Clinical trial NCT03474679
Conditions: Graft vs Host Disease
Sponsor: Janssen Pharmaceutical K.K.
Start date: 2018-05-01; Completion date: 2021-11-29
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate efficacy of ibrutinib in Japanese participants with steroid dependent/refractory chronic graft versus host disease (cGVHD) by measuring overall cGVHD response (complete response \[CR\] and partial response \[PR\] defined by National Institutes of Health \[NIH\] consensus development project criteria \[2014\]).

Detailed description:

Arms: arm 1: Participants will receive 420 milligram (mg) oral ibrutinib once daily starting on Week 1 Day 1, unless they have intervening unacceptable toxicity or meet other criteria for participants discontinuation.
Interventions: intervention 1: Ibrutinib
Intervention descriptions: intervention 1: Participants will receive 420 mg (3 \* 140 mg capsules) oral ibrutinib once daily starting on Week 1 Day 1, unless they have intervening unacceptable toxicity or meet other criteria for participants discontinuation.

Protocol documents:
Prot_000.pdf: 
1 
Status: Approved,  Date: 24 July 2018 
Janssen Pharmaceutical K.K.* 
Clinical Protocol 
A Phase 3 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Subjects 
with Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD) 
Protocol 54179060GVH3001; Phase 3 
AMENDMENT 1 
JNJ-54179060 (Ibrutinib) 
*This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K.
Status: 
Approved 
Date:
24 July 2018
Prepared by: Janssen Pharmaceutical K.K. 
EDMS number: 
EDMS-ERI-150355182, 2.0 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential. 
NCT03474679


JNJ-54179060  (Ibrutinib)  
 
Clinical Protocol 54179060GVH3001 Amendment 1 
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Approved, Date: 24 July 2018 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
LIST OF ATTACHMENTS ............................................................................................................................ 4 
LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 4 
PROTOCOL AMENDMENTS ....................................................................................................................... 5 
SYNOPSIS .................................................................................................................................................... 7 
TIME AND EVENTS SCHEDULE .............................................................................................................. 10 
ABBREVIATIONS ...................................................................................................................................... 14 
1. 
INTRODUCTION ................................................................................................................................ 16 
1.1. 
Chronic Graft Versus Host Disease ............................................................................................... 16 
1.2. 
Pathogenesis of Chronic Graft Versus Host Disease .................................................................... 17 
1.3. 
Current Treatment Options for cGVHD .......................................................................................... 17 
1.4. 
Background .................................................................................................................................... 18 
1.4.1. 
Nonclinical Studies ..................................................................................................................... 18 
1.4.2. 
Clinical Studies ........................................................................................................................... 19 
1.4.3. 
Risks ........................................................................................................................................... 22 
1.5. 
Overall Rationale for the Study ...................................................................................................... 23 
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS ........................................................................... 24 
2.1. 
Objectives and Endpoints .............................................................................................................. 24 
2.2. 
Hypothesis ..................................................................................................................................... 26 
3. 
STUDY DESIGN AND RATIONALE ................................................................................................. 26 
3.1. 
Overview of Study Design .............................................................................................................. 26 
3.2. 
Study Design Rationale .................................................................................................................. 27 
4. 
SUBJECT POPULATION .................................................................................................................. 28 
4.1. 
Inclusion Criteria ............................................................................................................................ 28 
4.2. 
Exclusion Criteria ........................................................................................................................... 31 
4.3. 
Prohibitions and Restrictions ......................................................................................................... 33 
5. 
INTERVENTION ALLOCATION AND BLINDING ............................................................................ 33 
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 33 
6.1. 
Dose Modifications ......................................................................................................................... 34 
6.1.1. 
Dose Modification for Adverse Reactions ................................................................................... 34 
6.1.2. 
Dose Modification for Subjects with Hepatic Impairment ........................................................... 35 
6.1.3. 
Ibrutinib Hold After Withdrawal of All Immunosuppressants ...................................................... 35 
7. 
INTERVENTION COMPLIANCE ....................................................................................................... 36 
8. 
CONCOMITANT THERAPY .............................................................................................................. 36 
8.1. 
Permitted Concomitant Medications .............................................................................................. 36 
8.1.1. 
Ancillary Therapy and Supportive Care ...................................................................................... 36 
8.1.2. 
Systemic Immunosuppressant Therapy ..................................................................................... 36 
8.1.3. 
Systemic Steroids ....................................................................................................................... 36 
8.2. 
Prohibited Concomitant Medications ............................................................................................. 37 
8.3. 
Medications to be Used With Caution ............................................................................................ 37 
8.3.1. 
CYP3A Inhibitors or Inducers ..................................................................................................... 37 
8.3.2. 
Substrates of P-glycoprotein ...................................................................................................... 38 
8.3.3. 
Antiplatelet Agents and Anticoagulants ...................................................................................... 38 


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9. 
STUDY EVALUATIONS .................................................................................................................... 38 
9.1. 
Study Procedures ........................................................................................................................... 38 
9.1.1. 
Overview ..................................................................................................................................... 38 
9.1.2. 
Screening Phase ........................................................................................................................ 39 
9.1.3. 
Treatment Phase ........................................................................................................................ 40 
9.1.4. 
Follow-up Phase ......................................................................................................................... 41 
9.2. 
Efficacy ........................................................................................................................................... 42 
9.2.1. 
Efficacy Evaluations .................................................................................................................... 42 
9.3. 
Pharmacokinetics ........................................................................................................................... 42 
9.3.1. 
Evaluations ................................................................................................................................. 42 
9.3.2. 
Analytical Procedures ................................................................................................................. 43 
9.3.3. 
Pharmacokinetic Parameters ..................................................................................................... 43 
9.4. 
Pharmacodynamic Evaluations ...................................................................................................... 43 
9.5. 
Safety Evaluations ......................................................................................................................... 43 
9.6. 
Sample Collection and Handling .................................................................................................... 46 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY INTERVENTION/ 
WITHDRAWAL FROM THE STUDY ................................................................................................. 46 
10.1. 
Completion ..................................................................................................................................... 46 
10.2. 
Discontinuation of Study Intervention/Withdrawal from the Study ................................................. 46 
11. 
STATISTICAL METHODS ................................................................................................................. 47 
11.1. 
Subject Information ........................................................................................................................ 47 
11.2. 
Sample Size Determination ........................................................................................................... 48 
11.3. 
Efficacy Analyses ........................................................................................................................... 48 
11.4. 
Pharmacokinetic Analysis .............................................................................................................. 48 
11.5. 
Pharmacodynamic Analyses .......................................................................................................... 49 
11.6. 
Pharmacokinetic/Pharmacodynamic Analyses .............................................................................. 49 
11.7. 
Safety Analyses ............................................................................................................................. 49 
12. 
ADVERSE EVENT REPORTING ...................................................................................................... 50 
12.1. 
Definitions ...................................................................................................................................... 50 
12.1.1. 
Adverse Event Definitions and Classifications ........................................................................... 50 
12.1.2. 
Attribution Definitions .................................................................................................................. 52 
12.1.3. 
Severity Criteria .......................................................................................................................... 52 
12.2. 
Special Reporting Situations .......................................................................................................... 52 
12.3. 
Procedures ..................................................................................................................................... 53 
12.3.1. 
All Adverse Events ...................................................................................................................... 53 
12.3.2. 
Serious Adverse Events ............................................................................................................. 54 
12.3.3. 
Adverse Events of Special Interest ............................................................................................. 55 
12.3.4. 
Other Malignancies ..................................................................................................................... 55 
12.3.5. 
Pregnancy ................................................................................................................................... 55 
12.4. 
Contacting Sponsor Regarding Safety ........................................................................................... 56 
13. 
PRODUCT QUALITY COMPLAINT HANDLING .............................................................................. 56 
13.1. 
Procedures ..................................................................................................................................... 56 
13.2. 
Contacting Sponsor Regarding Product Quality ............................................................................ 56 
14. 
STUDY INTERVENTION INFORMATION ........................................................................................ 56 
14.1. 
Physical Description of Study Drug ................................................................................................ 56 
14.2. 
Packaging ...................................................................................................................................... 57 
14.3. 
Labeling .......................................................................................................................................... 57 
14.4. 
Preparation, Handling, and Storage ............................................................................................... 57 
14.5. 
Intervention Accountability ............................................................................................................. 57 
15. 
STUDY-SPECIFIC MATERIALS ....................................................................................................... 58 
16. 
ETHICAL ASPECTS ......................................................................................................................... 58 
16.1. 
Study-Specific Design Considerations ........................................................................................... 58 


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16.2. 
Regulatory Ethics Compliance ....................................................................................................... 59 
16.2.1. 
Investigator Responsibilities ....................................................................................................... 59 
16.2.2. 
Independent Ethics Committee or Institutional Review Board ................................................... 59 
16.2.3. 
Informed Consent and Assent Form ........................................................................................... 60 
16.2.4. 
Privacy of Personal Data ............................................................................................................ 62 
17. 
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 62 
17.1. 
Protocol Amendments .................................................................................................................... 62 
17.2. 
Regulatory Documentation ............................................................................................................ 63 
17.2.1. 
Regulatory Approval/Notification ................................................................................................ 63 
17.2.2. 
Required Prestudy Documentation ............................................................................................. 63 
17.3. 
Subject Identification, Enrollment, and Screening Logs ................................................................ 64 
17.4. 
Source Documentation ................................................................................................................... 64 
17.5. 
Case Report Form Completion ...................................................................................................... 65 
17.6. 
Data Quality Assurance/Quality Control ........................................................................................ 65 
17.7. 
Record Retention ........................................................................................................................... 66 
17.8. 
Monitoring ...................................................................................................................................... 67 
17.9. 
Study Completion/Termination ....................................................................................................... 67 
17.9.1. 
Study Completion/End of Study .................................................................................................. 67 
17.9.2. 
Study Termination ....................................................................................................................... 67 
17.10. On-Site Audits ................................................................................................................................ 68 
17.11. Use of Information and Publication ................................................................................................ 68 
REFERENCES ............................................................................................................................................ 70 
INVESTIGATOR AGREEMENT ................................................................................................................. 89 
 
LIST OF ATTACHMENTS 
Attachment 1: Diagnosis of cGVHD − Signs and Symptoms of cGVHD .................................................... 73 
Attachment 2: Karnofsky/Lansky Performance Status ............................................................................... 76 
Attachment 3: Lee cGVHD Symptom Scale ............................................................................................... 77 
Attachment 4: Chronic GVHD Activity Assessment-Clinician ..................................................................... 79 
Attachment 5: Response Determination for Chronic GVHD Clinical Trials based on Clinician 
Assessments ...................................................................................................................... 82 
Attachment 6: Chronic GVHD Activity Assessment − Patient Self Report ................................................. 84 
Attachment 7: Inhibitors and Inducers of CYP3A ....................................................................................... 85 
Attachment 8: Child-Pugh Score ................................................................................................................. 86 
Attachment 9: Summary of Ancillary Therapy and Supportive Care Interventions ..................................... 87 
 
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES 
Table 1: Most Frequently Reported Treatment-emergent Adverse Events With Ibrutinib 
Monotherapy (Pooled Data from 1,523 Subjects) .................................................................... 20 
Table 2: Most Frequently Reported TEAEs in Subjects Receiving Ibrutinib in Combination 
Therapy (Pooled Data From 422 Subjects) .............................................................................. 21 
Table 3: Most frequently reported TEAEs in subjects receiving ibrutinib for cGVHD ................................. 21 
Table 4: Ibrutinib Dose Modifications .......................................................................................................... 34 
Table 5: Ibrutinib Dose Reduction Levels ................................................................................................... 34 
Table 6: Ibrutinib Dose Modifications for Subjects with Hepatic Impairment .............................................. 35 
Table 7: Ibrutinib Dose Modifications for Concomitant Use of CYP3A Inhibitors ....................................... 37 
 


JNJ-54179060  (Ibrutinib)  
 
Clinical Protocol 54179060GVH3001 Amendment 1 
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PROTOCOL AMENDMENTS 
 
Protocol Version 
Date 
Original Protocol 
28 Dec 2017 
Amendment 1 
24 Jul 2018 
 
Amendments below are listed beginning with the most recent amendment. 
Amendment 1 (24 Jul 2018) 
The overall reason for the amendment: To modify a definition of steroid-dependent in inclusion criteria 1 so that 
the definition further fit the clinical practices. And to add explanation to cGVHD response criteria of Complete 
Response in Liver (Attachment 5). 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: To modify a definition of steroid dependent in inclusion criteria 1 so that the definition further fit the 
clinical practices. 
4.1. Inclusion Criteria 
1 
Following description was added to definition of steroid-dependent cGVHD: 
In case of inability to taper the dose to ≤0.25 mg/kg/day or ≤0.5 mg/kg every other day 
(prednisolone doses) due to recurrence or progression of cGVHD manifestations, it is 
considered as steroid-dependent disease if the lowest tapering dose of the second occasion 
is equal or higher than the lowest tapering dose of the first occasion. 
Rationale: To add explanation to cGVHD response criteria of Complete Response in Liver (Attachment 5). 
Attachment 5 
Definition of liver score in Diagnosis and Staging Working Group Report by NIH cGVHD 
Consensus Development Project (2014) was added as an annotation. 
Rationale: The background safety information for ibrutinib was updated to align with the current ibrutinib 
Investigator’s Brochure. 
1.4.3. Risks 
Description of infections was updated. 
Rationale: To correct errors. 
3.1. Overview of 
Study Design 
“Approximately 20 subjects will be enrolled to have 17 response evaluable subjects.” was 
deleted. 
Table 6: Ibrutinib 
Dose Modifications 
for Subjects with 
Hepatic Impairment 
The case of bilirubin >1.5-3 x ULN at baseline was deleted. 
9.1.3. Treatment 
Phase 
Deleted that ibrutinib will dispensed at each visit. 
11.1. Subject 
Information 
Regarding response evaluable population, “this population will be used for the primary 
efficacy analysis.” was deleted. 
Rationale: To clarify the procedure, some descriptions were modified. 
4.1. Inclusion Criteria 
8 
Descriptions around criteria for transfusion or growth factor support were modified. 
4.2. Exclusion 
Criteria 24 
To be consistent with inclusion criteria 15, length of time that subjects should avoid 
planning to father a child after the last dose of ibrutinib was corrected from 1 month to 
3 months. 


JNJ-54179060  (Ibrutinib)  
 
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Applicable Section(s) 
Description of Change(s) 
9.1.1. Overview 
Procedure of after cGVHD progression in The Posttreatment Follow-up Phase was added. 
“Other measurements may be done earlier than specified timepoints if needed.” was 
deleted because there were no applicable measurements. 
9.1.2. Screening 
Phase 
Procedure of cGVHD assessment at the day of informed consent was clarified. 
9.5. Safety 
Evaluations 
Added a procedure of the case if donor/host chimerism cannot be performed due to any 
specific reason such as no donor information. 
TIME AND EVENTS 
SCHEDULE, 9.5. 
Safety Evaluations 
Clarified timepoints of FEV1. Added that FEV1 evaluation other than mandatory 
timepoints is encouraged in cGVHD activity assessment for a subject who has cGVHD 
features in lung whenever possible. 
Rationale: Dose modification criteria was changed to align with Study PCYC-1129-CA. 
6.1.1. Dose 
Modification for 
Adverse Reactions 
Dose modification criteria regarding reescalation of ibrutinib after dose reduction for a 
toxicity was changed as below: 
If the dose of ibrutinib is reduced for a toxicity, at the investigator’s discretion, the dose of 
ibrutinib may be reescalated after 8 weeks of a dose reduction in the absence of a 
recurrence of the toxicity that led to the reduction. 
Rationale: To clarify the procedure of study enrollment. 
9.1.2. Screening 
Phase 
Added that a subject will be enrolled in this study within 3 days before the planned first 
dose of ibrutinib. 
Rationale: To simplify evaluations of Week 1 Day 1. 
TIME AND EVENTS 
SCHEDULE, 9.1.3. 
Treatment Phase 
Specified that clinical laboratory tests and spirometry of Week 1 Day 1 do not need to 
repeat if the screening tests were performed within 3 days of the first dose of ibrutinib. 
Rationale: To correct minor errors and to unify description. 
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes were made. To unify description, 
several words were changed. 
 
 
 


JNJ-54179060  (Ibrutinib)  
 
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SYNOPSIS 
A Phase 3 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Subjects with Steroid 
Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD) 
Ibrutinib (PCI-32765; JNJ-54179060) is a potent, orally administered covalently-binding inhibitor of 
Bruton’s tyrosine kinase (BTK), which is also an irreversible inhibitor of interleukin-2-inducible T cell 
kinase (ITK). It is being codeveloped by Janssen Research & Development LLC and Pharmacyclics LLC 
for the treatment of B-cell malignancies. Investigations in other indications including chronic graft versus 
host disease (cGVHD) have also been initiated. Ibrutinib is approved in the United States (US) for the 
treatment of adult patients with cGVHD after failure of one or more lines of systemic therapy. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS 
Objectives 
Endpoints 
Primary 
 
Evaluate efficacy of ibrutinib in Japanese 
subjects with steroid dependent/refractory 
cGVHD 
by 
measuring 
overall 
cGVHD 
response (Complete Response [CR] and partial 
response [PR] defined by National Institutes 
of Health (NIH) Consensus Development 
Project Criteria [2014]) 
 
The overall response rate (ie, the proportion of 
responders [CR or PR]). Response will be 
defined by the NIH Consensus Development 
Project Criteria (2014) and must occur: 
 
In the absence of new therapy for 
cGVHD 
 
In the absence of progression of the 
underlying disease, or death 
Secondary 
 
Evaluate efficacy by measuring: 
 
Rate of sustained response for at least 20 
weeks 
 
Duration of response (DOR) 
 
cGVHD response rate at each timepoint 
of efficacy evaluation 
 
Corticosteroid requirement changes over 
time 
 
Change in symptom burden measured by 
the Lee cGVHD Symptom Scale 
 
Rate of sustained response for at least 
20 weeks is defined as rate of NIH-defined CR 
or PR that was sustained for at least 20 weeks 
 
DOR is defined as the duration from the date 
of initial response (CR or PR) to the date of 
progressive cGVHD or death, whichever 
occurs first 
 
cGVHD response rate at each timepoint of 
efficacy evaluation is defined as rate of NIH-
defined CR or PR at each timepoint 
 
Corticosteroid requirement changes over time: 
Corticosteroid requirement will be monitored 
cross the study.  
 
Change in symptom burden measured by the 
Lee cGVHD Symptom Scale: A change in ≥7 
points on the Lee cGVHD Symptom Scale 
will be considered significant and relates to 
improvement in quality of life (QoL). 
 
Evaluate the safety of ibrutinib in Japanese 
subjects with steroid dependent/refractory 
cGVHD 
 
Safety parameters of ibrutinib, including 
adverse events (AE) and clinical laboratory 
assessments 
 
Evaluate 
the 
pharmacokinetics 
(PK) 
of 
ibrutinib in Japanese subjects with cGVHD 
 
Pharmacokinetic parameters of ibrutinib and 
the metabolite PCI-45227 (if possible and 


JNJ-54179060  (Ibrutinib)  
 
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Objectives 
Endpoints 
judged relevant) 
Exploratory 
 
Evaluate efficacy of ibrutinib by measuring:  
 
Failure free survival (FFS)  
 
Overall survival (OS) 
 
Number and proportion of subjects with 
all immunosuppressants withdrawn 
 
FFS is defined as the duration from the date of 
initial dose to the date of relapse of 
malignancy, 
initiation 
of 
new 
immunosuppressive therapy for GVHD or 
death, whichever occurs first.  
 
OS is defined as the duration from the date of 
initial dose to the date of the subject’s death. 
 
Number and proportion of subjects with all 
immunosuppressants withdrawn 
 
Evaluate the BTK and ITK binding site 
occupancy as a pharmacodynamic (PD) 
parameters 
 
Proportion of BTK and ITK binding site 
occupancy in subjects with cGVHD 
Hypothesis: Ibrutinib is an effective agent as measured by an overall cGVHD response rate (the lower 
bound of 95% confidence interval >25%) in Japanese subjects with steroid dependent/refractory cGVHD. 
OVERVIEW OF STUDY DESIGN 
This is an open-label, single arm, multicenter Phase 3 study to evaluate the efficacy, safety, and PK of 
single-agent ibrutinib 420 mg in Japanese subjects 12 years of age or older with steroid 
dependent/refractory cGVHD. Subject participation will include a Screening Phase, a Treatment Phase, 
and a Posttreatment Follow-up Phase. The Screening Phase assessments will be performed within 42 days 
prior to study treatment initiation. The Treatment Phase will extend from first dose of study treatment 
until treatment discontinuation. During the Treatment Phase, efficacy and safety evaluations, sampling of 
PK and PD will be performed. The Posttreatment Follow-up Phase will begin once a subject discontinues 
ibrutinib treatment. Subjects who discontinue for reasons other than cGVHD progression will complete 
an End-of-treatment Visit and will be followed for the cGVHD evaluations until cGVHD progression, 
death, loss to follow-up, consent withdrawal, or study end, whichever occurs first. Subjects who 
discontinue due to cGVHD progression will complete an End-of-treatment Visit and be followed for 
survival status and the use of subsequent cGVHD treatment. 
SUBJECT POPULATION 
Key eligibility criteria include: Male or female subjects ≥12 years of age. Subjects with steroid 
dependent/refractory cGVHD defined at any time post-hematopoietic cell transplant (HCT). Subjects 
receiving baseline systemic glucocorticoid therapy for cGVHD at study entry with no more than 3 
previous systemic treatments for cGVHD. 
DOSAGE AND ADMINISTRATION 
Ibrutinib 420 mg (3×140 mg capsules) will be administered orally once daily. It is expected that many 
subjects enrolled in the trial will require antifungal prophylaxis. Dose adjustments will be required for 
concomitant use of moderate or strong CYP3A inhibitors. 
STUDY EVALUATIONS 
Efficacy evaluations: Response will be defined using the NIH Consensus Panel cGVHD Activity 
Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal tract (GI), esophagus, lung, eye, 


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and joint/fascia are the organs or sites considered in evaluating overall response. All subjects in the study 
will complete the Lee cGVHD Symptom Scale at all response assessment visits. 
Pharmacokinetic/Pharmacodynamic evaluations: Venous blood samples will be collected to determine 
plasma concentration of ibrutinib and the metabolite PCI-45227 at the timepoints specified in TIME AND 
EVENTS SCHEDULE. The plasma concentration data of ibrutinib and PCI-45227 will be used to 
determine PK parameters by noncompartmental method, including: AUClast, AUC24h, Cmax, Tmax, and t1/2. 
Venous blood samples for PD evaluation (BTK and ITK binding site occupancy) will be collected at the 
timepoints specified in the TIME AND EVENTS SCHEDULE. 
Safety evaluations: This includes AEs, physical examination, Karnofsky/Lansky Performance Scale, vital 
signs, electrocardiogram (ECG), forced expiratory volume in 1 second (FEV1), and laboratory tests as 
described in TIME AND EVENTS SCHEDULE. All AEs will be reported from the time a signed and 
dated informed consent form is obtained until 30 days following the last dose of ibrutinib or the time of 
starting a subsequent systemic treatment for cGVHD, if earlier. 
STATISTICAL METHODS 
With a sample size of 17 subjects and assuming an expected overall cGVHD response rate of 
approximately 60%, it is expected to have at least 80% power to show the efficacious treatment effect (the 
lower bound of 95% confidence interval of the response rate >25%). The primary efficacy endpoint is 
overall cGVHD response rate (CR+PR). Its 95% confidence interval will be calculated with the exact test 
for binomial distribution in the all treated population (defined as all enrolled subjects who will receive at 
least 1 dose of study drug). The study will be considered to be positive if the lower limit of the exact 
2-sided 95% confidence interval based on binominal distribution exceeds the threshold value (0.25). The 
primary analysis for all efficacy and safety endpoints will be conducted at the time when the last subject 
has completed the efficacy assessment at Week 37 or has discontinued treatment before Week 37. Final 
analysis will be conducted at the study end. 
 






