Clinical trial NCT04235036
Conditions: Graft Vs Host Disease
Keywords: ibrutinib rituximab cGVHD chronic GVHD
Sponsor: Northside Hospital, Inc.
Start date: 2019-12-16; Completion date: 2022-12-23
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II trial evaluating the safety and efficacy of the combination of Ibrutinib and Rituximab as primary treatment of chronic GVHD. We plan to enroll 35 patients on this study. Patients will be formally monitored monthly for 12 months to evaluate for outcome and safety endpoints. All other assessments will be done at the physician's discretion or institutional standards. All patients, responders and treatment failures, will be followed for a period of one year from the time of initiation of therapy. The primary endpoint will be the proportion of patients that are alive and off all systemic IST at 12 months following initiation of treatment.

Detailed description:

Arms: arm 1: Eligible patients will be those with a first episode of symptomatic cGVHD, requiring systemic immunosuppression for control of symptoms. Following study entry, patients will be started on rituximab plus ibrutinib.
Interventions: intervention 1: Rituximab intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Rituximab is given IV weekly x 4 weeks (to be started on study day 7 ± 3 days), then IV q3months x 4 doses (months 4, 7, 10, 13). intervention 2: Ibrutinib is given orally every day (28-day cycles) for a total of 12 cycles.

Protocol documents:
Prot_SAP_000.pdf: 
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PROTOCOL 
 
 
TITLE: 
Phase II Trial Evaluating the Safety and Efficacy of Combined 
CD20- and BTK-Targeted B cell Depleting Therapy with 
Rituximab and Ibrutinib in the Primary Treatment of Chronic 
Graft-Versus-Host Disease 
 
PROTOCOL NUMBER: 
NSH 1219 
STUDY DRUG: 
Ibrutinib (PCI-32765) 
 
 
INVESTIGATOR: 
Scott R. Solomon, MD, Principal Investigator 
Melhem Solh, MD, Associate Investigator 
Asad Bashey, MD, Associate Investigator 
Lawrence E. Morris, MD, Associate Investigator 
H. Kent Holland, MD, Associate Investigator 
Lizamarie Bachier-Rodriguez, MD, Associate Investigator 
 
SPONSOR: 
Pharmacyclics 
 
DATE FINAL: 
8/12/2022 version 4.0 
 
 
 
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 conduct of the 
clinical study without the prior written consent of Pharmacyclics LLC. 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
LIST OF APPENDICES ...............................................................................................................4 
LIST OF IN-TEXT TABLES AND FIGURES ...........................................................................5 
SYNOPSIS ......................................................................................................................................6 
ABBREVIATIONS ......................................................................................................................11 
1. 
BACKGROUND ..........................................................................................................13 
1.1. 
Chronic GVHD ..........................................................................................……………13 
1.1.1. 
Chronic GVHD Background .........................................................................................13 
1.1.2. 
B Cell depleting therapy for treatment of cGVHD ...........……………………………14 
1.1.3. 
Targeting the Bruton’s tyrosine kinase .........................................................................15 
1.1.4. 
Rationale for combining Rituximab with Ibrutinib .......................................................15 
1.2. 
Ibrutinib Overview ........................................................................................................15 
1.2.1.1. 
Bleeding-Related Events..…………………………………………………….........…16 
1.2.1.2. 
Infections .......................................................................................................................16 
1.2.1.3. 
Cytopenias .....................................................................................................................16 
1.2.1.4. 
Interstitial Lung Disease (ILD) .....................................................................................17 
1.2.1.5. 
Cardiac Arrythmias .......................................................................................................17 
1.2.1.6. 
Tumor Lysis Syndrome .................................................................................................17 
1.2.1.7. 
Non-melanoma Skin Cancer .........................................................................................17 
1.2.1.8.  Diarrhea .......................................................................................................................177 
1.2.1.9. 
Rash ...............................................................................................................................17 
1.2.1.10. Hypertension .................................................................................................................18 
1.3. 
Study Rationale .............................................................................................................18 
2. 
STUDY OBJECTIVE .................................................................................................19 
2.1. 
Primary Objective ..........................................................................................................19 
2.2. 
Secondary Objective(s) .................................................................................................19 
2.3. 
Exploratory Objective(s) (if applicable) ........................................................................20 
3. 
STUDY DESIGN .........................................................................................................20 
3.1. 
Overview of Study Design ............................................................................................20 
3.2. 
Study Schema ................................................................................................................21 
4. 
SUBJECT SELECTION ...........................................................................................221 
4.1. 
Inclusion Criteria .........................................................................................................221 
4.2. 
Exclusion Criteria ..........................................................................................................22 
5. 
TREATMENT OF SUBJECTS .................................................................................23 
5.1. 
Study Medication ..........................................................................................................23 
5.1.1. 
Ibrutinib  ......................................................................................................................233 
5.1.1.1. 
Formulation/Packaging/Storage ....................................................................................23 
5.1.1.2. 
Dose and Administration .............................................................................................233 
5.1.1.3. 
Overdose ........................................................................................................................24 
5.1.1.4. 
Dose Modification for Non-CardiacAdverse Reactions ...............................................24 
5.1.1.5 
Dose Modification Guidance for Cardiac Toxicity .......................................................26 
5.1.1.6. 
Dose Modification for Hepatic Impaired Subjects ........................................................26 
5.1.1.7. 
Dose Modification for Concomitant Use of CYP3A Inhibitors ....................................26 


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5.1.2. 
Rituximab  ...................................................................................................................277 
5.1.2.1 
Formulation/Packaging/Storage ..................................................................................267 
5.1.2.2. 
Dose and Administration .............................................................................................267 
5.1.2.3. 
Overdose ......................................................................................................................268 
5.1.2.4. 
Dose Modification for Adverse Reactions ....................................................................26 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES .............................................29 
6.1. 
Permitted Concomitant Medications .............................................................................29 
6.2. 
Medications to be Used with Caution ...........................................................................30 
6.2.1. 
CYP3A Inhibitors/Inducers ...........................................................................................30 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib ...................30 
6.2.3. 
Antiplatelet Agents and Anticoagulants ........................................................................30 
6.3. 
Other Systemic immunosuppression .............................................................................30 
6.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures ............................30 
6.4.1. 
Minor Surgical Procedures ............................................................................................30  
6.4.2 
Major Surgical Procedures……………………………………………………………31 
7. 
STUDY EVALUATIONS ...........................................................................................31 
7.1. 
Description of Procedures .............................................................................................31 
7.1.1. 
Assessments ...................................................................................................................31 
7.1.1.1. 
ICF .................................................................................................................................31 
7.1.1.2. 
Confirm Eligibility ........................................................................................................31 
7.1.1.3. 
Medical History and Demographics ..............................................................................31 
7.1.1.4. 
Prior and Concomitant Medications ..............................................................................31 
7.1.1.5. 
Adverse Events ............................................................................................................332 
7.1.1.6. 
Physical Examination ....................................................................................................32 
7.1.1.7. 
Karnofsky Performance Status ......................................................................................32 
7.1.1.8. 
Vital Signs .....................................................................................................................32 
7.1.2. 
Laboratory .....................................................................................................................32 
7.1.3. 
Diagnostics/Procedures .................................................................................................32 
7.2. 
Efficacy Evaluations ......................................................................................................33 
7.3. 
Correlative Blood Collection and Handling ................................................................334 
8. 
STUDY PROCEDURES .............................................................................................34 
8.1. 
Screening Phase .............................................................................................................34 
8.1.1. 
Screening/Consenting Visit ...........................................................................................34 
8.2. 
Treatment Phase ............................................................................................................35 
8.2.1. 
Treatment Visits ............................................................................................................35 
8.2.1.1. 
C1D1Ibrutinib ...............................................................................................................35 
8.2.2. 
Response Follow Up .....................................................................................................34 
9. 
SUBJECT COMPLETION AND WITHDRAWAL ................................................36 
9.1. 
Completion ....................................................................................................................36 
9.2. 
Criteria for Study Discontinuaion .................................................................................36 
10. 
STATISTICAL METHODS AND ANALYSES .......................................................36 
10.1. 
Analysis Population .......................................................................................................36 
10.2. 
Endpoints .......................................................................................................................37 
10.2.1. 
Primary Endpoints .........................................................................................................37 
10.2.2. 
Secondary Endpoints .....................................................................................................37 


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10.2.3. 
Exploratory Endpoints  ..................................................................................................37 
10.3. 
Sample Size Determination ...........................................................................................38 
10.4. 
Efficacy Analysis Methods ...........................................................................................38 
11. 
ADVERSE EVENT REPORTING ............................................................................39 
11.1. 
Definitions .....................................................................................................................39 
11.1.1. 
Adverse Events ..............................................................................................................39 
11.1.2. 
Serious Adverse Events .................................................................................................40 
11.1.3. 
Severity Criteria (Grade 1-5) .........................................................................................40 
11.1.4. 
Causality (Attribution) ..................................................................................................40 
11.2. 
Unexpected Adverse Events ..........................................................................................40 
11.3. 
Special Reporting Situations .........................................................................................41 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ..................................................................................................................41 
11.4.1. 
Assessment of Adverse Events ......................................................................................41 
11.4.2. 
Adverse Event Reporting Period ...................................................................................41 
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events ................................42 
11.4.4. 
Pregnancy ......................................................................................................................43 
11.4.5. 
Other Malignancies .......................................................................................................44 
11.4.6. 
Adverse Events of Special Interest (AESI) ...................................................................44 
11.4.6.1. Major Hemorrhage ........................................................................................................45 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .............45 
12.1. 
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval ................................................................................45 
12.2. 
Informed Consent ..........................................................................................................45 
12.3. 
Protected Subject Health Information Authorization ....................................................45 
12.4. 
Study Files and Record Retention .................................................................................46 
12.5. 
Investigational Study Drug Accountability ...................................................................46 
12.6. 
Study Monitoring/Audit Requirements .........................................................................46 
12.7. 
Investigator Responsibilities .........................................................................................46 
12.8. 
Protocol Amendments ...................................................................................................46 
12.9. 
Publication of Study Results .........................................................................................47 
12.10. 
Study Discontinuation ...................................................................................................47 
12.11. 
Study Completion ..........................................................................................................47 
13. 
REFERENCES ............................................................................................................48 
14. 
APPENDICES .............................................................................................................51 
 
LIST OF APPENDICES 
Appendix A. 
Schedule of Assessments  ................................................................................... 51 
Appendix B. 
KPS Status Scores ............................................................................................... 55 
Appendix C. 
Inhibitors and Inducers of CYP3A ...................................................................... 56 
Appendix D. 
Child-Pugh Score for Subjects with Liver Impairment ....................................... 57 
Appendix E. 
Chronic GVHD Assessment Form .................................................................... 577 
 


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Appendix F. 
Patient Self Report form ...................................................................................... 61 
Appendix G. 
Chronic GVHD Response Criteria ...................................................................... 62 
LIST OF IN-TEXT TABLES AND FIGURES 
Tables 
Table 1. Ibrutinib Dose Modifications ....................................................................................... 25 
Table 2. Ibrutinib Dose Reduction Levels  ................................................................................ 25 
Table 3 
Dose Modification for Cardiac Toxicity 
Table 4. Dose Modification Guidance for Hepatic Impaired Subjects ...................................... 26 
Table 5. Dose Modification Guidance for CYP3A4 Inhibitors ................................................. 26 
 
 
 
 


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SYNOPSIS 
Study Title: 
Phase II Trial Evaluating the Safety and Efficacy of Combined CD20- 
and BTK-Targeted B cell Depleting Therapy with Rituximab and 
Ibrutinib in the Primary Treatment of Chronic Graft-Versus-Host 
Disease 
Protocol Number: 
NSH 1219 
Study Phase: 
II 
Study Duration: 
Estimated to be 3 years 
Investigational Product 
and Reference Therapy: 
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration.  70mg hard gelatin capsules will also be provided for 
patients requiring dose reduction. 
 
