G])  
• Lee cGVHD Symptom Scale (Appendix E) 
• Obtain vital signs (including blood pressure, heart rate, respiratory rate, and body 
temperature) after the subject has rested in the sitting position for ≥3 minutesObtain 
blood specimens for the following laboratory tests: 
o Hematology 
o Serum chemistry 
o Coagulation studies: PT/INR, aPTT 


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o Hepatitis serologies/PCR 
o Quantitative serum immunoglobulins (IgA, IgG, and IgM) 
• Donor/host Chimerism testing 
• T/B/NK sampling for PCYC 
• Perform oxygen saturation and/or PFT (if O2 not assessed within 6 months of study entry) 
• Obtain triplicate 12-lead ECG (≥1 minute apart) after the subject has been in a supine 
position and resting for at least 10 minutes 
• Immunosuppressant level – if applicable 
• Obtain serum pregnancy test for women of childbearing potential only 
• Complete enrollment-eligibility checklist and submit to Sponsor for review and approval 
prior to enrollment  
8.2. 
Treatment Phase 
Following completion of the Screening Visit and once eligibility has been confirmed, subjects 
are enrolled. Enrollment should occur as close to the time of the expected first dose as possible, 
ie, not more than 3 business days prior to expected first dose with study drug. 
During the treatment/follow-up period, DLT assessment will occur over a 28-day period. DLTs 
are defined in Section 5.2.2. Local labs will be used to guide all dosing-related decisions.  
Week 1 Day 1 
Predose 
• Complete physical exam including weight.  
• Vital signs and performance status (KPS) 
• cGVHD assessment per NIH (Appendix F and Appendix G). This assessment must be a 
minimum of 14 days after the prior response assessment unless the subject's cGVHD is 
worsening. If the subject's cGVHD is clinically improved from the prior response 
assessment, then the first dose must be delayed and subject will need to be re-assessed at 
least 14 days later to confirm stable or worsening cGVHD. Please contact the Medical 
Monitor for any questions related to eligibility. 
• Lee cGVHD Symptom Scale (Appendix E) 
• Photographic imaging of cGVHD  
• Hematology 
• Serum chemistry 
• Urine pregnancy test for women of childbearing potential 
• Review of baseline adverse events and concomitant medications (including corticosteroid 
requirements) 
• Review of inclusion and exclusion criteria to confirm subject eligibility prior to first 
dosing 
• Pharmacokinetic sampling (pre-dose) 


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• Pharmacodynamic sampling for PCYC (pre-dose) 
• T/B/NK sampling for PCYC (pre-dose) 
• Biomarkers sampling  
• 
Immunosuppressant level – if applicable 
Post Dose 
• Administer ibrutinib at specified dose level, and then dispense remaining amount to 
subject for at-home dosing  
• Provide drug diary and dosing instructions to subject  
• Pharmacokinetic sampling for PCYC at 1, 2, 4, and 6 hours post-dose 
• Pharmacodynamic sampling for PCYC (4 hours after first dose administration) 
• T/B/NK sampling for PCYC (4 hours after first dose administration) 
• 
Review adverse events  
Week 1 Day 2 
Predose  
• 
a.Pharmacokinetic sampling for PCYC (pre-dose before Day 2 drug administration) 
• 
a.Pharmacodynamic sampling for PCYC (pre-dose before Day 2 drug administration) 
• 
a.T/B/NK sampling (pre-dose) 
a. 
Within 24 hours of the first ibrutinib dose. 
Week 2  
Predose 
• Symptom-directed physical examination 
• Hematology 
• Serum chemistry 
• Vital signs 
• Immunosuppressant level – if applicable 
• Review adverse events and concomitant medications (including corticosteroid 
requirements) 
• Pharmacokinetic sampling for PCYC (pre-dose) 
• Pharmacodynamic sampling for PCYC (pre-dose) 
• T/B/NK sampling for PCYC (pre-dose before Day 2 drug administration) 
 
During and Post Dose 
• Administer ibrutinib at specified dose level 
• Pharmacokinetic sampling for PCYC at 1, 2, 4, and 6 hours post-dose 
• Pharmacodynamic sampling for PCYC (4 hours after first dose administration) 
• T/B/NK sampling for PCYC (4 hours after drug administration) 


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Week 5, 9, 13, 17, 21, 25 (± 3 days) 
Predose 
• DLT assessment period ends (Phase 1b Week 5 only) 
• Symptom-directed physical examination 
• Vital signs and performance status (KPS) 
• Photographic imaging of cGVHD (Weeks 5, 13 and 25) 
• Hematology 
• Serum chemistry 
• cGVHD assessment per NIH (Weeks 5, 13 and 25) (Appendix F and Appendix G) 
• Lee cGVHD Symptom Scale (Weeks 5, 13 and 25) (Appendix E) 
• Donor/host chimerism testing (Weeks 13 and 25) 
• Quantitative serum immunoglobulins (IgA, IgG, and IgM) (Weeks 13 and 25) 
• Biomarker sampling (Weeks 5, 12 and 25) 
• Pharmacodynamic sampling for PCYC (pre-dose on Weeks 9 and 13) 
• T/B/NK sampling for PCYC (pre-dose on Weeks 9 and 13) 
• Immunosuppressant level – if applicable 
• Review returned subject dosing diary 
• 
Review adverse events and concomitant medications (including corticosteroid 
requirements) 
Post Dose 
• Administer ibrutinib at specified dose level, and then dispense remaining amount to 
subject  
• Pharmacodynamic sample collection (4 hours after drug administration on Weeks 9 and 
13) 
• 
T/B/NK sampling for PCYC (4 hours after drug administration on Weeks 9 and 13) 
Week 37 and every 12 weeks thereafter  
Predose 
• Complete physical examination 
• Vital signs and performance status (KPS) 
• Photographic imaging of cGVHD  
• Hematology 
• Serum chemistry 
• cGVHD assessment per NIH (Appendix F and Appendix G) 
• Lee cGVHD Symptom Scale (Appendix E) 
• Donor/host chimerism testing 
• Quantitative serum immunoglobulins (IgA, IgG, and IgM) 
• Biomarker sampling (Weeks 37 and 49) 


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• Immunosuppressant level – if applicable 
• Review returned subject dosing diary 
• 
Review adverse events and concomitant medications (including corticosteroid 
requirements) 
Post Dose 
• Administer ibrutinib at specified dose level, and then dispense remaining amount to 
subject  
8.2.1. 
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, or if the subject 
discontinues treatment for any other reason. If possible, the visit should be performed within 
24 hours after the subject’s previous dose.  
• Complete physical examination 
• Vital signs and performance status (KPS) 
• Hematology 
• Serum chemistry 
• Donor/host chimerism testing 
• Immunosuppressant level – if applicable 
• cGVHD NIH Form assessment (Appendix F and Appendix G) 
• Lee cGVHD Symptom Scale (Appendix E) 
• Photographic imaging of cGVHD  
• Quantitative serum immunoglobulins (IgA, IgG, and IgM) 
• Review adverse events and concomitant medications (including corticosteroid 
requirements) 
• Review returned subject dosing diary 
• Final drug accountability 
8.2.2. 
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.  
The following procedures will be performed at the End-of-Treatment visit: 
• Complete physical examination 
• Vital signs and performance status (KPS) 
• Hematology 


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• Serum chemistry 
• Donor/host chimerism testing Lee cGVHD Symptom Scale (Appendix E) 
• cGVHD NIH Form assessment (Appendix F and Appendix G) 
• Photographic imaging of cGVHD  
• Immunosuppressant level – if applicable 
• Quantitative serum immunoglobulins (IgA, IgG, and IgM) 
• Review returned subject dosing diary 
• Review adverse events and concomitant medications (including corticosteroid 
requirements and any new cGVHD treatment if applicable) 
• Final drug accountability 
• Biomarker sampling 
8.3. 
Follow-up Phase 
Once a subject has completed the End-of-Treatment Visit they will enter the Follow-Up Phase 
(Visits every 12 Weeks).  
8.3.1. 
Response Follow-up 
Subjects who discontinue the study for reasons other than progressive disease will be followed 
every 12 weeks (±7 days) by clinic visit until progressive disease. During this period, the 
following procedures will be performed: 
• Symptom-directed physical examination 
• Vital signs and performance status (KPS) 
• Hematology 
• Serum chemistry 
• Donor/host chimerism testingcGVHD NIH Form assessment (Appendix F and 
Appendix G) 
• Lee cGVHD Symptom Scale (Appendix E) 
• Photographic imaging of cGVHD  
• 
Review corticosteroid requirements and any new cGVHD treatment if applicable 
8.3.2. 
Long-Term Follow-up 
Once subjects progress (for subjects who have not withdrawn consent), they will be contacted 
approximately every 3 months (±14 days) by clinic visit or telephone to assess survival. Subjects 
will be contacted until death, subject withdrawal, lost to follow-up, or study termination by the 
Sponsor, whichever occurs first. 


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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. 
Withdrawal from Study Treatment 
Study treatment will be discontinued in the event of any of the following events: 
• cGVHD progression (see definition in Section 7.2.1) 
• Unacceptable toxicity: an intercurrent illness or AE that prevents further ibrutinib 
administration. 
• Noncompliance with study medication. 
• Investigator’s decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject) 
• Withdrawal of consent for treatment by subject 
• Malignancy progression/relapse. 
• Subject’s condition no longer requires study treatment. 
• Subject becomes pregnant 
• Study termination by Sponsor 
• Death 
All subjects, regardless of reason for discontinuation of study treatment will undergo an 
End-of-Treatment Visit and be followed for progression and survival.  
9.3. 
Withdrawal from Study 
Withdrawal from study (including all follow-up) will occur under the following circumstances: 
• Withdrawal of consent for follow-up observation by the subject 
• Lost to follow-up 
• Study termination by Sponsor 
• Death 
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: 
• Reason for withdrawal; 
• Whether the subject withdraws consent (ie, withdraws consent to treatment and all further 
contact) or withdraws consent to treatment but agrees to participate in follow-up visits.  


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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 (SAP).  
The primary analysis for all efficacy and safety endpoints will be conducted at approximately 
12 months after the last subject’s first dose of study drug. 
10.1. 
Subject Information 
The following definitions will be used for the safety and efficacy analysis, respectively: 
• Safety population: All enrolled subjects who receive at least one dose of study drug.  
• Efficacy population: All enrolled subjects who receive at least one RP2D of study drug. 
Additional analysis populations, which might be used for sensitivity analyses and biomarker 
studies, are defined in the SAP. 
10.2. 
Endpoints  
10.2.1. 
Primary Endpoints 
Phase 1b: 
Safety and Tolerability 
Drug toxicity will be described and graded according to CTCAE v. 4.03 criteria. Dose limiting 
toxicities are defined in Section 5.2.2. Only toxicities which occur during the first 28 days on 
ibrutinib will count towards the assessment of DLTs.  
Toxicities which occur after the first 28 days for Phase 1b subjects will be described and graded 
according to CTCAE v. 4.03 criteria and presented in tabulated form. This will also be 
performed for subjects enrolled in the Phase 2 portion of the study.  
Phase 2: 
The primary efficacy endpoint is the best overall cGVHD response rate. Best overall cGVHD 
response rate is defined the proportion of subjects who achieve a NIH-defined complete response 
or partial response.  
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10.2.2. 
Secondary Efficacy Endpoints 
10.2.2.1. Rate of Sustained Response for at Least 5 Months 
Sustained response for at least 5 months is defined as NIH-defined complete response or partial 
response that was sustained for at least 5 months.  
10.2.2.2. Duration of Response (DOR) 
Duration of response is defined as the interval between the date of initial documentation of a 
response, and the date of first documented evidence of progressive disease, death, or date of 
censoring if applicable, for responders only. Percentage of subjects with sustained response and 
its 95% confidence interval will be calculated using normal approximation to the binomial 
distribution. Subjects who stop the study drug and start new GVHD treatment before 
documentation of disease progression will be censored on the date of the last adequate disease 
assessment that is on or before the start date of new GVHD therapy. Responders are subjects 
who achieve a NIH-defined complete response or partial response during the study. 
Non-responders will be excluded from the analysis for DOR. 
10.2.2.3. Corticosteroid Requirement Changes Over Time 
Corticosteroid requirement will be monitored cross the study. The decrease of corticosteroid 
need will be viewed as the benefit of the ibrutinib.  
10.2.2.4. Change in cGVHD Symptom Scale 
Subject reported improvement in symptom burden. The symptom burden will be measured 
according to the Lee cGVHD Symptom Scale. A change in >7 points on the Lee cGVHD 
Symptom Scale will be considered significant and relates to improvement in quality of life 
(Lee 2006). 
10.2.3. 
Safety Endpoints 
Safety assessments will consist of monitoring and recording AEs and SAEs; measurements of 
protocol-specified hematology, clinical chemistry, urinalysis, and other laboratory variables; 
measurement of protocol-specified tests that are deemed critical to the safety evaluation of the 
study drug. 
10.2.4. 
Exploratory Endpoints 
10.2.4.1. Photographic Changes in Skin and Mucocutaneous Manifestations. 
Skin and mucocutaneous manifestations will be monitored across the study. The decrease of area 
with skin and mucocutaneous manifestations will be view as the benefit of the ibrutinib.  