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d. 
Forced expiratory volume in 1 second (FEV1) required for all subjects at screening and Week 1 Day 1. After Week 1 Day 1, if prior FEV1 result is abnormal 
FEV1 should be obtained every 12 weeks. If prior FEV1 result is normal FEV1 should be obtained every 24 weeks. If a subject has cGVHD features in lung, FEV1 
evaluation other than these mandatory timepoints is encouraged in cGVHD activity assessment whenever possible. 
e. 
At screening, ECG is mandatory to confirm eligibility. Other ECGs will be performed at the investigator’s discretion, particularly in subjects with arrhythmic 
symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea.  
f. 
Women of childbearing potential only. Serum pregnancy test required at screening and urine pregnancy test required at Day 1 prior to first dose. If the test result is 
positive, the pregnancy must be ruled out by ultrasound to be eligible. 
g. 
Pharmacokinetic (PK) sampling will be performed for all subjects according to Section 9.3 and the schedule in BLOOD SAMPLING SCHEDULE FOR PK AND 
PD 
h. 
Pharmacodynamic (PD) sampling will be performed for all subjects according to Section 9.4 and the schedule in BLOOD SAMPLING SCHEDULE FOR PK 
AND PD 
i. 
For Week 1 Day 1 only, clinical laboratory tests and spirometry do not need to be repeated if the screening tests were performed within 3 days of the first dose of 
ibrutinib. 
 
 


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BLOOD SAMPLING SCHEDULE FOR PK AND PD 
PK Sampling Schedule 
Week 
Study Day of 
Study Week 
Predose 
Time After Dosing 
1 h ±15 min 
2 h ±15 min 
4 h ±30 min 
6 h ±1 h 
1 
1 
x 
x 
x 
x 
x 
1 
2 
xa 
 
 
 
 
2 
1 
xa 
x 
x 
x 
x 
a Sample collected 24 hours (±2 hours) after dosing on the previous day and prior to dosing on the study day. Record exact times of both drug administrations. 
 
 
PD (BTK and ITK Occupancy) Sampling Schedule 
Week 
Study Day of Study Week 
Predose 
Time After Dosing 
4 h ±30 min 
1 
1 
x 
x 
1 
2 
xa 
 
2 
1 
xa 
 
13 
1 
xa 
 
a Sample collected 24 hours (±2 hours) after dosing on the previous day and prior to dosing on the study day. 
 


JNJ-54179060  (Ibrutinib)  
 
Clinical Protocol 54179060GVH3001 Amendment 1 
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ABBREVIATIONS 
allo-HCT 
allogeneic hematopoietic cell transplant 
aPTT 
activated partial thromboplastin time  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
BAFF 
B cell-activating factor 
β-hCG 
beta-human chorionic gonadotropin 
BTK 
Bruton’s tyrosine kinase 
cGVHD 
chronic graft versus host disease 
CI 
calcineurin inhibitor  
CLL 
chronic lymphocytic leukemia 
CR 
complete response 
CRF 
case report form(s) (paper or electronic as appropriate for this study) 
CYP 
cytochrome P450 
DOR 
duration of response 
ECG 
electrocardiogram 
eDC 
electronic data capture 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
ECP 
extracorporeal photopheresis 
ERK 
extracellular signal-regulated kinase 
FFS 
failure free survival 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GVT 
graft versus tumor 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
HBsAb 
hepatitis B surface antibody 
HBV 
hepatitis B virus 
IB 
investigator’s brochure 
IC50 
minimum concentration of drug required to inhibit activity by 50%  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
Ig 
immunoglobulin 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITK 
interleukin-2-inducible T cell kinase 
LAR 
legally acceptable representative 
MCL 
mantle cell lymphoma 


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MMF 
mycophenolate mofetil 
NIH 
National Institutes of Health 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NRM 
nonrelapse mortality 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
PQC 
product quality complaint 
PR 
partial response 
PRO 
patient reported outcome(s) 
PTLD 
posttransplant lymphoproliferative disease 
PTT 
partial thromboplastin time 
QoL 
quality of life 
SD 
standard deviation 
SAE 
serious adverse event 
SLL 
small lymphocytic lymphoma 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
Th 
T helper 
ULN 
upper limit of normal 
US 
United States 
WM 
Waldenström's macroglobulinemia 
 
 
 


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1. 
INTRODUCTION 
JNJ-54179060 (PCI-32765; ibrutinib) is an orally administered covalently-binding small 
molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is also an irreversible inhibitor of 
interleukin-2 inducible T cell kinase (ITK). Codeveloped by Janssen Research & Development 
LLC and Pharmacyclics LLC as an anticancer agent, ibrutinib is the focus of an extensive 
clinical development program in the treatment of B cell malignancies. Investigations in other 
indications including chronic graft-versus-host disease (cGVHD) have also been initiated. 
Ibrutinib has been approved in the United States (US) for the treatment of adult patients with 
cGVHD after failure of one or more lines of systemic therapy and other indications. Ibrutinib is 
currently under investigation in various indications as a single agent and in treatment 
combinations.  
For the most comprehensive nonclinical and clinical information regarding ibrutinib, refer to the 
latest version of the Investigator's Brochure (IB).21 The term "sponsor" used throughout this 
document refers to the entities listed in the Contact Information page(s), which will be provided 
as a separate document. 
1.1. 
Chronic Graft Versus Host Disease 
Since the first report in 1957, allogeneic hematopoietic cell transplant (allo-HCT) has become a 
standard therapy for many hematologic malignancies and hematopoietic progenitor cell 
disorders.55 Hematopoietic cell transplant can cure patients with chemotherapy resistant 
malignancies through graft versus tumor (GVT) effects generated by the donor immune system 
against the recipient’s tumor.3 However, just as the donor immune system can sense and attack 
the recipient’s malignant cells, so can it sense and attack the recipient’s normal tissues resulting 
in graft versus host disease (GVHD). According to retrospective analysis of patients received 
allo-HCT by the Japan Society of Hematopoietic Cell Transplantation (JSHCT) in 2009, the 
incidence of cGVHD at 2 years after HCT was 37% in 4,818 patients.25 Risk factors for 
developing cGVHD include older patient age, use of peripheral blood stem cells versus bone 
marrow, and lack of T cell depletion.27 The prevalence of cGVHD is increasing due to both the 
increased use of allogeneic transplantation in older adults and the use of peripheral stem cells as 
a graft source. 
Chronic GVHD is a serious and life threatening impediment to the otherwise curative potential 
of HCT,4,6,30,41 and is a leading cause of nonrelapse mortality (NRM).27 Chronic GVHD is an 
important cause of late morbidity and mortality after allo-HCT.29,49 Chronic GVHD is also 
associated with decreased quality of life (QoL) and the continued need for immunosuppressive 
medications.15,28,30,51 
In the past, timing of manifestations of GVHD were used to classify GVHD into two subsets, 
acute GVHD classified as occurring within 100 days of HCT and chronic GVHD classified as 
manifestations beyond 100 days after HCT.12 In 2005, the National Institutes of Health (NIH) 
sponsored a consensus development conference that proposed new criteria for diagnosis and 
classification of cGVHD for clinical trials.12 The consensus met again in 2014 and proposed 


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minor changes to the diagnostic criteria.23 The published criteria for diagnosis emphasize the 
distinction between acute and chronic GVHD as different subsets of GVHD that can be 
distinguished by clinical manifestations and not time after transplant.23 
1.2. 
Pathogenesis of Chronic Graft Versus Host Disease 
The immunopathology underlying development of cGVHD may be quite variable and is not 
entirely characterized. Recent information implicates B cells as well as T cells in the generation 
of cGVHD.1,14,24,45 T cells have long been known to be critically important in the development of 
cGVHD. Higher rates of cGVHD are seen in recipients of colony-stimulating factor mobilized 
peripheral blood grafts compared with marrow grafts and in patients who receive a higher T cell 
dose.2 In vivo T cell depletion with antithymocyte globulin or alemtuzumab can reduce the 
incidence of cGVHD, but at the cost of higher rates of viral or opportunistic infections and 
relapse of underlying disease.17,40 Alloreactive T helper (Th) cells, including Th1, Th2, Th17, 
and T follicular helper cells, produce effector cytokines resulting in antibody deposition, tissue 
fibrosis, and autoimmunity. 
More recently, alloreactive B cells have been implicated in the development of 
cGVHD.1,14,24,35,36,45 In addition to the production of alloantibodies, B cells contribute to the 
immune response via antibody-independent processes, such as antigen presentation, cytokine and 
chemokine production, and immunoregulatory function.44 Following activation via the B cell 
receptor signaling pathways, B cells become potent antigen-presenting cells. Activated B cells 
produce a variety of inflammatory cytokines, and antigen presentation by autoreactive B cells is 
critical in autoimmune disorders.47 Dysfunctional B cells have been identified in cGVHD, where 
patients have a relatively higher number of activated memory B cells, higher levels of B cell-
activating factor (BAFF) of the tumor necrosis family, and donor-derived alloantibodies.46 
1.3. 
Current Treatment Options for cGVHD 
Therapy for cGVHD is primarily broad-spectrum immunosuppressants that increase the risk of 
infections and tumor relapse by inhibiting GVT immunity.18 Available therapies for cGVHD in 
Japan are only corticosteroids and calcineurin inhibitor (CI), such as cyclosporine and tacrolimus. 
After allo-HCT, a CI is commonly used as preventive treatment of GVHD.53 The initial and 
current standard of care treatment for cGVHD is corticosteroids. Approximately 50% to 60% of 
the cGVHD subjects become dependent on or refractory to steroids, requiring second-line 
treatment within 2 years.13 There is no standard of care treatment for these patients. 
Corticosteroids are the primary therapy for cGVHD. An early double-blind, randomized trial 
compared prednisone and placebo with prednisone and azathioprine as initial treatment for 
standard risk cGVHD.50 The NRM was significantly lower (21% versus 40%, p=0.003) and 
overall survival significantly higher (61% versus 47%, p=0.03) in the prednisone and placebo 
arm with a minimum follow-up of 42 months after study entry, establishing prednisone as the 
primary therapy for cGVHD. During corticosteroid treatment, patients may experience the side 
effects of corticosteroids: more frequent infections, avascular necrosis, adrenal insufficiency, 
cataracts, altered mental states, and disturbed sleep patterns.50 Koc tested the addition of 
cyclosporine to prednisone as a steroid-sparing agent and observed fewer complications such as 


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avascular necrosis.26 However, the relapse rate was increased resulting in no overall survival 
benefit compared to the prednisone only arm. 
Second line therapy for cGVHD patients who fail corticosteroids is not well established. Second-
line treatment is chosen from same agents as are used for initial treatment, because there are no 
other available therapies in Japan. In the Japanese guideline for GVHD, mycophenolate mofetil 
(MMF), sirolimus, hydroxychloroquine, extracorporeal photopheresis (ECP), rituximab, 
pentostatin and steroid pulse therapy are mentioned as cGVHD treatments that are used in the 
US and Europe.53 However, these treatments are not approved for cGVHD in Japan. Until the 
approval of ibrutinib in the US in August 2017 for adult patients with cGHVD after failure of 
one or more lines of systemic therapy, there had been no approved therapies for cGVHD in these 
countries. 
Treatment with immunosuppressants is typically needed for a median duration of 2 to 3 years, 
further contributing to morbidity.52 Because of the frequent morbidity associated with prolonged 
corticosteroid use, many other immunosuppressant agents have been investigated in cGVHD, 
both in the front line and second line setting. Several controlled, phase 3 studies where these 
agents have been added on to corticosteroid therapy were all unsuccessful in providing benefit 
despite showing efficacy in early phase studies.5,16,26,34,50 An analysis of clinical study quality 
measures in 60 studies of cGVHD primarily conducted before the NIH standardized response 
criteria39 were developed, revealed that poor study design (eg, lack of rigorous entry criteria, 
organ response criteria, and overall response criteria) likely biased efficacy in the early phase 
trials33 thereby leading to later unsuccessful controlled studies with the same agents. Agents such 
as cyclosporine, tacrolimus, sirolimus, or MMF are often added to corticosteroid therapy in both 
frontline and second line settings despite the lack of efficacy. There is a lack of a standard of 
care and high unmet need for new therapeutic options to effectively suppress immune and 
fibrotic cascades while preserving GVT and immunity against infection. 
1.4. 
Background 
1.4.1. 
Nonclinical Studies 
Pharmacologic Profile 
Ibrutinib was designed as a selective and covalent inhibitor of the BTK.38 In vitro, ibrutinib is a 
potent inhibitor of BTK activity (minimum concentration of drug required to inhibit activity by 
50% [IC50] =0.39 nM). The irreversible binding of ibrutinib to cysteine-481 in the active site of 
BTK results in sustained inhibition of BTK catalytic activity and enhanced selectivity over other 
kinases that do not contain a cysteine at this position. A cellular signal transduction assay 
conducted to investigate ibrutinib inhibition of B-cell receptor signaling showed concentration-
dependent inhibition of autophosphorylation of BTK by ibrutinib, phosphorylation of the 
physiological substrate of BTK, phospholipase-Cγ, and phosphorylation of a further downstream 
kinase, extracellular signal-regulated kinase (ERK).19 In addition to BTK activity, ibrutinib 
inhibits ITK activity with a biochemical IC50 of 26.9 nM. Ibrutinib also blocks T cell receptor-
induced IL-2 secretion by a T cell line (Jurkat cells) with an EC50 of 200 nM. In chronic 


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lymphocytic leukemia (CLL) patients receiving ibrutinib, binding to ITK also has been 
demonstrated.10 
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current IB.21 
1.4.2. 
Clinical Studies 
A summary of pharmacokinetic (PK) and safety data (monotherapy and combination therapy 
studies) is provided below. For more comprehensive safety information please refer to the 
current version of the IB. Additional safety information may be available for approved 
indications in regional prescribing labels where the study is conducted. 
Human Pharmacokinetics 
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally to doses. The mean half-life (t1/2) of ibrutinib ranged from 4 to 
13 hours, with a median time to maximum plasma concentration (Tmax) of 2 hours. Ibrutinib is 
extensively metabolized primarily by cytochrome P450 (CYP) 3A4 enzymes. Following single 
dose administration, the area under plasma concentration versus time curve (AUC) of ibrutinib 
increased 2.7-, 8.2-, and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-
Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with 
normal liver function. A higher proportion of Grade 3 or higher adverse reactions were reported 
in patients with B cell malignancies (CLL, mantle cell lymphoma [MCL] and Waldenström's 
macroglobulinemia [WM]) with mild hepatic impairment based on National Cancer Institute- 
organ dysfunction working group (NCI-ODWG) criteria for hepatic dysfunction compared to 
patients with normal hepatic function. In a Phase 1b/2 study (PCYC-1129-CA) in subjects with 
cGVHD, there were no differences in ibrutinib exposure between subjects with normal (n=29) 
and mild hepatic impairment based on baseline liver function test per NCI criteria (n=13). 
Summary of Clinical Data in Chronic GVHD 
A Phase 1b/2 study (PCYC-1129-CA) to evaluate the safety and efficacy of ibrutinib treatment 
in subjects with cGVHD who had failed steroid therapy was initiated in June 2014. The NIH 
Consensus Panel Response Assessment 2005 was used to determine overall response. As of 
01 September 2016, 42 subjects have been recruited and received at least one dose of study drug 
in the study. The median age is 56 years (19-74 years) with a median duration of GVHD of 
13.6 months prior to study entry. The median number of prior therapeutic regimens is 2.0. 
Thirty-seven subjects have had a response assessment and 5 subjects discontinued prior to the 
first response assessment. Of the 42 subjects with response assessments (37 subjects) or who 
discontinued ibrutinib prior to response assessment (5 subjects), 28 subjects were responders 
(ORR=67%) based on NIH response criteria. Best responses include 9 complete responses (CRs), 
19 partial responses (PRs), 7 stable disease, 2 progressive disease, and 5 unknown due to the 
early discontinuation of study drug without post baseline efficacy assessment. Twenty of the 28 
responders (71%) achieved a sustained response for at least 20 weeks. Median corticosteroid 
dose in responding subjects was 0.29 mg/kg/day at baseline, 0.24 mg/kg/day at Week 12, 
0.19 mg/kg/day at Week 24, 0.18 mg/kg/day at Week 36, and 0.13 mg/kg/day at Week 48. Five 


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subjects discontinued steroids. Overall response rate results were supported by exploratory 
analyses of patient-reported symptom bother which showed at least a 7-point decrease in Lee 
Symptom Scale overall summary score in 24% (10/42) of patients on at least 2 consecutive visits. 
These efficacy results are consistent with a response rate and durability that is considered 
clinically compelling in this high-risk population and with an acceptable safety profile. Based on 
data from the PCYC-1129 study the US Food and Drug Administration (FDA) approved 
ibrutinib for the treatment of adult patients with cGVHD after failure of one or more lines of 
systemic therapy. 
Safety 
Monotherapy studies 
Integrated safety data for 1,523 subjects with B cell malignancies treated with ibrutinib 
monotherapy in 17 studies that have completed primary analysis or final analysis included in the 
CSRs as of the 31 July 2017 cutoff date for this IB (09 November 2017) are summarized in 
Table 1. 
The most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1,523) are summarized in Table 1: 
Table 1: Most Frequently Reported Treatment-emergent Adverse Events With Ibrutinib Monotherapy 
(Pooled Data from 1,523 Subjects) 
Most frequently reported TEAEs 
>15%a 
Most frequently reported Grade 3 
or 4 TEAEs >5%a 
Most frequently reported Serious 
TEAEs >2%b 
Diarrhea 
Fatigue 
Nausea 
Cough 
Pyrexia 
Anemia 
Upper respiratory tract infection 
Neutropenia 
Oedema peripheral 
Thrombocytopenia 
Muscle spasms 
Neutropenia 
Pneumonia 
Thrombocytopenia 
Anemia 
Pneumonia 
Atrial fibrillation 
Pyrexia 
Febrile neutropenia 
 
a Source is Table 5 of IB,21 
b Source is Table 6 of IB,21 
Combination Studies 
Pooled safety data from a total of 422 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in subjects with B cell malignancies are briefly summarized 
below. Therapies used in combination with ibrutinib in these studies included bendamustine and 
rituximab (BR); fludarabine, cyclophosphamide, and rituximab (FCR); ofatumumab; and 
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP).  
The most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy 
(N=422) are summarized in Table 2: 


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Table 2: Most Frequently Reported TEAEs in Subjects Receiving Ibrutinib in Combination Therapy (Pooled 
Data From 422 Subjects) 
Most frequently reported TEAEs 
>10%a 
Most frequently reported Grade 3 
or 4 TEAEs >2%a 
Most frequently reported Serious 
TEAEs >1%b 
Neutropenia 
Diarrhoea 
Nausea 
Thrombocytopenia 
Fatigue 
Anaemia 
Pyrexia 
Infusion related reaction 
Upper Respiratory tract infection 
Constipation 
Vomiting 
Rash 
Headache 
Cough 
Muscle spasms 
Pneumonia 
Oedema peripheral 
Arthralgia 
Decreased appetite 
Contusion 
Insomnia 
Chills 
Peripheral sensory neuropathy 
Stomatitis 
Febrile neutropenia 
Abdominal pain 
Back pain 
Bronchitis 
Neutropenia 
Thrombocytopenia 
Febrile neutropenia 
Pneumonia 
Neutrophil count decreased 
Anemia 
Fatigue 
Hypertension 
Diarrhea 
Pyrexia 
Cellulitis 
Leukopenia 
Tumor lysis syndrome 
Atrial fibrillation 
Hyperuricaemia 
Urinary tract infection 
White blood cell count decreased 
Febrile neutropenia 
Pneumonia 
Atrial fibrillation 
Pyrexia 
Cellulitis 
Sepsis 
Neutropenia 
Tumor lysis syndrome 
Urinary tract infection 
a Source is Table 7 of IB,21 
b Source is Table 8 of IB,21 
Summary of Clinical Data in Chronic GVHD 
Safety data from the 42 subjects enrolled in the PCYC-1129-CA study demonstrated that 100% 
of subjects have experienced a TEAE with a total of 73.8% of subjects reported Grade 3 or 
higher adverse events (AEs). Fifty-two percent (52.4%) of subjects reported serious adverse 
events (SAEs). The most frequent TEAEs and SAEs are summarized in Table 3.  
Table 3: Most frequently reported TEAEs in subjects receiving ibrutinib for cGVHD 
Most frequently reported 
TEAEs > 20% 
Most frequently reported  
Grade 3 or 4 TEAEs > 10% 
Serious TEAEs occurred 
in > 1 subject 
Fatigue 
Fatigue 
Cellulitis 
Diarrhea 
Pneumonia 
Headache  
Muscle spasms 
Pneumonia  
Nausea 
 Pyrexia 
Increased tendency to bruise 
 
Septic shock 
Thirty of the 42 subjects (71.4%) were taking moderate or strong CYP3A inhibitors during the 
study with 42.9% taking fluconazole, 14.3% taking voriconazole and 9.5% of subjects taking 
posaconazole. Concomitant use of moderate and strong CYP3A inhibitors resulted in higher 
ibrutinib exposure but there was no association between concurrent CYP3A inhibitor use and 


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dose reductions or discontinuations or with TEAEs leading to dose reductions or 
discontinuations. 
1.4.3. 
Risks 
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 (eg, palpitations, lightheadedness, syncope, chest discomfort or new onset dyspnea) 
should be evaluated clinically, and if indicated, have an electrocardiogram (ECG) performed. For 
cardiac arrhythmias which persist, consider the risks and benefits of ibrutinib treatment, and 
follow the dose modification guidelines. 
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 (GI) 
bleeding, subdural intracranial hemorrhage, and hematuria. Use of ibrutinib in subjects requiring 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding. 
Subjects with congenital bleeding diathesis have not been studied. In an in vitro platelet function 
study, inhibitory effects of ibrutinib on collagen induced platelet aggregation were observed. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Subjects should be monitored for fever, weakness, or 
easy bruising and/or bleeding. 
Diarrhea 
Diarrhea is the most frequently reported nonhematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported GI events include nausea, vomiting, and 
constipation. These events are rarely severe. Should symptoms be severe or prolonged, ibrutinib 
should be considered to follow dose modification guidelines (see Section 6.1.1). 
Infections 
Infections (including sepsis, bacterial, viral, aspergillus or other fungal infections) were observed 
in subjects treated with ibrutinib therapy. Some of these reported infections have been associated 
with hospitalization and death. Consider prophylaxis according to standard of care in subjects 
who are at increased risk for opportunistic infections (see Section 8.1). 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 
symptoms (fever, chills, weakness, confusion, vomiting and jaundice) and appropriate therapy 
should be instituted as indicated. 