Rituximab will be utilized at a concentration of 10 mg/mL in either 100 
mg (10 mL) or 500 mg (50 mL) single-use vials. 
 
Objectives: 
Primary Objective: 
Efficacy  The primary endpoint is to estimate the proportion of patients 
that are alive and off systemic immunosuppression therapies (IST) at 12 
months following initiation of treatment.  To meet this endpoint, 
patients need to remain off IST (e.g. sirolimus, tacrolimus, steroids, 
etc). for at least 8 weeks.  The use of rituximab and ibrutinib are not 
considered IST for this endpoint. 
 
Secondary Objectives: 
Efficacy 
To estimate: 
1. Chronic GVHD response (CR + PR, both individual organ response 
and overall response, according to 2014 NIH Response Criteria 
Working Group Report) – See Appendix G. 
2. Cumulative steroid exposure (total mg methylprednisolone or 
equivalent). 
3. Time to discontinuation of systemic immunosuppression, defined as 
the date that all systemic IST such as sirolimus, tacrolimus, 
steroids, etc. have been discontinued after resolution of all 
reversible manifestations of cGVHD.  The use of rituximab and 
ibrutinib are not considered IST for this endpoint. Discontinuation 
of immunosuppressive medications for the purpose of inducing an 
anti-tumor response after the development of recurrent or secondary 
malignancy will not be counted as successful discontinuation of 
IST. 


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4. Failure-free survival (defined as being alive without the 
requirement for second-line cGVHD therapy).  See section 6.3 for 
definition of second-line cGVHD therapy. 
5. Non-relapse and overall mortality 
Safety 
 
To estimate: 
1. Incidence of grade ≥3 adverse events, possibly or probably 
related to either ibrutinib and/or rituximab. 
Study Design: 
This is an open-label, Phase 2 study designed to evaluate the safety and 
efficacy of ibrutinib and rituximab as primary treatment of cGVHD.   
Population: 
35 patients 
Centers: 
One 
Inclusion Criteria: 
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria. 
1. First episode of systemic immunosuppression-requiring  cGVHD, 
defined as classic or overlap cGVHD by the NIH consensus 
criteria. 
2. Previously untreated cGVHD, defined by having received <10 days 
of corticosteroids or alternative systemic immunosuppressive agent 
started specifically for a new diagnosis of cGVHD. 
3. Age ≥18 years 
4. Karnofsky performance status ≥70% 
5. Patient willing and able to provide informed consent 
6. Adequate hematologic function defined as:  
• 
Absolute neutrophil count (ANC)  ≥1.0 x 109/L and off growth 
factor support for 7 days. 
• 
Platelet count ≥30 x 109/L and no platelet transfusions for 7 
days. 
 
7. Adequate hepatic function as defined by: 
• 
Total bilirubin of ≤ 1.5 x ULN (unless of non-hepatic origin or 
due to Gilbert’s Syndrome) or 
• 
Total bilirubin of > 1.5 x ULN to 3.0 x ULN if due to cGVHD. 
8. 
Women of childbearing potential and men who are sexually active 
with a woman of childbearing potential must be practicing a 


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highly effective, preferably user-independent method of birth 
control (failure rate of <1% per year when used consistently and 
correctly) during treatment and for up to 90 days after the last dose 
of ibrutinib, consistent with local regulations regarding the use of 
birth control methods for subject participating in clinical studies. 
Exclusion Criteria: 
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria. 
 
Active uncontrolled infection 
History of HIV infection 
Active HBV or HCV infection.  Subjects who are positive for hepatitis 
B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C 
antibody must have a negative polymerase chain reaction (PCR) result 
before enrollment. Those who are PCR positive will be excluded 
Inability to tolerate oral medications. 
Progressive or recurrent malignancy following allogeneic transplant 
1. Known severe or life-threatening hypersensitivity to ibrutinib or 
rituximab 
Uncontrolled hypertension 
Known bleeding disorder 
Major surgery within 4 weeks of first dose of study drug 
History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment 
Unable to swallow capsules 
Subjects with chronic liver disease and hepatic impairment meeting 
Child-Pugh Class C (Appendix D). 
Female subjects who are pregnant, or breastfeeding, or planning to 
become pregnant while enrolled in this study or within 90 days of last 
dose of study drug. Male subjects who plan to father a child while 
enrolled in this study or within 90 days after the last dose of study drug. 
Unwilling or unable to participate in all required study evaluations and 
procedures 
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) 
Exposure to BTK inhibitor following transplant.  Prior exposure to 
BTK inhibitor pre-transplant is allowed. 
Vaccinated with live, attenuated vaccines within 4 weeks of first dose 
of study drug 
Unresolved toxicities from prior anticancer therapy, defined as having 
not resolved to Common Terminology Criteria for Adverse Event 
(CTCAE, v5.0), Grade ≤ 1, or to the levels dictated in the 
inclusion/exclusion criteria with the exception of alopecia 


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Any life-threatening illness, medical condition, or organ system 
dysfunction that, in the investigator’s opinion, could compromise the 
subject’s safety or put the study outcomes at undue risk 
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 study entry 
Subject who received a strong cytochrome P450 (CYP) 3A inhibitor 
within 7 days prior to the first dose of ibrutinib or subject who requires 
continuous treatment with a strong CYP3A inhibitor (Appendix C), 
with the exception of voriconazole or posaconazole which are permitted 
on study with appropriate dose modification. 
Subjects who have received prior treatment with extracorporeal 
photopheresis (ECP) for cGVHD. 
Study Treatment: 
1. Ibrutinib 420mg PO QDAY (28-day cycles) for a total of 12 cycles 
(dose adjustment required in patient with hepatic impairment or 
those receiving concomitant voriconazole or posaconazole or other 
strong CyP 3A4 inhibitor). 
2. Rituximab 375mg/m2 IV weekly x 4 weeks (to be started on study 
day 7 ± 3 days) , then 375mg/m2 IV q3months x 4 doses (months 4, 
7, 10, 13). 
Concomitant Therapy: 
 
1. Sirolimus (target level 4-10 ng/mL) – patients currently receiving 
a calcineurin inhibitor (tacrolimus or cyclosporine) and/or 
mycophenolate mofetil for GVHD prophylaxis will be converted 
to sirolimus per institutional guidelines.  In the case of 
contraindication or intolerance to sirolimus, another systemic 
immunosuppressive (IS) drug (i.e. tacrolimus or cyclosporine) 
may be substituted at the discretion of the treating investigator. 
2. Short-course corticosteroids may be used, if necessary, for more 
rapid symptom control (≤1mg/kg Medrol, with planned taper to be 
completed no longer than 4 weeks). 
 
Statistical Methods/ Data 
Analysis:  
Refer to Section 10 for 
additional details. 
This is a phase II trial evaluating the safety and efficacy of ibrutinib and 
rituximab as primary treatment of cGVHD.  We plan to enroll 35 
patients on this study. Patients will be formally monitored for 12 
months to evaluate for outcome and safety endpoints.  All patients, 
responders and treatment failures, will be followed for a period of one 
year.  The primary outcome measure will be the proportion of patients 
that are alive and off systemic immunosuppression therapies (IST) at 12 
months following initiation of treatment.. Secondary outcome measures 
will be cGVHD response, cumulative steroid exposure, time to 
discontinuation of systemic immunosuppression, requirement for 
second-line GVHD therapy, non-relapse and overall mortality, and 
safety. 


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Sample Size 
Determination 
The study will be powered to detect a clinically meaningful 
improvement in treatment success at 12 months post-treatment, defined 
as being alive and off all systemic immunosuppression.  Experience 
from our phase II study of rituximab in the upfront treatment of 
cGVHD found that 56% of patients were alive and free of systemic 
immunosuppression at 12 months post treatment.  It is hoped that under 
this protocol, this rate will be at least 75%. Thus we statistically 
formalize this study by testing the null hypothesis that p, the treatment 
success rate is 0.55 or less versus the alternative hypothesis that p is at 
least 0.75  A sample size of 35 patients gives 80% power with an 
alpha=0.05, using the formula for a one sample binomial (one-sided) 
test of a proportion. 
 
 


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ABBREVIATIONS 
 
AE  
adverse event  
AESI 
adverse events of special interest  
ALT  
alanine aminotransferase  
ANC 
absolute neutrophil count  
ASCO 
American Society of Clinical Oncology 
AST  
aspartate aminotransferase  
AUC 
area under the concentration-time curve 
BCR  
B-cell receptor  
BTK  
Bruton’s tyrosine kinase  
CLL 
chronic lymphocytic leukemia  
Cmax 
maximum observed plasma concentration 
CR  
complete response  
CrCl 
creatinine clearance 
CRF 
case report form (paper or electronic as appropriate for this study) 
CT 
computed tomography 
CTCAE 
NCI Common Terminology Criteria for Adverse Events  
CYP  
cytochrome P450 
DMC 
Data Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
electrocardiogram 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV  
hepatitis C virus 
HIV 
human immunodeficiency virus 
HIPAA 
Health Insurance Portability and Accountability Act 
IAC 
Interim Analysis Committee 
IB 
Investigator's Brochure 
IC50  
concentration that inhibits a process by 50% 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ILD 
interstitial lung disease 
IEC 
Independent Ethics Committee 
INR 
International normal ratio 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
MRU 
medical resource utilization 


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MTD 
maximum tolerated dose 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PR  
partial response  
PRO 
patient-reported outcome(s) 
aPTT 
activated partial thromboplastin time 
PT 
prothrombin time  
QTc  
QT interval corrected for heart rate  
SAE  
serious adverse event 
SCARs 
severe cutaneous adverse reactions 
SJS 
Stevens-Johnson syndrome 
SLL 
small lymphocytic lymphoma  
t1/2 
half-life 
Tmax 
time to maximum plasma concentration  
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
ULN 
upper limit of normal 
 
 
 


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1. 
BACKGROUND 
1.1. 
Chronic GVHD  
1.1.1. 
Chronic GVHD Background 
Chronic GVHD (cGVHD) is the most important cause of late morbidity and mortality after 
allogeneic stem cell transplantation, occurring in up to 60% of long-term survivors(Higman and 
Vogelsang 2004; Schmitz, Eapen et al. 2006; Bhatia, Francisco et al. 2007; Abou-Mourad, Lau 
et al. 2010)    With the increasing number of allogeneic transplants using peripheral blood stem 
cells (PBSCs), mismatched and unrelated donors and the increasing age of transplant recipients, 
cGVHD will continue to be a serious challenge following allogeneic transplantation. Chronic 
GVHD requires therapy for many months and often years(Vogelsang 2001; Koc, Leisenring et 
al. 2002) and is the cause of death in up to one third of all long-term survivors after 
transplantation for leukemia(Ratanatharathorn, Ayash et al. 2001). In addition to the effects on 
mortality, moderate-to-severe cGVHD markedly reduces quality of life (Sutherland, Fyles et al. 
1997; Chiodi, Spinelli et al. 2000; Kiss, Abdolell et al. 2002; Fraser, Bhatia et al. 2006).  Despite 
its prevalence and importance, an effective treatment strategy for cGVHD has been difficult to 
achieve due to the heterogeneous nature of the problem and the lack of clear evidence for the 
majority of treatment options.   
 
Standard immunosuppressive therapy (IST) for cGVHD using glucocorticoids with a calcineurin 
inhibitor has not changed in several decades even though most patients respond inadequately.  If 
the total time to discontinue all systemic IST is measured as a surrogate for allograft tolerance, it 
takes a median of 2-3 years from the onset of cGVHD therapy depending on stem cell source and 
other factors(Stewart, Storer et al. 2004). Unfortunately, despite the relationship between 
cGVHD and reduced relapse risk, the prolonged duration of cGVHD makes it the leading cause 
of infection, morbidity, and late treatment-related deaths (Sullivan, Witherspoon et al. 1988; 
Wingard, Piantadosi et al. 1989; Syrjala, Chapko et al. 1993; Duell, van Lint et al. 1997; 
Sutherland, Fyles et al. 1997; Socie, Stone et al. 1999). Furthermore, the widespread and 
sometimes irreversible manifestations of cGVHD may negatively impact quality of life even 
after tolerance is achieved. New approaches to the treatment of cGVHD are needed to achieve 
early control of cGVHD manifestations and facilitate tolerance. 
  