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10.2.4.2. Pharmacokinetic Analysis  
Plasma concentrations of ibrutinib and metabolite PCI-45227 will be determined using a 
validated analytical method. Other potential metabolites of ibrutinib may be explored. 
Bioanalytical data from this study will be used in noncompartmental PK analysis and also may 
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 correlate with plasma PK parameters 
will be evaluated. The results of the population PK analyses (if performed) will be presented in a 
separate report. 
10.2.4.3. Biomarker and Pharmacodynamic Studies 
Pharmacodynamic studies will be conducted to determine alloreactive B cell depletion, T-helper 
cell composition, BTK occupancy and ITK blockade. Specifically, the following PD studies will 
be conducted: 
• HY antigen-specific allogeneic B cell depletion in males who receive HCT from a female 
donor. 
• Quantification of HY IgG and IgM alloreactive antibodies males who receive HCT from 
a female donor. 
• BTK and ITK binding site occupation (PCYC). 
• B cell depletion, flow cytometric analysis of T-helper cell composition, T and B cell 
cytokine analysis, and phosphoflow analysis of CD4+ T-cell ITK blockade. 
10.2.4.4. Failure Free Survival  
Failure free survival is defined as no death, no relapse of malignancy, and no new 
immunosuppressive therapy for GVHD. 
10.3. 
Sample Size Determination 
With a sample size of 40 subjects and assuming an best overall cGVHD response rate of 
approximately 50%, it is expected to have at least 90% power to show the efficacious treatment 
effect (the lower bound of 95% CI of the response rate >0.25). 
10.4. 
Efficacy Analysis  
Best overall cGVHD response rate and its 95% confidence interval will be calculated with the 
exact test for binomial distribution.  
The secondary efficacy endpoint rate of sustained response for at least 5 months will be 
evaluated in the same manner as best overall cGVHD response rate.  


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The distribution (median and Kaplan-Meier curves) and estimates of DOR will be provided 
using Kaplan-Meier estimates for responders. 
Other secondary endpoints, such as on corticosteroid requirement changes over time, change in 
symptom burden measured by the Lee cGVHD Symptom Scale will be summarized by 
descriptive statistics.  
Exploratory endpoints will be will be summarized by descriptive statistics. 
10.5. 
Safety Analysis 
 The safety variables to be analyzed include adverse events, clinical laboratory test results 
(hematology and chemistry), and other safety measurements. They will be summarized by 
descriptive statistics. No formal statistical testing is planned.  
Exposure to ibrutinib first dose and reasons for discontinuation from study treatment will be 
tabulated. 
Adverse Events 
Adverse event parameters to be evaluated are the type, incidence, and intensity of adverse 
events; the relationship of adverse events to ibrutinib; and the action taken with respect to 
ibrutinib treatment due to adverse events. 
The verbatim terms used in the eCRF will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  
Treatment-emergent adverse events are those adverse events occurring after the first dose of 
study drugs and within 30 days following the last dose of study drug; any adverse event that is 
considered study drug-related regardless of the start date of the event; or any adverse event that 
is present at baseline but worsens after the first administration of study drug in severity or is 
subsequently considered drug-related by the Investigator. All treatment-emergent adverse events 
will be included in the analysis.  
For each adverse event, the percentage of subjects who experience at least 1 occurrence of the 
given event will be summarized. The number and percent of subjects with treatment-emergent 
adverse events will be summarized according to intensity (NCI CTCAE v. 4.03) and drug 
relationship as well as categorized by system organ class and preferred term. Summaries, 
listings, datasets, or subject narratives may be provided, as appropriate, for those subjects who 
die, who discontinue treatment due to an adverse event, or who experience a severe or a serious 
adverse event. 


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Clinical Laboratory Tests 
All laboratory values will be converted to standard international units and will be graded using 
the NCI CTCAE v. 4.03. 
A summary of the shifts in selected laboratory hematology and serum chemistry parameters from 
baseline to the worst toxicity grade during the study will be tabulated.  
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 adverse event 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: 
• Subjective or objective symptoms provided by the patient and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
• Any AEs experienced by the patient through the completion of final study procedures. 
• AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with cGVHD that were not 
present before the AE reporting period  
• Complications that occur as a result of protocol-mandated interventions (eg, invasive 
procedures such as biopsies). 


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The following are NOT considered AEs: 
• 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. 
• Pre-planned or elective hospitalization: A hospitalization planned before signing the 
informed consent form 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. 
• Diagnostic Testing and Procedures: Testing and procedures should not to 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 serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
• Results in death (ie, the AE actually causes or leads to death). 
• Is life-threatening. Life-threatening is defined as an AE in which the patient 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. 
• Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the patient’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• 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 patient or patient 
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 
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. 


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11.1.3. 
Severity Criteria (Grade 1-5) 
Definitions found in the Common Terminology Criteria for Adverse Events version 4.0 
(CTCAE v. 4.03) will be used for grading the severity (intensity) of AEs. The CTCAE v. 
4.03displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced 
AE. Should a patient experience any AE not listed in the CTCAE v. 4.03, the following grading 
system should be used to assess severity: 
• Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the patient’s daily activities 
• Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the patient, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the patient’s usual daily activity, and require systemic drug therapy or other 
treatment 
• Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in 
imminent danger of death 
• Grade 5 (Death related to AE) – experiences which result in patient 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. 
11.2. 
Unexpected Adverse Events 
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/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 Investigator's Brochure referred only 


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to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents. "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure 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: 
• Overdose of any study drug 
• Suspected abuse/misuse of a study drug 
• Inadvertent or accidental exposure to a study drug 
• Medication error involving a product (with or without subject/patient 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 adverse event, it should be recorded on the adverse 
events eCRF. If the adverse event is considered serious, it should be recorded on the adverse 
events eCRF as serious and should be reported on the Serious Adverse Event Report Form. The 
SAE 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 adverse events and serious adverse events at all 
subject evaluation timepoints during the study. All adverse events and serious adverse events 
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 Adverse Event CRF and, when applicable, on 
the Serious Adverse Event Report Form. 
Each recorded adverse event or serious adverse event 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 in the source documents from the 
time signed and dated ICF is obtained until 30 days following the last dose of study drug. SAEs 
will be reported to the Sponsor from the time of ICF signing. Both serious and non-serious AEs 
will be recorded in the eCRF from the first dose of study drug until 30 days after the last dose of 
study drug. 
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.  
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported. 
All adverse events, 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 adverse event to study therapy. All measures required for 
adverse event 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. The primary cause of death on the 
autopsy report should be the term reported. Autopsy and postmortem reports must be forwarded 
to the Sponsor, or designee, as outlined above. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a serious adverse event.  
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events (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. 
All serious adverse events that have not resolved by the end of the study, or that have not 


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resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
• 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. 
Adverse Events of Special Interest (AESI) 
Specific adverse events, or groups of adverse events, 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.  
11.4.4.1. Major Hemorrhage 
Major hemorrhage is defined as any of the following:  
• 
Any treatment-emergent hemorrhagic AEs of Grade 3 or higher*. Any treatment-
emergent serious adverse events of bleeding of any grade 
• 
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 11.4.4 above. 
11.4.5. 
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. 


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A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 30 days after the last dose of study drug. A male subject must immediately 
inform the Investigator if his partner becomes pregnant from the time of consent to 3 months 
after the last dose of study drug. 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 adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 30 days after the last dose of study drug must be reported. 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 serious adverse event. 
11.4.6. 
Other Malignancies 
In addition to all routine AE reporting, all new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies are to be reported for the duration of study treatment 
and during any protocol-specified follow-up periods including post-progression follow-up for 
overall survival. If observed, enter data in the corresponding eCRF. 
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.  
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 informed consent form 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. 


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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. 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 FDA regulations (21 CFR 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 12.3), 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 


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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 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 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 
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 


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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 
CRFs 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 exist 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 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 PCI-32765 or comparator to other Investigators, 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-1129-CA) 
2. Subject identification number 


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3. Lot number(s) of ibrutinib or comparator 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 and/or two authorized study site personnel. 
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. During the review of source documents, every 
effort will be made to maintain the anonymity and confidentiality of all subjects during 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. 


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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. 
For this study, each Investigator and Subinvestigator (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. 
If a bodily injury is sustained, resulting directly from the use of the study drug, Pharmacyclics 
will reimburse for reasonable physician fees and medical expenses necessary for treatment of 
only the bodily injury which is not covered by the subject’s medical or hospital insurance, 
provided that the injury is not due to a negligent or wrongful act or omission by the Investigator/ 


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study staff. The ICF will include a description of this reimbursement policy, 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. 
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. 


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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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Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
ChemMedChem 2007;2:58-61. 
Parker PM, Chao N, Nademanee A, et al. Thalidomide as salvage therapy for chronic graft-versus-host 
disease. Blood 1995; 86:3604-9. 
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. 