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Interstitial Lung Disease 
Cases of interstitial lung disease have been reported in subjects treated with ibrutinib. Monitor 
subjects for pulmonary symptoms indicative of interstitial lung disease. 
Nonmelanoma Skin Cancer 
Nonmelanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects for 
the appearance of nonmelanoma skin cancer. 
Rash 
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Most rashes were mild to moderate in severity. Isolated cases 
of severe cutaneous adverse reactions including Stevens-Johnson syndrome have been reported 
in subjects treated with ibrutinib. Subjects should be closely monitored for signs and symptoms 
suggestive of severe cutaneous adverse reaction including Stevens-Johnson syndrome. 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. 
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 antihypertensive medications and/or initiate antihypertensive treatment 
as appropriate. 
1.5. 
Overall Rationale for the Study 
Available therapies for cGVHD in Japan are only corticosteroids and CI, such as cyclosporine 
and tacrolimus. After allo-HCT, a CI is commonly used as preventive treatment of GVHD. The 
initial and current standard treatment for cGVHD is corticosteroid. However, approximately 50-
60% of the cGVHD subjects become dependent on or refractory to steroids, requiring second-
line treatment within 2 years.13 There is no standard of care for these patients. Second-line 
treatment is chosen from the same agents that are used for initial treatment, because there are no 
other available therapies in Japan. In addition, treatment of cGVHD including corticosteroids is 
needed for a median duration of 2 to 3 years. Long treatment period of high dose systemic 
corticosteroids will lead to the occurrence of side effects of steroids including hypertension, bone 
loss, weight gain, diabetes, cataracts, and adrenal disorder as well as increasing the risk of 
infection.50,52 These issues highlight the need for well-tolerated and effective treatment options in 
Japan. 
Ibrutinib is a potent inhibitor of BTK, and inhibits ITK. Through this novel mechanism, ibrutinib 
has shown the potential to affect B and T cells that are critical in the pathogenesis of cGVHD.11 
Preclinical results have demonstrated a substantial therapeutic benefit of ibrutinib treatment to 
reduce the prolonged allo-immune effects of cGVHD in animal models and supported 
investigation in clinical studies. In addition, the results of ibrutinib administration in the 


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Phase 1b/2 PCYC-1129-CA study in subjects with active cGVHD who have failed first line 
corticosteroid therapy demonstrate that ibrutinib has beneficial clinical activity with high 
response rate by NIH criteria as well as an overall favorable safety profile. Ibrutinib was 
approved for the treatment of subjects with cGVHD by the FDA on the basis of this promising 
early data in June 2016. These findings suggest that ibrutinib may also demonstrate clinical 
benefit for Japanese cGVHD subjects. 
Appropriateness of enrolling adolescent (12 - 17 years old) subjects 
Not only in adult patients but also in pediatric patients, cGVHD is a leading cause of mortality, 
side effects, and loss of QoL after allo-HCT. Treatment algorithm for pediatric cGVHD is same 
as adult and treatment option is also very limited. Because of this treatment situation and the 
expectation of long-term survival for pediatric subjects, novel, well-tolerated and effective 
treatment option is strongly required for pediatric cGVHD. 
So far, there is no clinical data of ibrutinib in cGVHD subjects 17 years of age or younger, but it 
is considered that the PK profile of ibrutinib in adolescents (12 to 17 years of age) is similar to 
adults. Cytochrome P450 (CYP3A4), which predominantly metabolizes ibrutinib, reaches adult 
expression levels before 1 year of age9 and ibrutinib is not a substrate of major transporters. In 
addition, physiological characteristics (eg, body size, liver weight, and blood flow) have reached 
adult proportions in adolescents (median body weight in Japanese adolescent at 12 years of age: 
40.74 kg [male] and 41.51 kg [female])54 and population PK analysis including 1,202 adult 
subjects with B cell malignancy did not suggest significant effect of body weight on the exposure 
of ibrutinib (median 77.2 kg; range 38.5 to 152 kg). In addition, preliminary PK data in pediatric 
population is available from a clinical study for ibrutinib in pediatric patients with B cell 
malignancy (study PCI-32765LYM3003) where body surface area-based dose (329 mg/m2, 
corresponds to 560 mg in adults) was adopted. In the 12- to 17-year age group (N=7; body 
weight range 33 to 103 kg; actual dose range 350 to 560 mg per body), in general, exposures fell 
within the target exposure range in adults at 560 mg dose.42 Overall, it is considered appropriate 
to enroll adolescent subjects in this study. 
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS 
2.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
Evaluate efficacy of ibrutinib in Japanese 
subjects with steroid dependent/refractory 
cGVHD 
by 
measuring 
overall 
cGVHD 
response (Complete Response [CR] and partial 
response [PR] defined by NIH Consensus 
Development Project Criteria [2014]) 
 
The overall response rate (ie, the proportion of 
responders [CR or PR]). Response will be 
defined by the NIH Consensus Development 
Project Criteria (2014) and must occur: 
 
In the absence of new therapy for 
cGVHD 
 
In the absence of progression of the 
underlying disease that was the indication 
for 
transplant 
(or 
posttransplant 
lymphoproliferative disease [PTLD]), or 


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Objectives 
Endpoints 
death 
Secondary 
 
Evaluate efficacy of ibrutinib in Japanese 
subjects with steroid dependent/refractory 
cGVHD by measuring: 
 
Rate of sustained response for at least 20 
weeks 
 
Duration of response (DOR) 
 
cGVHD response rate at each timepoint 
of efficacy evaluation 
 
Corticosteroid requirement changes over 
time 
 
Change in symptom burden measured by 
the Lee cGVHD Symptom Scale 
 
Rate of sustained response for at least 
20 weeks is defined as rate of NIH-defined CR 
or PR that was sustained for at least 20 weeks 
 
DOR is defined as the duration from the date 
of initial response (CR or PR) to the date of 
progressive cGVHD or death, whichever 
occurs first 
 
cGVHD response rate at each timepoint of 
efficacy evaluation is defined as rate of NIH-
defined CR or PR at each timepoint 
 
Corticosteroid requirement changes over time: 
Corticosteroid requirement will be monitored 
cross the study 
 
Change in symptom burden measured by the 
Lee cGVHD Symptom Scale: A change in ≥7 
points on the Lee cGVHD Symptom Scale 
will be considered significant and relates to 
improvement in QoL 
 
Evaluate the safety of ibrutinib in Japanese 
subjects with steroid dependent/refractory 
cGVHD 
 
Safety parameters of ibrutinib, including AEs 
and clinical laboratory assessments 
 
Evaluate 
the 
pharmacokinetics 
(PK) 
of 
ibrutinib in Japanese subjects with cGVHD 
 
Pharmacokinetic parameters of ibrutinib and 
the metabolite PCI-45227 (if possible and 
judged relevant) 
Exploratory 
 
Evaluate efficacy of ibrutinib by measuring: 
 
Failure free survival (FFS)  
 
Overall survival (OS) 
 
Number and proportion of subjects with 
all immunosuppressants withdrawn 
 
FFS is defined as the duration from the date of 
initial dose to the date of relapse of 
malignancy, 
initiation 
of 
new 
immunosuppressive therapy for GVHD or 
death, whichever occurs first 
 
OS is defined as the duration from the date of 
initial dose to the date of the subject’s death 
 
Number and proportion of subjects with all 
immunosuppressants withdrawn 
 
Evaluate the BTK and ITK binding site 
occupancy as a pharmacodynamic (PD) 
parameters 
 
Proportion of BTK and ITK binding site 
occupancy in subjects with cGVHD 


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2.2. 
Hypothesis 
The primary hypothesis of this study is that ibrutinib is an effective agent as measured by an 
overall cGVHD response rate (the lower bound of 95% confidence interval is greater than 25%) 
in Japanese subjects with steroid dependent/refractory cGVHD. 
3. 
STUDY DESIGN AND RATIONALE 
3.1. 
Overview of Study Design 
This is an open-label, single arm, multicenter Phase 3 study to evaluate the efficacy, safety, and 
PK of single-agent ibrutinib 420 mg in Japanese subjects 12 years of age or older with steroid 
dependent/refractory cGVHD. At least 1 adolescent subject (12-17 years of age) will be enrolled 
in this study. 
Subject participation will include a Screening Phase, a Treatment Phase, and a Posttreatment 
Follow-up Phase. 
The Screening Phase assessments will be performed within 42 days prior to study treatment 
initiation. Eligible subjects will have clinically determined cGVHD and are dependent on or 
refractory to steroids. Subjects may have had no more than 3 previous therapies for cGVHD. 
Clinical assessment of cGVHD must be clinically stable or worsening for a minimum of 14 days 
between screening and first dose of ibrutinib. If cGVHD assessment shows clinical improvement 
during this period, subject may be reassessed. Reassessment should be performed at least 14 days 
later from the last assessment. If cGVHD assessment is stable or worsening between the last 2 
assessments then the subject may receive first dose of ibrutinib. 
The Treatment Phase will extend from first dose of study treatment until treatment 
discontinuation. Subjects will receive 420 mg of oral ibrutinib once daily unless they have 
intervening unacceptable toxicity or meet other criteria for subject discontinuation. Dose 
modification of ibrutinib should be taken for the defined toxicities in Section 6.1.1 and 
Section 6.1.2. During the Treatment Phase, efficacy and safety evaluations, sampling of PK and 
PD will be performed according to the TIME AND EVENTS SCHEDULE. All subjects will be 
evaluated for response according to NIH Consensus Development Project Criteria (2014). 
The Posttreatment Follow-up Phase will begin once a subject discontinues ibrutinib treatment. 
Subjects who discontinue for reasons other than cGVHD progression (ie, for an AE or 
Investigator decision) will complete an End-of-treatment Visit (30+7 days from the last dose of 
ibrutinib) and will be followed for the disease evaluation until death, lost to follow-up, consent 
withdrawal, or study end, whichever occurs first. Subjects who discontinue due to cGVHD 
progression will complete an End-of-treatment Visit and be followed for survival status and the 
use of subsequent cGVHD treatment (clinic visits or telephone contacts). A clinical data cut off 
is planned at the time when the last subject has completed the efficacy assessment at Week 37 or 
has discontinued treatment before Week 37. Subjects will continue to be followed until the study 
completion or withdrawal from the study. The study is considered completed with the last visit 


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scheduled study assessment shown in the TIME AND EVENTS SCHEDULE for the last subject 
participating in the study. 
3.2. 
Study Design Rationale 
This is an open label study and no randomization will occur. The results of ibrutinib 
administration in the Phase 1b/2 PCYC-1129-CA study in subjects with active cGVHD who 
have failed first line corticosteroid therapy demonstrate that ibrutinib has beneficial clinical 
activity with high response rate by NIH criteria as well as an overall favorable safety profile. 
This study is conducted to confirm the evidence of reproducibility of PCYC-1129-CA study in 
Japanese steroid dependent/refractory cGVHD. 
Study population 
For patients with steroid dependent/refractory cGVHD, there are currently no standard treatment 
options. Efficacy and safety of ibrutinib for steroid dependent/refractory cGVHD were shown in 
PCYC-1129-CA study and ibrutinib may also demonstrate clinical benefit for Japanese steroid 
dependent/refractory cGVHD subjects. The study population (patients with 1-3 previous 
systemic treatments for cGVHD) is considered to be appropriate because this is the same 
criterion as PCYC-1129-CA study and responses in patients with 3 previous treatments for 
cGVHD were shown in PCYC-1129-CA study. Refer to Section 1.5. for appropriateness of 
enrolling adolescent (12 to 17 years old) subjects in this study. 
Study Treatments 
The 420 mg daily dose of ibrutinib in this study was selected as the recommended dose for 
cGVHD and it was determined based on clinical studies for B cell malignancy and 
PCYC-1129-CA. In Japan, approved doses of ibrutinib are 420 mg/day for CLL/small 
lymphocytic lymphoma (SLL) and 560 mg/day for MCL. Common AEs reported in clinical trials 
of ibrutinib for B cell malignancies were GI upset (diarrhea, nausea, vomiting), fatigue, 
respiratory infections, and rash. Because these AEs may overlap with cGVHD manifestations, a 
conservative dose of 420 mg will be used as the starting does for this trial. At 420 mg daily dose, 
40% to 80% ITK occupancy was reported.10 The tolerability of 420 mg/day was confirmed in the 
phase 1 part of PCYC-1129-CA study and favorable efficacy at the dose was confirmed in total 
subjects in the study. 
Endpoints 
While limited progress related to prevention or treatment of cGVHD has been made, the 
development of the NIH Consensus Criteria for grading and staging of cGVHD represents a 
significant advancement, providing a clinically useful disease burden measure for use in clinical 
trials.23 In addition, the NIH Consensus Response Criteria have been shown to correlate with 
clinical outcomes.22,37 Per the NIH Clinical Trial Design Response Criteria Working Group 
Report, use of response assessment is recommended as a primary endpoint in clinical trials.31 
Response evaluation must occur in the absence of new therapy for cGVHD, and in the absence 
of relapse of the underlying disease that was the indication for transplant, or death. These 


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additional restrictions on ascertaining response have been added as they support the finding that 
cGVHD was adequately controlled because no new systemic treatment was added. 
The assessment of PK is important in understanding both safety and efficacy of ibrutinib in 
Japanese cGVHD patients. In addition, it is expected that substantial number of patients are 
expected to receive a prophylactic antifungal (which is a CYP3A inhibitor) as a concomitant 
medication. Since ibrutinib is metabolized primarily by CYP3A, assessment of ibrutinib PK with 
a concomitant CYP3A inhibitor in Japanese cGVHD patients in this study will provide valuable 
information. 
4. 
SUBJECT POPULATION 
Screening for eligible subjects will be performed within 42 days before administration of the 
study intervention. 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed. 
4.1. 
Inclusion Criteria 
Each potential subject must satisfy all of the following criteria to be enrolled in the study: 
1. 
Steroid dependent/refractory cGVHD defined as modified NIH criteria (2014) below at 
any time post-HCT: 
 
Dependent disease - defined when glucocorticoid (prednisolone doses 
a.
≥0.25 mg/kg/day or ≥0.5 mg/kg every other day) are needed to prevent 
recurrence or progression of manifestations as demonstrated by unsuccessful 
attempts to taper the dose to lower levels on at least 2 occasions, separated by at 
least 8 weeks. 
In case of inability to taper the dose to ≤0.25 mg/kg/day or ≤0.5 mg/kg every 
other day (prednisolone doses) due to recurrence or progression of cGVHD 
manifestations, it is considered as steroid-dependent disease if the lowest 
tapering dose of the second occasion is equal or higher than the lowest tapering 
dose of the first occasion. 
 Refractory disease - defined when cGVHD manifestations progress despite the 
b.
use of a regimen containing glucocorticoid (prednisolone at ≥1 mg/kg/day for at 
least 1 week) or persist without improvement despite continued treatment with 
glucocorticoid (prednisolone at ≥0.5 mg/kg/day or 1 mg/kg every other day) for 
at least 4 weeks. 
2. 
Subjects must be receiving baseline systemic glucocorticoid therapy for cGVHD at study 
entry. The dose of steroids must be stable for 14 days prior to starting ibrutinib. 
3. 
At the time of trial enrollment, participants may be receiving other immunosuppressive 
therapies in addition to glucocorticoids. Immunosuppressant doses must be stable for 


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14 days prior to starting ibrutinib. 
4. 
Clinically stable or worsening cGVHD for a minimum of 14 days between screening and 
Day 1 cGVHD response assessment. 
5. 
Male or female ≥12 years of age. 
6. 
Karnofsky or Lansky (subjects <16 years) performance status ≥60 (see Attachment 2). 
7. 
Adequate hepatic and renal function as defined as: 
 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤3×upper 
a.
limit of normal (ULN), (unless of nonhepatic origin). If AST/ALT increase is 
associated with cGVHD then ≤5×ULN is acceptable 
 Total bilirubin ≤1.5×ULN (neither nonhepatic origin nor due to Gilbert's 
b.
syndrome) 
 
Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault formula) 
c.
8. 
Adequate hematological function defined as: 
 
Absolute neutrophil count (ANC) ≥1,000/µL and off growth factor support in 
a.
7 days prior the laboratory test 
 Platelets ≥30,000/µL and no transfusion support in 7 days prior the laboratory 
b.
test 
 
Hemoglobin ≥8 g/dL and no transfusion or growth support in 7 days prior the 
c.
laboratory test 
9. 
Prothrombin time (PT)/international normalized ratio (INR) <1.5 × ULN and partial 
thromboplastin time (PTT) (activated PTT [aPTT]) <1.5 × ULN (unless abnormalities are 
unrelated to coagulopathy or bleeding disorder). 
10. 
Must sign an informed consent form (ICF) (or their legally acceptable representative must 
sign) indicating that he or she understands the purpose of, and procedures required for, the 
study and is willing to participate in the study. Assent is also required of children capable 
of understanding the nature of the study. 
11. 
History of allo-HCT for underlying hematological disease. 
12. 
A woman of childbearing potential must have a negative highly sensitive serum (β-human 
chorionic gonadotropin [β-hCG]) at screening and a negative urine pregnancy test at 
Day 1 prior to first dose of ibrutinib. 
13. 
Before the first dose of ibrutinib, a woman must be either: 
a. Not of childbearing potential defined as: 
o 
postmenopausal  
A postmenopausal state is defined as no menses for 12 months without an 


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alternative medical cause. 
o 
permanently sterile 
 
Permanent 
sterilization 
methods 
include 
hysterectomy, 
bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral 
oophorectomy.  
b. Of childbearing potential* and 
o 
practicing a highly effective method of contraception (failure rate of <1% 
per year when used consistently and correctly). 
Examples of highly effective contraceptives include: 
intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
vasectomized partner; sexual abstinence; combined (estrogen- and progestogen-
containing) oral hormonal contraception 
o 
agrees to remain on a highly effective method throughout the study and for 
at least 1 month after the last dose of ibrutinib. 
*In this study, a premenarchal (defined as menarche has not yet occurred) woman is 
considered as having childbearing potential because menarche might occur during the 
study. 
14. 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study and for at least 1 month after receiving the last dose of 
ibrutinib. 
15. 
During the study and for a minimum of 1 spermatogenesis cycle (defined as 
approximately 3 months) after receiving the last dose of ibrutinib, in addition to the highly 
effective method of contraception, a man 
a. who is sexually active with a woman of childbearing potential must agree to use a 
double- barrier method of contraception (eg, condom with spermicidal foam/gel) 
b. who is sexually active with a woman who is pregnant must use a condom 
c. must agree not to donate sperms 
Typical use failure rates may differ from those when used consistently and correctly. 
Contraceptive (birth control) use by men or women should be consistent with the Japanese 
regulations regarding the acceptable methods of contraception for those participating in 
clinical studies. 
16. 
Must be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol. 