 
The morbidity and mortality associated with chronic GVHD is caused not only by cGVHD-
associated immunodeficiency and organ dysfunction, but also by the immunosuppressive 
medications used treat it.  Long-term glucocorticoid treatment impairs immune function and can 
therefore increase the risk of opportunistic infections. Other glucocorticoid therapy-related 
complications include avascular necrosis, glucose intolerance, hypertension, weight gain, 
changes in body habitus, cataracts, osteoporosis, myopathy, and disturbances of mood and sleep.  
Attempts to improve upon corticosteroids and a calcineurin inhibitor as initial therapy for 
cGVHD have been unsuccessful. 
 


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1.1.2. 
B cell depleting therapy for the treatment of cGVHD utilizing Rituximab, an 
anti-CD20 monoclonal antibody. 
Failure to improve cGVHD therapy may be partly attributed to an incomplete understanding of 
the pathophysiology of cGVHD. Chronic GVHD was traditionally thought to be mediated by 
donor-derived, alloreactive T cells, although studies have not consistently shown a favorable 
impact of T-cell depletion on cGVHD (Champlin, Passweg et al. 2000; Pavletic, Carter et al. 
2005). There is now mounting evidence implicating B cells in the pathophysiology of chronic 
GVHD. Antibodies to Y chromosome–encoded minor histocompatibility antigens are generated 
after sex-mismatched allogeneic transplantation (Miklos, Kim et al. 2004) and the presence of 
these antibodies has been correlated with the occurrence of cGVHD (Miklos, Kim et al. 2005). 
The findings led to the hypothesis that an anti-B-cell monoclonal antibody may be an effective 
therapy for cGVHD.  Clinical studies have subsequently confirmed the efficacy of rituximab in 
steroid-refractory cGVHD with objective responses noted in 50-70% of patients, allowing 
tapering, and in some cases withdrawal of immunosuppressant therapy (Ratanatharathorn, Ayash 
et al. 2003; Canninga-van Dijk, van der Straaten et al. 2004; Cutler, Miklos et al. 2006; 
Okamoto, Okano et al. 2006; Zaja, Bacigalupo et al. 2007).  Early evidence also suggests a role 
for rituximab during the early post-transplant period for prevention of cGVHD (Cutler, Kim et 
al. 2013; Sauter, Barker et al. 2014). 
 
In a completed phase II trial, our group tested rituximab in the upfront treatment of patients with 
cGVHD, and the results of this study were recently published in Biology of Blood and Marrow 
Transplantation: Corticosteroid-Free Primary Treatment of Chronic Extensive Graft-versus-Host 
Disease Incorporating Rituximab (Solomon, Sizemore et al. 2015).  We hypothesized that the 
early use of rituximab would allow for more rapid discontinuation of immunosuppression while 
obviating the need for long courses of systemic corticosteroids, which would translate into 
reduced treatment-related morbidity and mortality associated with cGVHD.  
  
Twenty-five patients (median age 56 years [range 29 – 77]) with extensive cGVHD were 
enrolled on a prospective phase II trial at our institution.  Enrollment was limited to patients with 
first onset extensive cGVHD requiring systemic immunosuppression and without residual or 
concurrent acute GVHD.  All patients received Rituximab 375mg/m2 x 4 weekly doses, then one 
dose q3months x 4 doses. Twenty-two of 25 patients (88%) responded to treatment.  Of the 22 
responding patients, median time to maximum response was 161 days (range 35 – 300 days) with 
maximum response being complete in 21/22 patients and partial in 1 patient.  Corticosteroids 
were used sparingly or not at all in the majority of patients.  Immunosuppression was 
discontinued in 17 of 22 evaluable patients (77%) with median time to discontinuation of 300 
days (range 138 – 488 days).  With a median f/u of 27 months, estimated 2-year overall survival 
is 82%.  Following immunosuppression discontinuation, cGVHD did recur in 7 patients after a 
median of 166 days (range 21-393 days), requiring reinstitution of systemic immunosuppression.   
When patients were analyzed 12 months following treatment initiation, 56% were alive, free of 
active GVHD, and off all systemic immunosuppression. 


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1.1.3. 
Targeting the Bruton’s tyrosine kinase (BTK) and IL-2 inducible T-cell kinase 
(ITK) pathways with Ibrutinib for the treatment of cGVHD  
BTK and ITK are enzymes responsible for the phosphorylation and activation of downstream 
effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, 
respectively. Murine studies suggest that both BTK and ITK are required for the development of 
cGVHD and that ibrutinib treatment can ameliorate cGVHD severity (Dubovsky, Flynn et al. 
2014).  Similar to murine studies, CD4 T cells and B cells appear essential in humans for the 
induction of cGVHD (Cooke, Luznik et al. 2017). Ibrutinib is a potent inhibitor of both BTK and 
ITK that impairs both B-cell and T-cell function. In response to these preclinical findings, 
ibrutinib was studied in a phase II trial in 42 steroid-refractory cGVHD patients (Miklos, Cutler 
et al. 2017).  This study demonstrated an overall response rate of 67%, with a durable response at 
≥20 weeks and ≥32 weeks of 71% and 48% respectively.  Five of the 28 responders discontinued 
corticosteroids entirely.  Based on the results of this trial, ibrutinib received FDA approval in 
August 2017 for the treatment of adult patients with cGVHD following the failure of 1 or more 
lines of systemic therapy.   
1.1.4. 
Rationale for combining Rituximab with Ibrutinib for the treatment of cGVHD 
The clinical efficacy of rituximab has provided compelling evidence that B cells play an 
important role in human cGVHD, but the mechanisms that promote and sustain B-cell 
involvement remain poorly studied. The durability of clinical responses to rituximab in patients 
with cGVHD remains unclear (Cutler, Miklos et al. 2006; Zaja, Bacigalupo et al. 2007).  In 
patients with autoimmune diseases, initial clinical responses to rituximab are inevitably followed 
by clinical relapse in the majority of patients. Thus, although clinical responses to rituximab are 
compelling, incomplete elimination of potentially autoreactive B cells may lead to cGVHD 
recurrence.  Therefore, there is a rationale for combining CD20-targenting antibodies with B cell 
signaling inhibitors in the hopes of improving the efficacy and durability of the response. 
 
The combination of Rituximab and Ibrutinib has been used successfully to treat patients with 
chronic lymphocytic leukemia (Burger, Keating et al. 2014) and mantle cell lymphoma (Wang, 
Lee et al. 2016), demonstrating safety for this combination. 
1.2. 
Ibrutinib Overview  
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of Bruton’s tyrosine kinase (BTK) co-developed by Pharmacyclics LLC and Janssen 
Research & Development LLC for the treatment of B-cell malignancies.   
Ibrutinib has been approved in over 80 countries, including the United States (US) and European 
Union (EU), for indications covering the treatment of patients with mantle cell lymphoma 
(MCL) who have received at least 1 prior therapy, patients with chronic lymphocytic leukemia 
(CLL)/small lymphocytic lymphoma (SLL), including CLL/SLL with a deletion of the short arm 
of chromosome 17 (del17p), patients with Waldenström’s macroglobulinemia (WM), patients 
with Marginal Zone Lymphoma (MZL) who require systemic therapy and have received at least 
one prior anti-CD20-based therapy, and adult patients with cGVHD after failure of 1 or more 


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lines of systemic therapy. For the most up to date and comprehensive nonclinical and clinical 
information regarding ibrutinib background, safety, in vitro and in vivo preclinical activity, 
pharmacokinetics, and toxicology of ibrutinib, always refer to the latest version of the ibrutinib 
Investigator's Brochure (IB) and/or the applicable regional labeling information. 
1.2.1. 
Risks 
1.2.1.1. 
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 major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. 
Initially, subjects were excluded from participation in specific ibrutinib Phase 2 and 3 studies if 
they required warfarin or other vitamin K antagonists. Warfarin or other vitamin K antagonists 
should not be administered concomitantly with ibrutinib unless specified in the protocol. 
Supplements such as fish oil and vitamin E preparations should be avoided.  In an in vitro 
platelet function study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation 
were observed, refer to Section 6.2.3. Use of ibrutinib in subjects requiring other anticoagulants 
or medications that inhibit platelet function may increase the risk of bleeding. See Section 6.2.3 
for guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. 
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 for guidance on ibrutinib management with 
surgeries or procedures. Patients with congenital bleeding diathesis have not been studied.  
1.2.1.2. 
Infections  
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib. Some of these infections have been associated with hospitalization and 
death. Consider prophylaxis according to standard of care in subjects who are at increased risk 
for opportunistic infections (reference Section 6.1). Although causality has not been established, 
cases of progressive multifocal leukoencephalopathy (PML) and hepatitis B reactivation have 
occurred in subjects treated with ibrutinib. Subjects should be monitored for signs and symptoms 
(fever, chills, weakness, confusion, vomiting and jaundice) and appropriate therapy should be 
instituted as indicated. 
1.2.1.3. 
Cytopenias  
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Monitor complete blood counts monthly.  


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1.2.1.4. 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt 
ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines as needed (see Section 
5.1.1.4). 
1.2.1.5. 
Cardiac Arrhythmias  
Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac 
risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmia. 
Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic 
symptoms (e.g., palpitations, lightheadedness, syncope, chest discomfort or new onset of 
dyspnea) should be evaluated clinically, and if indicated, have an ECG performed. For cardiac 
arrhythmias which persist, consider the risks and benefits of ibrutinib treatment and follow the 
protocol dose modification guidelines (see Section 5.1.1.4).  
1.2.1.6. 
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions. 
1.2.1.7. 
Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer. 
1.2.1.8. 
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 and are generally managed with supportive 
therapies including antidiarrheals and antiemetics. Subjects should be monitored carefully for 
gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration. Medical 
evaluation should be made to rule out other etiologies such as Clostridium difficile or other 
infectious agents. Should symptoms be severe or prolonged follow the protocol dose 
modification guidelines (see Section 5.1.1.4). 
1.2.1.9. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Most rashes were mild to moderate in severity. Isolated cases 


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of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have 
been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs 
and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate. In addition, hypersensitivity-related events including erythema, urticaria, 
and angioedema have been reported. 
1.2.1.10. 
Hypertension 
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate.  
1.3. 
Study Rationale  
Despite the importance of cGVHD as a major cause of morbidity and mortality following 
allogeneic transplant, therapies for this common post-transplant complication remain inadequate.   
Standard initial therapy of cGVHD is based on prolonged use of corticosteroids and a calcineurin 
inhibitor and has not changed for over 3 decades, despite limited efficacy and long-term toxicity.  
New treatments are clearly needed. 
 
There is now considerable evidence from animal and human studies implicating B cells as an 
important player in the pathophysiology of cGVHD.  This is best exemplified by the efficacy of 
both Rituximab (anti-CD20 B cell depleting antibody) and Ibrutinib (BTK inhibitor effecting B 
cell signaling) in the treatment of steroid-refractory cGVHD.   
 
Given the effectiveness and favorable safety profile of both Rituximab and Ibrutinib in the 
steroid-refractory cGVHD patients, it is natural to study these agents in the upfront cGVHD 
setting.  Rituximab has been studied in the upfront treatment of cGVHD in two recently 
published phase II studies, showing efficacy as a steroid-sparing agent with relatively low 
toxicity.  We have previously shown that upfront Rituximab therapy can reduce the time to 
discontinuation of systemic immunosuppression, while limiting a patient’s cumulative exposure 
to corticosteroids. 
 