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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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Ratanatharathorn V, Ayash L, Reynolds C, et al. Treatment of chronic graft-versus-host disease with anit-
CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant. 2003;9:505-511. 
Response Criteria for Partial Response and Progression in cGVHD. 
http://asbmt.affiniscape.com/associations/11741/files/ResponseCriteriaAPPENDIXC_DCalculations.pdf 
Sahaf B, Arai S, Otani J, et al. Rituximab Provides Steroid-Sparing Therapy in New-Onset Chronic Graft-
Versus-Host Disease. ASBMT 2013 (manuscript in preparation). 
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.  
Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B cell development and function: a 
genetic perspective. Immunol Rev 2000;175:120-7. 
Schroeder MA, DiPersio JF. Mouse models of graft-versus-host disease: advances and limitations. Dis 
Model Mech;2011;4:318-333. 
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. 
Shinners NP, Carlesso G, Castro I, et al. Bruton's Tyrosine Kinase Mediates NF-kappa B Activation and 
B Cell Survival by B Cell-Activating Factor Receptor of the TNF-R Family. The Journal of Immunology. 
2007;179:3872-3880. 
Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease: 
National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic 
Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 
2006;12:31-47. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood 
cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187-205.  
Socie G, Stone JV, Wingard JR, et al. Long-term survival and late deaths after allogeneic bone marrow 
transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. 
N Engl J Med. 1999;341:14-21. 
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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Sutherland HJ, Fyles GM, Adams G et al. Quality of life following bone marrow transplantation: a 
comparison of patient reports with population norms. Bone Marrow Transplant. 1997;19:1129-1136. 
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 
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14. APPENDICES 


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Appendix A. Schedule of Assessments 
 
Screening 
Phase 
Treatment Phase 
Post-Treatment/ 
Follow-up Phase 
Study Weeks 
 
1 
1 
2 
5 
9, 13, 17,  
21, 25 
q4 weeks 
37 and every 
12 weeks 
thereafter 
Progressive 
Disease Visit 
End-of- 
Treatment 
Visit 
(30 days from 
last dose of 
study drug) 
Response Follow-
up Visits 
(Until progressive 
disease) 
q12 weeks 
Survival 
Follow-up
q12 weeks 
Study Day of study week 
 
1 
2 
1 
1 
1 
1 
 
 
 
 
Study Windows 
-42 days 
On time 
±3 days 
anytime 
± 7 days 
± 7 days
± 7 days 
Study Drug Administration 
ibrutinib 420mg/280mg/140mg 
dispensing 
 
x 
 
 
x 
x 
x 
 
 
 
 
ibrutinib administration 
 
Continuous daily dosing 
 
 
 
 
Administrative Procedures 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility/enrollment 
checklist 
x 
x 
 
 
 
 
 
 
 
 
 
Medical history and Demographics 
x 
 
 
 
 
 
 
 
 
 
 
GVHD/Transplant History 
x 
 
 
 
 
 
 
 
 
 
Safety Assessments 
DLT Assessment (Phase 1b) 
 
 
 
 
x 
 
 
 
 
 
 
Physical exam (height at Screening 
only) 
xa 
xa 
 
xb 
xa 
xb 
xa 
xa 
xa 
xb 
 
KPS status 
x 
x 
 
 
x 
x 
x 
x 
x 
x
 
Vital signs 
x 
x 
 
x 
x 
x 
x 
x 
x 
x
 
Oxygen saturation/PFTc 
x 
 
 
 
 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
 
 
 
 
x 
ECG d 
x 
 
If clinically indicated (eg, subjects with palpitations, lightheadedness) 
Clinical Laboratory Assessments 
Hematology 
x 
x 
 
x 
x 
x 
x 
x 
x 
x
 
Serum Chemistry 
x 
x 
 
x 
x 
x 
x 
x 
x 
x
 
Coagulation (PT, INR, and aPTT) 
x 
 
 
 
 
 
 
 
 
 
 
Pregnancy test e 
x 
x 
 
 
 
 
 
 
 
 
 
Hepatitis serologies 
x 
 
 
 
 
 
 
 
 
 
 
Donor/host chimerism 
x 
 
 
 
 
Weeks 13, 25 
x 
x 
x 
x 
 
Quantitative serum immunoglobulins 
(IgA, IgG and IgM) 
x 
 
 
 
 
Weeks 13, 25 
x 
x 
x 
 
 
Immunosupressant Levels 
x 
As needed during treatment 
 
 
PK 
 
xg 
xg 
xg 
 
 
 
 
 
 
 
PD 
 
xh 
xh 
xh 
 
Week 9, 13 
 
 
 
 
 


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Screening 
Phase 
Treatment Phase 
Post-Treatment/ 
Follow-up Phase 
Study Weeks 
 
1 
1 
2 
5 
9, 13, 17,  
21, 25 
q4 weeks 
37 and every 
12 weeks 
thereafter 
Progressive 
Disease Visit 
End-of- 
Treatment 
Visit 
(30 days from 
last dose of 
study drug) 
Response Follow-
up Visits 
(Until progressive 
disease) 
q12 weeks 
Survival 
Follow-up
q12 weeks 
Study Day of study week 
 
1 
2 
1 
1 
1 
1 
 
 
 
 
Study Windows 
-42 days 
On time 
±3 days 
anytime 
± 7 days 
± 7 days
± 7 days 
Efficacy Assessments 
cGVHD Assessment (NIH Form) 
x 
x 
 
 
x 
Weeks 13, 25 
x 
x 
x 
x 
 
Lee cGVHD Symptom Scale f 
x 
x 
 
 
x 
Weeks 13, 25 
x 
x 
x 
x 
 
Photographic imaging of cGVHD 
symptoms 
 
x 
 
 
x 
Weeks 13, 25 
x 
x 
x 
x 
 
Corticosteroid Requirements 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
Ongoing Subject Assessments 
Concomitant medications 
x 
Continuous from Informed Consent to 30 days after last dose of study drug 
 
 
Adverse events 
x 
Continuous from Informed Consent to 30 days after last dose of study drug 
 
 
Biomarkers 
T/B/NK cell counts 
xi 
xi 
xi 
xi 
 
Week 9, 13 
 
 
 
 
 
Biomarkers 
 
x
 
 
x 
Weeks 13, 25
Weeks 37, 49 
 
x 
 
 
Abbreviations: AEs=adverse events; aPTT=activated partial thromboplastin time; ECG=electrocardiogram; KPS=Karnofsky Performance Status; EOT=end-of-treatment; 
INR=international normalized ration; PD=pharmacodynamic; PK=pharmacokinetics; PO=orally; PT=prothrombin time; q4 weeks=every 4 weeks; q12 weeks=every 12 weeks 
 
Footnote: 
a. 
Physical Examination includes: general appearance of subject, examination of skin, eyes and fundi, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, lymphatic system, and nervous system. 
b. 
Only a limited symptom-directed physical examination is required. Review of symptoms should include inquiry of ocular symptoms; subjects should be 
referred to an ophthalmologist for a formal examination if any Grade ≥2 symptoms are reported. 
c. 
Oxygen saturation by pulse oximeter is permitted. If not done, then PFT with FEV1 required within 6 months of Screening. 
d. 
ECG’s may be performed at the Investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset 
of dyspnea. 
e. 
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. 
f. 
Lee cGVHD Symptom Scale should be completed prior to any assessments, and before being clinically evaluated by the study nurse or physician.  
g. 
Pharmacokinetic (PK) samples will be drawn for all subjects according to the schedule in Section 7.1.13.1. Additional PK samples will be collected for 
subjects treated with concomitant a moderate or strong CYP3A inhibitors while on ibrutinib treatment according to the schedule in Section 7.1.13.1. 
h. 
Pharmacodynamic (PD) sampling for PCYC will be performed on selected days at predose and post-dose. Refer to Table 3 for more details. 
i. 
T/B/NK sampling for PCYC will be performed on selected days at predose and post-dose. Refer to Table 4 for more details. 


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Appendix B. NIH Defined Diagnostic or Distinctive Features of Chronic GVHD 
Organ or Site 
Diagnostic  
(Sufficient to Establish 
the Diagnosis of 
Chronic GVHD) 
Distinctive  
(Seen in Chronic GVHD, 
but Insufficient Alone to 
Establish a Diagnosis of 
Chronic GVHD) 
Other Features* 
Common  
(Seen with Both Acute 
and Chronic GVHD) 
Skin 
Poikiloderma  
Lichen planus-like 
features 
Sclerotic features 
Morphea-like features  
Lichen sclerosus-like 
features 
Depigmentation  
Sweat impairment 
Ichthyosis  
Keratosis pilaris 
Hypopigmentation 
Hyperpigmentation 
Erythema 
Maculopapular rash  
Pruritus 
Nails 
 
Dystrophy 
Longitudinal ridging, 
splitting, or brittle features 
Onycholysis 
Pterygium unguis 
Nail loss (usually symmetric; 
affects most nails)† 
 
 
Scalp and 
body hair 
 
New onset of scarring or 
nonscarring scalp alopecia 
(after recovery from 
chemoradiotherapy) 
Scaling, papulosquamous 
lesions 
Thinning scalp hair, 
typically patchy, coarse, 
or dull (not explained by 
endocrine or other 
causes) 
Premature gray hair 
 
Mouth 
Lichen-type features 
Hyperkeratotic plaques 
Restriction of mouth 
Xerostomia 
Mucocele 
Mucosal atrophy 
Pseudomembranes† 
Ulcers† 
 
Gingivitis 
Mucositis 
Erythema 
Pain 
Eyes 
 
New onset dry, gritty, or 
painful eyes‡ 
Cicatricial conjunctivitis 
Keratoconjunctivitis sicca‡ 
Confluent areas of punctate 
keratopathy 
Photophobia 
Periorbital 
hyperpigmentation 
Blepharitis (erythema of 
the eyelids with edema) 
 
Genitalia 
Lichen planus-like 
features  
Vaginal scarring or 
stenosis 
Erosions† 
Fissures† 
Ulcers† 
 
 
GI tract 
Esophageal web 
Strictures or stenosis in 
the upper to mid third 
of the esophagus† 
 
Exocrine pancreatic 
insufficiency 
Anorexia 
Nausea 
Vomiting 
Diarrhea 
Weight loss 
Failure to thrive (infants 
and children) 
Liver 
 
 
 
Total bilirubin, alkaline 
phosphatase >2 ULN† 
ALT or AST >2 ULN† 
Lung 
Bronchiolitis obliterans 
diagnosed with lung 
biopsy 
Bronchiolitis obliterans 
diagnosed with PFTs and 
radiology‡ 
 
BOOP 


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Organ or Site 
Diagnostic  
(Sufficient to Establish 
the Diagnosis of 
Chronic GVHD) 
Distinctive  
(Seen in Chronic GVHD, 
but Insufficient Alone to 
Establish a Diagnosis of 
Chronic GVHD) 
Other Features* 
Common  
(Seen with Both Acute 
and Chronic GVHD) 
Muscles, 
fascia, joints 
Fasciitis 
Joint stiffness or 
contractures secondary 
to sclerosis 
Myositis or polymyositis‡ 
Edema 
Muscle cramps 
Arthralgia or arthritis 
 
Hematopoietic 
and immune 
 
 
Thrombocytopenia 
Eosinophilia 
Lymphopenia 
Hypo- or 
hypergammaglobulinemia
Autoantibodies 
(AIHA and ITP) 
 
Other 
 
 
Pericardial or pleural 
effusions 
Ascites 
Peripheral neuropathy 
Nephrotic syndrome 
Myasthenia gravis 
Cardiac conduction 
abnormality or 
cardiomyopathy 
 
GVHD indicates graft-versus-host disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BOOP, 
bronchiolitis obliterans organizing pneumonia; PFTs, pulmonary function tests; AIHA, autoimmune hemolytic anemia; ITP, 
idiopathic thrombocytopenic purpura. 
* Can be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed. 
† In all cases, infection, drug effects, malignancy, or other causes must be excluded. 
‡ Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes). 
Source: Filipovich 2005 
 
 
 


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Appendix C. Karnofsky Performance Status Scores 
% 
Karnofsky Performance Status 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Care for self. Unable to carry on normal activity or do active work. 
60 
Requires occasional assistance but is able to care for most of his or her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled; hospitalization is indicated though death not imminent. 
20 
Hospitalization necessary; very sick; active supportive treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead. 
 
 
 


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Appendix D. Non-Investigational Treatments for cGVHD 
Medications or procedures not considered to be investigational for the treatment of chronic graft-
versus-host disease. 
 