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4.2. 
Exclusion Criteria 
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study: 
1. 
Active acute GVHD 
2. 
More than 3 previous systemic treatments for cGVHD. Treatment with glucocorticoids is 
considered a treatment for cGVHD and should be included in determining the number of 
previous treatments. 
3. 
History of treatment with a tyrosine kinase inhibitor (eg, imatinib), purine analogs, or other 
cancer chemotherapy in the 4 weeks prior to starting ibrutinib. Participants may have 
received ibrutinib pretransplant for other reasons besides cGVHD such as for the treatment 
of leukemia or lymphoma. 
4. 
History of treatment with monoclonal T and B cell antibodies in the 8 weeks prior to 
starting ibrutinib. 
5. 
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of ibrutinib. 
6. 
Received an investigational drug or used an invasive investigational medical device within 
4 weeks before the first dose of ibrutinib. 
7. 
Current treatment with sirolimus and either cyclosporine or tacrolimus 
8. 
Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (Attachment 7) with 
the exception of strong CYP3A inhibitors used for antifungal prophylaxis. 
9. 
Concomitant use of warfarin or other Vitamin K antagonists. 
10. More than 6 stools per day 
11. Forced expiratory volume in 1 second (FEV1) <50% on pulmonary function tests. 
12. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class III or IV 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 the first dose of ibrutinib. 
13. Uncontrolled active systemic infection or infection requiring systemic treatment that was 
completed ≤7 days before the first dose of ibrutinib. 
14. History of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or 
hepatitis B virus (HBV) infection. Subjects who are positive for hepatitis B core antibody, 
hepatitis B surface antibody (HBsAb), hepatitis B surface antigen (HBsAg), or hepatitis C 
antibody must have a negative polymerase chain reaction (PCR) result before enrollment. 


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Those who are PCR positive will be excluded. 
15. Progressive underlying malignant disease including posttransplant lymphoproliferative 
disease (PTLD). 
16. History of prior malignancy (not including the underlying malignancy that was the 
indication for transplant), except: 
 
Malignancy treated with curative intent and with no known active disease present 
a.
for ≥24 months before enrollment; 
 Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence 
b.
of disease; 
 
Adequately treated cervical carcinoma in situ without current evidence of disease;
c.
 Malignancy, which is considered cured with minimal risk of recurrence. 
d.
17. Severe hepatic impairment (Child-Pugh classification, see Attachment 8). 
18. Bleeding disorder (eg, von Willebrand’s disease or hemophilia). 
19. Stroke or intracranial hemorrhage within 6 months prior to enrollment. 
20. Major surgery (eg, requiring general anesthesia), within 4 weeks of first dose of ibrutinib, 
or will not have fully recovered from surgery, or has surgery planned during the time the 
subject is expected to participate in the study. 
21. Allergy or hypersensitivity to ibrutinib. 
22. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting GI 
function, or resection of the stomach or small bowel, symptomatic inflammatory bowel 
disease or ulcerative colitis, or partial or complete bowel obstruction.  
23. Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or 
within 1 month after the last dose of ibrutinib. 
24. Plans to father a child while enrolled in this study or within 3 months after the last dose of 
ibrutinib. 
25. Any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, 
or confound the protocol-specified assessments. 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study intervention is given 
such that he or she no longer meets all eligibility criteria, then the subject should be excluded 


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from participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria. 
4.3. 
Prohibitions and Restrictions 
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation: 
1. 
Refer to Section 8 Concomitant Therapy for details regarding prohibited and restricted 
therapy during the study. 
2. 
Agree to follow all requirements that must be met during the study as noted in the Inclusion 
and Exclusion Criteria (eg, contraceptive requirements). 
3. 
The following guidance should be applied during the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving study medication: 
 For any surgery or invasive procedure requiring sutures or staples for closure, study 
medication should be held at least 7 days prior to the intervention and should be held at 
least 7 days after the procedure, and restarted at the discretion of the investigator when 
the surgical site is reasonably healed without serosanguineous drainage or the need for 
drainage tubes. 
 For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or 
paracentesis), study medication 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 study medication, it is not necessary 
to hold study medication for these procedures. 
 For emergency procedures, study medication should be held after the procedure until 
the surgical site is reasonably healed, for at least 7 days after the urgent surgical 
procedure. 
5. 
INTERVENTION ALLOCATION AND BLINDING 
Intervention Allocation 
As this is a single-arm study, all eligible subjects will receive treatment with ibrutinib. 
Blinding 
As this is an open study, blinding procedures are not applicable. 
6. 
DOSAGE AND ADMINISTRATION 
Ibrutinib 420 mg (3 × 140 mg capsules) will be administered orally once daily. It is expected that 
many subjects enrolled in the trial will require antifungal prophylaxis. Please see Section 8.3.1 
for dose modification guidelines with concomitant use of CYP3A inhibitors or inducers. 
The capsules are to be taken around the same time each day with approximately 240 mL of water. 
The capsules should be swallowed intact and subjects should not attempt to open capsules or 


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dissolve them in water. The first dose will be delivered at the study site on Week 1 Day 1, after 
which subsequent dosing will occur on an outpatient basis except for PK and PD sampling days 
on Week 1 Day 2, Week 2 Day 1, and Week 13 Day 1. 
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. 
Ibrutinib will be dispensed to subjects in bottles at each visit. Study-site personnel will instruct 
subjects on how to store study drug for at-home use as indicated for this protocol. Unused 
ibrutinib dispensed during previous visits must be returned to the site and drug accountability 
records updated at each visit. Returned capsules must not be redispensed to anyone. 
6.1. 
Dose Modifications 
6.1.1. 
Dose Modification for Adverse Reactions 
The dose of ibrutinib must be modified according to the dose modification guidance in Table 4 
and Table 5 if any of the following toxicities occur: 
 
Grade 4 neutropenia (ANC <500/μL) for more than 7 days 
 
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 antiemetic and/or 
antidiarrheal therapy 
 
Any other Grade 4 or unmanageable Grade 3 toxicity 
Table 4: Ibrutinib Dose Modifications 
Occurrence 
Action 
First 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at original dose level 
Second 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 dose level lower 
(ie, 280 mg/day for 420 mg/day dose) 
Third 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 2 dose levels lower 
(ie, 140 mg/day for 420 mg/day dose) 
Fourth 
Discontinue ibrutinib 
 
Table 5: Ibrutinib Dose Reduction Levels 
Starting Dose Level 
420 mg 
280 mg 
140 mg 
Dose Reduction Level 1 
280 mg 
140 mg 
70 mg 
Dose Reduction Level 2 
140 mg 
70 mg 
Discontinue 
Dose Reduction Level 3 
Discontinue 
Discontinue 
-- 
Refer to Section 8.3.1 for instructions on dose modifications or temporary hold during 
concomitant administration of CYP3A inhibitors or inducers and Section 8.3.3 for subjects 
requiring the initiation of anticoagulants while receiving ibrutinib. Refer to Section 4.3 for 


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guidance on dose delays during the perioperative period for subjects who require surgical 
intervention or an invasive procedure while receiving ibrutinib. 
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation. 
Study drug may be held for a maximum of 28 consecutive days. Discontinue ibrutinib 
permanently if ibrutinib cannot be restarted within 28 days due to toxicity. If the dose of 
ibrutinib is reduced for a toxicity, at the investigator’s discretion, the dose of ibrutinib may be 
reescalated after 8 weeks of a dose reduction in the absence of a recurrence of the toxicity that 
led to the reduction. 
When a toxicity which does not meet the above definition occurs and a dose modification is 
considered by the investigator due to the toxicity, the investigator should consult with the 
sponsor’s medical monitor. 
6.1.2. 
Dose Modification for Subjects with Hepatic Impairment 
Dose modifications for hepatic impairment will depend on baseline total bilirubin level and 
subsequent changes in bilirubin levels per Table 6 below. If the elevation of bilirubin is due to a 
nonhepatic cause or Gilbert’s Syndrome then no dose modifications are necessary. 
Table 6: Ibrutinib Dose Modifications for Subjects with Hepatic Impairment 
Starting Dose Level 
Bili ≤1.5 x ULN at baseline: 420 mg 
On-study bilirubin level ≤1.5×ULN 
Continue 420 mg 
On-study bilirubin level >1.5-3×ULN 
Reduce to 140 mg 
On-study bilirubin level >3×ULN 
Hold* until bili level >1.5-3×ULN restart at 140 mg 
When bili level ≤1.5×ULN restart at 420 mg 
Bili = bilirubin; ULN = upper limit of normal 
* In cases where the investigator wishes to restart ibrutinib after ibrutinib has been held for more than 28 days for 
hepatic impairment, please contact the medical monitor for approval. 
6.1.3. 
Ibrutinib Hold After Withdrawal of All Immunosuppressants 
At the physician’s discretion, ibrutinib may be held if all of the following conditions are met: 
 All systemic immunosuppressants used for the treatment of cGVHD have been discontinued. 
 cGVHD response has been maintained for 12 weeks after complete withdrawal of all 
immunosuppressants (not including ibrutinib). 
 The subject has received a minimum of 48 weeks of ibrutinib. 
If cGVHD returns/worsens after ibrutinib has been held for the above criteria, ibrutinib may be 
restarted after consulting with the medical monitor. 


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7. 
INTERVENTION COMPLIANCE 
The first dose of ibrutinib will be delivered at the study site on Week 1 Day 1, after which 
subsequent dosing will occur on an outpatient basis. Intervention compliance will be assessed 
based on clinical interview with subjects at each study visit. Subjects will be instructed to return 
unused ibrutinib capsules dispensed during previous visits to the site. The theoretical number of 
ibrutinib capsules dispensed will be recorded and compared with the number returned and the 
drug accountability records will be updated by the study-site personnel at each visit. 
During the study, the investigator or designated study-site personnel will be responsible for 
providing additional instruction to reeducate any subject who is not compliant with taking the 
study drug. Additional details may be provided in a pharmacy manual/study site investigational 
product and procedures manual that is provided separately and noted in Section 15, Study-
specific Materials. 
8. 
CONCOMITANT THERAPY 
8.1. 
Permitted Concomitant Medications 
8.1.1. 
Ancillary Therapy and Supportive Care 
Ancillary therapy and supportive care for cGVHD is permitted as outlined in the NIH Consensus 
Development Project 2014 Ancillary Therapy and Supportive Care Working Group Report 
(Carpenter 2015, Attachment 9).7 In particular, the use of regimen to specifically treat or prevent 
bronchiolitis obliterans are allowed (eg, inhaled steroids/azithromycin/montelukast) and will not 
be considered systemic treatment for cGVHD. 
Other supportive medications in accordance with standard clinical practice (such as for emesis, 
diarrhea, etc) are permitted. Use of neutrophil growth factors (filgrastim and pegfilgrastim) or 
red blood cell growth factors (erythropoietin) is permitted per institutional policy. Transfusions 
may be given in accordance with institutional policy. 
8.1.2. 
Systemic Immunosuppressant Therapy 
Participants may be receiving other immunosuppressive therapies in addition to glucocorticoids. 
In addition, due to potential drug-drug interactions with ibrutinib, monitoring of drug levels for 
immunosuppressant agents such as cyclosporine, tacrolimus, or sirolimus are highly 
recommended during the clinical trial. The doses for these immunosuppressants should be 
adjusted (increased or decreased) per institutional practices based on the measured drug level. 
Concurrent use of sirolimus and a CI (tacrolimus or cyclosporine) are prohibited. 
Use of immunosuppressants for reasons other than treatment for cGVHD should be discussed 
with the medical monitor. 
8.1.3. 
Systemic Steroids 
Systemic corticosteroids may be decreased at the treating physician’s discretion. The initial taper 
of corticosteroids may begin 2 weeks following initiation of ibrutinib if a clinical response is 


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seen. The recommendation is to not taper below 50% of the original dose by the 12-week 
assessment period unless there is a medical reason (eg, uncontrolled diabetes, infection) for 
steroid reduction below 50%. A specific steroid taper schedule will not be mandated. 
By its nature, cGVHD is a protean disease with clinical manifestations that wax and wane over 
time. Closely spaced clinical evaluations will detect temporary exacerbations of cGVHD 
manifestations but may not accurately reflect the long-term trajectory of a subject’s cGVHD and 
response to treatment. Therefore, in the event a participant experiences a flare of cGVHD, 
temporary reescalation of corticosteroids dose will be allowed at the physician’s discretion. 
Tapering of increased corticosteroids dose for a flare will begin within 4 weeks. If criteria are 
met for progressive cGVHD, the participant will be scored as a treatment failure and dropped-off. 
8.2. 
Prohibited Concomitant Medications 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is 
prohibited while the subject is receiving ibrutinib treatment. Localized, hormonal, or bone 
sparing treatment for malignancies, and localized radiotherapy for medical conditions other than 
the underlying disease may be considered with prior approval of the medical monitor. The 
Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered. 
8.3. 
Medications to be Used With Caution 
8.3.1. 
CYP3A Inhibitors or Inducers 
Ibrutinib is metabolized primarily by CYP3A4. Avoid coadministration with strong CYP3A 
inhibitors and consider alternative agents with less CYP3A inhibition. The dose of ibrutinib 
should be adjusted for concomitant use of CYP3A inhibitors as per Table 7 below: 
Table 7: Ibrutinib Dose Modifications for Concomitant Use of CYP3A Inhibitors 
CYP inhibitor class 
Dose modification instructions 
Mild CYP3A inhibitors 
420 mg once daily. No dose adjustment required. 
Moderate CYP3A inhibitors 
420 mg once daily. No dose adjustment required. 
Voriconazolea 
280 mg once daily 
Strong CYP3A inhibitors 
140 mg once daily or consider alternative with less CYP3A 
inhibitory potential 
a Itraconazole and ketoconazole will be replaced with voriconazole for study subjects. Avoid concomitant use of 
clarithromycin with ibrutinib. 
When these antifungal agents will be discontinued, the ibrutinib dose will be increased to 420 mg, 
considering the half-lives of the antifungal agents. Avoid concomitant use of strong CYP3A 
inducers. Consider alternative agents with less CYP3A induction. Grapefruit and Seville oranges 
should be avoided during the study period. A list of common CYP3A inhibitors and inducers is 
provided in Attachment 7. For further information, please refer to the current version of the 
ibrutinib IB and examples of inhibitors, inducers, and substrates may be found at 


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http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is continually revised and 
should be checked frequently for updates. 
8.3.2. 
Substrates of P-glycoprotein 
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor. Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. 
However, it cannot be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic 
dose. There is no clinical data available. Therefore, to avoid a potential interaction in the GI tract, 
narrow therapeutic range P-gp substrates such as digoxin, should be taken at least 6 hours before 
or after ibrutinib. 
8.3.3. 
Antiplatelet Agents and Anticoagulants  
Warfarin or other vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with 
caution in subjects requiring other anticoagulants or medications that inhibit platelet function. 
Subjects with congenital bleeding diathesis have not been studied. Ibrutinib should be withheld 
at least 3 to 7 days pre and postsurgery depending upon the type of surgery and the risk of 
bleeding (see Section 4.3). 
For subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
(other than warfarin or a vitamin K antagonist) the risks and benefits of continuing ibrutinib 
treatment should be considered. If therapeutic anticoagulation is clinically indicated during the 
course of the study, treatment with ibrutinib should be held and ibrutinib should 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 ibrutinib is 
restarted. 
9. 
STUDY EVALUATIONS 
9.1. 
Study Procedures 
9.1.1. 
Overview 
The TIME AND EVENTS SCHEDULE summarizes the frequency and timing of efficacy, PK, 
PD, and safety assessments applicable to this study. The study visits scheduled should occur at 
the times delineated in the TIME AND EVENTS SCHEDULE. The Week 1 and Week 2 visits 
should occur on the specified day and visits from Week 5 and onwards that are to occur every 
4th week should occur within ±3 days of the scheduled visit date. Visits from Week 37 and 
onwards that are to occur every 12th week and all the other study visits in the treatment period 
should occur within ±7 days of the scheduled visit date. The End-of-treatment visit is scheduled 
after 30 days from last dose of ibrutinib. Posttreatment follow-up visit will occur every 12th 
week after End-of-treatment visit, until cGVHD progression. After cGVHD progression, survival 
status and the use of subsequent cGVHD treatment will be followed every 12th week by clinic 
visits or telephone contacts. 


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Lee cGVHD Symptom Scale assessment (whenever assessment is scheduled) should be 
conducted/completed before any tests, procedures, or other consultations to prevent influencing 
subject perceptions. Blood collections for PK and PD assessments should be kept as close to the 
specified time as possible. Actual dates and times (if applicable), of assessments will be recorded 
in the source documentation and case report form (CRF). 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator, to establish the absence of pregnancy at any time during the subject's participation 
in the study. 
The total blood volume to be collected from each subject will be approximately 319.5 mL in the 
first year [from screening to Week 49], 135 mL per year after the first year [5 times visits per 
year], and 27 mL on the End of Treatment Visit. If a subject continues treatment phase until 
Week 109, the total blood volume is approximately 481.5 mL (255 mL for safety [85 mL for 
hematology and 170 mL for serum chemistry], 5 mL for coagulation studies, 3 mL for serology, 
2 mL for serum β-hCG pregnancy test [women only], 77 mL for donor/host chimerism, 55 mL 
for quantitative serum immunoglobulins [Igs], 22 mL for PK, and 62.5 mL for PD). Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
9.1.2. 
Screening Phase 
The Screening Phase assessments will be performed within 42 days prior to study treatment 
initiation. The subjects (legally acceptable representatives [LARs], if the subject is incapable of 
providing consent) will be asked to sign the consent form at the screening visit before any study 
related procedures are conducted. 
During the Screening Phase, eligibility criteria will be reviewed and a complete clinical 
evaluation will be performed. A relevant medical history and physical exam (including vital 
signs, height, and weight), along with medical history details of transplant history and indication 
will be captured. Karnofsky/Lansky performance status, malignant disease restaging for relapse 
and cGVHD activity assessment will be conducted. The subject’s baseline cardiovascular status 
will be assessed using an ECG. All concomitant medications including corticosteroids 
requirement, over-the counter drugs, vitamins and herbs will be recorded. Lee cGVHD Symptom 
Scale will be used for efficacy assessment. Laboratory test for Hematology, Serum chemistry, 
Coagulation studies: PT/INR, aPTT, Hepatitis serologies/PCR, and FEV1 by spirometry will be 
done. Serum pregnancy test will be done only for women of childbearing potential. Eligible 
subjects will have clinically determined cGVHD and are dependent on or refractory to steroids. 
Subjects may have had no more than 3 previous therapies for cGVHD. 
Clinical assessment of cGVHD must be clinically stable or worsening for a minimum of 14 days 
between screening and first dose of ibrutinib. If cGVHD assessment shows clinical improvement 
during this period, subject may be reassessed. Reassessment should be performed at least 14 days 
later from the last assessment. If cGVHD assessment is stable or worsening between the last 2 
assessments then the subject may receive first dose of ibrutinib. When cGVHD assessment is 
performed at the day of informed consent for this confirmation, clinical laboratory test results 


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which have been obtained in clinical practice at the same day before signing of the informed 
consent can be referred to the cGVHD assessment. 
After reviewing all eligibility criteria, a subject will be enrolled in this study within 3 days before 
the planned first dose of ibrutinib. Adverse events and concomitant medication recording will 
start after the signing of the informed consent and will continue until 30 days after the last dose 
of ibrutinib or the time of starting a subsequent systemic treatment for cGVHD, if earlier. 
9.1.3. 
Treatment Phase 
On Day 1 of Study Week 1, subjects who satisfy all inclusion and exclusion criteria will start 
treatment with ibrutinib. All required tests and evaluations must be conducted before start of 
study drug administration on Day 1 of Study Week 1. 
Subsequently, throughout the Treatment Phase, subjects will continue to receive ibrutinib unless 
they have intervening unacceptable toxicity or meet other criteria for subject discontinuation (see 
Section 10.2). All visit procedures will be performed as specified in the TIME AND EVENTS 
SCHEDULE. 
During the Treatment Phase, efficacy and safety evaluations (See Section 9.2 and 9.5), sampling 
of PK and PD (See Section 9.3 and 9.4) will be performed according to the TIME AND 
EVENTS SCHEDULE. Adverse events and changes to concomitant medications will be 
recorded. 
The measurements collected at the time closest to, but prior to, the first dose of study drug 
administration will be defined as the baseline values. The frequency of study procedures and 
assessment to be conducted during the Treatment Phase are outlined in the TIME AND EVENTS 
SCHEDULE. However, clinical evaluations and laboratory studies may be repeated more 
frequently, if clinically indicated. 
For Week 1 Day 1 only, clinical laboratory tests and spirometry do not need to be repeated if the 
screening tests were performed within 3 days of the first dose of ibrutinib. The eligible subjects 
will be sequentially assigned to the study drug. Ibrutinib 420 mg (3 × 140 mg capsules) will be 
administered orally once daily. The first dose will be delivered at the study site on Day 1, after 
which subsequent dosing will occur on an outpatient basis except for PK and PD sampling days 
on Week 1 Day 2, Week 2 Day 1, and Week 13 Day 1 (see Section 9.3 and 9.4). Subjects should 
refrain from taking the study drug in the morning of the study visits designated for PK and PD 
sampling until seen at the site. When all evaluations will be completed, and it will be determined 
that the subject can continue treatment, ibrutinib capsules will be dispensed. 
Ibrutinib will be dispensed to subjects in bottles. Study-site personnel will instruct subjects on 
how to store study drug for at-home use as indicated for this protocol. The evaluations will be 
done as per timepoints specified in the TIME AND EVENTS SCHEDULE. Subjects will be 
evaluated throughout the Treatment Phase for possible toxicities, and modifications in dosing 
will be made as required according to the criteria in Section 6.1. 