We hypothesize that combined CD20- and BTK-targeted B cell depleting therapy (BCDT) with 
Rituximab and Ibrutinib in the primary treatment of extensive cGVHD will produce quicker, 
better and more durable responses and improve outcomes in patients with cGVHD.  The 
combination of Rituximab and Ibrutinib has been used successfully to treat patients with chronic 
lymphocytic leukemia (Burger, Keating et al. 2014) and mantle cell lymphoma (Wang, Lee et al. 
2016), demonstrating safety for this combination. 


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2. 
STUDY OBJECTIVE 
2.1. 
Primary Objective 
The primary objective is to evaluate the efficacy of the combination of rituximab and ibrutinib 
versus the historical experience with rituximab alone in the upfront treatment of cGVHD.  The 
primary efficacy endpoint is to estimate the proportion of patients that are alive and off IST at 12 
months following initiation of treatment.  To meet this endpoint, patients need to remain off IST 
(e.g. sirolimus, tacrolimus, steroids, etc). for at least 8 weeks.  The use of rituximab and ibrutinib 
are not considered IST for this endpoint.  
 
2.2. 
Secondary Objective(s) 
Efficacy 
 
To estimate: 
• Chronic GVHD response (CR + PR, both individual organ response and overall response, 
according to 2014 NIH Response Criteria Working Group Report) – See Appendix G. 
• Cumulative steroid exposure (total mg methylprednisolone or equivalent). 
• Time to discontinuation of systemic immunosuppression (defined as the date that all systemic 
IST has been discontinued after resolution of all reversible manifestations of cGVHD.  
Discontinuation of immunosuppressive medications for the purpose of inducing an anti-
tumor response after the development of recurrent or secondary malignancy will not be 
counted as successful discontinuation of IST). 
• Failure-free survival (defined as being alive without the requirement for second-line cGVHD 
therapy).  See section 6.3 for definition of second-line cGVHD therapy. 
• Non-relapse and overall mortality 
 
Safety 
 
To estimate: 
• Incidence of grade ≥3 adverse events, possibly or probably related to either ibrutinib and/or 
rituximab. 
 
 
 


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• To evaluate the safety and tolerability of combination of rituximab and ibrutinib versus 
the historical experience with rituximab alone in the upfront treatment of cGVHD. 
2.3. 
Exploratory Objective 
• To evaluate laboratory-based correlates associated with response to treatment. 
3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
The rationale for the study concept is provided in Section 1.3. 
This is a phase II trial evaluating the safety and efficacy of the combination of Ibrutinib and 
Rituximab as primary treatment of cGVHD.  We plan to enroll 35 patients on this study. Patients 
will be formally monitored monthly for 12 months to evaluate for outcome and safety endpoints.  
All other assessments will be done at the physician’s discretion or institutional standards. All 
patients, responders and treatment failures, will be followed for a period of one year from the 
time of initiation of therapy.  The primary endpoint will be the proportion of patients that are 
alive and off all systemic IST at 12 months following initiation of treatment.   
Eligible patients will be those with a first episode of symptomatic cGVHD, requiring systemic 
immunosuppression for control of symptoms.  Following study entry, patients will be started on: 
1. Ibrutinib 420mg PO QDAY (28-day cycles) for a total of 12 cycles unless discontinued early 
due to toxicity (see stopping rules in section 5.1.1.4). Dose adjustments are required for 
patients with hepatic impairment or those receiving concomitant voriconazole or 
posaconazole or other strong CyP 3A4 inhibitor according to sections 5.1.1.5 and 5.1.1.6. 
2. Rituximab 375mg/m2 IV weekly x 4 weeks (to be started on study day 7 ± 3 days), then 
375mg/m2 IV q3months x 4 doses (months 4, 7, 10, 13). 
 
Additional cGVHD treatment will include: 
• 
Sirolimus (target level 4-10 ng/mL) – patients currently receiving a calcineurin inhibitor 
(tacrolimus or cyclosporine) and/or mycophenolate mofetil for GVHD prophylaxis will be 
converted to sirolimus per institutional guidelines.  In the case of contraindication or 
intolerance to sirolimus, another systemic immunosuppressive (IS) drug (i.e. tacrolimus or 
cyclosporine) may be substituted at the discretion of the treating investigator. 
 
• 
Short-course corticosteroids may be used, if necessary, for more rapid symptom control 
(≤1mg/kg Medrol, with planned taper to be completed no longer than 4 weeks). 
 
When cGVHD manifestations have been quiescent for at least 4 weeks, sirolimus (or other IS 
medication) should be tapered over 4 weeks or per investigator discretion.   


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3.2. 
Study schema  
 
 
 
4. 
SUBJECT SELECTION 
4.1. 
Inclusion Criteria 
Prior to enrollment, each potential subject must satisfy all of the following inclusion criteria: 
1. First episode of systemic immunosuppression-requiring cGVHD, defined as classic or 
overlap cGVHD by the NIH consensus criteria.  
2. Previously untreated cGVHD, defined by having received <10 days of corticosteroids or 
alternative systemic immunosuppressive agent started specifically for a new diagnosis of 
cGVHD 
3. Age ≥18 years 
4. Karnofsky performance status ≥70% 
5. Patient willing and able to provide informed consent 
6. Adequate hematologic function defined as:  
• Absolute neutrophil count (ANC) ≥1.0 x 109/L and off growth factor support for 7 days. 
• Platelet count ≥30 x 109/L and no platelet transfusions for 7 days. 
7. Adequate hepatic function as defined by: 
• Total bilirubin of ≤ 1.5 x ULN (unless of non-hepatic origin or due to Gilbert’s 
Syndrome) or 
• Total bilirubin of > 1.5 x ULN to 3.0 x ULN if due to cGVHD. 
8. Women of childbearing potential and men who are sexually active with a woman of 
childbearing potential must be practicing a highly effective, preferably user-independent 
method of birth control (failure rate of <1% per year when used consistently and correctly) 


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during treatment and for up to 90 days after the last dose of ibrutinib, consistent with local 
regulations regarding the use of birth control methods for subject participating in clinical 
studies. 
 
4.2. 
Exclusion Criteria 
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria: 
1. Patients with late persistent or recurrent acute GVHD 
2. Active uncontrolled infection 
3. History of HIV infection 
4. Active HBV or HCV infection.  Subjects who are positive for hepatitis B core antibody, 
hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative 
polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will 
be excluded. 
5. Inability to tolerate oral medications. 
6. Progressive or recurrent malignancy following allogeneic transplant 
7. Known severe or life-threatening hypersensitivity to ibrutinib or rituximab 
8. Creatinine > 2 mg/dl or calculated CrCl < 30ml/min 
9. Requirement for anticoagulation therapy 
10. Uncontrolled hypertension 
11. Known bleeding disorder 
12. Major surgery within 4 weeks of first dose of study drug 
13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment 
14. Unable to swallow capsules 
15. Subjects with chronic liver disease and hepatic impairment meeting Child-Pugh Class C 
(Appendix D). 
16. Female subjects who are pregnant, or breastfeeding, or planning to become pregnant while 
enrolled in this study or within 90 days of last dose of study drug. Male subjects who plan to 
father a child while enrolled in this study or within 90 days after the last dose of study drug. 
17. Unwilling or unable to participate in all required study evaluations and procedures 
18. 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) 
19. Exposure to BTK inhibitor following transplant.  Prior exposure to BTK inhibitor pre-
transplant is allowed.  
20. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug 
21. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, v5.0), Grade ≤ 1, or to the levels 
dictated in the inclusion/exclusion criteria with the exception of alopecia 


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22. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk 
23. 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 
24. Subjects who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior to 
the first dose of ibrutinib or subject who requires continuous treatment with a strong CYP3A 
inhibitor (Appendix C), with the exception of voriconazole or posaconazole which are 
permitted on study with appropriate dose modification. 
25. Subjects who have received prior treatment with extracorporeal photopheresis (ECP) for 
cGVHD. 
5. 
TREATMENT OF SUBJECTS 
5.1. 
Study Medications 
5.1.1. 
Ibrutinib 
5.1.1.1. 
Formulation/Packaging/Storage  
Ibrutinib capsules are provided as a hard gelatin capsule containing 70 mg and 140 mg of 
ibrutinib. All formulation excipients are compendial and are commonly used in oral 
formulations. Refer to the ibrutinib IB for a list of excipients. 70 mg capsules will only be used 
for subjects who have dose reductions that require a dose of 70 mg and will not be used to 
constitute a dose larger than 70 mg (eg, 2 x 70 mg capsules to give 140 mg). 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies. All study 
drug will be dispensed in child-resistant packaging.  
Study drug labels will contain information to meet the applicable regulatory requirements. 
5.1.1.2. 
Dose and Administration 
Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily.  It is expected that 
many subjects commencing therapy for cGVHD will require anti-fungal prophylaxis.  Please see 
Section 6.2.1 for dose modification guidelines with concomitant use of CYP3A inhibitors. 
The capsules are to be taken around the same time each day with 8 ounces (approximately 
240 mL) of water. The capsules should be swallowed intact and subjects should not attempt to 
open capsules or dissolve them in water. The use of strong CYP3A inhibitors/inducers (other 


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than those specifically permitted on study), and grapefruit and Seville oranges should be avoided 
for the duration of the study (Appendix C). 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day. The subject should not take extra 
capsules to make up the missed dose. 
The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically 
on an outpatient basis. Ibrutinib will be dispensed to subjects in bottles at each visit. Study drug 
may not be shipped to the subject without approval from PCYC and may not be dispensed to 
anyone other than the subject. Unused ibrutinib dispensed during previous visits must be 
returned to the site and drug accountability records (Section 12.5) updated at each visit. Returned 
capsules must not be redispensed to anyone. 
5.1.1.3. 
Overdose  
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose (MTD) was reached in the Phase 1 study in which subjects received up 
to 12.5 mg/kg/day (1,400 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 ingest more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. 
Refer to Section 11.3 for further information regarding special reporting situations as a result of 
overdose.  
5.1.1.4. 
Dose Modification for Non-Cardiac Adverse Reactions 
The dose of study drug must be modified according to the dose modification guidance in Table 1 
and Table 2 if any of the following non-cardiac toxicities occur: 
• Grade 4 neutropenia (ANC <500/µL) for more than 7 days. See Section 6.1 for 
instructions regarding the use of growth factor support.  
• Grade 3 thrombocytopenia (platelets <50,000/µL) in the presence of clinically 
significant bleeding events. 
• Grade 4 thrombocytopenia (platelets <25,000/µL). 
• 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 non-cardiac toxicity 
Adverse events that are considered related to concomitant high dose corticosteroids (e.g. 
hyperglycemia, insomnia) do not require dose modification or holding of ibrutinib. 


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If the dose of ibrutinib is reduced, at the investigator’s discretion, the dose of ibrutinib may be 
re-escalated after 4 weeks of a dose reduction in the absence of a recurrence of the toxicity that 
led to the reduction. Dose changes must be recorded in the CRF.  
Table 1. 
Ibrutinib Dose Modifications 
 
Occurrence 
Action to be Taken  
First 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at original dose 
level 
Second 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (i.e., 280 mg/day for 420 mg/day dose) 
Third 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower (i.e., 140 mg/day for 420 mg/day dose; 280 mg/day) 
Fourth 
Discontinue study drug 
 
Table 2. 
Ibrutinib Dose Reduction Levels  
Starting Dose Level 
140 mg 
280 mg 
420 mg 
Dose Reduction 
Level 1 
70 mg 
140 mg 
280 mg 
Dose Reduction 
Level 2 
Discontinue 
70 mg 
140 mg 
Dose Reduction 
Level 3 
NA 
Discontinue 
Discontinue 
For required dose modification for hepatic impairment refer to Section 5.1.1.5 and for 
concomitant treatment with CYP3A inhibitors refer to Section 5.1.1.6.  
 