Cellcept 
Cyclosporine 
Etanercept or other FDA-approved TNFα inhibitors 
Extracorpeal photophoresis (ECP) 
Imatinib 
Methotrexate 
Pentostatin 
Rituximab 
Sirolimus 
Tacrolimus 
 
 
 


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Appendix E. Lee cGVHD Symptom Scale 
Identification (Name):__________________________  
Date:_____________  
chronic GVHD Symptom Scale 
By circling one (1) number per line, please indicate how much you have been bothered by the following problems 
in the past month:  
SKIN:  
Not at 
all  
Slightly  
Moderately  
Quite a 
bit  
Extremely  
1.  
Abnormal skin color………………..  
0  
1  
2  
3  
4  
2.  
Rashes………………………………  
0  
1  
2  
3  
4  
3.  
Thickened skin………… ………...  
0  
1  
2  
3  
4  
4.  
Sores on skin……………………….  
0  
1  
2  
3  
4  
5.   
Itchy skin………….  
0  
1  
2  
3  
4  
EYES AND MOUTH:  
Not at 
all  
Slightly  
Moderately  
Quite a 
bit  
Extremely  
6.  
Dry eyes…………………………….  
0  
1  
2  
3  
4  
7.  
Need to use eye drops frequently..  
0  
1  
2  
3  
4  
8.  
Difficulty seeing clearly……………  
0  
1  
2  
3  
4  
9.  
Need to avoid certain foods due to 
mouth pain………………………….  
0 
1 
2 
3 
4 
10.  
Ulcers in mouth…………………….  
0 
1 
2 
3 
4 
11.  
Receiving nutrition from an 
intravenous line or feeding tube....  
0 
1 
2 
3 
4 
BREATHING:  
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
12.  
Frequent cough…………………….  
0 
1 
2 
3 
4 
13. .  
Colored sputum…………………… 
0 
1 
2 
3 
4 
14.  
Shortness of breath with exercise..  
0 
1 
2 
3 
4 
15.  
Shortness of breath at rest……...  
0 
1 
2 
3 
4 
16. 
Need to use oxygen…………….. 
0 
1 
2 
3 
4 


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EATING AND DIGESTION: 
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
17. 
Difficulty swallowing solid foods…. 
0 
1 
2 
3 
4 
18. 
Difficulty swallowing liquids………. 
0 
1 
2 
3 
4 
19. 
Vomiting……………………………. 
0 
1 
2 
3 
4 
20. 
Weight loss………………………… 
0 
1 
2 
3 
4 
MUSCLES AND JOINTS:  
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
21. 
Joint and muscle aches.............…. 
0 
1 
2 
3 
4 
22. 
Limited joint movement…......……. 
0 
1 
2 
3 
4 
23. 
Muscle cramps…………………….. 
0 
1 
2 
3 
4 
24. 
Weak muscles……………………... 
0 
1 
2 
3 
4 
Energy:  
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
25. 
Loss of energy…………………….  
0 
1 
2 
3 
4 
26. 
Need to sleep more/take naps…..  
0 
1 
2 
3 
4 
27. 
Fevers………………………………  
0 
1 
2 
3 
4 
MENTAL AND EMOTIONAL:  
Not at 
all 
Slightly 
Moderately 
Quite a 
bit 
Extremely 
28. 
Depression…………………………  
0 
1 
2 
3 
4 
29. 
Anxiety……………………………...  
0 
1 
2 
3 
4 
30. 
Difficulty sleeping………………….  
0 
1 
2 
3 
4 
 
 
Source:  
http://www.uniklinikum-regensburg.de/imperia/md/content/kliniken-institute/haematologie-
onkologie/gvhd/deutsch/lee-symptom_scale.pdf 
 


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Appendix F. Chronic GVHD Activity Assessment – Clinician 
Guidelines for completing the Chronic GVHD Activity Assessment – Clinician Form: 
 
 
EYES- If Schirmer’s Tear test is not performed please complete the NIH eye score. 
 
LUNGS-Complete full PFTs if possible but FEV1 is required. 
 
--If FEV1 is normal at baseline, repeat assessment not required unless progression is suspected. Complete NIH lung 
score in place of FEV1 at each visit. 
 
--If FEV1 is abnormal at baseline then reassessment Q12 weeks is required. 
 
GRIP STRENGTH-Not necessary to complete 
 
2 MIN WALK TEST-Complete only at baseline 
 
RANGE OF MOTION—Complete photographic ROM score and NIH joint/fascia score 
 
** If a change in score is considered to be due to a cause other than cGVHD please note and mark NE (not evaluable) for cGVHD 
score.  
 


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FORM A  
Current Patient Weight: ___________________ 
Today’s Date: ________________________ MR#/Name: ____________________  
 
CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN 
 
Component  
Findings
Scoring (see skin score worksheet) 
Skin 
 
Erythematous rash of any sort 
% BSA (max 100%) 
Moveable sclerosis 
% BSA (max 100%) 
Non-moveable sclerosis (hidebound/non-pinchable) or subcutaneous 
sclerosis/fasciitis 
% BSA (max 100%) 
Ulcer(s): select the largest ulcerative lesion, and measure its largest dimension in cm 
and mark location of ulcer 
Location: ___________________ 
Largest dimension: __________cm 
Eyes 
Bilateral Schirmer’s Tear Test 
(without anesthesia) 
in persons 9 years or older 
Right Eye:                                             mm of wetting 
Left Eye:                                                         mm of wetting 
Mouth 
 
Mucosal change 
 No evidence of 
cGVHD  
 Mild  
 Moderate 
 Severe 
 Erythema  
 None  
0  
 Mild erythema or moderate 
erythema (<25%)  
1  
 Moderate (≥25%) or Severe 
erythema (<25%)  
2  
 Severe erythema (≥25%) 
3 
  
 Lichenoid  
 None  
0  
 Hyperkeratotic changes(<25%) 
1  
 Hyperkeratotic changes(25-
50%)  
2  
 Hyperkeratotic changes 
(>50%)  
3 
  
 Ulcers  
 None  
0  
 None  
0  
 Ulcers involving (≤20%)  
3  
 Severe ulcerations 
(>20%)  
6 
  
 Mucoceles* 
 None  
0  
 1-5 mucoceles  
1  
 6-10 scattered mucoceles  
2  
 Over 10 mucoceles  
3 
  
 
 
 
 
 
 
 
 
 
 
*Mucoceles scored for lower labial and 
soft palate only 
 
Total score for all 
mucosal changes 
 
Blood Counts 
Platelet Count 
K/uL 
ULN 
K/uL 
Total WBC 
K/uL 
ULN 
K/uL 
% Eosinophils 
% 
Liver Function Tests 
Total serum bilirubin 
mg/dL 
ULN 
mg/dL 
ALT 
U/L 
ULN 
U/L 
Alkaline Phosphatase 
U/L 
ULN  
U/L 


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Gastrointestinal-Upper    
• Early satiety OR  
• Anorexia OR  
• Nausea & Vomiting  
0= no symptoms  
1=mild, occasional symptoms, with little reduction in oral intake during the past week  
2=moderate, intermittent symptoms, with some reduction in oral intake during the past week  
3=more severe or persistent symptoms throughout the day, with marked reduction in oral intake, on almost every day of the past week  
Gastrointestinal-Esophageal  
• Dysphagia OR  
• Odynophagia  
0= no esophageal symptoms  
1=Occasional dysphagia or odynophagia with solid food or pills during the past week  
2=Intermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or soft foods, during the past week  
3=Dysphagia or odynophagia for almost all oral intake, on almost every day of the past week  
Gastrointestinal-Lower =  
• Diarrhea  
0= no loose or liquid stools during the past week  
1= occasional loose or liquid stools, on some days during the past week  
2=intermittent loose or liquid stools throughout the day, on almost every day of the past week, without requiring intervention to prevent or correct volume depletion  
3=voluminous diarrhea on almost every day of the past week, requiring intervention to prevent or correct volume depletion  
Lungs  
• Bronchiolitis Obliterans  
 
Pulmonary Function Tests with Diffusing Capacity (attach 
report for person> 5 yrs old)  
FEV-1  
 
% Predicted 
Single Breath DLCO (adjusted for hemoglobin)  
 
% Predicted 
Health Care Provider Global Ratings:  
In your opinion, do you think that this 
patient’s chronic GVHD is mild, 
moderate or severe?  
0=none  
1= mild  
2=moderate  
3=severe  
 
Where would you rate the severity of this patient’s chronic GVHD symptoms on the following scale, 
where 0 is cGVHD symptoms that are not at all severe and 10 is the most severe cGVHD symptoms 
possible:  
 
 0          1          2           3            4           5           6           7           8           9         10 
 
cGvHD symptoms                                                                                                       Most severe cGvHD  
not at all severe                                                                                                             symptoms possible  
Over the past month would you say that this 
patient’s cGVHD is  
+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  
Functional Performance (in 
persons >4 years old) 
• Walk Time 
• Grip Strength 
Total Distance Walked in 2 Minutes: 
 
Number of laps: _______ (x 50 feet) + final partial lap: _____ feet 
= ______ feet walked in 2 minutes 
Grip Strength (Dominant Hand) 
Range of Motion: 
o Not performed 
o Physical Therapy Report Attached 
Trial #1 
 
psi 
Trial #2 
 
psi 
Trial #3 
 
psi 
Score 
Lansky Performance Status Scale Definitions (circle from 0-100)  
(persons < 16 years old) 
Karnofsky Performance Status Scale Definitions (circle from 0-100) 
(persons 16 years or older) 
100  
Fully active, normal  
Normal no complaints; no evidence of disease  
90  
Minor restrictions in physically strenuous activity  
Able to carry on normal activity; minor signs or symptoms of disease  
80  
Active, but tires more quickly  
Normal activity with effort; some signs or symptoms of disease  
70  
Both greater restriction of and less time spent in play activity  
Cares for self; unable to carry on normal activity or to do active work  
60  
Up and around, but minimal active play; keeps busy with quieter activities  
Requires occasional assistance but is able to care for most personal needs 
50  
Gets dressed but lies around much of the day, no active play but able to participate in all quiet play 
and activities  
Requires considerable assistance and frequent medical care  
40  
Mostly in bed; participates in quiet activities  
Disabled; requires special care and assistance  
30  
In bed; needs assistance even for quiet play  
Severely disabled; hospital admission is indicated although death not 
imminent  
20  
Often sleeping; play entirely limited to very passive activities  
Very sick; hospital admission necessary; active supportive treatment 
necessary  
10  
No play; does not get out of bed  
Moribund; fatal processes progressing rapidly  
0  
Unresponsive  
Dead  
Source: http://asbmt.affiniscape.com/associations/11741/files/ResponseCriteriaAPPENDIXAFormA.pdf 
 
 
 


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Score 0 
Score 1 
Score 2 
Score 3 
JOINTS AND FACIA 
□ 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):____________________________ 
 
Score 0 
Score 1 
Score 2 
Score 3 
EYES 
□ No symptoms 
□ Moderate dry eye 
symptoms not affecting ADL 
(requirement of lubricant eye 
drops ≤ 3 x per day) 
□ Moderate dry eye 
symptoms partially affecting 
ADL, (requiring eye drops > 
3 x per day or punctual 
plugs), WITHOUT new 
vision impairment due to 
KCS 
□ Severe dry eye symptoms 
significantly affecting, ADL 
(special eyeware to relieve 
pain) OR unable to work 
because of ocular symptoms 
OR loss of vision due to KCS 
□ Abnormality present but explained entirely by non-GVHD documented cause (specify):_____________________________ 
 
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 surface) 
□ Severe symptoms 
(shortness of breath at rest; 
requiring O2) 
□ Abnormality present but explained entirely by non-GVHD documented cause (specify):____________________________ 
 
 
 


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RANGE OF MOTION: 
 
□  Not done  
□  Not done  
□  Not done  


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Appendix G. Chronic GVHD Activity Assessment − Patient Self Report 
FORM B  
Today’s Date: ________________________ MR#/Name: ________________________  
 
CHRONIC GVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT 
 
Symptoms  
 
 
 
Not                                                                                                                       As Bad As You 
Present                                                                                                                    Can Imagine 
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.  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Your skin itching at its WORST? 
 