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Treatment will continue until study discontinuation criteria (refer Section 10.2) are met. If 
progressive cGVHD is confirmed, the subject will discontinue taking the study drug, complete 
the End-of-treatment Visit, and enter the Posttreatment Follow-up Phase. 
For subjects who have reached the time of the study end in Treatment Phase, study treatment will 
be discontinued at the first visit after the study end. Then the End of Treatment Visit will be 
completed and the subject’s study participation will be ended. 
End of Treatment Visit 
An End of Treatment Visit will be scheduled within 30 days after the last dose of study drug 
(+7 days) for all subjects, including those discontinuing treatment for any reason except for loss 
to follow-up, death, or withdrawal of consent for study participation. Subjects who are 
discontinued from treatment due to cGVHD progression, AEs, or other reasons should complete 
the End of Treatment Visit before starting any subsequent cGVHD treatment. If a subject is 
unable to return to the study site for the End of Treatment Visit, the subject should be contacted 
and any available information regarding AEs that occur within 30 days after the last dose of 
study drug or the time of starting a subsequent systemic treatment for cGVHD, if earlier should 
be collected. 
9.1.4. 
Follow-up Phase 
The Posttreatment Follow-up Phase will begin once a subject discontinued ibrutinib treatment. 
Subjects who discontinue for reasons other than cGVHD progression (ie, for AE or Investigator 
decision) will complete an End-of-treatment Visit (30+7 days from the last dose of ibrutinib) and 
will be followed for the evaluations listed below until death, lost to follow-up, consent 
withdrawal, or study end, whichever occurs first: 
 Continued cGVHD disease evaluations 
 Follow-up for recurrence of malignancy 
 Follow-up for new cGVHD treatments 
Subjects who discontinue due to cGVHD progression will complete an End-of-treatment Visit 
and be followed for survival status and the use of subsequent cGVHD treatment (clinic visits or 
telephone contacts). 
Investigators may recontact the subject to obtain long-term follow-up information regarding the 
subject's safety or survival status as noted in the ICF (refer to Section 16.2.3, Informed Consent 
and Assent Form). 
Subjects will be instructed that study drug will not be made available to them after they have 
completed/discontinued study drug and that they should return to their primary physician to 
determine standard of care. 


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9.2. 
Efficacy  
9.2.1. 
Efficacy Evaluations 
NIH Consensus Panel Criteria for Overall Response 
Response will be defined using the NIH Consensus Panel Chronic GVHD Activity Assessment 
(2014) (Attachment 4, Attachment 5, and Attachment 6). Skin, mouth, liver, upper and lower GI, 
esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall 
response. 
 Complete Response (CR) is defined as resolution of all manifestations in each organ or site.  
 Partial Response (PR) is defined as improvement in at least 1 organ or site without 
progression in any other organ or site.  
 cGVHD Progression is defined as clinically meaningful worsening in one or more organs 
regardless of improvement in other organs. Note that mixed response (ie, improvement in at 
least 1 organ accompanied by progression in another organ) is considered cGVHD 
progression. 
 Stable disease (SD): response that does not meet the criteria for CR, PR, or cGVHD 
progression. 
Please refer to NIH Response Assessment Manual provided by the sponsor for further details. 
Lee cGVHD Symptom Scale 
All subjects in the study will complete the Lee cGVHD Symptom Scale (Attachment 3) at all 
response assessment visits. 
9.3. 
Pharmacokinetics 
Venous blood samples will be collected to determine plasma concentrations of ibrutinib and the 
metabolite PCI-45227 at the timepoints specified in TIME AND EVENTS SCHEDULE. Plasma 
samples used for PK evaluation may additionally be used to evaluate safety or efficacy aspects 
that address concerns arising during or after the study period. 
9.3.1. 
Evaluations 
Venous blood samples of approximately 2 mL per sampling will be collected for measurement of 
plasma concentrations of ibrutinib and PCI-45227 according to the timepoints specified in the 
TIME AND EVENTS SCHEDULE and the BLOOD SAMPLING SCHEDULE FOR PK AND 
PD. Other metabolites of ibrutinib may be explored. 
The subject should refrain from taking the study drug in the morning of study visits designated 
for PK sampling. The time of the last meal prior to the dosing is to be recorded in the CRF. The 
investigator or designee will supervise administration of the study drug and record the exact time 
of study drug administration and blood samplings. 


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9.3.2. 
Analytical Procedures 
Plasma concentrations of ibrutinib and PCI-45227 will be determined using a validated, specific, 
and sensitive liquid chromatography/tandem mass spectrometry method under the supervision of 
the sponsor. 
9.3.3. 
Pharmacokinetic Parameters 
The plasma concentration data of ibrutinib and PCI-45227 will be used to determine PK 
parameters by noncompartment method. At least following PK parameters will be included: area 
under the plasma concentration-time curve from time zero to time of last measurable 
concentration (AUClast), area under the plasma concentration-time curve from time zero to 
24 hours (AUC24h), maximum plasma concentration (Cmax), time to reach the maximum plasma 
concentration (Tmax), and elimination half-life (t1/2). 
In addition, the plasma concentration data of ibrutinib may be used for population PK analysis 
and further analyses to explore correlation between exposure and relevant clinical/PD 
information. 
9.4. 
Pharmacodynamic Evaluations 
Venous blood samples for PD evaluation (BTK and ITK binding site occupancy) will be 
collected according to the timepoints specified in the TIME AND EVENTS SCHEDULE and the 
BLOOD SAMPLING SCHEDULE FOR PK AND PD. The exact time of blood sampling will be 
recorded. 
9.5. 
Safety Evaluations 
The study will include the following evaluations of safety according to the timepoints outlined in 
the TIME AND EVENTS SCHEDULE. Any clinically relevant changes occurring during the 
study must be recorded on the AE section of the CRF. Any clinically significant abnormalities 
persisting at the end of the treatment/early withdrawal will be followed by the investigator until 
resolution or until a clinically stable endpoint is reached or until the end of the study. 
Adverse Events 
All AEs will be reported from the time a signed and dated ICF is obtained until 30 days 
following the last dose of ibrutinib or the time of starting a subsequent systemic treatment for 
cGVHD, if earlier. Adverse events reported after 30 days following the last dose of ibrutinib or 
the time of starting the subsequent systemic treatment for cGVHD should also be reported if 
considered related to ibrutinib. Progression of the disease under study is not considered an 
adverse event (or SAE), even if it results in death during the AE reporting period. If a clinical 
sign or symptom or a laboratory test abnormality is observed in a patient with disease 
progression, but is not related to progression of the disease under study, then the usual AE 
reporting requirements apply. Adverse events will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. 


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Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative). Adverse events will be followed by the 
investigator as specified in Section 12, Adverse Event Reporting. 
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the CRF. The laboratory reports must 
be filed with the source documents. 
The following tests will be performed by the local laboratory: 
 Hematology Panel 
-hemoglobin 
-absolute neutrophil count (ANC) 
-platelet count 
-absolute lymphocyte count 
-white blood cell (WBC) count  
-absolute eosinophil count 
 
 Serum Chemistry Panel 
-sodium 
-alkaline phosphatase 
-potassium 
-alanine aminotransferase (ALT) 
-glucose  
-lactic acid dehydrogenase (LDH) 
-total bilirubin 
-uric acid 
-blood urea nitrogen (BUN) 
-aspartate aminotransferase (AST) 
-creatinine 
-albumin  
-total protein 
 
 Coagulation Studies 
Measurement of PT/INR and aPTT will be performed at local laboratory at screening. 
 Pregnancy test: 
Serum pregnancy tests are required at screening by local laboratory and only for women of 
childbearing potential. A urine pregnancy test will also be performed on Day 1 prior to first dose. 
If the test result is positive, the pregnancy must be ruled out by ultrasound to be eligible. 
 Serology 
 
Serologies include HIV antibody, hepatitis C antibody, HBsAb, HBsAg, and 
Hepatitis B core antibody (HBcAb) will be evaluated. If HBsAb, HBcAb, HBsAg or 
hepatitis C antibody is positive, then PCR to quantitate hepatitis B DNA or C RNA 
must be performed and must be negative prior to enrollment. 
 
Clinical and laboratory signs of active HBV infection should be closely monitored for 
HBV carriers or subjects who have history of hepatitis B during and following study 
treatment, according to the Guidelines for Prevention of Immunosuppressive Therapy or 
Chemotherapy-Induced Reactivation of HBV Infection. Consultation with a hepatitis 
specialist is also recommended. 


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 Donor/Host Chimerism 
 
Donor/host chimerism for the evaluation of engraftment status of the stem cell 
transplantation will be evaluated at local laboratory, except if donor/host chimerism 
cannot be performed due to any specific reason such as no donor information.  
 Quantitative Serum Immunoglobulins 
 
Testing for Ig A, IgG, and IgM levels will be performed at a local laboratory. 
Electrocardiogram (ECG)  
During the collection of ECGs, subjects will be in a quiet setting without distractions (eg, 
television, cell phones). Subjects should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. At screening, ECG is 
mandatory to confirm eligibility. Other ECGs will be performed at the investigator’s discretion, 
particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new 
onset of dyspnea. 
Vital Signs  
Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature. Blood 
pressure and pulse rate measurements will be preceded by at least 5 minutes of rest in a quiet 
setting without distractions (eg, television, cell phones). 
Physical Examination 
The complete physical examination will be performed at timepoints specified in the TIME AND 
EVENTS SCHEDULE and will include height (screening only) and weight, and examination per 
clinical practice. Review of symptoms should include inquiry of ocular symptoms; subjects 
should be referred to an ophthalmologist for a formal examination if any Grade ≥2 symptoms are 
reported. 
Karnofsky/Lansky Performance Scale 
The Karnofsky/Lansky Performance Scale is provided in Attachment 2. The Lansky scale is to 
be used for all subjects less than 16 years of age. 
Forced Expiratory Volume in 1 Second 
Subjects should be evaluated for FEV1 using spirometry at screening and Week 1 Day 1. After 
Week 1 Day 1, if the prior FEV1 result is abnormal then subsequent FEV1 measurements should 
be obtained every 12 weeks. If the prior FEV1 result is normal, then subsequent FEV1 
measurements should be obtained every 24 weeks. If a subject has cGVHD features in lung, 
FEV1 evaluation other than these mandatory timepoints is encouraged in cGVHD activity 
assessment whenever possible. The NIH Lung score should be ascertained with every cGVHD 
activity assessment regardless of whether a FEV1 is performed. 


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9.6. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Instructions for the collection, handling, and shipment of samples are found in 
the laboratory manual that will be provided for sample collection and handling. 
Refer to the TIME AND EVENTS SCHEDULE for the timing and frequency of all sample 
collections. 
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY INTERVENTION/ 
WITHDRAWAL FROM THE STUDY 
10.1. 
Completion 
The study will be terminated before the defined end of study (see Section 17.9) is reached if 
marketing approval is received for the indication under study from the Ministry of Health Labor 
and Welfare (MHLW) in Japan. A subject who is in the treatment period at this time will 
discontinue the study drug and will complete an End-of-treatment Visit before the study end. A 
subject who is in the follow-up period at this time will stop the further follow-up. Both subjects 
will be considered to have completed the study. 
10.2. 
Discontinuation of Study Intervention/Withdrawal from the Study 
Discontinuation of Study Intervention 
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
study drug before the end of the intervention regimen. 
A subject's study drug must be discontinued if: 
 The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the subject to discontinue study drug 
 Subject begins treatment with another systemic therapy (including extracorporeal 
photopheresis) for cGVHD 
 cGVHD progression 
 Noncompliance with study medication 
 Investigator’s decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject) 
 Progression or relapse of the malignancy that was the indication for transplantation or 
development of posttransplant lymphoproliferative disease (PTLD) 
 The subject becomes pregnant 
If a subject discontinues study drug for any reason before the end of the study, posttreatment 
phase assessments should be obtained and scheduled assessments should be continued. 


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Withdrawal From the Study 
A subject will be withdrawn from the study for any of the following reasons: 
 Lost to follow-up 
 Withdrawal of consent 
 Death 
 Study termination by Sponsor 
If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. 
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Additional subjects will not be entered. If a 
subject discontinues study drug and withdraws from the study, end-of-treatment and 
posttreatment assessments should be obtained, if possible. If the reason for withdrawal from the 
study is withdrawal of consent then no additional assessments are allowed. 
11. 
STATISTICAL METHODS 
Statistical analysis will be done by the sponsor. A general description of the statistical methods 
to be used to analyze the efficacy and safety data is outlined below. Specific details will be 
provided in the Statistical Analysis Plan. 
The primary analysis for all efficacy and safety endpoints will be conducted at the time when the 
last subject has completed the efficacy assessment at Week 37 or has discontinued treatment 
before Week 37. Final analysis will be conducted at the study end. 
11.1. 
Subject Information 
The following definitions will be used for the safety, efficacy, PK and PD (BTK and ITK 
binding site occupancy) analysis populations, respectively: 
 All treated population: All enrolled subjects who will receive at least 1 dose of study drug. 
 Safety population: All enrolled subjects who will receive at least 1 dose of study drug. 
Safety population is identical to all treated population. 
 Response evaluable population: All enrolled subjects who will receive at least 1 dose of 
study drug and who have at least 1 adequate postbaseline efficacy assessment. 
 PK evaluable population: All enrolled subjects who will receive at least 1 dose of study 
drug and have at least 1 postdose PK sample obtained. 
 PD evaluable population: All enrolled subjects who will receive at least 1 dose of study 
drug and have at least 1 BTK and ITK binding site occupancy data. 


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11.2. 
Sample Size Determination 
With a sample size of 17 subjects and assuming an expected overall cGVHD response rate of 
approximately 60%, it is expected to have at least 80% power to show the efficacious treatment 
effect (the lower bound of 95% confidence interval of the response rate >25%). At least 1 
adolescent subject (12-17 years of age) will be enrolled in this study. 
11.3. 
Efficacy Analyses 
The all treated population will be used for all efficacy endpoints. The response evaluable 
population will be used for the overall cGVHD response rate as a sensitivity analysis.  
Primary Endpoint 
The overall cGVHD response rate (CR + PR) and its 95% confidence interval will be calculated 
with the exact test for binomial distribution in the all treated population. The study is considered 
to be positive if the lower limit of the exact 2-sided 95% confidence interval based on binominal 
distribution exceeds the threshold value (0.25). 
Secondary Endpoints 
Rate of sustained response for at least 20 weeks and cGVHD response rate at each timepoint of 
efficacy evaluation will be calculated with the exact 2-sided 95% confidence interval based on 
binominal distribution.  
The DOR for responders will be calculated by the Kaplan-Meier method descriptively. Median 
DOR and the corresponding 95% confidence interval will be provided if estimable with Kaplan-
Meier plot. 
Corticosteroid requirement changes over time and change in symptom burden measured by the 
Lee cGVHD Symptom Scale will be summarized by descriptive statistics. 
Exploratory Endpoints 
The Kaplan-Meier method will be used to descriptively summarize the FFS. Median FFS and the 
corresponding 95% confidence interval will be provided if estimable with Kaplan-Meier plot. 
The OS will be evaluated in the same manner as FFS, if necessary. Number and proportion of 
subjects with all immunosuppressants withdrawn will be summarized by descriptive statistics. 
11.4. 
Pharmacokinetic Analysis 
Pharmacokinetic evaluable population will be used for PK analyses. The individual plasma 
concentration data of ibrutinib and PCI-45227 will be listed and graphically displayed. 
Concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration data presentation. The data will be summarized at each timepoint using 
descriptive statistics (mean, standard deviation [SD], coefficient of variation, median, minimum 
and maximum) and mean (±SD) concentration-time profile will be graphically displayed. 
Concentration data below the lowest quantifiable concentration will be treated as zero in the 


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summary statistics. Additional analyses (eg, subgroup analyses by concomitant CYP3A 
inhibitors) may be performed as deemed necessary. 
The individual PK parameters of ibrutinib and PCI-45227 derived by noncompartment method 
will be listed and summarized using descriptive statistics (mean, SD, coefficient of variation, 
geometric mean, median, minimum and maximum). Additional analyses (eg, subgroup analyses 
by concomitant CYP3A inhibitors) may be performed as deemed necessary. 
Data or subjects will be excluded from the analysis if the data do not allow for accurate 
assessment of the PK. All subjects and samples excluded from the analysis will be clearly 
documented in the study report. 
If the data is subjected to population PK analysis, details will be given in a population PK 
analysis plan and the results will be presented in a separate report. The data may be combined 
with data from other ibrutinib studies. 
11.5. 
Pharmacodynamic Analyses 
Pharmacodynamic evaluable population will be used for PD analyses. The BTK and ITK binding 
site occupancy will be tabulated and summarized at each timepoint using descriptive statistics 
(mean, SD, coefficient of variation, median, minimum and maximum). Additional analyses (eg, 
subgroup analyses by ibrutinib dose or concomitant CYP3A inhibitors) may be performed as 
deemed necessary. 
11.6. 
Pharmacokinetic/Pharmacodynamic Analyses 
Relationships between PK of ibrutinib and PD measures may be explored as deemed necessary. 
11.7. 
Safety Analyses 
Safety population will be used for safety analyses. The safety parameters to be evaluated are the 
incidence, intensity, relationship to study drug, action taken with regards to the study drug, and 
type of adverse events, vital signs measurements, and clinical laboratory results in the safety 
population. Exposure to and reasons for discontinuation from study treatment will be tabulated in 
the all treated population. 
Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
will be included in the analysis. Treatment-emergent adverse events are adverse events with 
onset during the treatment phase or that are a consequence of a preexisting condition that has 
worsened since baseline, and occur during treatment or within 30 days following the last dose of 
study treatment, or any adverse event that is considered study treatment-related regardless of the 
start date of the event. The number and percent of subjects with treatment-emergent adverse 
events will be summarized according to intensity using the NCI-CTCAE (Version 4.03), drug 
relationship, and outcome. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized. Summaries, listings, datasets, or 


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subject narratives may be provided, as appropriate, for those subjects who die, who discontinue 
study drug due to an adverse event, or who experience a severe or an SAE. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and for observed values and changes from baseline at each scheduled timepoint. Frequency 
tabulations of the changes from baseline results will be presented in pre versus postintervention 
cross-tabulations (with classes for below, within, and above normal ranges). Frequency 
tabulations of the abnormalities will be made. A listing of subjects with any laboratory results 
outside the reference ranges will be provided. A listing of subjects with any markedly abnormal 
laboratory results will also be provided. 
Parameters with predefined NCI-CTCAE toxicity grades will be summarized. Change from 
baseline to the worst adverse event grade experienced by the subject during the study will be 
provided as shift tables. 
Vital Signs 
Descriptive statistics of temperature, pulse rate, respiratory rate, and blood pressure (systolic and 
diastolic) supine values and changes from baseline will be summarized at each scheduled 
timepoint. The percentage of subjects with values beyond clinically important limits will be 
summarized. 
12. 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about adverse 
event occurrence. 
12.1. 
Definitions 
12.1.1. 
Adverse Event Definitions and Classifications 
Adverse Event 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 


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have a causal relationship with the intervention. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) product, 
whether or not related to that medicinal (investigational or non-investigational) product. 
(Definition per International Conference on Harmonisation [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording). 
Serious Adverse Event 
An SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening  
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is a suspected transmission of any infectious agent via a medicinal product 
 Is Medically Important* 
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious. 
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality), other than progression of cGVHD. 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For ibrutinib, the expectedness of an adverse 
event will be determined by whether or not it is listed in the IB. 


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Adverse Event Associated With the Use of the Intervention 
An adverse event is considered associated with the use of the intervention if the attribution is 
possible, probable, or very likely by the definitions listed in Section 12.1.2, Attribution 
Definitions. 
12.1.2. 
Attribution Definitions 
Not Related 
An adverse event that is not related to the use of the intervention. 
Doubtful 
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event that might be due to the use of the intervention. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event that might be due to the use of the intervention. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant drug(s), concomitant disease(s). 
Very Likely 
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
12.1.3. 
Severity Criteria  
An assessment of severity grade will be made using the NCI-CTCAE Version 4.03. The 
investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities). 
12.2. 
Special Reporting Situations 
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to: 
 Overdose of a sponsor study drug 
 Suspected abuse/misuse of a sponsor study intervention 
 Accidental or occupational exposure to a sponsor study drug 


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 Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor study drug, eg, name confusion) 
 Exposure to a sponsor study drug from breastfeeding 
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the CRF. 
12.3. 
Procedures 
12.3.1. 
All Adverse Events 
All adverse events and special reporting situations, whether serious or nonserious, will be 
reported from the time a signed and dated ICF is obtained until 30 days after the last dose of 
ibrutinib, or the start of subsequent cGVHD treatment, if earlier. Adverse events reported after 
30 days following the last dose of ibrutinib or the time of starting the subsequent systemic 
treatment for cGVHD should also be reported if considered related to ibrutinib. Resolution 
information after 30 days should be provided, if it can be obtained. All Grade 3 or Grade 4 
adverse events considered related to ibrutinib must be followed until recovery to baseline or 
Grade ≤1 or until no further improvement is expected. Cardiac adverse events of Grade 2 or 
higher will be followed until improvement to baseline or Grade ≤1 or until no further 
improvement is expected. The unresolved aforementioned events will be followed for a 
maximum of 24 weeks. All adverse events of special interest as defined in Section 12.3.3 related 
to bleeding or resulting in bleeding complications must be followed until recovery or until there 
is no further improvement. Serious adverse events, including those spontaneously reported to the 
investigator within 30 days after the last dose of ibrutinib, must be reported using the Serious 
Adverse Event Form. The sponsor will evaluate any safety information that is spontaneously 
reported by an investigator beyond the time frame specified in the protocol. 
Progressive disease of cGVHD should not be reported as an adverse event, but 
symptoms/clinical signs in a patient with disease progression may be reported (see 
Section 12.3.2). Otherwise, all events that meet the definition of an SAE will be reported as 
SAEs, regardless of whether they are protocol-specific assessments. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the CRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the CRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions. 
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 


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Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:  
 Study number 
 Statement, in the local language(s), that the subject is participating in a clinical study 
 Investigator's name and 24-hour contact telephone number 
 Local sponsor's name and 24-hour contact telephone number (for medical staff only) 
 Site number 
 Subject number 
12.3.2. 
Serious Adverse Events 
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event. 
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form and Safety Report Form of the CRF, which must be completed and reviewed by a 
physician from the study site, and transmitted to the sponsor within 24 hours. The initial and 
follow-up reports of an SAE should be transmitted electronically or by facsimile (fax). 
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) 
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a study must be reported as an SAE, except hospitalizations 
for the following: 
 Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility). 