 


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5.1.1.5. 
Dose Modification for Cardiac Toxicity 
The dose of study drug must be modified for cardiac toxicity according to the guidance in Table 
3: 
Table 3:  Dose Modification Guidance for Cardiac Toxicity 
Adverse Reaction 
Occurrence 
Dose Modification 
After Recovery 
Starting Dose=420mg 
Dose Modification 
After Recovery 
Starting 
Dose=280mg 
Dose Modification 
After Recovery 
Starting 
Dose=140mg 
Grade 2 cardiac failure1 
First 
Restart at 280 mg 
Restart at 140 mg 
Restart at 70 mg 
Second 
Restart at 140 mg 
Restart at 70 mg 
Discontinue Drug 
Third 
Discontinue Drug 
Discontinue Drug 
N/A 
Grade 3 cardiac 
arrhythmias1,2 
First 
Restart at 280mg 
Restart at 140 mg 
Restart at 70 mg 
Second 
Discontinue Drug 
Discontinue Drug 
Discontinue Drug 
Grade 3 or 4 cardiac 
failure 
Grade 4 cardiac 
arrythmias 
First 
Discontinue Drug 
Discontinue Drug 
Discontinue Drug 
1Evaluate the risk-benefit before resuming ibrutinib treatment 
2If clinically indicated, the use of anticoagulants or antiplatelet agents may be considered for thromboprophylaxis of 
atrial fibrillation. 
 
 
5.1.1.6. 
Dose Modification for Hepatic Impairment 
Dose modifications for hepatic impairment will depend on total bilirubin level and subsequent 
changes in bilirubin levels per Table 3 below.  If the elevation of bilirubin is due to a non-hepatic 
cause or Gilbert’s Syndrome, then no dose modifications are necessary. Ibrutinib is metabolized 
in the liver and therefore subjects with clinically significant chronic hepatic impairment at the 
time of Screening (Child- Pugh class C) are excluded from study participation. Refer to 
Appendix D for Child-Pugh classification. Please refer to Table 3 for dose modifications due to 
hepatic impairment.  Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or 
higher while on study should be managed per standard dose modification guidelines for 
unmanageable Grade 3 toxicity in Section 5.1.1.4.   
Table 4. 
Dose Modification Guidance for Hepatic Impaired Subjects 


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Starting Dose Level by 
Bilirubin Levels 
Bili ≤1.5 x ULN at baseline 
420 mg 
Bili >1.5-3 x ULN at baseline 
140 mg 
On-study Bili ≤1.5 x ULN 
Continue 420 mg 
Increase to 420 mg 
On-study Bili >1.5-3 x ULN 
Reduce to 140 mg 
Continue 140 mg 
On-study Bili >3 x ULN 
Hold until Bili >1.5-3 x ULN, 
then restart 140 mg 
When bili level ≤1.5 x ULN 
restart at 420mg 
Hold until Bili >1.5-3 x ULN, 
then restart 140 mg 
When bili level ≤1.5 x ULN 
restart at 420mg 
In the event a patient has had a dose reduction due to a non-hepatic toxicity and then develops 
elevated bilirubin (or vice versa) that requires a dose reduction, the lower of the two dose 
reductions should be used.  
5.1.1.7. 
Dose Modification for Concomitant Use of CYP3A Inhibitors 
Dose adjustment of ibrutinib secondary to concomitant use of CYP 3A4 inhibitors should follow 
Table 4.  Concomitant use of strong CYP inhibitors is not permitted in subjects with chronic 
hepatic impairment. 
Table 5. 
Dose Modification Guidance for CYP3A4 Inhibitors 
Co-administered Drug 
Recommended Ibrutinib Dose for the 
Duration of the Inhibitor Use 
Mild CYP3A4 inhibitors 
420 mg once daily. No dose adjustment 
required. 
Moderate CYP3A4 inhibitors  
420 mg once daily. No dose adjustment 
required. 
Voriconazole  
Posaconazole at doses less than or 
equal to suspension 200 mg BID or 
delayed-release tablet 300mg QD  
280 mg once daily. 
Posaconazole at higher doses 
140 mg once daily. 
Other strong CYP3A4 inhibitors 
Avoid concomitant use. 
If these inhibitors will be used short 
term (such as anti-infectives for seven 
days or less), interrupt IMBRUVICA. 
 
After discontinuation of a CYP3A4 inhibitor, resume previous dose of ibrutinib. 
If Bili >1.5 x ULN, avoid and/or discontinue voriconazole, posaconazole, or other strong 
CYP3A4 inhibitor. 


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5.1.2. 
Rituximab  
5.1.2.1. 
Formulation/Packaging/Storage 
Rituximab is a highly purified, 1328-amino acid antibody with an approximate molecular mass 
of 145 kD.  The chimeric mouse/human anti-CD20 antibody is a glycosylated IgG1 κ 
immunoglobulin containing murine light and heavy chain variable regions and human γ1 heavy 
chain and κ light chain constant regions. 
 
Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) 
administration. Rituximab is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) 
or 500 mg (50 mL) single-use vials. The product is formulated for intravenous administration in 
9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, 
and Sterile Water for Injection. The pH is adjusted to 6.5. 
 
Rituximab vials are stable at 2° to 8°C (36° to 46°F).  Rituximab vials should be protected from 
direct sunlight.  Rituximab solutions for infusion are stable at 2° to 8°C (36° to 46°F) for 24 
hours and at room temperature for an additional 24 hours. However, since rituximab solutions do 
not contain a preservative, diluted solutions should be stored refrigerated (2° to 8°C).  No 
incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been 
observed. 
5.1.2.2. 
Dose and Administration 
The recommended dosage of rituximab is 375 mg/m2 given as an IV infusion. 
Preparation for Administration: Use appropriate aseptic technique. Withdraw the necessary 
amount of rituximab and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag 
containing either 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the 
bag to mix the solution. Discard any unused portion left in the vial.  Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to administration.  
 
Administration: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
Infusion and hypersensitivity reactions may occur.  Premedication, consisting of acetaminophen 
and diphenhydramine, should be considered before each infusion of rituximab.  Premedication 
may attenuate infusion-related events. Since transient hypotension may occur during rituximab 
infusion, consideration should be given to withholding anti-hypertensive medications 12 hours 
prior to rituximab infusion. 
 
First Infusion: The rituximab solution for infusion should be administered intravenously at an 
initial rate of 50 mg/hr. Rituximab should not be mixed or diluted with other drugs. If 
hypersensitivity or infusion-related events do not occur, escalate the infusion rate in 50 mg/hr 
increments every 30 minutes, to a maximum of 400 mg/hr.   
 
Rituximab infusion should be interrupted for severe reactions.  In most cases, the infusion can be 
resumed at a 50% reduction in rate (e.g., from 100mg/hr to 50mg/hr) when symptoms have 


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completely resolved.  Most patients who have experienced non-life-threatening infusion-related 
reactions have been able to complete the full course of rituximab therapy 
5.1.2.3. 
Subsequent infusions: If the subject tolerated the first infusion well, 
subsequent Rituximab doses may be mixed in a total volume of 250 mL NS and 
administered at an initial rate of 100mL/hr for 30 minutes, then 200mL/hr for 60 minutes 
such that the entire dose is delivered over 90 minutes.  If the first infusion was not well 
tolerated, the guidelines for the first infusion should be followed for the subsequent 
infusions. Overdose  
There has been no experience with over-dosage of rituximab in human clinical trials. Single 
doses higher than 500 mg/m2 have not been tested in controlled studies. 
 
5.1.2.4. 
Dose Modification for Adverse Reactions 
The dose of rituximab generally remains constant throughout the trial. Rituximab infusion should 
be interrupted for severe reactions, e.g., rapid tumor lysis.  Treatment of infusion-related 
symptoms with diphenhydramine and acetaminophen is recommended.  Additional treatment 
with bronchodilators or IV saline may be indicated.  Epinephrine, antihistamines, and 
corticosteroids should be available for immediate use in the event of a hypersensitivity reaction 
to rituximab (e.g., anaphylaxis).  In most cases, the infusion can be resumed at a 50% reduction 
in rate (e.g., from 100mg/hr to 50mg/hr) when symptoms and laboratory abnormalities have 
completely resolved. 
   
Infusions should be discontinued in the event of serious or life-threatening cardiac arrhythmias.  
Subjects who develop clinically significant arrhythmias should undergo cardiac monitoring 
during and after subsequent infusions.   
 
Subjects who meet the following criteria should be discontinued from the study: 
• Active HBV infection or hepatitis 
• Severe or life-threatening anaphylaxis or hypersensitivity reaction 
6. 
CONCOMITANT MEDICATIONS/PROCEDURES 
6.1. 
Permitted Concomitant Medications  
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.  
Usage of antimicrobial prophylaxis in accordance with standard practice is permitted and should 
be considered in subjects who are at increased risk for opportunistic infections.  
Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell growth factors 
(erythropoietin) and transfusion is permitted in accordance with institutional policy.  


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Short courses (< 28 days) of steroid treatment are permitted at doses that do not exceed 1.0 
mg/kg per day of methylprednisolone or equivalent. 
Ancillary therapy and supportive care for cGVHD is permitted as outlined in the NIH Consensus 
Development Project 2014 Ancillary Therapy and Supportive Care Working Group Report 
(Carpenter 2015).  In particular, the use of topical therapies (e.g. inhaled steroids, azithromycin, 
and monteleukast for bronchiolitis obliterans, budesonide for anorexia/nausea, steroid and/or 
tacrolimus rinses for oral symptoms, cyclosporine eye drops for xeropthalmia) will not be 
considered systemic therapy for cGVHD. 
6.2. 
Medications to be Used with Caution 
6.2.1. 
CYP3A Inhibitors/Inducers  
Ibrutinib is metabolized primarily by CYP3A4. Concomitant use of ibrutinib with drugs that 
strongly or moderately inhibit CYP3A4 can increase ibrutinib exposure. Dose adjustment of 
ibrutinib due to concomitant use of CYP3A4 inhibitors should follow Table 4 (Section 5.1.1.6) 
Avoid concomitant use of systemic strong CYP3A4 inducers (e.g., carbamazepine, rifampin, 
phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A4 induction. 
A list of common CYP3A4 inhibitors and inducers is provided in Appendix C. For further 
information, please refer to the current version of the IB and examples of inhibitors, inducers, 
and substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. This 
website is continually revised and should be checked frequently for updates. 
6.2.2. 
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib  
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor. Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. 
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp and BCRP 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 or methotrexate, should be 
taken at least 6 hours before or after ibrutinib.  
6.2.3. 
Antiplatelet Agents and Anticoagulants  
Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet 
function. In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen-induced 
platelet aggregation were observed. Supplements such as fish oil and vitamin E preparations 
should be avoided during treatment with ibrutinib. Bleeding events of any grade, including 
bruising and petechiae, occurred in subjects treated with ibrutinib. 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 with congenital bleeding diathesis have not been studied. 


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Subjects requiring the use of therapeutic anticoagulation therapy (e.g. Atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment.  If therapeutic anticoagulation is 
clinically indicated, treatment with ibrutinib should be held while anticoagulation is being 
initiated and not be restarted until the subject is clinically stable and has no signs of bleeding.  
Subjects should be observed closely for signs and symptoms of bleeding.  No dose reduction is 
required when study drug is restarted. 
6.3. 
  Other Systemic Immunosuppression Therapy for cGVHD 
Addition of any new systemic immunosuppressant therapy (including ECP) to treat worsening 
cGVHD is prohibited.  This will be considered a treatment failure, patient will be removed from 
study and treated according to institutional standard-of-care.   
Any increase in the dose of methylprednisolone (or equivalent) and any resumption of treatment 
with methylprednisolone, after previous discontinuation, is not considered as secondary systemic 
therapy. 
Any increase in the dose of sirolimus or calcineurin inhibitor, or resumption of treatment 
following discontinuation, is not considered as secondary systemic therapy, if the treatment in 
question was included in the immunosuppressive regimen at study initiation. 
A substitution of the systemic immunosuppressant drug (e.g. tacrolimus for sirolimus) for 
reasons other than cGVHD progression (e.g. toxicity) may be permitted after discussion with the 
principal investigator and is not considered as secondary systemic therapy. 
Topical therapy, including steroid creams, topical tacrolimus, oral budesonide, inhaled steroids 
and ophthalmic solutions are not considered as secondary therapy. 
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 subjects 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, skin or needle biopsy, lumbar 
puncture [other than shunt reservoir access], 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.  