 
 
 
 
 
 
 
 
 
 
Your mouth dryness at its WORST? 
 
 
 
 
 
 
 
 
 
 
 
Your mouth sensitivity at its 
WORST? 
 
 
 
 
 
 
 
 
 
 
 
 
Eyes 
What is your main complaint with regard to your eyes? 
 
 
Please rate how severe is this eye symptom, between 0 
(not at all severe) and 10 (most severe): 
0   1   2   3   4   5   6   7   8   9   10 
 
Vulvovaginal Symptoms 
(females only) 
Do you have any burning, pain or discomfort in the 
area of your vagina, vulva or labia? 
OR 
Do you have any discomfort or pain with sexual 
intercourse? 
 
o 
Yes 
o 
No 
o 
Not applicable 
 
Patient Global Ratings:  
1. Overall, do you think that your chronic graft versus host disease is mild, moderate or severe?  
0= none  
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  
Attach copies of:  
 
Adults (persons 18 years or older):  
o 
Lee cGvHD Symptom Scale  
o 
Human Activity Profile  
o 
SF-36 v.2  
o 
FACT-BMT  
 
 
Children/Adolescents (persons 17 years or younger):  
o 
Lee cGVHD Symptom Scale (persons 8-12 years old may 
complete with help of the health care professional)  
o 
ASK - Activities Scale for Kids  
o 
CHRIs - Generic and Disease Specific Inventory  
Source: http://asbmt.affiniscape.com/associations/11741/files/ResponseCriteriaAPPENDIXBFormB.pdf
 
 


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Appendix H. Response Criteria for Partial Response and Progression in cGVHD 
Proposed calculations for partial response in chronic GVHD 
 
Organ and Starting Score or Value  
Partial Response Criterion*  
Skin (percent of body surface)  
  
> 50  
e/s ≤ 0.5 and e > 0  
25 – 50  
s – e ≥ 25 and e > 0  
< 25  
only CR; no PR possible  
Eye (mm Schirmer’s test)  
  
< 5 mm  
e – s ≥ 5 mm and e < LLN  
5 – 10 mm  
only CR; no PR possible  
Mouth (15-point Schubert scale)  
  
≥8  
e/s ≤ 0.5 and e > 0  
4 – 7  
s – e ≥ 4 and e > 0  
< 4  
only CR; no PR possible  
Platelet count  
e – s ≥ 100,000/uL and e < LLN  
Gastrointestinal (and other 0 – 3 scales)†  
  
3  
e = 1 or 2  
2  
e = 1  
1  
only CR; no PR possible  
Liver function tests (ALT, alkaline phosphatase and 
bilirubin) and eosinophil count  
  
≥ 3x ULN  
e/s ≤0.5 and e > ULN  
< 3 x ULN  
only CR; no PR possible  
* s, starting score or value; e, ending score or value; ULN, upper limit of normal; LLN, lower limit of normal 
† The proposed response criterion could be appropriate for shorter-term phase II studies. For longer-term pivotal 
phase III studies, a 1-point change might not be sufficient for PR. 
 
Examples : 
1. Skin: start score = 85, end score = 30; e/s = 30/85 = 0.35 = PR  
2. Skin: start score = 65, end score = 45; e/s = 45/65 = 0.75 = not PR  
3. Skin: start score = 45, end score = 15; s – e = 30 = PR  
4. Skin: start score = 30, end score = 15; s – e = 15 = not PR  
 
 


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Appendix H. Response Criteria for Partial Response and Progression in cGVHD (Cont'd) 
 
Proposed calculations for progression in chronic GVHD 
 
Organ and Starting Score or Value  
Progression Criterion*  
Skin (percent of body surface)  
e – s ≥ 25  
Eye  
s – e ≥ 5 mm  
Mouth (15-point Schubert scale)  
e – s ≥ 3  
Platelet count  
s – e ≥ 50,000/uL and e < LLN 
Gastrointestinal (and other 0 – 3 scales)  
e – s ≥ 1  
Liver (ALT, alkaline phosphatase and bilirubin), eosinophil count  
  
s ≥ 3x ULN  
e – s ≥ 3 x ULN  
s < 3x ULN  
e – s ≥ 2 x ULN  
Lungs (12-point Lung Function Scale)  
e – s ≥ 3†  
**Score changes from 0 to 1 are not considered progression. 
 
*s, starting score or value; e, ending score or value; ULN, upper limit of normal  
† If the starting lung function score is ≥ 10, progression is defined as ≥ 5% decrease of FEV1 in two tests measured 
at least 2 weeks apart. This time interval was selected because these syndromes can progress rapidly. 
http://asbmt.affiniscape.com/associations/11741/files/ResponseCriteriaAPPENDIXC_DCalculations.pdf 
 
 
 


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Appendix I. Guidelines for Chronic GVHD Activity Assessment – Clinician (FORM A) 
Any measure that is normal and does not have cGVHD involvement at Day 1 = NE (not evaluable), 
remains NE unless criteria for PD is met. 
Any measure that changes but is not felt to be related to cGVHD should be marked as NE. Organs with 
more than one component will have each component evaluated, and then an organ score will be assigned. 
Overall cGVHD assessment: SD: no PR, no PD, no CR 
PR: if no PD and ≥1 PR 
PD: if ≥1 PD 
CR: all CR 
Measures 
Individual 
Response* 
Overall organ response 
Skin (percent of body surface) 
Body surface area of erythematous rash 
 
NE: no cGVHD 
SD: no PR, no PD, no CR 
PR: if no PD and ≥1 PR 
PD: if ≥1 PD 
CR: all CR 
Skin Body surface area of moveable sclerosis  
 
Skin Body surface area of non-moveable sclerosis 
 
Eyes – Right eye Schirmer Tear Test (mm wetting) 
 
NE: no cGVHD 
SD: no PR, no PD, no CR 
PR: if no PD and ≥1 PR 
PD: if ≥1 PD 
CR: all CR 
Eyes – Left Eye Schirmer Tear Test (mm wetting) 
 
Mouth  
Mucosal change  
(Scores range from 0-15) 
 
NE: no cGVHD 
SD: no PR, no PD, no CR 
PR 
PD 
CR 
Blood Counts 
Platelet count and absolute eosinophil count  
 
NE: no cGVHD 
SD: no PR, no PD, no CR 
PR: if no PD and ≥1 PR 
PD: if ≥1 PD 
CR: all CR 
Liver Function Tests 
ALT, total serum bilirubin and alkaline phosphatase 
 
NE: no cGVHD 
SD: no PR, no PD, no CR 
PR: if no PD and ≥1 PR 
PD: if ≥1 PD 
CR: all CR 
GI – Upper 
 
 
NE: no cGVHD 
SD: no PR, no PD, no CR 
PR: if no PD and ≥1 PR 
PD: if ≥1 PD 
CR: all CR 
GI – Esophageal 
 
 
GI – Lower 
 
 
Lung response  
Pulmonary Function Tests with Diffusing Capacity, 
FEV1 and DLCO  
 
NE: no cGVHD 
SD: no PD 
PD  
No possible PR or CR 
Overall cGVHD Response 
 
SD: no PR, no PD, no CR 
PR: if no PD and ≥1 PR 
PD: if ≥1 PD 
CR: all CR 
*See Appendix H for individual response 
 
 


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Appendix J. Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A are defined as follows. A comprehensive list of inhibitors can be found at 
the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The general categorization into 
strong, moderate, and weak inhibitors according to the website is displayed below. Refer to Section 6.2.1 on 
instructions for concomitant use of CYP3A inhibitors and inducers with ibrutinib. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
Carbamazepine 
INDINAVIR 
Efavirenz 
NELFINAVIR 
Nevirapine 
RITONAVIR 
Barbiturates 
CLARITHROMYCIN 
Glucocorticoids 
ITRACONAZOLE 
Modafinil 
KETOCONAZOLE 
Oxcarbarzepine 
NEFAZODONE 
Phenobarbital 
SAQUINAVIR 
Phenytoin 
SUBOXONE 
Pioglitazone 
TELITHROMYCIN 
Rifabutin  
Moderate inhibitors: 
Rifampin  
aprepitant 
St. John’s Wort  
erythromycin 
Troglitazone  
diltiazem  
 
fluconazole 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
Weak inhibitors: 
 
cimetidine 
 
All other inhibitors: 
 
amiodarone 
 
NOT azithromycin 
 
chloramphenicol 
 
boceprevir 
 
ciprofloxacin 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
fluvoxamine 
 
gestodene 
 
imatinib 
 
mibefradil 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
telaprevir 
 
troleandomycin 
 
voriconazole 
 
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 
 
 
 


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Appendix K. Child-Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<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 
 
Source:  
1. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R . “Transection of the oesophagus for bleeding 
oesophageal varices”.  The British journal of surgery, 1973;60: 646-9. 

SAP_001.pdf: 
Statistical Analysis Plan 
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Statistical Analysis Plan 
 
A Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid Dependent or 
Refractory Chronic Graft Versus Host Disease 
 
Protocol PCYC-1129-CA 
 
 
 
 
Version:   1.0 
Version Date:  August 31, 2016 
 
 
  
 
 
 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics LLC that must not be 
disclosed to anyone other than the recipient study staff and members of the institutional review 
board/ethics committee.  This information cannot be used for any other purpose other than the 
evaluation or conduct of the clinical study without the prior written consent of Pharmacyclics 
LLC. 
 


Statistical Analysis Plan 
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Table of Contents 
ABBREVIATIONS ......................................................................................................................................... 4 
1. 
INTRODUCTION .................................................................................................................................. 5 
1.1 
Study Objectives ............................................................................................................................... 5 
1.1.1 
Primary Objective .......................................................................................................................... 5 
1.1.2 
Secondary Objectives ................................................................................................................... 5 
1.1.3 
Exploratory Objectives .................................................................................................................. 6 
1.2 
Study Design .................................................................................................................................... 6 
1.3 
Dosage and Administration .............................................................................................................. 6 
1.4 
Sample Size Justification .................................................................................................................. 6 
1.5 
Randomization and Blinding ............................................................................................................. 7 
2. 
STUDY POPULATIONS ...................................................................................................................... 7 
2.1 
Subgroups ........................................................................................................................................ 7 
3. 
GENERAL ANALYSIS CONSIDERATIONS ....................................................................................... 7 
3.1 
Definitions ......................................................................................................................................... 7 
3.1.1 
Study Day ...................................................................................................................................... 7 
3.1.2 
Baseline Value .............................................................................................................................. 8 
3.1.3 
Postbaseline Value ....................................................................................................................... 8 
3.1.4 
Duration of Treatment ................................................................................................................... 8 
3.1.5 
Time on Study ............................................................................................................................... 8 
3.1.6 
Age ................................................................................................................................................ 8 
3.1.7 
Dose Intensity................................................................................................................................ 9 
3.1.8 
Relative Dose Intensity ................................................................................................................. 9 
3.1.9 
Estimate Creatinine Clearance Rate ............................................................................................. 9 
3.1.10 
Absolute neutrophil count .............................................................................................................. 9 
3.2 
Visit Windows ................................................................................................................................... 9 
3.3 
Missing and Incomplete Data ......................................................................................................... 10 
3.3.1 
Missing Date of the Last Dose of Study drug .............................................................................. 10 
3.3.2 
Missing Date Information for Safety Endpoints ........................................................................... 10 
3.4 
Conventions .................................................................................................................................... 11 
4. 
SUBJECT INFORMATION ................................................................................................................ 11 
4.1 
Subject Enrollment ......................................................................................................................... 11 
4.2 
Subject Disposition ......................................................................................................................... 11 
4.3 
Important Protocol Deviations ........................................................................................................ 12 
4.4 
Demographics and Baseline Characteristics .................................................................................. 12 
4.5 
Baseline Disease Characteristics and Baseline Medications ......................................................... 12 
4.6 
Concomitant Medications ............................................................................................................... 12 
4.7 
Extent of Study drug Exposure ....................................................................................................... 13 
5. 
EFFICACY ANALYSIS ...................................................................................................................... 13 
5.1 
Primary Endpoint ............................................................................................................................ 13 
5.2 
Secondary Endpoints ..................................................................................................................... 14 
5.2.1 
Rate of Sustained Response ...................................................................................................... 14 
5.2.2 
Duration of Response ................................................................................................................. 14 
5.2.3 
Corticosteroid Requirement Changes over Time ........................................................................ 15 
5.2.4 
Change in Lee cGVHD Symptom Scale ..................................................................................... 15 
5.3 
Exploratory Endpoints .................................................................................................................... 16 
6. 
SAFETY ............................................................................................................................................. 16 
6.1 
Adverse Events .............................................................................................................................. 16 
6.1.1 
Adverse Events of Special Interest – Major Bleeding ................................................................. 17 