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 Surgery or procedure planned before entry into the study (must be documented in the CRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE. 
 For convenience the investigator may choose to hospitalize the subject for the duration of the 
intervention period. 
 The administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable SAE. 
Progression of the disease under study is not considered an adverse event (or SAE), even if it 
results in death during the AE reporting period. If a clinical sign or symptom or a laboratory test 
abnormality is observed in a patient with disease progression, but is not related to progression of 
the disease under study, then the usual AE reporting requirements apply. 
12.3.3. 
Adverse Events of Special Interest 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities by the sponsor. These events, meeting the definition of major hemorrhage 
listed below, will be reported to the sponsor within 24 hours of awareness irrespective of 
seriousness (ie, serious and nonserious AEs) following the procedure described above for SAEs 
and will require enhanced data collection. 
Major hemorrhage is defined as: 
 Any treatment-emergent hemorrhagic adverse event of Grade 3 or higher. All hemorrhagic 
events requiring a transfusion of red blood cells should be reported as Grade 3 or higher 
adverse events per NCI-CTCAE. 
 Any treatment-emergent SAE of bleeding of any grade. 
 Any treatment-emergent central nervous system hemorrhage/hematoma of any grade. 
12.3.4. 
Other Malignancies 
In addition to all routine adverse event reporting; all new malignant tumors, including solid 
tumors, skin malignancies, and hematologic malignancies; are to be reported for the duration of 
study treatment and during any protocol-specified follow-up periods including postprogression 
follow up for overall survival. 
12.3.5. 
Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs 
and must be reported using the Serious Adverse Event Form. Any subject who becomes pregnant 
during the study must discontinue further study intervention. 


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Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
12.4. 
Contacting Sponsor Regarding Safety 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document. 
13. 
PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures. 
13.1. 
Procedures 
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event. 
If the defect is combined with an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor. 
13.2. 
Contacting Sponsor Regarding Product Quality 
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document. 
14. 
STUDY INTERVENTION INFORMATION 
14.1. 
Physical Description of Study Drug 
Ibrutinib capsules are provided as a hard gelatin capsule containing 70 mg and 140 mg of 
ibrutinib. It will be manufactured and provided under the responsibility of the sponsor. All 
formulation excipients are compendial and are commonly used in oral formulations. Refer to the 
IB for a list of excipients. 


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14.2. 
Packaging 
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. 
14.3. 
Labeling 
Study interventions labels will contain information to meet the applicable regulatory 
requirements. 
14.4. 
Preparation, Handling, and Storage 
Ibrutinib capsules should be stored according to the storage conditions indicated on the label. 
The recommended storage condition for ibrutinib capsules is 15°C to 25°C with excursions 
permitted to 30°C. Current stability data indicate that the capsules will be stable for the duration 
of the clinical study under the labeled storage conditions. Study staff will instruct subjects on 
how to store medication for at-home use as indicated for this protocol. Refer to the pharmacy 
manual/study site investigational product and procedures manual for additional guidance on 
study intervention preparation, handling, and storage. 
14.5. 
Intervention Accountability 
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject (if applicable), must be documented on the intervention 
accountability form. Subjects or their legally acceptable representatives where applicable, must 
be instructed to return all original containers, whether empty or containing study drug. All study 
drug will be stored and disposed of according to the sponsor's instructions. Study-site personnel 
must not combine contents of the study drug containers. The subjects must return unused study 
drug to the study site. 
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study site monitor during on-site monitoring visits. The 
return to the sponsor of unused study drug, or used returned study drug for destruction, will be 
documented on the intervention return form. When the study site is an authorized destruction unit 
and study drug supplies are destroyed on-site, this must also be documented on the intervention 
return form. 
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for intervention accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 


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the same subject. Whenever a subject brings his or her study drug to the study site for pill count, 
this is not seen as a return of supplies. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor. 
15. 
STUDY-SPECIFIC MATERIALS 
The investigator will be provided with the following supplies: 
 Investigator's Brochure 
 Pharmacy manual/study site investigational product and procedures manual 
 Laboratory manual 
 NCI-CTCAE Version 4.03 
 Patient reported outcome (PRO) questionnaires and PRO completion guidelines  
 Electronic data capture (eDC) Manual 
 Sample ICF 
 Subject diaries 
16. 
ETHICAL ASPECTS 
16.1. 
Study-Specific Design Considerations 
This is an open-label, single-arm study and all subjects will receive the study drug. For the study 
population (Japanese patients with steroid dependent/refractory cGVHD), there are currently no 
standard treatment options. As ibrutinib has been approved in the US for the treatment of adult 
patients with cGVHD after failure of one or more lines of systemic therapy based on beneficial 
results of phase 1b/2 PCYC-1129-CA study in subjects with steroid dependent/refractory cGVHD, 
ibrutinib may also demonstrate clinical benefit for the population of this study. The total blood 
volume to be collected is considered to be an acceptable amount of blood to be collected over this 
time period from the population in this study. 
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled. 
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize 
participation in research. For each subject, his or her parent(s) (preferably both parents, if 
available) or legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has been 
fully explained and before the performance of any study-related assessments. Assent must be 


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obtained from children (minors) capable of understanding the nature of the study, typically subjects 
7 years of age and older, depending on the institutional policies. For the purposes of this study, all 
references to subjects who have provided consent (and assent as applicable) refers to the subjects 
and his or her parent(s) or the subject's legal guardian(s) or legally acceptable representative(s) 
who have provided consent according to this process. Minors who assent to a study and later 
withdraw that assent should not be maintained in the study against their will, even if their parent(s) 
still want them to participate. 
16.2. 
Regulatory Ethics Compliance 
16.2.1. 
Investigator Responsibilities 
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible. 
16.2.2. 
Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations): 
 Final protocol and, if applicable, amendments 
 Sponsor-approved ICF (and any other written materials to be provided to the subjects) 
 Investigator's Brochure (or equivalent information) and amendments/addenda 
 Sponsor-approved subject recruiting materials 
 Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
 Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB) 
 Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects 
 Any other documents that the IEC/IRB requests to fulfill its obligation 
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials, 
and subject compensation programs, and the sponsor has received a copy of this approval. This 


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approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved. 
During the study, the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate: 
 Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct) 
 Revision(s) to ICF and any other written materials to be provided to subjects 
 If applicable, new or revised subject recruiting materials approved by the sponsor 
 Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
 New edition(s) of the IB and amendments/addenda 
 Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually) 
 Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
drug 
 New information that may adversely affect the safety of the subjects or the conduct of the 
study 
 Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
 Report of deaths of subjects under the investigator's care 
 Notification if a new investigator is responsible for the study at the site 
 Development Safety Update Report and Line Listings, where applicable 
 Any other requirements of the IEC/IRB 
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s). 
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution). 
16.2.3. 
Informed Consent and Assent Form 
Each subject or a legally acceptable representative must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) and assent form that is/are used 


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must be approved by both the sponsor and by the reviewing IEC/IRB and be in a language that 
the subject can read and understand. The informed consent should be in accordance with 
principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, 
applicable regulatory requirements, and sponsor policy. 
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, which includes permission to obtain information about 
his or her survival status. It also denotes that the subject agrees to allow his or her study 
physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, and subsequent disease-related treatments, if needed. The physician may also 
recontact the subject for the purpose of obtaining consent to collect information about his or her 
survival status. 
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject. 
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained. 
Children (minors) or subjects who are unable to comprehend the information provided can be 
enrolled only after obtaining consent of a legally acceptable representative. Assent must be 
obtained from children (minors) capable of understanding the nature of the study, typically 
subjects 7 years of age and older, depending on the institutional policies. Written assent should 
be obtained from subjects who are able to write. A separate assent form written in language the 
subject can understand should be developed for adolescents. After having obtained the assent, a 
copy of the assent form must be given to the subject, and to the subject's parent or if applicable 
legally acceptable representative. 


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When prior consent of the subject is not possible and the subject's legally acceptable 
representative is not available, enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and well-
being of the subject and to ensure compliance with applicable regulatory requirements. The 
subject or legally acceptable representative must be informed about the study as soon as possible 
and give consent to continue. 
16.2.4. 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential. 
The informed consent obtained from the subject or his or her legally acceptable representative 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-
related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries. 
The subject or a legally acceptable representative has the right to request through the investigator 
access to his or her personal data and the right to request rectification of any data that are not 
correct or complete. Reasonable steps will be taken to respond to such a request, taking into 
consideration the nature of the request, the conditions of the study, and the applicable laws and 
regulations. 
Exploratory PD, PK and PK/PD research is not conducted under standards appropriate for the 
return of data to subjects. In addition, the sponsor cannot make decisions as to the significance of 
any findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data. 
17. 
ADMINISTRATIVE REQUIREMENTS 
17.1. 
Protocol Amendments 
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, 
or when the relevant competent authority has raised any grounds for nonacceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 


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promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When 
the change(s) involves only logistic or administrative aspects of the study, the IEC/IRB (where 
required) only needs to be notified. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it. 
17.2. 
Regulatory Documentation 
17.2.1. 
Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met. 
17.2.2. 
Required Prestudy Documentation 
The following documents must be provided to the sponsor before shipment of study drug to the 
study site: 
 Protocol and amendment(s), if any, signed and dated by the principal investigator 
 A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee. 
 Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study. 
 Regulatory authority approval or notification, if applicable 
 Signed and dated statement of investigator (eg, Form FDA 1572), if applicable 
 Documentation of investigator qualifications (eg, curriculum vitae) 
 Completed investigator financial disclosure form from the principal investigator, where 
required 


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 Signed and dated clinical trial agreement, which includes the financial agreement 
 Any other documentation required by local regulations 
 
The following documents must be provided to the sponsor before enrollment of the first subject: 
 Completed investigator financial disclosure forms from all subinvestigators 
 Documentation of subinvestigator qualifications (eg, curriculum vitae) 
 Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable 
 Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable 
17.3. 
Subject Identification, Enrollment, and Screening Logs 
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness. 
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth (as allowed by local regulations). In cases where the subject is not enrolled into 
the study, the date seen and date of birth (as allowed by local regulations) will be used. 
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study. 
17.4. 
Source Documentation 
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
intervention receipt/dispensing/return records; study drug administration information; and date of 
study completion and reason for early discontinuation of study drug or withdrawal from the 
study, if applicable. The author of an entry in the source documents should be identifiable. 
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document). 
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows: 


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 Referral letter from treating physician or 
 Complete history of medical notes at the site 
 Discharge summaries 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents. 
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the CRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the CRF. Data in this system 
may be considered source documentation. 
17.5. 
Case Report Form Completion 
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All CRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the CRF are accurate 
and correct. 
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor. 
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
CRF in English. The CRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit. 
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. 
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done in either of the following ways: 
 Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool). 
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel. 
17.6. 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 


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study-site personnel before the study, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples.  
Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRF for accuracy and completeness during on-site 
monitoring visits and after their return to the sponsor; any discrepancies will be resolved with the 
investigator or designee, as appropriate. The data will be entered into the study database and 
verified for accuracy and consistency with the data sources. 
The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and 
after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources. 
17.7. 
Record Retention 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor. 
For CRF completed on pressure-sensitive paper, a copy is to be retained in the archives of the 
sponsor. A second copy must be archived by the investigator. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports. 


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17.8. 
Monitoring 
The sponsor will use a combination of monitoring techniques (central, remote, or on-site 
monitoring) to monitor this study. 
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the CRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF are known to the sponsor and study-site personnel and are accessible for verification by the 
sponsor study-site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related documents. 
The monitor will meet with the investigator on a regular basis during the study to provide 
feedback on the study conduct. 
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. Central monitoring will take place for data identified by the sponsor as 
requiring central review. 
17.9. 
Study Completion/Termination 
17.9.1. 
Study Completion/End of Study 
The study is considered completed with the last scheduled study assessment shown in the TIME 
AND EVENTS SCHEDULE for the last subject participating in the study. The final data from 
the study site will be sent to the sponsor (or designee) after completion of the final subject 
assessment at that study site, in the time frame specified in the Clinical Trial Agreement. 
17.9.2. 
Study Termination 
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 


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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the investigator  
 Discontinuation of further study drug development 
17.10. On-Site Audits 
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
17.11. Use of Information and Publication 
All information, including but not limited to information regarding ibrutinib or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory research data, generated as a result of 
this study, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent. 
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of ibrutinib, and thus may be disclosed as 
required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. Study subject identifiers will 


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not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 18 months after study end date, or the sponsor 
confirms there will be no multicenter study publication. Authorship of publications resulting 
from this study will be based on the guidelines on authorship, such as those described in the 
ICMJE Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical Journals, which state that the named authors must have made a significant 
contribution to the conception or design of the work; or the acquisition, analysis, or interpretation 
of the data for the work; and drafted the work or revised it critically for important intellectual 
content; and given final approval of the version to be published; and agreed to be accountable for 
all aspects of the work in ensuring that questions related to the accuracy or integrity of any part 
of the work are appropriately investigated and resolved. 
Registration of Clinical Studies and Disclosure of Results 
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law. 
 
 


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42. Preliminary Safety and Pharmacokinetic Summary for Part 1 of Study LYM3003. A Randomized, Open-label, 
Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Patients with Relapsed or Refractory 
Mature B-cell non-Hodgkin Lymphoma. Janssen Research & Development (21 November 2017). 
43. 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. 
44. Sahaf B, Arai S, Otani J, et al. Rituximab Provides Steroid-Sparing Therapy in New-Onset Chronic Graft- 
Versus-Host Disease. ASBMT 2013 (manuscript in preparation). 
45. Sarantopoulos S, Blazar BR, Cutler C, et al. B cells in chronic graft-versus-host disease. Biol Blood Marrow 
Transplant. 2015;21:16-23. 
46. Sarantopoulos S, Stevenson KE, Kim HT, et al. Altered B-cell homeostasis and excess BAFF in human 
chronic graft-versus-host disease. Blood. 2009;113:3865-3874. 
47. Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, von Bergwelt-Baildon MS. The role of B cells in the 
pathogenesis of graft-versus-host disease. Blood. 2009;114:4919-4927. 
48. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among 
patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 
2013;309:1359-67. 
49. Socie G, Stone JV, Wingard JR, et al. Long-term survival and late deaths after allogeneic bone marrow 
transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N 
Engl J Med. 1999;341:14-21. 
50. Sullivan KM, Witherspoon RP, Storb R, et al. Prednisone and azathioprine compared with prednisone and 
placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia 
after allogeneic marrow transplantation. Blood. 1988 Aug, 72(2): 546-54. 
51. Sutherland HJ, Fyles GM, Adams G et al. Quality of life following bone marrow transplantation: a comparison 
of patient reports with population norms. Bone Marrow Transplant. 1997;19:1129-1136. 
52. Syrjala KL, Martin PJ, Lee SJ. Delivering care to long-term adult survivors of hematopoietic cell 
transplantation. J Clin Oncol. 2012 Oct 20, 30(30): 3746-51. 
53. Takanori Teshima. 2. GVHD 3rd Edition. In: Japan Society for Hematopoietic Cell Transplantation Guidelines 
Committee, ed. Hematopoietic Cell Transplantation Society Guidelines Volume 1. Osaka: Iyaku (Medicine and 
Drug) Journal Co., Ltd. 2014. P. 60- 125. 
54. The Japanese Society for Pediatric Endocrinology. Height and weight percentiles in 2000. The physical growth 
of Japanese children: Cross-sectional growth curve (Height and weight percentile curves) Appendix 2, 
http://jspe.umin.jp/medical/files/fuhyo2.pdf (Accessed 14-Jun 2017). 
55. Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving 
radiation and chemotherapy. N Engl J Med 1957; 257:491-6. 
 


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Attachment 1: Diagnosis of cGVHD − Signs and Symptoms of cGVHD 
ORGAN OR SITE 
DIAGNOSTIC 
(Sufficient to establish the 
diagnosis of chronic GVHD) 
DISTINCTIVEa 
(Seen in chronic GVHD, but 
insufficient alone to establish a 
diagnosis) 
OTHER FEATURES OR 
UNCLASSIFIED ENTITIESb 
COMMONc 
(Seen with both acute and 
chronic GVHD) 
Skin 
Poikiloderma  
Lichen planus-like features  
Sclerotic features  
Morphea-like features 
Lichen sclerosus-like features 
Depigmentation 
Papulosquamous lesions 
Sweat impairment 
Ichthyosis 
Keratosis pilaris 
Hypopigmentation 
Hyperpigmentation 
Erythema 
Maculopapular rash 
Pruritus 
Nails 
 
Dystrophy 
Longitudinal ridging, splitting or 
brittle features 
Onycholysis 
Pterygium unguis 
Nail loss (usually symmetric, affects 
most nails) 
 
 
Scalp and body hair 
 
New onset of scarring or nonscarring 
scalp alopecia (after recovery from 
chemoradiotherapy) 
Loss of body hair 
Scaling 
Thinning scalp hair, typically 
patchy, coarse or dull (not 
explained by endocrine or other 
causes) 
Premature gray hair 
 
Mouth  
Lichen planus-like changes 
Xerostomia 
Mucoceles 
Mucosal atrophy 
Ulcers 
Pseudomembranes 
 
Gingivitis 
Mucositis 
Erythema 
Pain 
Eyes 
 
New onset dry, gritty, or painful 
eyes 
Cicatricial conjunctivitis 
Keratoconjunctivitis sicca  
Confluent areas of punctate 
keratopathy 
Photophobia 
Periorbital hyperpigmentation 
Blepharitis (erythema of the 
eyelids with edema) 
 
Genitalia 
Lichen planus-like features 
Lichen sclerosus-like features 
Erosions 
Fissures 
 
 
Females 
Vaginal scarring or clitoral/labial 
agglutination 
Ulcers 
 
 
Males 
Phimosis or urethral/meatus 
scarring or stenosis 
 
 
 


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ORGAN OR SITE 
DIAGNOSTIC 
(Sufficient to establish the 
diagnosis of chronic GVHD) 
DISTINCTIVEa 
(Seen in chronic GVHD, but 
insufficient alone to establish a 
diagnosis) 
OTHER FEATURES OR 
UNCLASSIFIED ENTITIESb 
COMMONc 
(Seen with both acute and 
chronic GVHD) 
GI Tract 
Esophageal web 
Strictures or stenosis in the upper to 
mid third of the esophagus 
 
Exocrine pancreatic insufficiency
Anorexia 
Nausea 
Vomiting 
Diarrhea 
Weight loss 
Failure to thrive (infants 
and children) 
Liver 
 
 
 
Total bilirubin, alkaline 
phosphatase >2 x upper limit 
of normal 
ALT >2 x upper limit of 
normal 
Lung 
Bronchiolitis obliterans diagnosed 
with lung biopsy 
Bronchiolitis obliterans syndrome 
(BOS)d 
Air trapping and bronchiectasis on 
chest CT 
Cryptogenic organizing 
pneumonia (COP)e 
Restrictive lung diseasee 
 
Muscles, fascia, 
joints 
Fasciitis 
Joint stiffness or contractures 
secondary to fasciitis or sclerosis 
Myositis or polymyositisf
Edema 
Muscle cramps 
Arthralgia or arthritis 
 
Hematopoietic and 
Immune 
 
 
Thrombocytopenia 
Eosinophilia 
Lymphopenia 
Hypo- or hyper-
gammaglobulinemia 
Autoantibodies (AIHA, ITP) 
Raynaud’s phenomenon 
 
Other 
 
 
Pericardial or pleural effusions 
Ascites 
Peripheral neuropathy 
Nephrotic syndrome 
Myasthenia gravis 
Cardiac conduction abnormality 
or cardiomyopathy 
 
Abbreviations: ALT indicates alanine aminotransferase; AIHA, autoimmune hemolytic anemia; CT= computed tomography; GI= gastrointestinal; GVHD= graft versus 
host disease; ITP, idiopathic thrombocytopenic purpura. 
a  In all cases, infection, drug effect, malignancy, or other causes must be excluded. 