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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 (except for emergency procedures) and should be 
held at least 7 days after the procedure and restarted at the discretion of the investigator when the 
surgical site is reasonably healed without serosanguinous drainage or the need for drainage tubes.  
7. 
STUDY EVALUATIONS  
7.1. 
Description of Procedures 
7.1.1. 
Assessments  
7.1.1.1. 
ICF 
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved ICF confirming his or her 
willingness to participate in this study before any study-specific screening procedures are 
performed. Subjects in the US must also grant permission to use protected health information per 
the Health Insurance Portability and Accountability Act (HIPAA). In addition, subjects must sign 
all approved ICF amendments per the site IRB/REB/IEC guidelines during the course of the 
study.  
7.1.1.2. 
Confirm Eligibility 
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria until first dose of study drug 
(Section 4). 
7.1.1.3. 
Medical History and Demographics 
The subject’s relevant medical history through review of medical records and by interview will 
be collected and recorded. Concurrent medical signs and symptoms must be documented to 
establish baseline severities.  
7.1.1.4. 
Prior and Concomitant Medications 
All medications at least 14 days prior to first dose through 30 days after the last dose of study 
drug will be documented.  
7.1.1.5. 
Adverse Events 
The accepted regulatory definition for an adverse event (AE) is provided in Section 11.1. The 
occurrence of an 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 


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until 30 days after the last dose of study drug that meet the AE definition below must be recorded 
as AEs in the CRF.  
• Grade 1 adverse events do not need recorded 
• Grade 2 unexpected and possibly/probably/definitely related  
• Grade 3 requiring hospitalization and unexpected/expected regardless of 
relationship 
• Grade 3 unexpected without hospitalization and possibly/probably/definitely 
related  
• All grades 4 & 5 regardless of unexpected/expected or relationship 
7.1.1.6. 
Physical Examination 
The Screening and follow-up visit physical examination will include, at a minimum, the general 
appearance of the subject, height (screening only) and weight, and examination of the skin, eyes, 
ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, 
and lymphatic system.  
7.1.1.7. 
Karnofsky Performance Status (KPS) 
The KPS performance index is provided in Appendix B. 
7.1.1.8. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate and body temperature.  
7.1.2. 
Laboratory 
Laboratory evaluation will be performed per institutional guidelines and include CBC with 
differential, glucose, BUN, creatinine, total bilirubin, alkaline phosphatase, albumin, 
SGOT(AST), SGPT (ALT), magnesium and calcium.  Relevant immunosuppressive drug levels 
(e.g. sirolimus) will be checked per institutional guidelines. 
7.1.3. 
Diagnostics/Procedures 
Radiology (e.g. plain films, CT), pulmonary function tests (PFTs), biopsies (e.g. skin, liver, GI 
tract) will be performed according to institutional standards. 
7.2. 
Efficacy Evaluations 
Formal efficacy assessments will be performed at baseline and post-treatment, monthly x 3 (1, 2, 
and 3 months), then q3months x 3 (6, 9, and 12 months).  See section 8.2.2 for detailed study 
assessments.  All other assessments will be done at the physician’s discretion or institutional 
standards.  


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7.3. 
Correlative Blood Collection and Handling 
Research blood samples (30-60ml) will be drawn at baseline, prior to ibrutinib dosing, and at 
each study visit (month 1, 2, 3, 6, 9, 12) for a total of 7 samples.  From each blood sample, 
peripheral blood mononuclear cells (PBMCs) and serum will be collected and cryopreserved for 
correlative studies.   
 
At each timepoint: 
• Serum – draw 10 ml of serum  
• PBMCs – If ALC >/= 1000/ul, draw 30ml.  If ALC <1,000/ul, draw 50ml  
 
Samples will be frozen in -800 C or liquid nitrogen. 
 
8. 
STUDY PROCEDURES 
(See Appendix A for details regarding timing of study procedures and testing.) 
8.1. 
Screening Phase 
8.1.1. 
Screening/Consenting Visit 
Required testing for the screening visit: 
• Medical History 
• Physical examination with vital signs, height, weight 
• Schirmer’s Test 
• Karnofsky Performance Status (Appendix B) 
• Serum Pregnancy test 
• Hepatitis Serologies (HepBsAg, HepBsAB, HepC) 
• Fasting lipid panel 
• Laboratory evaluation per institutional guidelines including CBC with differential, 
glucose, BUN, creatinine, total bilirubin, alkaline phosphatase, LDH, albumin, 
SGOT(AST), SGPT (ALT), CRP, CK, calcium, and magnesium. 
• IgG level 
• Biomarkers (correlative lab studies) 


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• Pulmonary Function Test 
• GVHD assessment form (Appendix E) 
• GVHD self-report form (Appendix F) 
Eligibility criteria will be verified, and ineligible patients will proceed off study and no further 
follow-up will be obtained. 
8.2. 
Treatment Phase 
8.2.1. 
Treatment Visits 
8.2.1.1. 
C1D1 Ibrutinib 
Required testing for the visit: 
• CBC with differential 
• Comprehensive metabolic panel 
Blood count and hepatic function criteria for dosing will be verified. 
8.2.2. 
Response Follow-up 
Required testing for the response follow-up visits (months 1, 2, 3, 6, 9, 12): 
• Medical history 
• Physical examination, including vital signs, weight, and Karnofsky performance status 
• Laboratory evaluation per institutional guidelines including CBC with differential, glucose, 
BUN, creatinine, total bilirubin, alkaline phosphatase, LDH, albumin, SGOT(AST), SGPT 
(ALT), CRP, CK, calcium, and magnesium. 
• Biomarkers (correlative lab studies) 
• Documentation of concomitant medications 
• Completion of institutional GVHD assessment form (see Appendix E) 
• Completion of a GVHD patient self-report form (see Appendix F) 
• Document cumulative corticosteroid use 
• Document any new systemic IST and reason for use 


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• Document treatment-emergent toxicities and adverse events 
• Document any IVIG use 
• PFTs (at 3, 6, 9 and 12 month visits only) 
9. 
SUBJECT COMPLETION AND WITHDRAWAL  
9.1. 
Completion 
Patients will be considered to be off study if any new systemic immunosuppressant therapy 
(including ECP) to treat worsening cGVHD is received.  No subsequent adverse or serious 
adverse event reporting will be done.  Further follow up off study will be according to 
institutional requirements.   
 
Patients will be considered to have completed study follow up at 12 months or 30 days after 
the last dose of ibrutinib whichever comes last.  Further off study follow up will be according 
to institutional requirements. 
9.2. 
Criteria for Study Discontinuation  
Patients may be withdrawn from the study if: 
• 
The patient requests withdrawal 
• 
If the patient develops side effects that are considered life-threatening 
• 
If the patient refuses to have treatment as recommended 
• 
If the patient refuses to have tests that are needed to determine whether the treatment is 
safe and effective 
• 
If the agents used in this study cease to be available 
• 
If other causes prevent continuation of the study 
• 
For any other reason that the physician feels it may be necessary that the patient 
discontinue the study 
 
10. STATISTICAL METHODS AND ANALYSES  
10.1. 
Analysis Population  
All treated subjects 


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10.2. 
Endpoints  
10.2.1. 
Primary Endpoint 
The primary endpoint is to estimate the proportion of patients that are alive and off all systemic 
IST at 12 months following initiation of treatment.  To meet this endpoint, patients need to 
remain off IST for at least 8 weeks after discontinuing systemic immunosuppression (e.g. 
sirolimus). The use of rituximab and ibrutinib are not considered IST for this endpoint. 
10.2.2. 
Secondary Endpoints  
Secondary efficacy endpoints: 
To estimate: 
• Chronic GVHD response (CR + PR, both individual organ response and overall response, 
according to 2014 NIH Response Criteria Working Group Report) – See Appendix G. 
• Cumulative steroid exposure (total mg methylprednisolone or equivalent). 
• Time to discontinuation of systemic immunosuppression (defined as the date that all 
systemic IST has been discontinued after resolution of all reversible manifestations of 
cGVHD.  Discontinuation of immunosuppressive medications for the purpose of 
inducing an anti-tumor response after the development of recurrent or secondary 
malignancy will not be counted as successful discontinuation of IST). 
• Failure-free survival (defined as being alive without the requirement for second-line 
cGVHD therapy).  See section 6.3 for definition of second-line cGVHD therapy. 
• Non-relapse and overall mortality 
 
Safety endpoints: 
To estimate: 
• Incidence of grade ≥3 adverse events, possibly or probably related to either ibrutinib 
and/or rituximab. 
10.2.3. 
Exploratory Endpoints  
Biomarkers: 
B-cell numbers and subsets, T cell numbers and subsets, T regulatory cells, serum BAFF 
levels and serum cytokine levels will be measured at baseline, months 1, 2, 3, 6, 9, and 12 
to explore biomarkers which predict cGVHD response.   


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10.3. 
Sample Size Determination 
The study will be powered to detect a clinically meaningful improvement in treatment success at 
12 months post-treatment, defined as being alive and off systemic immunosuppression.  
Experience from our phase II study of rituximab in the upfront treatment of cGVHD found that 
56% of patients were alive and off systemic immunosuppression at 12 months post treatment.  It 
is hoped that under this protocol, this rate will be at least 75%.  Thus we statistically formalize 
this study by testing the null hypothesis that p, the treatment success rate is 0.55 or less versus 
the alternative hypothesis that p is at least 0.75.  A sample size of 35 patients gives 80% power 
with an alpha=0.05, using the formula for a one sample binomial (one-sided) test of a proportion.  
Replacement of subjects may be possible for those who are lost to follow-up or withdraw from 
study before 12 months due to non-treatment related reasons, in order to ensure statistical power 
of the study. 
10.4. 
Efficacy Analysis Methods 
This is a phase II trial evaluating the safety and efficacy of ibrutinib and rituximab as primary 
treatment of cGVHD.  Efficacy and safety endpoints will be estimated according to the 
cumulative incidence and Kaplan-Meier methodology in the presence of competing risks. 
Outcomes will be compared to historical values based on the Gray’s test and log rank test 
respectively.  We plan to enroll 35 patients on this study. Patients will be formally monitored for 
12 months to evaluate for outcome and safety endpoints (efficacy/safety visits at the completion 
of month 1, 2, 3, 6, 9, and 12).  All other assessments will be done at the physician’s discretion 
or institutional standards. All patients, responders and treatment failures, will be followed for a 
period of one year.  The primary outcome measure will be the proportion of patients that are 
alive and off all systemic immunosuppression at 12 months following initiation of treatment.  
The primary endpoint will be estimated according to the Kaplan-Meier methodology in the 
presence of competing risks. Outcome will be compared to historical values based on the log 
rank test.  Secondary outcome measures will be cGVHD response, cumulative steroid exposure, 
time to discontinuation of systemic immunosuppression, requirement for second-line cGVHD 
therapy, non-relapse and overall mortality, failure-free survival and safety.  Secondary survival 
endpoints will be estimated according to the Kaplan-Meier methodology in the presence of 
competing risks, and outcomes will be compared to historical values based on the log rank test.  
Secondary time-to-event endpoints will be estimated according to cumulative incidence 
methodology, and outcomes will be compared to historical values based on the Gray’s test (Gray 
1988). 