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6.1.2 
Other Safety Observations .......................................................................................................... 17 
6.2 
Clinical Laboratory Tests ................................................................................................................ 18 
6.3 
Vital Signs ....................................................................................................................................... 18 
7. 
REFERENCES ................................................................................................................................... 19 
8. 
APPENDIX ......................................................................................................................................... 20 
8.1 
Visit Window for Analysis ............................................................................................................... 20 
8.2 
SAS code to calculate Lee cGVHD symptom scale ....................................................................... 20 
 
 
 


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
cGVHD 
chronic graft versus host disease 
CI 
Confidence interval 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CTCAE v. 4.03 
Common Terminology Criteria for Adverse Events version 4.03 
CYP 
cytochrome P450 
DLT 
dose limiting toxicity 
DOR 
Duration of response 
eCcr 
estimated creatinine clearance 
ECG 
Electrocardiogram 
EDC 
electronic data capture  
FDA 
Food and Drug Administration 
FFS 
failure free survival 
ILD 
Interstitial Lung Disease 
IRRC 
Independent Response Review Committee 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
PCYC 
Pharmacyclics, LLC 
PR 
partial response 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SI 
Système international d'unités 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TEAE 
Treatment emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 
 


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1. Introduction 
Study PCYC-1129-CA is a Phase 1b/2 open-label study designed to evaluate the safety 
and efficacy of ibrutinib in subjects with steroid-dependent/refractory chronic graft 
versus host disease (cGVHD). 
Phase 1b will begin with the evaluation of the 420 mg/day dose level of ibrutinib with the 
potential for subsequent dose reductions if dose limiting toxicities (DLTs) are detected.  
A modified 3+3+3 design will be used to determine a safe dose to carry forward to Phase 
2 of the study (recommended Phase 2 dose [RP2D]). 
Phase 2 will evaluate the efficacy of the RP2D of ibrutinib determined in Phase 1b. 
Subjects will be given ibrutinib continuously along with any pre-existing 
immunosuppressants for cGVHD and followed for signs of progression/resolution of 
cGVHD. 
The purpose of this statistical analysis plan (SAP) is to provide a comprehensive 
description of the statistical analyses for efficacy and safety data that have been outlined 
within the protocol of Study PCYC-1129-CA (Amendment 2, dated 21 October 2015). 
The analyses will be executed by the Biometrics department of Pharmacyclics unless 
otherwise specified. 
This plan does not cover the pharmacokinetic or pharmacodynamic analyses and 
biomarker analysis, which will be performed and reported by the separate groups of 
Pharmacyclics. 
1.1 Study Objectives 
1.1.1 Primary Objective 
The primary objective of the Phase 1b part of the study is to evaluate the safety and 
tolerability of ibrutinib in subjects with steroid dependent/refractory cGVHD.  
The primary objective of the Phase 2 part of the study is to evaluate the clinical efficacy 
of ibrutinib in steroid dependent/refractory cGVHD by measuring best overall cGVHD 
response (National Institutes of Health [NIH]-defined complete response and partial 
response). 
1.1.2 Secondary Objectives 
Phase 1b: 
• To evaluate the clinical efficacy of ibrutinib in steroid dependent/refractory cGVHD 
by measuring: 
Best overall cGVHD response (complete and partial response per NIH-defined 
cGVHD criteria) 
Rate of sustained response for at least 5 months  
Duration of response (DOR) 
Corticosteroid requirement changes over time 
Change in symptom burden measured by the Lee cGVHD Symptom Scale 


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Phase 2: 
• To evaluate the clinical efficacy of ibrutinib in steroid dependent/refractory cGVHD 
by measuring: 
Rate of sustained response for at least 5 months  
Duration of response (DOR) 
Corticosteroid requirement changes over time 
Change in symptom burden measured by the Lee cGVHD Symptom Scale 
• To evaluate the safety and tolerability of ibrutinib in steroid dependent/refractory 
cGVHD  
1.1.3 Exploratory Objectives 
The exploratory objective covered by this analysis plan is: 
• To evaluate the clinical efficacy of ibrutinib by measuring failure free survival at 6 
and 12 months  
1.2 Study Design  
The study will be conducted in two phases. 
Phase 1b will begin with the evaluation of the safety of once daily dose (420 mg) 
ibrutinib with the potential for subsequent dose reductions if DLTs are detected. A 
modified 3+3+3 design will be used to determine a safe dose to carry forward to Phase 2 
of the study. Once the RP2D is determined, Phase 2 will commence. 
Phase 2 will evaluate the efficacy of the RP2D of ibrutinib determined in Phase 1b. 
Subjects will be given ibrutinib continuously along with their pre-existing 
immunosuppressant for cGVHD and followed for signs of progression/resolution of 
cGVHD. Approximately 34 subjects will be enrolled in Phase 2 to reach approximately 
40 subjects (Phase 1b + Phase 2 subjects) treated at the RP2D. 
1.3 Dosage and Administration 
Three dose levels of ibrutinib may be tested: 140 mg/day, 280 mg/day, and 420 mg/day. 
The starting dose level is 420 mg/day and the dose level might be modified based on the 
DLTs. 
The decision to proceed with a RP2D or to reduce the dose will be made in a Dose Level 
Review Meeting by the Sponsor in conjunction with the investigators after careful 
consideration of all available safety and laboratory information. 
Following the establishment of the RP2D, the Phase 2 portion of the study will begin 
enrolling additional subjects.  
1.4 Sample Size Justification 
The Phase 1b part of the study is a modified 3+3+3 dose-finding design that is described 
in the protocol. 


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With a sample size of 40 subjects receiving the RP2D, and assuming an overall cGVHD 
response rate of 50%, the study is expected to have at least 90% power to show the 
efficacious treatment effect (the lower bound of 95% confidence interval [CI] of the 
response rate >25%). 
1.5 Randomization and Blinding 
As an open-label, single arm study, there will be no randomization or blinding of 
subjects. 
2. Study Populations 
Safety Population includes all subjects who receive at least 1 dose of ibrutinib from 
either Phase 1 or Phase 2 portion of the study.  
All Treated Population includes all subjects who receive at least 1 dose of RP2D of 
ibrutinib from either the Phase 1 or Phase 2 portion of the study.  
Since the Phase 1 part of the study confirmed that the first dose level is safe for cGVHD 
subjects and is used as RP2D, the safety population is the same as the all treated 
population. Therefore, the All Treated Population will be used as the primary analysis 
population.  
Subject 003-201 was excluded from the All Treated Population because the subject had 
laboratory evidence of a relapse of underlying disease (AML) that was drawn before the 
first dose of study drug but results were available after the start of ibrutinib.  The separate 
listings will be provided for this subject. 
Response Evaluable Population includes all subjects who are in the all treated 
population and have an evaluable response assessment. 
Response evaluable population is used for sensitivity analysis population. It will be used 
to evaluate dose exposure and best overall cGVHD response. 
2.1 Subgroups 
Subgroup analysis will be performed on the primary efficacy endpoint as well as TEAEs 
to assess the effect of the following factors (subgroups that have high levels of imbalance 
will be omitted):  
1. Age  (<65 vs. ≥65)  
2. Gender (male vs. female). 
3. General Analysis Considerations 
3.1 Definitions 
3.1.1 Study Day 
Study day will be calculated in reference to the first dose of study drug.  Study Day 1 
corresponds to the date that the subject takes the first dose of study drug.   


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For dates before Study Day 1: 
Study Day n = Date of assessment/event – Date of Study Day 1 
For dates on or after Study Day 1: 
Study Day n = Date of assessment/event – Date of Study Day 1 + 1 day 
There will not be a Study Day 0.   
3.1.2 Baseline Value 
Unless otherwise specified, the baseline value is defined as the last valid measurement on 
or prior to the first dose of study drug 
3.1.3 Postbaseline Value 
The postbaseline value is defined as a measurement taken after the first dose of study 
drug.   
For subjects with a valid, nonzero baseline value: 
Change from baseline = postbaseline value – baseline value; 
% change from baseline = (change from baseline/baseline)*100. 
3.1.4 Duration of Treatment 
Duration of treatment will be calculated from the date of the first dose of study drug to 
the date of the last dose of study drug, as follows:  
Duration of treatment = date of last dose of study drug – date of first dose of study 
drug + 1 day. 
3.1.5 Time on Study 
Time on Study will be calculated from the date of the first dose of study drug to the study 
exit date or the last known alive date if the subjects are still in the study, as follows:  
Time on Study = study exit date/last known alive date – date of first dose of study 
drug + 1 day. 
For subjects who did not take the study drug, Time on Study is calculated from the date 
of enrollment to the study exit date.  
3.1.6 Age 
Age in years will be the subject age at the date of enrollment. 


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3.1.7 Dose Intensity 
Dose intensity (mg/day) is defined as the ratio of total dose received in mg and treatment 
duration in days. 
3.1.8 Relative Dose Intensity 
Relative dose intensity (%) is defined as the percentage of total cumulative dose 
administered (mg) versus the total expected dose (mg). Total cumulative dose 
administered is the sum of daily dose taken over the whole study course; and total 
expected dose (mg) is the product of the duration of the treatment (day) and the protocol 
assigned daily dose. Relative dose intensity is calculated by total cumulative dose 
administered / total expected dose × 100%.  
3.1.9 Estimate Creatinine Clearance Rate 
Estimated creatinine clearance rate (eCcr) will be calculated using the Cockcroft-Gault formula  
[
]
)
/
(
72
85
.0
)
(
)
140
(
min)
/
(
dL
mg
Creatinine
Serum
Female
if
kg
Weight
Age
mL
eCcr
×
×
×
−
=
 
When serum creatinine is measured in µmol/L, the formula is  
)
/
(
)
(
)
140
(
min)
/
(
L
mol
Creatinine
Serum
C
kg
Weight
Age
mL
eCcr
μ
×
×
−
=
 
using a constant C of 1.23 for men and 1.04 for women.  
In this calculation, if weight is not measured at the same visit as creatinine, the weight measured 
prior and closest to the creatinine collection time will be used. 
3.1.10 Absolute neutrophil count  
Absolute neutrophil count (ANC) is calculated by  
ANC = (% neutrophil+% bands) × White blood cell / 100 
where white blood cell is in 109/L. 
3.2 Visit Windows 
Visit windows have been given in the Time and Events Schedule of the protocol. For by-
visit analysis, visit will be used to associate assessment with a scheduled visit and will be 
created in reference to the date of first dose of study drug to assign visit number based on 
evaluation date. Details for target date for each scheduled visit and time interval between 
scheduled visits are provided in 20.  
• 
If more than one assessment falls into a given visit window, the non-missing one 
closest to the target date will be used.  If two assessments are equally close to the 
target day, the earlier assessment will be used.  