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ORGAN OR SITE 
DIAGNOSTIC 
(Sufficient to establish the 
diagnosis of chronic GVHD) 
DISTINCTIVEa 
(Seen in chronic GVHD, but 
insufficient alone to establish a 
diagnosis) 
OTHER FEATURES OR 
UNCLASSIFIED ENTITIESb 
COMMONc 
(Seen with both acute and 
chronic GVHD) 
b  Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed. 
c  Common refers to shared features by both acute and chronic GVHD. 
d  BOS can be diagnostic for lung chronic GVHD only if distinctive sign or symptom present in another organ. 
e  Pulmonary entities under investigation or unclassified. 
f  Diagnosis of chronic GVHD requires biopsy. 
Source: 
Jagasia MH, Greinix HT, Arora M, et al. Biol Blood Marrow Transplant.2015;21:389-401.23 
 


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Attachment 2: Karnofsky/Lansky Performance Status  
Karnofsky Scale (recipient age ≥16 years) 
Lansky Scale (recipient age <16 years) 
Able to carry on normal activity; no special care 
is needed 
Able to carry on normal activity; no special 
care is needed 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active 
90 
Able to carry on normal activity 
90 
Minor restriction in physically strenuous 
play 
80 
Normal activity with effort 
80 
Restricted in strenuous play, tires more 
easily, otherwise active 
Unable to work, able to live at home, cares for 
most personal needs, a varying amount of 
assistance is needed 
Mild to moderate restriction 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
70 
Both greater restrictions of, and less time 
spent in active play 
60 
Requires occasional assistance but is able to 
care for most needs 
60 
Ambulatory up to 50% of time, limited 
active play with assistance/supervision 
50 
Requires considerable assistance and 
frequent medical care 
50 
Considerable assistance required for any 
active play, fully able to engage in quiet 
play 
Unable to care for self, requires equivalent of 
institutional or hospital care, disease may be 
progressing rapidly 
Moderate to severe restriction 
40 
Disabled, requires special care and 
assistance 
40 
Able to initiate quiet activities 
30 
Severely disabled, hospitalization indicated, 
although death not imminent 
30 
Needs considerable assistance for quiet 
activity 
20 
Very sick, hospitalization necessary 
20 
Limited to very passive activity initiated 
by others (eg, TV) 
10 
Moribund, fatal process progressing rapidly
10 
Completely disabled, not even passive 
play 
 
 
 










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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
LUNGS 
 No symptoms 
 Mild 
symptoms 
(shortness of 
breath after 
climbing one 
flight of steps)
 Moderate 
symptoms 
(shortness of 
breath after 
walking on flat 
ground) 
 Severe symptoms 
(shortness of breath 
at rest; requiring 02)
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_______________________ 
JOINTS AND 
FASCIA 
 No symptoms 
 Mild tightness 
of arms or 
legs, normal or 
mild decreased 
range of 
motion (ROM) 
AND not 
affecting ADL
 Tightness of arms 
or legs OR joint 
contractures, 
erythema thought 
due to fasciitis, 
moderate decrease 
ROM AND mild 
to moderate 
limitation of ADL 
 Contractures WITH 
significant decrease 
of ROM AND 
significant 
limitation of ADL 
(unable to tie shoes, 
button shirts, dress 
self, etc.) 
 Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_______________________ 
Reference: 
Lee SJ, Wolff D, Kitko C, et al. Biol Blood Marrow Transplant. 2015;21:984-999.31 
 


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Attachment 5: Response Determination for Chronic GVHD Clinical Trials based on Clinician Assessments 
 
*Liver score 1 or more in Diagnosis and Staging Working Group Report by NIH cGVHD Consensus Development Project (2014) 23:  
Score 0: Normal total bilirubin and ALT or alkaline phosphatase <3 x ULN  
Score 1: Normal total bilirubin with ALT ≥3 to 5 x ULN or alkaline phosphatase ≥3 x ULN 
Score 2: Elevated total bilirubin but ≤3 mg/dL or ALT >5 ULN 
Score 3: Elevated total bilirubin >3 mg/dL 
* 


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Overall Response: 
Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall 
response.  
 Complete Response (CR) is defined as resolution of all manifestations in each organ or site. 
 Partial Response (PR) is defined as improvement in at least 1 organ or site without progression in any other organ or site. 
 cGVHD Progression is defined as clinically meaningful worsening in one or more organs regardless of improvement in other organs. 
Mixed Response: CR or PR in at least 1 organ accompanied by progression in another organ is considered cGVHD progression. 
 Stable disease (SD): response that do not meet the criteria for CR, PR, or cGVHD progression. 
If a patient shows overall cGVHD improvement while organ responses indicate progression in one or more organs, cGVHD assessment 
should be repeated at a different timepoint, to confirm progression, before discontinuing study drug.  If progression is confirmed, time to 
progression will be calculated using first date of cGVHD progression. Lack of Response includes categories of cGVHD progression or 
stable disease. 
Reference: 
Lee SJ, Wolff D, Kitko C, et al. Biol Blood Marrow Transplant. 2015;21:984-999.31 
Jagasia MH, Greinix HT, Arora M, et al. Biol Blood Marrow Transplant.2015;21:389-401.23 
 


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Attachment 6: Chronic GVHD Activity Assessment − Patient Self Report 
 
 
CHRONIC GVHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT 
 
Reference: 
Lee SJ, Wolff D, Kitko C, et al. Biol Blood Marrow Transplant. 2015;21:984-999. 31 
 
 
Symptoms 
 
 
 
Not                                                                                                                 As Bad As You 
Present                                                                                                            Can Imagine 
 
 
  0         1           2           3          4         5          6          7          8          9         10 
Please rate how severe the 
following symptoms have been in 
the last seven days. Please fill in 
the circle below from 0 (symptom 
has not been present) to 10 (the 
symptom was as bad as you can 
imagine it could be) for each item. 
Your skin itching at its WORST? 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Your skin and/or joint tightening at 
their WORST? 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Your mouth sensitivity at its 
WORST? 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Your genital discomfort at its 
WORST? 
(Women – vagina, vulva, or labia) 
(Men – penis) 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Eyes 
What is your main complaint with regard to your eyes? 
 
 
Please rate how severe this symptom is, from 0 (not 
at all severe) to 10 (most severe):
0    1     2    3    4    5     6    7    8    9    10
 
Patient Global Ratings: 
 
1. Overall, do you think that your chronic graft versus host disease is mild, moderate or severe? 
1= mild 
2=moderate 
3=severe 
 
2. Please circle the number indicating how severe your chronic graft versus host disease symptoms are, where 0 is cGvHD 
symptoms that are not at all severe and 10 is the most severe chronic GvHD symptoms possible. 
 
          0         1           2           3           4           5           6           7           8            9           10 
 
cGvHD symptoms                                                                                                        Most severe cGvHD                                                    
not at all severe                                                                                                             symptoms  possible 
 
3. Compared to a month ago, overall would you say that your cGvHD symptoms are: 
 
+3= Very much better 
+2= Moderately better 
+1=A little better 
 0= About the same 
-1=A little worse 
-2=Moderately worse 
-3=Very much worse 
FORM B 


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Attachment 7: Inhibitors and Inducers of CYP3A 
Inhibitors and inducers of CYP3A enzymes are defined as follows. Refer to Section 6.1 and 8.3.1 on 
instructions for concomitant use of CYP3A inhibitors and inducers with ibrutinib. Further information 
can be found at the following website: http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
 
Inhibitors of CYP3A 
Inducers of CYP3A 
Strong inhibitors: 
carbamaze 
indinavir 
nevirapine 
nelfinavir 
barbiturates 
ritonavir 
glucocorticoids 
Clarithromycina 
modafinil 
Itraconazoleb 
oxcarbazepine 
Ketoconazoleb 
pioglitazone 
nefazodone 
troglitazone 
saquinavir 
pioglitazone 
suboxone 
Strong CYP3A inducers
telithromycin 
avasimibe 
cobicistat 
carbamazepine 
boceprevir 
phenobarbital 
mibefradil 
phenytoin  
telaprevir 
rifabutine 
troleandomycin 
St. John’s Wort 
posaconazole 
 
voriconazole 
 
Moderate inhibitors: 
 
aprepitant 
 
amprenavir 
 
amiodarone 
 
atazanavir 
 
ciprofloxacin 
 
isavuconazole 
 
crizotinib 
 
darunavir 
 
dronedarone 
 
erythromycin 
 
diltiazem  
 
fluconazole 
 
fosamprenavir 
 
grapefruit juice 
 
Seville orange juice 
 
verapamil 
 
imatinib 
 
Weak inhibitors: 
 
cimetidine 
 
fluvoxamine 
 
All other inhibitors: 
 
chloramphenicol 
 
delavirdine 
 
gestodene 
 
mifepristone 
 
norfloxacin 
 
star fruit 
 
a. Avoid concomitant use of clarithromycin with ibrutinib 
b. Itraconazole and ketoconazole will be replaced with voriconazole for study subjects 
 
 


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Attachment 8: Child-Pugh Score  
 
Source: 
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia: Saunders. 1964. pp. 50-64.8 
Pugh RN, Murray-Lyon IM, Dawson L, et al. “Transection of the oesophagus for bleeding oesophageal varices”. 
The British Journal of Surgery, 1973;60: 646-9.43 
 
 


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Attachment 9: Summary of Ancillary Therapy and Supportive Care Interventions 
Organ System 
Organ-Specific Intervention* 
 
Prevention 
Treatment 
Skin and 
appendages 
Photoprotection -sun avoidance and physical 
sunblocks (eg, protective clothing, UVA, 
and UVB sunscreens). Avoidance of 
photosensitizing agents (eg, voriconazole). 
Surveillance for malignancy.20, 32 
For intact skin topical emollients including 
urea containing products, corticosteroids, 
antipruritic agents, and others (eg, PUVA or 
narrow band UVB, calcineurin inhibitors). 
 
For erosions/ulcerations e microbiologic 
cultures, topical antimicrobials, protective 
films or other dressings, debridement, 
hyperbaric oxygen, wound care specialist 
consultation. 
Mouth and oral 
cavity 
Maintain good oral/dental hygiene. Routine 
dental cleaning and radiographs. 
Surveillance for infection and malignancy. 
Nutritional counseling, if needed. 
Topical high and ultra-high potency 
corticosteroids and topical calcineurin 
inhibitors. Topical analgesics. Therapy for 
oral dryness (eg, salivary stimulants, 
sialogogues) and for prevention of related 
complications (ie, dental decay). 
Eyes 
Photoprotection. Surveillance for infection, 
cataract formation, and increased intraocular 
pressure. 
Artificial tears, ocular ointments, topical 
corticosteroids or cyclosporine, punctal 
occlusion, humidified environment, occlusive 
eye wear, moisture chamber eyeglasses, 
cevimeline, pilocarpine, gas-permeable scleral 
contact lens, autologous serum, microbiologic 
cultures, topical antimicrobials, doxycycline. 
Vulva and vagina 
Surveillance for estrogen deficiency, 
infection (HSV, HPV, yeast, bacteria) and 
malignancy.32 
Water-based or silicone lubricants, topical 
estrogens, topical corticosteroids or 
calcineurin inhibitors, dilators or vibrators, 
surgery for extensive synechiae or 
obliteration, early gynecology consultation. 
Avoid glycerin, paraben, fragrance, and other 
additive products. 
Gastrointestinal 
tract and liver 
Surveillance for infection (viral, bacterial, 
fungal, parasites) 
Rule out other potential etiologies. Dietary 
modification, enzyme supplementation for 
pancreatic insufficiency, bile salt resins, 
gastroesophageal reflux management, 
esophageal dilatation, ursodeoxycholic acid, 
topical glucocorticoids, limitation of ethanol 
intake, avoidance of hepatotoxins. 
Lungs 
Surveillance for infection (Pneumocystis 
jiroveci, viral, fungal, bacterial). 
Rule out other potential etiologies (eg, 
infection, gastroesophageal reflux). Inhaled 
corticosteroids, bronchodilators, 
supplementary oxygen, pulmonary 
rehabilitation. Consideration of lung 
transplantation in appropriate candidates. 
Hematopoietic 
Surveillance for infection (CMV, 
parvovirus) 
Rule out other potential etiologies (eg, drug 
toxicity, infection). Hematopoietic growth 
factors, immunoglobulin for immune 
cytopenias 
Neurologic 
Calcineurin drug level monitoring. Seizure 
prophylaxis as indicated, including blood 
pressure control, electrolyte replacement, 
anticonvulsants. EMG monitoring and 
staging in symptomatic patients taking 
medications known to cause neuropathy. 
Close monitoring of distal extremities for 
Occupational and physical therapy to prevent 
falls and improve function, treatment of 
neuropathic syndromes with tricyclic 
antidepressants, SSRI, or anticonvulsants.48 
Orthotics and assistive devices (canes and 
walkers). Bracing, splinting or surgical release 
for entrapment neuropathies. 


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Organ System 
Organ-Specific Intervention* 
 
Prevention 
Treatment 
wounds in insensate patients. 
Immunologic and 
infectious diseases 
Immunizations and prophylaxis against 
Pneumocystis jirovecii, VZV, and 
encapsulated bacteria based on CDC 
guidelines. Consider immunoglobulin 
replacement based on levels and recurrent 
infections. Surveillance for infection (viral, 
bacterial, fungal, atypical). 
Organism-specific antimicrobial agents. 
Empiric parenteral broad-spectrum 
antibacterial coverage for fever. 
Musculoskeletal 
Surveillance for decreased ROM, bone 
densitometry, calcium levels and 25-OH 
vitamin D. Physical therapy, calcium, 
vitamin D, and bisphosphonates. Flexion-
extension x-rays to look for instability. 
Physical therapy, bisphosphonates for 
osteopenia, and osteoporosis. Spinal orthosis 
for instability and/or intractable pain. Walking 
program, resistance training, core 
strengthening. 
SSRI indicates selective serotonin reuptake inhibitors; CDC, Centers for Disease Control; UVA, ultraviolet-A; 
UVB, ultraviolet-B, PUVA, psoralen ultraviolet A; HSV, herpes simplex virus; HPV, human papilloma virus; CMV, 
cytomegalovirus; EMG, electromyography; VZV, varicella zoster virus; ROM, range of motion.  
*In general, close serial monitoring of all organ systems is recommended to promote early detection and 
intervention directed toward reversing or preventing progression of chronic GVHD manifestations and treatment-
associated toxicities. Ancillary and supportive care therapies are commonly employed in addition to systemic 
GVHD treatment, although in some cases their use may circumvent the need for systemic treatment or allow doses 
of systemic agents to be reduced. 
 
References: 
Carpenter PA, Kitko CL, Elad S. National Institutes of Health Consensus Development Project on Criteria for 
Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care 
Working Group Report. Biol Blood Marrow Transplant. 2015;21:1167-87.7 
Inamoto Y, Savani BN, Shaw BE, et al. Secondary solid cancer screening following hematopoietic cell 
transplantation. Bone Marrow Transplant. 2015;50:1013-1023.20 
Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for long-term survivors after 
hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:348-71.32 
Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients 
with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309:1359-
67.48 
 
 


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INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date:
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
 
Institution: 
Janssen Pharmaceutical K.K 
Signature: 
electronic signature appended at the end of the protocol 
Date:
 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 
PPD


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24Jul2018, 11:35:28 AM, UTC
Document Approval
PPD


CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
1 
Status: Approved,  Date: 14 May 2020 
Janssen Pharmaceutical K.K.* 
Clinical Protocol 
COVID-19 Appendix 
Protocol Title 
A Phase 3 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Subjects 
with Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD) 
Protocol 54179060GVH3001; Phase 3 
 JNJ-54179060 (Ibrutinib)  
* This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K.
Status: 
Approved 
Date: 
14 May 2020 
Prepared by: Janssen Pharmaceutical K.K. 
EDMS number: 
EDMS-RIM-61817, 1.0 
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL 
GCP Compliance:  This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements.  
Confidentiality Statement 
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise. 
NCT03474679


COVID-19 Appendix  
 
JNJ-54179060  (Ibrutinib)  
Clinical Protocol 54179060GVH3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
2 
Status: Approved,  Date: 14 May 2020 
COVID-19 APPENDIX 
GENERAL GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC 
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.  
In alignment with recent health authority guidance, the sponsor is providing options for 
study-related subject management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government requirements or the clinical judgement of 
the investigator to protect the health and well-being of subjects and site staff. If at any time the 
investigator assesses that the risk of treatment may outweigh the benefits, study treatment will be 
interrupted, and study follow-up will be conducted. 
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Subjects will also be questioned regarding general 
health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for subjects on study 
treatment, including follow up. Modifications to protocol-required assessments may be permitted 
after consultation between the subject and investigator, and with the agreement of the sponsor. 
Missed assessments/visits will be captured in the clinical trial management system for protocol 
deviations. Discontinuations of study treatment and withdrawal from the study should be 
documented with the prefix “COVID-19-related” in the Comments electronic case report form 
(eCRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
Modifications made to the study conduct as a result of the COVID-19 pandemic should be 
summarized in the clinical study report. 
 
 


COVID-19 Appendix  
 
JNJ-54179060  (Ibrutinib)  
Clinical Protocol 54179060GVH3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
3 
Status: Approved,  Date: 14 May 2020 
GUIDANCE SPECIFIC TO THIS PROTOCOL: 
Subject Visits and Assessments 
 
For subjects who are unable to come to the site for Response Follow-up Visits, the visit should 
be postponed and rescheduled as soon as possible.  
 
For subjects who are unable to come to the site for Treatment Phase Visits, contact (eg, 
telephone, videoconference, or other channels) with the subject should be made in advance, 
to collect information on the subject’s current health status and any new or ongoing adverse 
events and concomitant medications. The remote method that is used for contact with the 
subject must be allowable per local regulations and fully documented in the subject source 
record. Protocol-specified laboratory assessments and physical examinations should be 
obtained locally, if possible. Where local laboratories are used, it is important to ensure 
appropriate documentation of laboratory reference ranges. After reviewing all available 
information, and if the investigator assesses that continued treatment is acceptable, contact the 
site manager to discuss alternative solutions for the provision of study treatment to subjects 
(see alternatives below). The remote contact with the subject, the local laboratory results, and 
the sponsor discussion should be documented in the subject source record. Similarly, at a 
minimum, a comment must be entered in the Comments eCRF clearly designating as 
“COVID-19-related” and acknowledging the discussion between the investigator and the 
sponsor. 
 
If the subject is not willing or able to go to a local clinic/laboratory, remote contact 
(eg, telephone, videoconference, or other channels) with the subject is recommended, as well 
as a thorough review of the subject’s medical history, prior labs, and most recent disease 
evaluation. The remote method chosen must be allowable per local regulations and fully 
documented in the subject source record. If appropriate, treatment should be interrupted until 
new laboratory assessments are made. However, if the investigator assesses that continued 
treatment is acceptable despite the absence of new laboratory tests, contact the site manager 
to discuss alternative solutions for the provision of study medication to subjects (see possible 
alternatives below). Proper documentation of all discussions and decisions should be made in 
the subject source record and in the Comments eCRF. 
 
If any change in subject status is identified that may impact the subject’s safety, then study 
treatment should be interrupted until the subject can be assessed. Any changes in study 
treatment (dose, frequency, 
interruption) needs to be clearly documented as 
“COVID-19-related”. When pandemic conditions improve, travel restrictions are lifted, and 
the subject is willing and able to come to the clinic, subjects should be scheduled for an 
in-clinic, follow-up visit. 
 
All deviations from protocol-required assessments should be documented in detail within the 
subject’s source record and should be clearly designated as “COVID-19-related”. It must be 
documented if a visit is conducted remotely. Source documentation should detail how each 
assessment was collected (eg, remote vs. on-site, central vs. local laboratory, vital signs taken 
at home by caretaker vs. delegated in-home nursing). 


COVID-19 Appendix  
 
JNJ-54179060  (Ibrutinib)  
Clinical Protocol 54179060GVH3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
4 
Status: Approved,  Date: 14 May 2020 
Study Drug Supply 
If a subject is unable to travel to the site for a scheduled visit where study drug would be dispensed, 
the following alternate measures should be discussed with the study monitor and may be 
considered to ensure continuity of treatment, upon sponsor’s approval: 
 
A caregiver or family member may pick up study drug on behalf of the subject if first 
discussed and agreed by the subject. The conversation with the subject must be documented 
in the subject source records. The subject must name the individual who will pick up study 
drug on their behalf. This is necessary for site staff to confirm the study drug is provided to 
the appropriate individual, ensure proper chain of custody of study drug, and to maintain 
subject privacy. Identification of who will pick up the study drug must be confirmed and 
documented in the subject source record. 
 
Investigative site staff may deliver study drug directly to the subject’s home. The chain of 
custody and transit conditions must be clearly documented within the subject source record. 
 
If no other alternative is feasible, direct-to-patient shipment of study drug from the site may 
be considered with prior approval from the sponsor. Site staff need to obtain permission from 
the subject and record this in the subject source record for direct-to-patient shipments. It is 
important to note this process must be allowed by the local health authority and a specific 
approval process must be followed with the sponsor before moving forward. If requested by 
the site, the sponsor will investigate local requirements and confirm health authority 
requirements for direct-to-patient shipment. If approval is granted by the sponsor, specific 
procedures including shipment conditions, preferred courier services, and documentation 
requirements will be communicated by the sponsor to the site.  
 
If a subject is able to come to the site for a Treatment Phase Visit but anticipates being unable to 
come to the next visit, the investigator may dispense study treatment for the current visit and an 
additional visit, after agreement with the sponsor’s medical monitor. Prior to continuing treatment 
with the additional study treatment, the subject should obtain protocol-specified laboratory 
assessments and physical examinations locally, if possible, and the investigator should conduct a 
remote contact as described above. After reviewing all available information, if the investigator 
assesses that continued treatment is acceptable, the subject may continue treatment using the 
previously supplied additional study treatment. Proper documentation of all discussions and 
decisions should be made in the subject source record and in the Comments eCRF. 
For subjects who have reason to believe they have been exposed to COVID-19 but do not 
yet have a confirmed diagnosis and/or are not showing symptoms of infection: 
 
The investigator should consider the risk/benefit of continuing ibrutinib based on the 
individual subject’s underlying condition and the potential risks associated with COVID-19. 
 
If the subject becomes symptomatic at any point, refer to guidance below for subjects with 
symptomatic COVID-19 infection. 


COVID-19 Appendix  
 
JNJ-54179060  (Ibrutinib)  
Clinical Protocol 54179060GVH3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
5 
Status: Approved,  Date: 14 May 2020 
For subjects who have been diagnosed with COVID-19: 
 
The investigator should contact the sponsor’s responsible medical officer to discuss plans for 
study treatment and follow-up. 
 
The investigator should consider the risk/benefit of continuing ibrutinib based on the nature 
and status of the subject’s underlying condition and the potential risks associated with 
COVID-19. 
 
As with all infections, the investigator should follow the protocol guidance which is to 
interrupt therapy for Grade 4 or unmanageable Grade 3 toxicity (see Section 6.1.1), and 
resume once infection has resolved to Grade 1 or baseline (recovery). Given that severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new pathogen, a more cautious 
approach would be appropriate, with interruption for confirmed cases of SARS-CoV-2 
infection of any grade. 
On-site Monitoring Visits 
In case on-site monitoring visits are not possible, as per institution policies, the sponsor’s site 
managers may contact the investigator to arrange remote monitoring visits. Additional on-site 
monitoring visits may be needed in the future to catch up on source data verification. 
 