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11. 
ADVERSE EVENT REPORTING  
11.1. 
Definitions  
11.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A 1995). 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
The term “disease progression” should not be reported as an AE term. As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 
Adverse events may include, but are not limited to: 
• Subjective or objective symptoms provided by the subject and/or observed by the 
investigator or study staff including laboratory abnormalities of clinical significance. 
• Any AEs experienced by the subject through the completion of final study procedures. 
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease 
that were not present before the AE reporting period  
• Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
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 
ICF is not considered an SAE, but rather a therapeutic intervention. However, if during 
the pre-planned hospitalization an event occurs, which prolongs the hospitalization or 
meets any other SAE criteria, the event will be considered an SAE. Surgeries or 
interventions that were under consideration, but not performed before enrollment in the 
study, will not be considered serious if they are performed after enrollment in the study 
for a condition that has not changed from its baseline level. Elective hospitalizations for 
social reasons, solely for the administration of chemotherapy, or due to long travel 
distances are also not SAEs. 


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• 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 (SAE) based on International Conference on Harmonisation (ICH) and 
EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use is any untoward 
medical occurrence that at any dose: 
• Results in death (i.e., the AE actually causes or leads to death). 
• Is life-threatening. Life-threatening is defined as an AE in which the subject was at risk 
of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it were more severe. If either the investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered 
life-threatening. 
• Requires in-patient hospitalization >24 hours or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’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 subject or 
subject may require intervention to prevent one of the other outcomes listed in this 
definition. Examples of such events are intensive treatment in an emergency department 
or at home for allergic bronchospasm, blood dyscrasias, or convulsion that does not 
result in hospitalization; or development of drug dependency or drug abuse. 
Given that the investigator’s perspective may be informed by having actually observed the event, 
and Pharmacyclics LLC is likely to have broader knowledge of the drug and its effects to inform 
its evaluation of the significance of the event, if either Pharmacyclics LLC or the investigator 
believes that the event is serious, the event will be considered serious. 
11.1.3. 
Severity Criteria (Grade 1-5) 
Definitions found in the Common Terminology Criteria for Adverse Events version 5.0 
(CTCAE v5.0) will be used for grading the severity (intensity) of AEs. The CTCAE v5.0 
displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. 
Should a subject experience any AE not listed in the CTCAE v5.0, 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 subject’s daily activities 


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• Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
• Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment 
• Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be 
in imminent danger of death 
• Grade 5 (Death related to AE) – experiences which result in subject death 
11.1.4. 
Causality (Attribution)  
The investigator is to assess the causal relation (i.e., whether there is a reasonable possibility that 
the study drug(s) 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 IB or is not listed at the specificity or 
severity that has been observed. For example, hepatic necrosis would be “unexpected” (by virtue 
of greater severity) if the IB referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be “unexpected” (by virtue of greater 
specificity) if the IB listed only cerebral vascular accidents. "Unexpected" also refers to AEs that 
are mentioned in the IB as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
study drug under investigation. 


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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 exposure to the study 
drug, e.g., name confusion) 
If any special reporting situation meets the criteria of an AE, it should be reported on the Serious 
Adverse Event Report Form. The Serious Adverse Event Report Form should be sent via email 
or fax to Pharmacyclics Drug Safety, Pharmacovigilance & Epidemiology (DSP&E) or designee 
within 24 hours of awareness. 
11.4. 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
11.4.1. 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points 
during the study. All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, detected through physical examination, clinically significant 
laboratory test, or other means, will be recorded in the subject’s medical record and on the AEs 
CRF and, when applicable, on the Serious Adverse Event Report Form. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, 
regulatory seriousness criteria (if applicable), suspected relationship to the investigational 
product, and any actions taken. 
11.4.2. 
Adverse Event Reporting Period 
All AEs whether serious or non-serious, will be documented from the time signed and dated ICF 
is obtained until 30 days following the last dose of study drug or the start date of a new therapy 
for cGVHD. SAEs will be reported to the Sponsor Drug Safety via an SAE reporting form and 
will be recorded in the CRF from the time of ICF signing. Non-serious AEs will be recorded in 
the source documents from the time of ICF signing and will be recorded in the CRF from the 
first dose of study drug(s). 
SAEs 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 


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signs of disease progression may be reported. (See Section 11.1.1) 
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document. All records will need to capture the 
details of the duration and the severity of each episode, the action taken with respect to the study 
drug, investigator’s evaluation of its relationship to the study drug, and the event outcome. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection"). Investigators must record in the CRF their opinion concerning 
the relationship of the AE to study therapy. All measures required for AE management must be 
recorded in the source document and reported according to Sponsor instructions. 
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. Autopsy and postmortem reports must be 
forwarded to the Sponsor, or designee, as outlined above, if allowed per local regulatory 
guidelines. 
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a SAE.  
11.4.3. 
Expediting Reporting Requirements for Serious Adverse Events 
All serious adverse events and AESIs (initial and follow-up information) will be reported on 
FDA Medwatch (Form 3500A) or Suspect Adverse Event Report (CIOMS Form 1) IRB 
Reporting Form and sent via email (AEintakePM@pcyc.com) or fax ((408) 215-3372) to 
Pharmacyclics Drug Safety, Pharmacovigilance & Epidemiology (DSP&E) or designee, within 
24 hours of the event. Pharmacyclics may request follow-up and other additional information 
from the Sponsor Investigator. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs: 
• 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) 


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The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations.  
The investigator (or Sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB. 
11.4.4. 
Pregnancy 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject or female partner of a male subject must immediately inform the investigator if 
she becomes pregnant from the time of consent to 90 days after the last dose of study drug(s). 
Any female subjects receiving study drug(s) who become pregnant must immediately 
discontinue study drug. The investigator should counsel the subject, discussing any risks of 
continuing the pregnancy and any possible effects on the fetus.  
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. 
Any pregnancy occurring in a female subject or female partner of a male subject must be 
reported from the time of first dose up until 90 days after the last dose of study drug(s). Any 
occurrence of pregnancy must be recorded on the Pregnancy Report Form Part I and sent via 
email or fax to Pharmacyclics Drug Safety, Pharmacyclics Drug Safety, Pharmacovigilance & 
Epidemiology (DSP&E) or designee, per SAE reporting timelines of learning of the event. All 
pregnancies will be followed for outcome, which is defined as elective termination of the 
pregnancy, miscarriage, or delivery of the fetus. For pregnancies with an outcome of live birth, 
the newborn infant will be followed until 30 days old by completing the Pregnancy Report Form 
Part II. Any congenital anomaly/birth defect noted in the infant must be reported as a SAE. 
11.4.5. 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 
protocol-specified follow-up periods including post-progression follow-up for overall survival. If 
observed, enter data in the corresponding eCRF. 
11.4.6. 
Adverse Events of Special Interest (AESI) 
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities 
by the Sponsor. These events (regardless of seriousness) should be reported on the Serious 
Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, 
Pharmacovigilance & Epidemiology (DSP&E) or designee, within 24 hours of awareness.  


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11.4.6.1. 
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 v5.0 
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.4.6 above. 
12. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
12.1. 
Institutional Review Board (IRB), Research Ethics Board (REB) and 
Independent Ethics Committee (IEC) Approval 
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards.  The IRB/IEC will review all appropriate study documentation in order 
to safeguard the rights, safety and well-being of the patients.  The study will be conducted only 
at sites where IRB/IEC approval has been obtained.  The protocol, Investigator’s Brochure, 
informed consent form, advertisements (if applicable), written information given to the patients 
(including diary cards), safety updates, annual progress reports, and any revisions to these 
documents will be provided to the IRB/IEC by the investigator.  Pharmacyclics may request that 
informed consent documents be reviewed by Pharmacyclics or designee prior to IRB/IEC 
submission.   
12.2. 
Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative before study participation.  The method of 
obtaining and documenting the informed consent and the contents of the consent must comply 
with the ICH-GCP and all applicable regulatory requirements. 
12.3. 
Protected Subject Health Information Authorization 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
If requested, the investigator will grant monitor(s) and auditor(s) from Pharmacyclics or its 
designees and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection process.  


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The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
12.4. 
Study Files and Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).   
12.5. 
Investigational Study Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records indicating the drug’s delivery date to the site, inventory at 
the site, use by each patient, and amount returned to Pharmacyclics or a designee or disposal of 
the drug (if applicable and if approved by Pharmacyclics) will be maintained by the clinical site.  
Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and patient numbers.   
12.6. 
Study Monitoring/Audit Requirements 
Regulatory authorities, the IEC/IRB and/or Pharmacyclics may request access to all source 
documents, data capture records, and other study documentation for on-site audit or inspection.  
Direct access to these documents must be guaranteed by the investigator, who must provide 
support at all times for these activities. 
12.7. 
Investigator Responsibilities 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies).  Changes to the protocol 
will require approval from Pharmcyclics and written IRB/IEC approval/favorable opinion prior 
to implementation, except when the modification is needed to eliminate an immediate hazard(s) 
to patients.  The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval /favorable opinion of the IRB/IEC.  The investigator will submit all protocol 
modifications to Pharmacyclics and the regulatory authority(ies) in accordance with the 
governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   
12.8. 
Protocol Amendments 
Any amendments to the Protocol or Informed Consent Form must be sent to Pharmacyclics for 
review and approval prior to submission to the IRB.  Written verification of IRB approval will be 
obtained before any amendment is implemented. 


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12.9. 
Publication of Study Results 
The Investigator is required to submit to Pharmacyclics a copy of a planned publication (abstract, 
poster, oral presentation or manuscript) prior to the submission thereof for publication or 
disclosure.  Pharmacyclics may provide scientific comments and suggestions understanding that 
the Investigator has sole editorial responsibility, and retains the authority to make the final 
determination on whether or not to incorporate Pharmacyclics comments or requests for 
additional information. 
12.10. 
Study Discontinuation 
Patients may be withdrawn from the study if: 
• 
The patient requests withdrawal. 
• 
If the patient develops side effects that are considered life-threatening 
• 
If the patient refuses to have treatment as recommended. 
• 
If the patient refuses to have tests that are needed to determine whether the treatment is 
safe and effective. 
• 
If the agents used in this study cease to be available. 
• 
If other causes prevent continuation of the study 
• 
For any other reason that the physician feels it may be necessary that the patient 
discontinue the study 
12.11. 
Study Completion 
The study is expected to be completed approximately 1 year from last subject enrolled, the time 
point all subjects have exited the study for any reason, or study termination at the Sponsor’s 
discretion, whichever occurs first.   


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Blood 95(12): 3996-4003. 
Chang BY, Francesco M, De Rooij MF, et al. Egress of CD19+CD5+ cells into peripheral blood 
following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. 
Blood. 2013a;122:2412-24.  
Chang BY, Francesco M, Steggerda S, et al. Ibrutinib Inhibits Malignant Cell Adhesion and Migration 
and Reduces Tumor Burden in Lymph Node and Bone Marrow in a Murine Model of Mantle Cell 
Dissemination and Progression. 2013b AACR: Abstract 923. 
Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG. The liver and portal hypertension. 
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Chiodi, S., S. Spinelli, et al. (2000). "Quality of life in 244 recipients of allogeneic bone marrow 
transplantation." British Journal of Haematology 110(3): 614-619. 
Cooke, K. R., L. Luznik, et al. (2017). "The Biology of Chronic Graft-versus-Host Disease: A Task Force 
Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical 
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Cutler, C., H. T. Kim, et al. (2013). "Rituximab prophylaxis prevents corticosteroid-requiring chronic 
GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial." Blood 
122(8): 1510-1517. 
Cutler, C., D. Miklos, et al. (2006). "Rituximab for steroid-refractory chronic graft-versus-host disease." 
Blood 108(2): 756-762. 
Dubovsky, J. A., R. Flynn, et al. (2014). "Ibrutinib treatment ameliorates murine chronic graft-versus-host 
disease." The Journal of clinical investigation 124(11): 4867-4876. 
Duell, T., M. T. van Lint, et al. (1997). "Health and functional status of long-term survivors of bone 
marrow transplantation. EBMT Working Party on Late Effects and EULEP Study Group on Late Effects. 
European Group for Blood and Marrow Transplantation." Ann Intern Med 126(3): 184-192. 
Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever 
and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice 
guideline. J Clin Oncol. 2013;31:794-810. 