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3.3 Missing and Incomplete Data 
In order to achieve the goal of a well-conducted clinical study according to Good Clinical 
Practice, every effort will be made to collect all data. However, despite best efforts, it 
may be inevitable that some data may be missing or incomplete. In the subject data 
listing, the available data, including partial data will be presented as they are recorded on 
the case report forms (CRFs).  
Time-to-event or duration-of-event endpoints will be based on the study day rather than 
visit number or visit label. No imputation of missing values will be performed for 
efficacy data unless otherwise specified.  
No imputation of missing values for safety data will be performed unless otherwise 
specified.   
3.3.1 Missing Date of the Last Dose of Study drug  
When the date of the last dose of the study drug is missing for a subject in the All Treated 
Population, all efforts should be made to obtain the date from the Investigator. If it is still 
missing after all efforts are made, the information will not be imputed. The subject might 
be excluded from some analyses due to the missing information.   
3.3.2 Missing Date Information for Safety Endpoints 
For missing or partial start and end dates for AEs, medical history, prior therapy and 
concomitant medication, no imputation will be performed. However, a conservative 
approach will be taken when performing the related analyses. If the available information 
is not enough to judge whether an event or a therapy duration has overlapped with study 
treatment duration, events reported on AE pages will be taken as treatment emergent 
AEs, events reported on medical history page will be treated as prior medical condition, 
prior or concomitant therapy will be considered as continuing therapy which started prior 
to first study treatment. 
However, an intermediate imputation of partial dates may be taken in order to calculate 
the study day for AEs, medical history, prior therapy and concomitant medications. This 
is just for estimation of the timing of events relative to the study course. All missing or 
partial dates should remain the same values as they were recorded on the CRFs. The 
intermediate imputation rules are: 
If only day is missing, then the 15th of that month will be used. 
If only year is present, then June 30th will be used. 
If such imputed date for prior therapies or initial diagnosis is on or after the date of the 
first dose of study drug, then date of the first dose – 1 day will be used. If such imputed 
date for the start or end of subsequent therapies is before date of last dose of study drug, 
then date of last dose of study drug +1 day will be assumed. If an imputed start date of 
prior or subsequent therapy is after the end date, the end date will be used. If an imputed 
end date of prior or subsequent therapy is before its start date, the start date will be used. 
If an imputed AE start date is in the same month and year as the first dose date of study 
drug but on an earlier date, the first dose date will be used. If an imputed AE start date is 


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in the same month and year as the date of 30 days post the last dose of study drug but on 
a later date, the date of 30 days post the last dose will be used. If an imputed AE start date 
is after the AE end date, the AE end date will be used. 
If the imputed date is for an AE end date and is after the death date, then the death date 
will be used, or if the imputed AE end date is before the AE start date, then the AE start 
date will be used.  
The average daily use of corticosteroid will be used to evaluate the treatment effect. All 
efforts should be made to obtain the date from the Investigator. If it is still missing after 
all efforts are made, the information might be imputed with a conservative approach. If a 
date was missed in the middle of other corticosteroid uses, we might need to fill this dose 
to the whole gap between the records with imputation.   
3.4 Conventions 
Continuous variables will be summarized with descriptive statistics (mean, standard 
deviation, median, quartiles, minimum, and maximum). Standard deviation can be 
replaced by standard error for special requirement. Categorical variables will be 
summarized using frequencies and percentages.  
In efficacy analysis, month is calculated by cycle (28 days). For the analysis other than 
efficacy, the following rules will be used for the days to months/years conversion: 
• 1 month = 30.4375 days;   
• 1 year = 365.25 days. 
All data collected on the CRF will be presented in data listings upon request by the 
Regulatory agency. All statistical analyses will be performed using SAS® version 9.2 or 
higher. 
4. Subject Information  
4.1 Subject Enrollment 
Subject enrollment will be summarized by study center as based on all enrolled subjects. 
4.2 Subject Disposition 
The information will be summarized as follows for subject disposition:  
• 
Subject status for the study  
• 
Reason for study termination for subjects who were off the study 
• 
Time on study 
• 
Subject status for the study drug 
• 
Reason for study treatment discontinuation for subjects who discontinued study 
drugs 


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4.3 Important Protocol Deviations 
In general, protocol violations/deviations will be reviewed by the study team during the 
study, and important protocol deviations will be determined based on the review. The 
information of important protocol deviations will be generated based on the review 
outcome for all subjects.  
4.4 Demographics and Baseline Characteristics 
All demographic and baseline characteristics will be summarized for the all treated 
population.   
The demographics include:   
• Age  
• Gender,  race, and ethnicity 
The baseline characteristics include:  
• 
Weight and height 
• 
Estimated creatinine clearance rate (eCcr)  
• 
Estimated creatinine clearance rate groups (< 30 mL/min; 30 – < 60 mL/min, >= 60 
mL/min) 
• 
Baseline hemoglobin and platelets  
4.5 Baseline Disease Characteristics and Baseline Medications 
The history information related to the disease will be summarized. The key baseline 
characteristics include:  
• Months from Last Transplantation to Enrollment, which is defined as the time period 
between the last transplantation and enrollment  
• Months from Initial cGVHD Diagnosis Date, which is defined as the time period 
between the initial cGVHD diagnosis and enrollment 
• Months from Transplantation to initial cGVHD diagnosis date 
• 
Karnofsky performance status score at baseline 
• 
Number of prior cGVHD treatment regimens 
• 
Organs involved in cGVHD 
4.6 Concomitant Medications 
Reported medications will be coded to a generic name and an Anatomical Therapeutic 
Chemical (ATC) class according to World Health Organization (WHO) Drug dictionary 
and will be summarized. 
Medication that was taken before the first dose of the study drug is called prior 
medication. Concomitant medications are defined as medications that were taken 
between the date of the first dose of study drug and the date of the last dose of study drug. 


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Concomitant medications will be summarized by therapeutic class and preferred term. 
The summary of usage of CYP3A inhibitors as well CYP3A inducers will be provided 
separately.  
The summary of usage of anticoagulants and antiplatelets will also be provided.  
Subsequent cGVHD therapies taken after the start of study drug will be summarized 
separately. 
4.7 Extent of Study drug Exposure  
The exposure to study drugs will be summarized.  The following parameters will be 
summarized when applicable: 
• Duration of treatment  
• Cumulative dose received on study 
• Dose intensity 
• Relative dose intensity 
• Dose reduction due to AE 
• Dose interruption with 7 days or more due to AE 
5. Efficacy Analysis  
Unless specified otherwise, all information from the Phase 1b and Phase 2 parts of the 
study will be combined for efficacy analysis. The primary population used to evaluate 
efficacy is All Treated Population and where applicable, the response evaluable analysis 
set will be used as a sensitivity analysis to assess the robustness of the results.  
5.1 Primary Endpoint 
The primary efficacy endpoint is the best overall cGVHD response rate during the study 
based on investigator assessments. To assess the primary endpoint, the study used the 
2005 NIH Consensus Panel Response criteria with two modifications based on the 
updated 2014 NIH Consensus Panel Response criteria:  1) “Not Evaluable” can be used 
for assessments where there is another non-cGVHD cause for the abnormalities 
documented and 2) a change in cGVHD organ score from 0 to 1 is no longer considered 
progression as is the case per the 2005 NIH cGVHD Response Criteria.  
Best overall cGVHD response rate is defined as the proportion of subjects who achieve a 
NIH-defined complete response or partial response. The response rate and its 95% 
confidence interval (CI) will be calculated based on the exact test for binomial 
distribution. If the lower bound of the CI of the response rate is ≥25%, the primary 
efficacy objective is achieved.   


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5.2 Secondary Endpoints 
In order to preserve the study wise two-sided type I error rate of 0.05, rate of sustained 
response will be tested at the two-sided significance level of 0.05 if the primary endpoint, 
best overall cGVHD response rate, achieves statistical significance. Other secondary 
endpoints will be summarized with descriptive statistics. No formal statistical testing is 
planned for the other secondary endpoints.  
5.2.1 Rate of Sustained Response  
Sustained response is defined as NIH-defined response that sustain continuously for at 
least 5 months (140 days). Considering 3 days visit window allowed by protocol, the 
bound of sustained response is defined as 137 days. Intermittent SD assessment between 
response assessments is allowed. Of the total number of subjects who responded to study 
treatment, the proportion of subjects who meet the sustained response criterion will be 
summarized in the same manner as the primary endpoint. If the lower bound of the CI of 
the response rate is ≥25%, this secondary objective is achieved. 
5.2.2 Duration of Response  
Duration of Response (DOR) is defined as the interval between the date of initial 
documentation of a response, and the date of first documented evidence of progressive 
disease, death, or date of censoring if applicable, for responders only. The distribution 
(median and Kaplan-Meier curve) will be provided using Kaplan-Meier estimates to 
evaluate DOR. DOR will be right censored based on Table 1 for all responders: 
Table 1:  
Date of Event or Censoring for Duration of Response 
Situation 
Date of DOR event or Censoring 
Outcome 
Death or disease progression occurred on or 
before the start date of subsequent cGVHD 
treatment documented at scheduled disease 
assessments or between two scheduled 
disease assessments. 
Earliest date of adequate disease assessment 
documenting disease progression or date of 
death, whichever occurs first. 
Progressed 
New subsequent cGVHD treatment before 
disease progression 
Date of last adequate disease assessment 
prior to or on start date of the new 
subsequent cGVHD treatment 
Censored 
Not known to have progressed or died at 
the data analysis cutoff date (this includes 
subjects 
who 
were 
known 
to 
have 
progressed or died after the data analysis 
cutoff date) 
Date of last adequate disease assessment 
showing no evidence of disease progression. 
Censored 
For subjects who met more than one censoring condition, DOR will be censored 
according to the earliest censoring condition/date. For subjects who have incomplete date 
for initiation of subsequent cGVHD treatment, the partial date will be imputed as the 
earliest possible date that incorporates the available information from the partial date and 
does not contradict last dose date of study drug. 


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5.2.3 Corticosteroid Requirement Changes over Time  
Systemic corticosteroid therapy for cGVHD will be monitored throughout the study. The 
corticosteroid dose level will be measured by the daily dose amount versus the weight of 
subject (mg/kg/day). For the days without weight measurement, the last observed weight 
measurement will be used. Considering the frequency of corticosteroid use might not be 
once daily, we use weekly average daily dose instead of the actual daily dose. The 
average corticosteroid dose level in each week is calculated by  
 
Sum of total corticosteroid dose used in this week / 7 
If a subject terminated the study drug in the middle of the week, the average 
corticosteroid dose level in that week will be calculated by 
Sum of total corticosteroid dose used in the week before the study drug 
termination / actual days in the week up to the last dose of study drug. 
Evaluation of systemic use of corticosteroid therapy will be performed for those subjects 
with SD or PD as their best overall response, and separately for subject with a best 
overall response of PR or CR.   
5.2.4 Change in Lee cGVHD Symptom Scale  
Subject-reported improvement in symptom burden will be evaluated.  The symptom 
burden is measured according to the Lee cGVHD Symptom Scale (Lee 2002). There are 
7 domains, and each has several items.  
 
Subscale 
Related Items 
Maximum number of missing 
items to get a valid score 
Skin 
1, 2, 3, 4, 5 
2 
Energy 
14, 21, 22, 23, 24, 25, 26 
3 
Lung 
12, 13, 15, 16, 27 
2 
Eye 
6, 7, 8 
1 
Nutrition 
11, 17, 18, 19, 20 
2 
Mouth 
9, 10 
1 
Psychological 
28, 29, 30 
1 
A score is calculated for each subscale by taking the mean of all items completed if more 
than 50% were answered and normalizing to a 0 to 100 scale. A total summary score is 
calculated as the average of these 7 subscales if at least 4 subscales have valid scores. 
The SAS code copied from Lee’s website for the calculation is in Appendix 8.2. A 
summary of total scores as well as each subscale scores for Lee cGVHD symptom scale 
will be performed throughout the study.  
A change in >7 points on the Lee cGVHD Symptom Scale will be considered significant 
and relates to improvement in quality of life (Lee 2006). A summary of the proportion of 
subjects who have decreases of at least 7 points in Lee cGVHD symptom scale during the 
study will be performed.  