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Gray, R. (1988), “A Class of K-Sample Tests for Comparing the Cumulative Incidence of a Competing 
Risk,” The Annals of Statistics, 16: 1141–1154. 
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Higman, M. A. and G. B. Vogelsang (2004). "Chronic graft versus host disease." Br J Haematol 125(4): 
435-454. 
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patients with chronic myeloid leukemia followed at least 10 years after allogeneic bone marrow 
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Koc, S., W. Leisenring, et al. (2002). "Therapy for chronic graft-versus-host disease: a randomized trial 
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Miklos, D. B., H. T. Kim, et al. (2005). "Antibody responses to H-Y minor histocompatibility antigens 
correlate with chronic graft-versus-host disease and disease remission." Blood 105(7): 2973-2978. 
Miklos, D. B., H. T. Kim, et al. (2004). "Antibody response to DBY minor histocompatibility antigen is 
induced after allogeneic stem cell transplantation and in healthy female donors." Blood 103(1): 353-359. 
Okamoto, M., A. Okano, et al. (2006). "Rituximab is effective for steroid-refractory sclerodermatous 
chronic graft-versus-host disease." Leukemia 20(1): 172-173. 
Oken, MM, Creech RH, Tormey DC, et al.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 5:649-55, 1982. 
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
ChemMedChem. 2007;2:58-61. 
Pavletic, S. Z., S. L. Carter, et al. (2005). "Influence of T-cell depletion on chronic graft-versus-host 
disease: results of a multicenter randomized trial in unrelated marrow donor transplantation." Blood 
106(9): 3308-3313. 
Pugh RN, Murray-Lyon IM, Dawson L, et al. Transection of the oesophagus for bleeding oesophageal 
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Ratanatharathorn, V., L. Ayash, et al. (2001). "Chronic graft-versus-host disease: clinical manifestation 
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Ratanatharathorn, V., L. Ayash, et al. (2003). "Treatment of chronic graft-versus-host disease with anti-
CD20 chimeric monoclonal antibody." Biol Blood Marrow Transplant 9(8): 505-511. 
Sauter, C. S., J. N. Barker, et al. (2014). "A phase II study of a nonmyeloablative allogeneic stem cell 
transplant with peritransplant rituximab in patients with B cell lymphoid malignancies: favorably durable 
event-free survival in chemosensitive patients." Biol Blood Marrow Transplant 20(3): 354-360. 
Schmitz, N., M. Eapen, et al. (2006). "Long-term outcome of patients given transplants of mobilized 
blood or bone marrow: a report from the International Bone Marrow Transplant Registry and the 
European Group for Blood and Marrow Transplantation." Blood 108(13): 4288-4290. 
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., J. V. Stone, et al. (1999). "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 341(1): 14-21. 
Solomon, S. R., C. A. Sizemore, et al. (2015). "Corticosteroid-Free Primary Treatment of Chronic 
Extensive Graft-versus-Host Disease Incorporating Rituximab." Biol Blood Marrow Transplant. 
Stevenson FK, Krysov S, Davies AJ, et al. B-cell receptor signaling in chronic lymphocytic leukemia. 
Blood. 2011;118: 4313-20. 
Stewart, B. L., B. Storer, et al. (2004). "Duration of immunosuppressive treatment for chronic graft-
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Sullivan, K. M., R. P. Witherspoon, et al. (1988). "Prednisone and azathioprine compared with prednisone 
and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged 
thrombocytopenia after allogeneic marrow transplantation." Blood 72(2): 546-554. 
Sutherland, H. J., G. M. Fyles, et al. (1997). "Quality of life following bone marrow transplantation: a 
comparison of patient reports with population norms." Bone Marrow Transplant 19(11): 1129-1136. 
Syrjala, K. L., M. K. Chapko, et al. (1993). "Recovery after allogeneic marrow transplantation: 
prospective study of predictors of long-term physical and psychosocial functioning." Bone Marrow 
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Vogelsang, G. B. (2001). "How I treat chronic graft-versus-host disease." Blood 97(5): 1196-1201. 
Wang, M. L., H. Lee, et al. (2016). "Ibrutinib in combination with rituximab in relapsed or refractory 
mantle cell lymphoma: a single-centre, open-label, phase 2 trial." The Lancet. Oncology 17(1): 48-56. 
Wingard, J. R., S. Piantadosi, et al. (1989). "Predictors of death from chronic graft-versus-host disease 
after bone marrow transplantation." Blood 74(4): 1428-1435. 
Zaja, F., A. Bacigalupo, et al. (2007). "Treatment of refractory chronic GVHD with rituximab: a GITMO 
study." Bone Marrow Transplant 40(3): 273-277. 
 
 
 


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14. APPENDICES 


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Appendix A. Schedule of Assessments  
Study Day 
Screening 
(within 7 
days) 
Day 
1  
Day 7 
(+/- 3 
days) 
Month 1 
(+/- 7 
days) 
Month 2 
(+/- 7 
days) 
Month 3 
(+/- 7 
days) 
Month 6 
(+/- 7 
days) 
Month 9 
(+/- 7 
days) 
Month 12 
(+/- 7 
days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Eligibility Confirmation 
X 
 
 
 
 
 
 
 
 
Ibrutinib 420mg daily1 
 
X 
 
Continuous daily dosing 
Dispensed on D1 of each cycle through Cycle 12 
Rituximab 375mg/m2 
 
 
X2 
 
 
X3 
Medical History 
X 
 
 
X 
X 
X 
X 
X 
X 
Physical Exam w/vitals 
X 
 
 
X 
X 
X 
X 
X 
X 
Schirmer’s test 
X 
 
 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Status 
X 
 
 
 
 
 
 
 
 
Serum Pregnancy 
X 
 
 
 
 
 
 
 
 
Hepatitis serologies 
X 
 
 
 
 
 
 
 
 
Fasting Lipid Panel 
X 
 
 
 
 
 
 
 
 
CBC w/differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Metabolic Panel4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IgG level 
X 
 
 
 
 
X 
X 
X 
X 
CRP 
X 
 
 
X 
X 
X 
X 
X 
X 
CK 
X 
 
 
X 
X 
X 
X 
X 
X 
LDH 
X 
 
 
X 
X 
X 
X 
X 
X 
Biomarkers (Correlative studies) 
X 
 
 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
GVHD assessment5 
X 
 
 
X 
X 
X 
X 
X 
X 
GVHD patient self-report form6 
X 
 
 
X 
X 
X 
X 
X 
X 
Pulmonary Function Test 
X 
 
 
 
 
X 
X 
X 
X 
Calculate cumulative steroid dose 
 
 
 
X 
X 
X 
X 
X 
X 
Any new systemic IST 
 
 
 
X 
X 
X 
X 
X 
X 
Any IVIG therapy 
 
 
 
X 
X 
X 
X 
X 
X 
Adverse Event 
 
 
 
X 
X 
X 
X 
X 
X 
 


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1Dose reduction required when using strong Cyp 3A4 inhibitors (e.g. voriconazole or posaconazole, see Section 6.2.1, table 4) or with 
hepatic impairment (see Section 5.1.1.5, table 3). 
2Rituximab induction 375mg/m2 Q7days x 4 doses. 
3Rituximab maintenance 375mg/m2 q 3months (+/-7days) x 4 doses. 
4Glucose, BUN, creatinine, total bilirubin, alkaline phosphatase, albumin, SGOT (AST), SGPT (ALT), 
calcium, magnesium 
5See appendix E 
6See appendix F 
 
 
 
 
 
 


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Appendix B. Karnofsky Performance Status Score 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of 
disease. 
 
Able to carry on normal activity; 
no special care needed. 
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 to do work. 
Unable to work, able to live at 
home and care for most personal 
needs, 
varying 
amount 
of 
assistance needed. 
60 
Requires occasional assistance from others but 
able to care for most needs. 
50 
Requires considerable assistance from others 
and frequent medical care 
40 
Disabled, requires special care and assistance. Unable to care for self, requires 
institutional or hospital care or 
equivalent, disease may be rapidly 
progressing. 
 
30 
Severely disabled, hospitalization indicated, 
but death not imminent. 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10 
Moribund 
0 
Dead 
 


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Appendix C. Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A enzymes are defined as follows. Refer to Section 6.2.1 on instructions 
for concomitant use of CYP3A inhibitors and inducers with ibrutinib. Further information can be found at 
the following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
carbamazepine 
boceprevir 
barbiturates 
clarithromycin 
efavirenz 
cobicistat 
glucocorticoids 
indinavir 
modafinil 
itraconazole 
nevirapine 
ketoconazole 
oxcarbarzepine 
mibefradil 
phenobarbital 
nefazodone 
phenytoin 
nelfinavir 
pioglitazone 
posaconazolea 
rifabutin 
ritonavir 
rifampin 
saquinavir 
St. John’s Wort 
suboxone 
troglitazone 
telaprevir 
 
telithromycin 
 
troleandomycin 
 
Moderate inhibitors: 
 
amiodarone 
 
amprenavir 
 
aprepitant 
 
atazanavir 
 
ciprofloxacin 
 
crizotinib 
 
darunavir 
 
diltiazem  
 
dronedarone 
 
erythromycin 
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
imatinib 
 
Seville orange juice 
 
verapamil 
 
voriconazolea  
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delaviridine 
 
diethyl-dithiocarbamate 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
norfluoxetine 
 
star fruit 
 
a. 
Classification based on internal data. 
 


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Appendix D. Child-Pugh Score for Subjects with Liver Impairment 
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;50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, et al. Transection of the oesophagus for bleeding oesophageal varices.  
The British journal of surgery, 1973;60:646-9. 
 
 


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Appendix E. Chronic GVHD Assessment Form  
 


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Appendix F. Patient Self Report Form 
 
 
 


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Appendix G. Chronic GVHD Response criteria  
 
Organ-specific Response Criteria: 
 
 
 
Source:  
1. Lee et al.. Measuring Therapeutic Response in Chronic Graft-versus-Host Disease. National Institutes of Health 
Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 
2014 Response Criteria Working Group Report. Biol Blood Marrow Transplant 2015; 21:984-999.   
 
 
Overall Response Criteria: 
 
Complete response (CR):  defined as resolution of all manifestations in each organ or site. 
 
Partial response (PR):  defined as improvement in at least 1 organ or site without progression in 
any other organ or site as described above.   
 
Overall response (OR): CR + PR 
 
No response (NR): Defined as no response in any organ, mixed response, or progression. 
 
Stable Disease (SD): Does not meet criteria for CR, PR or disease progression. 
 
Organ improvement: clinically meaningful improvement defined as a decrease of 1 point or more 
on the 0 to 3 scale for skin, eye, mouth, esophagus, upper or lower GI tract.  For joint/fascia, a 
clinically meaningful improvement is represented by a decrease of at least 1 point on the 0 to 3 


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scale or increase in the photographic range of motion by at least 1 point for any site.  Liver 
improvement is defined as a 50% decrease in ALT, alkaline phosphatase or total bilirubin.  Lung 
improvement is defined as an increase by 10% of the predicted absolute value of %FEV1 (eg. 
50% to 60%). 
 
Organ progression: For skin, eye, mouth, esophagus, upper or lower GI tract, a worsening of 1 
point or more on the 0 to 3 scale is considered progression, except a change from 0 to 1, which is 
considered trivial progression since it often reflects mild, nonspecific, intermittent, self-limited 
symptoms and signs that do not warrant a change of therapy. For joint/fascia, a worsening of 1 
point or more on the 0 to 3 scale is considered progression, even if from 0 to 1.  For joints 
assessed by the photographic range of motion, a worsening of 1 or more points for the 7- point or 
4-point scales is considered progression. Worsening of liver GVHD is defined by an increase of 
2 or more times the upper limit of normal for the assay for alanine transaminase, alkaline 
phosphatase, or total bilirubin. For patients with lung involvement, absolute worsening of FEV1 
by 10% predicted or more (eg, 50% to 40%) is considered progression.