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Evaluation of Lee cGVHD Symptom Scale will be performed for those subjects with SD 
or PD as their best overall response, and separately for subject with a best overall 
response of PR or CR.    
5.3 Exploratory Endpoints 
The exploratory endpoint covered in this analysis plan is failure-free survival. 
Failure free survival (FFS) is defined as no death, no relapse of underlying malignancy, 
and no new systemic immunosuppressive therapy for cGVHD. FFS will be right censored 
based on Table 2: 
Table 2:  
Date of Event or Censoring for Failure Free Survival 
Situation 
Date of FFS event or Censoring 
Outcome 
Death. 
Date of death 
Event 
New subsequent cGVHD treatment  
Date of starting the new subsequent cGVHD 
treatment 
Event 
Recurrent of malignancy 
Start date of recurrent of malignancy  
Event 
Not known to have event at the data 
analysis cutoff date (this includes subjects 
who were known to have event after the 
data analysis cutoff date) 
Date of last known date showing no 
evidence of event. 
Censored 
The distribution (median and Kaplan-Meier curve) will be provided using Kaplan-Meier 
estimates to evaluate FFS. 
6. Safety 
DLT review to determine RP2D will be performed in the Dose Level Review Meeting by 
the Sponsor in conjunction with the investigators after careful consideration of all 
available safety and laboratory information. This analysis plan will not cover this 
procedure. 
Safety data collected in both Phase 1b and Phase 2 will be summarized together. Unless 
specified otherwise, all safety analyses will be based on All Treated Population. 
6.1 Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events (AEs) 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Adverse events will be graded by the investigator according the National Cancer Institute 
common terminology criteria for adverse events (CTCAE) Version 4.03.   
Drug-related adverse events are those assessed by investigator as being possibly related 
or related to study drug. 
Treatment-emergent AEs are defined as those events that 1) occur on or after the first day 
of study drug, and within 30 days following the last dose of study drug or initiation of 
subsequent cGVHD therapy; 2) any event with missing onset date and its resolution date 
is during the treatment phase unless the event was indicated in the CRF that was present 


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before the first day of study drug; 3) any event that is considered study drug-related 
regardless of the start date of the event; or 4) any event that is present at baseline but 
worsens in severity or is subsequently considered drug-related by the investigator.  
For each adverse event, the percentage of subjects who experience at least 1 occurrence 
of the given event will be summarized.  In the event a patient experiences repeat episodes 
of the same AE, then the event with the highest severity grade will be used for purposes 
of incidence tabulations. 
Summaries of AEs include: 
• Incidence of AEs and serious adverse events (SAEs) by System Organ Class 
(SOC) and preferred term 
• Incidence of AEs and SAEs by preferred term 
• Incidence of drug-related AEs and SAEs  
AE leading to study treatment discontinuation for the subjects who discontinued study 
drug due to AE, AE leading to dose reduction, and AEs leading to death will be 
summarized.  
6.1.1 Adverse Events of Special Interest – Major Bleeding  
Hemorrhagic events will be identified by hemorrhage Standardized MedDRA Query 
[SMQ] excluding laboratory terms and be tabulated. Major hemorrhage is a subset of 
hemorrhagic events which are grade ≥ 3 or serious or belong to central nervous system 
(CNS) hemorrhage/hematoma.  
6.1.2 Other Safety Observations 
Other Malignancies 
Other malignancies are defined as new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies and are to be reported. They will be 
summarized based on following categories: melanoma skin cancer, non-melanoma skin 
cancer and non-skin cancer. Relapse of the underlying malignancy that was the basis for 
transplantation will not be included in this analysis. 
Hypersensitivity Reactions 
Hypersensitivity Reactions include angioedema, anaphylactic reaction, anaphylactoid 
reaction, anaphylatic shock, anaphylactoid shock, urticaria, drug hypersensitivity, and 
hypersensitivity. All treatment emergent hypersensitivity reaction events will be 
evaluated based on preferred terms.  
Hypertension 
Hypertension includes hypertension, essential hypertension, hypertensive crisis, blood 
pressure increase, systolic hypertension, and retinopathy hypertensive. All treatment 
emergent hypertension events will be summarized by preferred terms.  
Interstitial Lung Disease 


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Interstitial Lung Disease (ILD) will be determined based on ILD SMQ excluding 
radiation alveolitis, radiation fibrosis - lung, and radiation pneumonitis, pulmonary 
radiation injury and transfusion-related acute lung injury. All treatment emergent ILD 
events will be summarized by preferred terms.  
Severe Cutaneous Adverse Reaction 
Severe Cutaneous Adverse Reaction (SCAR) will be determined based on following 
prefer terms: 
Skin and subcutaneous tissue disorders SOC
Acute generalised exanthematous pustulosis
Cutaneous vasculitis
Dermatitis bullous
Dermatitis exfoliative
Dermatitis exfoliative generalised
Drug reaction with eosinophilia and systemic symptoms 
Epidermal necrosis
Erythema multiforme
Exfoliative rash
Oculomucocutaneous syndrome
Skin necrosis
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Toxic skin eruption
 All treatment emergent SCAR events will be summarized by preferred terms.  
6.2 Clinical Laboratory Tests 
All laboratory values will be converted to SI units and classified as normal, low, or high 
based on normal ranges of University of California, San Francisco.   
The gradable laboratory parameters will be graded using the NCI CTCAE v4.03. The 
worst postbaseline toxicity grade will be summarized for hematologic and chemistry 
parameters.   
Shift table will also be used to evaluate creatinine clearance.   
6.3 Vital Signs 
Body temperature, heart rate, blood pressure, respiratory rate, and weight will be 
collected during the study. Descriptive statistics and change from baseline will be provided 
over time.  
 
 


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7. References 
1. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor (PCI-32765) has significant 
activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 2012;31:88-94. 
2. Measurement of Therapeutic Response in Chronic Graft-versus-Host Disease. American Society for 
Blood and Marrow Transplantation (ASBMT) Web site. http://www.asbmt.org/?29. Accessed April 9, 
2014. 
3. Anasetti C, Logan BR, Lee SJ, et al. Increased incidence of chronic graft-versus-host disease (GVHD) 
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. 
4. Brown LD, Cai TT, and DasGupta A. Interval estimation for a binomial proportion. Statistical Sci 
2001;16:101-133. 
5. Lee JW, Deeg HJ. Prevention of chronic GVHD. Best Pract Res Clin Haematol. 2008;21:259-270.  
6. Lee SJ, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure symptoms of 
chronic graft-versus-host disease. Biologyu of Blood and Marrow Transplantation 2002;8:444-452. 
7. Lee SJ, Klein JP, Barrett AJ, et al. Severity of chronic graft-versus-host disease: association with 
treatment-related mortality and relapse. Blood 2002;100: 406-14. 
8. Lee SJ, Kim HT, Ho VT, et al. Quality of life associated with acute and chronic graft-versus-host 
disease. Bone Marrow Transplant 2006;38:305-10. 
9. Lee SJ. Have we made progress in the management of chronic graft-vs-host disease? Best Pract Res 
Clin Haematol. 2010;23:529-535.  
10. 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. 
11. US Food & Drug Administration: Guidance for Industry: Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics. May 2007 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm07
1590.pdf). 
 
 
 


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8. Appendix 
8.1 Visit Window for Analysis  
Details for target date for each scheduled visit and time interval between scheduled visits 
are provided in the table below: 
Visit 
Start Day 
Target Day 
End Day 
Baseline  
Last measurement prior to or on the first dose date 
Cycle Visits 
Week 5 
2 
29 
43 
Week 13 
44 
85 
127 
Week 25 
128 
169 
211 
Week 37 
212 
253 
295 
Week 49 
296 
337 
379 
Week 61 
380 
421 
463 
Week 73 
464 
505 
547 
Week 85 
548 
589 
631 
Week 97 
632 
673 
715 
Week x (every 12 
weeks, where x ≥ 97) 
(x-1)*7-40 
(x-1)*7+1 
(x-1)*7+43 
 
8.2 SAS code to calculate Lee cGVHD symptom scale 
This code is copied from the website of Stephanie Lee Lab 
(http://research.fhcrc.org/lee/en/research-resources.html)  
data newdata; 
  set olddata; 
*********************************************************************** 
*** Lee chronic GVHD symptom scales *** 
*********************************************************************** 
  array oldsx{30} sx1-sx30; 
  array newsx{30} b3a b3b b3c b3d b3e b3f b3g b3h b3i b3j b3k b3l b3m  
                  b3n b3o b3p b3q b3r b3s b3t b3u b3v b3w b3x b3y b3z  
                  b3aa b3bb b3cc b3dd;   
  do i = 1 to 30;  
     newsx{i}=oldsx{i};  
     if newsx{i} not in (0,1,2,3,4) then newsx{i}=.; 
  end; 
  if nmiss(b3a,b3b,b3c,b3d,b3e) le 2 then sx_skin=mean(b3a,b3b,b3c,b3d,b3e)*25; 
  if nmiss(b3n,b3u,b3v,b3w,b3x,b3y,b3z) le 3 then  
     sx_energy=mean(b3n,b3u,b3v,b3w,b3x,b3y,b3z)*25; 
  if nmiss(b3l,b3m,b3o,b3p,b3aa) le 2 then  
     sx_lung=mean(b3l,b3m,b3o,b3p,b3aa)*25; 
  if nmiss(b3f,b3g,b3h) le 1 then sx_eye=mean(b3f,b3g,b3h)*25; 
  if nmiss(b3k,b3q,b3r,b3s,b3t) le 2 then  
     sx_nutrition=mean(b3k,b3q,b3r,b3s,b3t)*25; 
  if nmiss(b3i,b3j) le 1 then sx_mouth=mean(b3i,b3j)*25; 
  if nmiss(b3bb,b3cc,b3dd) le 1 then sx_psych=mean(b3bb,b3cc,b3dd)*25; 
  if nmiss(sx_skin,sx_energy,sx_lung,sx_eye,sx_nutrition,sx_mouth,sx_psych) le 3  


Statistical Analysis Plan 
Ibrutinib                                                     PCYC-1129-CA                                                       31August2016 
Pharmacyclics LLC.                       Proprietary and Confidential                                               Page 21 of 21 
     then sx_sum =  
           mean(sx_skin,sx_energy,sx_lung,sx_eye,sx_nutrition,sx_mouth,sx_psych); 
  label  
    sx_skin = "Lee symptom skin scale (0-100)" 
    sx_energy = "Lee symptom energy scale (0-100)" 
    sx_lung = "Lee symptom lung scale (0-100)" 
    sx_eye = "Lee symptom eye scale (0-100)" 
    sx_nutrition = "Lee symptom nutrition scale (0-100)" 
    sx_psych = "Lee symptom psychological scale (0-100)" 
    sx_mouth = "Lee symptom mouth scale (0-100)" 
    sx_sum = "Lee symptom overall summary scale (0-100)"; 
  drop i 
       b3a b3b b3c b3d b3e b3f b3g b3h b3i b3j b3k b3l b3m b3n b3o     
       b3p b3q b3r b3s b3t b3u b3v b3w b3x b3y b3z b3aa b3bb b3cc b3dd;   
run; 
 
proc print data=newdata noobs; 
run;