All of the above measures are recommended for consideration on a temporary basis during the 
COVID-19 pandemic to enable continuity of treatment and to ensure that subject assessments, 
particularly those assessing disease progression and safety, continue as outlined in the protocol 
without imposing health risk to subjects, their families, and site staff. Every effort should be made 
to complete all protocol-required assessments. Investigators should use their clinical judgment and 
risk/benefit assessment in determining if a subject can continue study treatment in the absence of 
on-site clinic visits. If remote visits are not possible, or if in the investigator’s judgment, 
appropriate safety monitoring is not feasible in a remote setting, the investigator should consider 
temporarily interrupting study treatment (for a maximum of 28 consecutive days, unless reviewed 
and approved by the sponsor) or discontinuing study treatment. 
 
 
 


COVID-19 Appendix  
 
JNJ-54179060  (Ibrutinib)  
Clinical Protocol 54179060GVH3001  
 
CONFIDENTIAL – FOIA Exemptions Apply in U.S. 
6 
Status: Approved,  Date: 14 May 2020 
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study intervention, the conduct of the study, and the obligations 
of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Sponsor's Responsible Medical Officer: 
 
Name (typed or printed): 
 
Institution: 
Janssen Pharmaceutical K.K. 
Signature: 
electronic signature appended at the end of the protocol 
Date: 
 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
PPD


Signature
User
Date
Reason
14-May-2020
12:01:18
(GMT)
Document Approval
PPD

SAP_001.pdf: 
1 
Approved, Date: 13 January 2022 
Janssen Pharmaceutical K.K.* 
Statistical Analysis Plan 
A Phase 3 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Subjects 
with Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD) 
Protocol 54179060GVH3001; Phase 3 
JNJ-54179060  (Ibrutinib) 
* This study is being conducted by Janssen Pharmaceutical K.K. in Japan. The term “sponsor” is used
throughout the protocol to represent Janssen Pharmaceutical K.K.
Status: 
Approved 
Date: 
13 January 2022 
Prepared by: 
Janssen Pharmaceutical K.K. 
Document No.: EDMS-ERI-158541154 
Compliance:  The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential. 
NCT03474679


JNJ-54179060  (Ibrutinib) 
Statistical Analysis Plan 54179060GVH3001  
2 
Approved, Date: 13 January 2022 
TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................................... 2 
AMENDMENT HISTORY......................................................................................................................... 4 
ABBREVIATIONS ................................................................................................................................... 5 
1.
INTRODUCTION ............................................................................................................................ 6 
1.1. 
Trial Objectives ........................................................................................................................... 6 
1.2. 
Trial Design................................................................................................................................. 6 
1.3. 
Statistical Hypotheses for Trial Objectives ................................................................................... 7 
1.4. 
Sample Size Justification ............................................................................................................ 7 
1.5. 
Randomization and Blinding ........................................................................................................ 7 
2.
GENERAL ANALYSIS DEFINITIONS ............................................................................................ 7 
2.1. 
Visit Windows ............................................................................................................................. 7 
2.2. 
Pooling Algorithm for Analysis Centers ........................................................................................ 7 
2.3. 
Analysis Sets .............................................................................................................................. 7 
2.3.1. 
All Treated Analysis Set ........................................................................................................... 7 
2.3.2. 
Response Evaluable Analysis Set ............................................................................................ 8 
2.3.3. 
Safety Analysis Set .................................................................................................................. 8 
2.3.4. 
Pharmacokinetics Evaluable Analysis Set ................................................................................ 8 
2.3.5. 
Pharmacodynamics Evaluable Analysis Set ............................................................................. 8 
2.4. 
Study Day and Relative Day ........................................................................................................ 8 
2.5. 
Baseline ...................................................................................................................................... 8 
2.6. 
Treatment Duration ..................................................................................................................... 8 
2.7. 
Time on Study ............................................................................................................................. 8 
2.8. 
Dose Intensity ............................................................................................................................. 9 
2.9. 
Relative Dose Intensity................................................................................................................ 9 
2.10. 
Imputation Rules for Missing Dates ............................................................................................. 9 
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW ..................................... 10 
4.
SUBJECT INFORMATION ........................................................................................................... 11 
4.1. 
Demographics and Baseline Characteristics .............................................................................. 11 
4.2. 
Disposition Information .............................................................................................................. 11 
4.3. 
Extent of Exposure .................................................................................................................... 12 
4.4. 
Protocol Deviations ................................................................................................................... 12 
4.5. 
Medical History ......................................................................................................................... 12 
4.6. 
Prior and Concomitant Medications ........................................................................................... 13 
5.
EFFICACY ................................................................................................................................... 13 
5.1. 
Analysis Specifications .............................................................................................................. 13 
5.1.1. 
Level of Significance .............................................................................................................. 13 
5.1.2. 
Data Handling Rules .............................................................................................................. 13 
5.2. 
Primary Efficacy Endpoint(s) ..................................................................................................... 13 
5.2.1. 
Definition ............................................................................................................................... 13 
5.2.2. 
Analysis Methods ................................................................................................................... 13 
5.3. 
Major Secondary Endpoints ...................................................................................................... 14 
5.3.1. 
Definition ............................................................................................................................... 14 
5.3.2. 
Analysis Methods ................................................................................................................... 15 
5.4. 
Other Efficacy Variable(s) ......................................................................................................... 16 
5.4.1. 
Definition ............................................................................................................................... 16 
5.4.2. 
Analysis Methods ................................................................................................................... 17 
6.
SAFETY ....................................................................................................................................... 17 
6.1. 
Adverse Events ......................................................................................................................... 17 


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Approved, Date: 13 January 2022  
6.1.1. 
AEs of special interest (AESI) ................................................................................................ 18 
6.2. 
Death ........................................................................................................................................ 19 
6.3. 
Clinical Laboratory Tests ........................................................................................................... 19 
6.4. 
Vital Signs and Physical Examination Findings .......................................................................... 20 
6.5. 
Death ........................................................................................................................................ 20 
6.6. 
Other Safety Parameters ........................................................................................................... 20 
7. 
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................ 20 
7.1. 
Pharmacokinetics ...................................................................................................................... 20 
7.2. 
Pharmacodynamics................................................................................................................... 21 
REFERENCES ...................................................................................................................................... 22 
ATTACHMENTS ................................................................................................................................... 23 
ATTACHMENT 1: PLANNED LISTINGS ............................................................................................... 23 
 
 
 
 


JNJ-54179060  (Ibrutinib)  
 
 
 
Statistical Analysis Plan 54179060GVH3001  
4 
Approved, Date: 13 January 2022  
AMENDMENT HISTORY 
SAP Version 
Issue Date 
Original SAP 
15 March 2018 
Amendment 1 
25 February 2020 
Amendment 2 
13 January 2022 
 
Amendment 2 (13 January 2022) 
The overall reason for the amendment: to update and clarify the details. 
 
Applicable Section(s) 
Description of Change (s) 
Section 4.4 
Added ‘COVID-19 related protocol deviations will be provided in a separate listing’. 
Section 6.1.1 
Updated the definition of Cardiac arrhythmia as ‘Cardiac arrhythmia will be 
determined based on Cardiac arrhythmias (SMQ, broad and narrow) and Ventricular 
tachyarrhythmias (SMQ, narrow).’. 
Section 6.1.1 
Updated the definition of CNS hemorrhage to remove manual medical review. 
Section 6.1.1 
Added ischemic stroke and cardiac failure for AE of special interest. 
 
 
Amendment 1 (25 February 2020) 
The overall reason for the amendment: to update and clarify the details. 
 
Applicable Section(s) 
Description of Change (s) 
Section 2.9 
Added ‘Assigned daily dose is 420 mg, unless dose is modified due to the use of 
CYP3A inhibitor or study drug discontinuation’. 
Section 4.1 
Added ‘Daily Steroid Dose per Weight at baseline (mg/kg/day)’ to baseline disease 
characteristics information. 
Section 4.3 
Added ‘Time on study’. 
Section 4.5 
Added ‘Medical history collected at baseline or screening visit will be summarized 
by system-organ class and preferred term for all treated analysis set’. 
Section 4.6 
Change from ‘the day of ICF (partial or complete) of study agent’ to ‘the first dose 
of the study agent’. 
Added ‘Concomitant use of additional immunosuppressants will be summarized and 
listed’. 
Section 6.1 
Updated planned tables. 
Section 6.1.1 
Added AEs of special interest, ‘Other Malignancies’, ‘Hypersensitivity’ and ‘CNS 
Hemorrhage’. 
Section 6.2 
Added subjects who died during the study. 
Section 6.5 
Added subjects who died in the study. 
Section 7.1 
Added Subgroup analysis by concomitant CYP3A inhibitors. 
 


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Statistical Analysis Plan 54179060GVH3001  
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ABBREVIATIONS 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase 
AST/SGOT 
aspartate aminotransferase 
BTK 
Bruton’s Tyrosine Kinase 
BUN 
blood urea nitrogen 
cGVHD 
Chronic Graft Versus Host Disease 
CI 
confidence interval 
Cmax 
maximum concentration 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DOR 
duration of response 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FEV1 
forced expiratory volume in 1 second 
FFS 
failure free survival 
LDH 
lactic acid dehydrogenase 
ILD 
interstitial lung disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
OS 
Overall survival 
PD 
pharmacodynamic 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
SMQs 
standardised MedDRA queries 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
WBC 
white blood cell 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


JNJ-54179060  (Ibrutinib)  
 
 
 
Statistical Analysis Plan 54179060GVH3001  
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Approved, Date: 13 January 2022  
1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) covers Primary Analysis and Final Analysis. It contains 
definitions of analysis sets, derived variables and statistical methods for analyses of efficacy, 
safety, pharmacokinetic (PK) and pharmacodynamics (PD) data of study 54179060GVH3001. 
1.1. 
Trial Objectives 
Primary objective: 
Evaluate efficacy of ibrutinib in Japanese subjects with steroid dependent/refractory cGVHD by 
measuring overall cGVHD response (Complete Response [CR] and partial response [PR] defined 
by NIH Consensus Development Project Criteria [2014]). 
 Secondary objectives: 
 
Evaluate efficacy of ibrutinib in Japanese subjects with steroid dependent/refractory 
cGVHD by measuring: 
 
Rate of sustained response for at least 20 weeks 
 
Duration of response (DOR) 
 
cGVHD response rate at each timepoint of efficacy evaluation 
 
Corticosteroid requirement changes over time 
 
Change in symptom burden measured by the Lee cGVHD Symptom Scale 
 
Evaluate the safety of ibrutinib in Japanese subjects with steroid dependent/refractory 
cGVHD 
 
Evaluate the pharmacokinetics (PK) of ibrutinib in Japanese subjects with cGVHD 
Exploratory objectives: 
 
Evaluate efficacy of ibrutinib by measuring: 
 
Failure free survival (FFS)  
 
Overall survival (OS) 
 
Number and proportion of subjects with all immunosuppressants withdrawn 
 
Evaluate the BTK and ITK binding site occupancy as a pharmacodynamic (PD) parameters 
1.2. 
Trial Design 
This is an open-label, single arm, multicenter Phase 3 study to evaluate the efficacy, safety, and 
PK of single-agent ibrutinib 420 mg in Japanese subjects 12 years of age or older with steroid 
dependent/refractory cGVHD. Approximately 20 subjects will be enrolled to have 17 response 
evaluable subjects. At least 1 adolescent subject (12-17 years of age) will be enrolled in this 
study. 


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Statistical Analysis Plan 54179060GVH3001  
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Subject participation will include a Screening Phase, a Treatment Phase, and a Posttreatment 
Follow-up Phase. The Screening Phase assessments will be performed within 42 days prior to 
study treatment initiation. The Treatment Phase will extend from first dose of study treatment 
until treatment discontinuation. During the Treatment Phase, efficacy and safety evaluations, 
sampling of PK and PD will be performed. The Posttreatment Follow-up Phase will begin once a 
subject discontinues ibrutinib treatment. Subjects who discontinue treatment for reasons other 
than cGVHD progression will complete an End-of-treatment Visit and will be followed for the 
cGVHD evaluations until cGVHD progression, death, loss to follow-up, consent withdrawal, or 
study end, whichever occurs first. Subjects who discontinue due to cGVHD progression will 
complete an End-of-treatment Visit and be followed for survival status and the use of subsequent 
cGVHD treatment. 
1.3. 
Statistical Hypotheses for Trial Objectives 
The primary hypothesis of this study is that ibrutinib is an effective agent as measured by an 
overall cGVHD response rate (the lower bound of 95% confidence interval is greater than 25%) 
in Japanese subjects with steroid dependent/refractory cGVHD. 
1.4. 
Sample Size Justification 
With a sample size of 17 subjects and assuming an expected overall cGVHD response rate of 
approximately 60%, it is expected to have at least 80% power to show the efficacious treatment 
effect (the lower bound of 95% confidence interval of the response rate >25%). At least 1 
adolescent subject (12-17 years of age) will be enrolled in this study. 
1.5. 
Randomization and Blinding 
This is an open label study, so no randomization and blinding will occur. 
2. 
GENERAL ANALYSIS DEFINITIONS 
2.1. 
Visit Windows 
For visitwise analysis, CRF-recorded visits will be followed. 
The visit windows are described in “Time and Events Schedule” of the protocol. For visitwise 
evaluation of pharmacokinetics and pharmacodynamics data of ibrutinib, allowance described in 
“Time and Events Schedule” will be applied to actual time of CRF-recorded time point. 
2.2. 
Pooling Algorithm for Analysis Centers 
No pooling of analysis centers will be performed in this study. 
2.3. 
Analysis Sets 
2.3.1. 
All Treated Analysis Set 
The all treated analysis set includes all enrolled subjects who received at least 1 dose of study 
drug. 


JNJ-54179060  (Ibrutinib)  
 
 
 
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Approved, Date: 13 January 2022  
2.3.2. 
Response Evaluable Analysis Set 
All enrolled subjects who will receive at least 1 dose of study drug and who have at least 1 
adequate postbaseline efficacy assessment. 
2.3.3. 
Safety Analysis Set 
The safety analysis set includes all enrolled subjects who received at least 1 dose of study drug. 
Safety analysis set is identical to all treated analysis set. 
2.3.4. 
Pharmacokinetics Evaluable Analysis Set 
The PK evaluable analysis set is defined as all enrolled subjects who have received at least one 
dose of study drug and have at least 1 postdose PK sample obtained. 
2.3.5. 
Pharmacodynamics Evaluable Analysis Set 
The PD evaluable analysis set is defined as all enrolled subjects who have received at least one 
dose of study drug and have at least 1 BTK and ITK binding site occupancy data. 
2.4. 
Study Day and Relative Day 
Study Day 1 or Day 1 refers to the start of the first study drug administration. All efficacy and 
safety assessments at all visits will be assigned a day relative to this date. 
Study day or relative day for a visit is defined as: 
 
Visit date - (date of Study Day 1) +1, if visit date is ≥date of Study Day 1 
 
Visit date - Date of Day 1, if visit date <date of Study Day 1 
There is no 'Day 0'. 
2.5. 
Baseline 
Baseline is defined as the last observation on or prior to the first study drug administration. 
2.6. 
Treatment Duration 
Treatment duration will be calculated from the date of the first dose of study drug to the date of 
the last dose of study drug, as follows:  
Treatment Duration = date of last dose of study drug – date of first dose of study drug +1 day. 
2.7. 
Time on Study 
Time on Study will be calculated from the first study drug administration date to the study exit 
date or the last known alive date if the subjects are still in the study, as follows:  
Time on Study = study exit date/last known alive date – first study drug administration date 
+1 day. 


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Statistical Analysis Plan 54179060GVH3001  
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2.8. 
Dose Intensity 
The dose intensity (mg/day) of study agent is calculated as (sum of total daily dose during the 
treatment phase)/study agent duration. 
2.9. 
Relative Dose Intensity 
Relative dose intensity (%) is defined as the percentage of total cumulative dose administered 
(mg) versus the total expected dose (mg). Total cumulative dose administered is the sum of daily 
dose taken over the whole study course; and total expected dose (mg) is the product of the 
duration of the treatment (day) and the assigned daily dose. Assigned daily dose is 420 mg, 
unless dose is modified due to the use of CYP3A inhibitor or study drug discontinuation. 
Relative dose intensity is calculated by total cumulative dose administered / total expected dose 
×100%. 
2.10. 
Imputation Rules for Missing Dates 
In general, imputation of missing dates will be made for AE onset date, AE resolution date, date 
of death, start and end dates of prior and concomitant and subsequent therapies, transplantation 
date, and date of initial diagnosis according to the following rules. 
 
If the date is completely missing, no imputation will be made. 
 
If the year is missing, then no imputation will be made. 
 
If only the year is present but the month and day are missing, then June 30th will be used. 
 
If only the day is missing but the year and month are available, then the 15th of the month 
will be used. 
In addition, for date of initial diagnosis, the imputed date will be adjusted sequentially using the 
following steps: 
 
If only the day is missing; 
 
if month and year of start of 1st line of prior therapy are the same year and month of 
diagnosis, and day of start date of 1st line of prior therapy is available, then the day of 
start date of 1st line of prior therapy will be used. 
 
otherwise, the 15th of the month will be used. 
 
If both month and day are missing; 
 
if year of diagnosis is the same as year of start of 1st line of prior therapy, and month 
info is available for start date of the 1st line of prior therapy, the month of start date of 
1st line of prior therapy will be used. 
o 
if day of start date of 1st line of prior therapy is available, then the day of start date 
of 1st line of prior therapy will be used. 
o 
otherwise, the 15th of the month will be used. 
 
otherwise, June 30th will be used. 


JNJ-54179060  (Ibrutinib)  
 
 
 
Statistical Analysis Plan 54179060GVH3001  
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 
If the imputed date for initial diagnosis is on or after the first dose date, then first 
dose date -1 day will be used.  
In addition, for date of prior and subsequent therapies, the imputed date will be adjusted 
sequentially using the following steps: 
 
If such imputed date for prior therapies is on or after the first dose date, then first 
dose date -1 day will be used. 
 
If such imputed date for subsequent therapies is before date of last dose, then date of last 
dose +1 day will be used. 
 
If prior or subsequent therapy start date is not missing and is after the imputed end date, then 
the start date will be used as the end date. 
 
If prior or subsequent therapy end date is not missing and is before the imputed start date, 
then the end date will be used as the start date.  
In addition, for AE date, the above imputations will be modified by the following rules: 
 
The imputed start date of adverse event will be adjusted sequentially using the following 
steps: 
 
If the imputed date is in the same year and month but before the first dose date, then the 
first dose date will be used, or if it is in the same year and month but after the last dose 
date +30 days, then the last dose date +30 days will be used. 
 
If end date of adverse event is not missing and the imputed start date of adverse event is 
after the end date of adverse event, then the end date of adverse event will be used. 
 
If the imputed start date of adverse event is after date of death, then the date of death 
will be used. 
 
If the imputed start date of adverse event is in the same month and year but after the 
start date of 1st subsequent therapy, then the start date of 1st subsequent therapy will be 
used. 
 
The imputed end date of adverse event will be adjusted sequentially using the following 
steps: 
 
If the imputed end date of adverse event is after the death date, then the death date will 
be used. 
 
If the imputed end date of adverse event is before the start date of adverse event, then 
the start date of adverse event will be used. 
In addition, for start and end dates of concomitant therapy, the adverse event imputation rule will 
be used for concomitant therapy. 
3. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW 
No interim analysis will be conducted in this study. 


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4. 
SUBJECT INFORMATION 
4.1. 
Demographics and Baseline Characteristics 
List of the demographic and baseline characteristics, presented in Table 1, will be summarized 
for the all treated analysis set. 
Table 1: Demographic and Baseline Characteristics Variables 
Continuous Variables: 
Summary Type 
Age (years) 
Descriptive statistics (N, mean, 
standard deviation [SD], median and 
range [minimum and maximum]. 
Weight (kg) 
Height (cm) 
Baseline hemoglobin (g/L) 
Baseline platelets (10^9/L) 
Baseline Absolute neutrophil count (10^9/L) 
Baseline Bilirubin 
Categorical Variables 
 
Sex (male, female, unknown,undifferentiated) 
Frequency distribution with the 
number and percentage of subjects 
in each category. 
Race (Asian) 
Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 
Following baseline disease characteristics information will be summarized for all treated 
subjects: 
 
cGVHD Disease State (Steroid Dependent, Steroid Refractory) 
 
Overall Severity of cGVHD (1, 2, 3, NA) 
 
Months from Last Transplantation to Enrollment, which is defined as the time period 
between the last transplantation and enrollment  
 
Months from Initial cGVHD Diagnosis Date, which is defined as the time period between 
the initial cGVHD diagnosis and enrollment 
 
Months from Transplantation to initial cGVHD diagnosis date 
 
Karnofsky performance status score at baseline 
 
Lansky performance status score at baseline 
 
Number of prior cGVHD treatment regimens 
 
Organs involved in cGVHD 
 
Daily Steroid Dose per Weight at baseline (mg/kg/day) 
4.2. 
Disposition Information 
The number of subjects in the following disposition categories will be summarized throughout 
the study using all treated analysis set: 
 
Subjects screening 
 
Subjects receiving study agent 
 
Subjects ongoing treatment 


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 
Subjects completing the study 
 
Subjects who discontinued study agent 
 
Reasons for discontinuation of study agent 
 
Subjects who terminated study prematurely 
 
Reasons for termination of study 
 
Analysis Sets 
Listings of subjects will be provided for the following categories: 
 
Subjects who discontinued study agent 
 
Subjects who terminated study prematurely 
4.3. 
Extent of Exposure 
Descriptive statistics (N, mean, SD, median, and range (minimum, maximum)) will be presented 
for the following parameters: 
 
Treatment duration 
 
Cumulative total dose 
 
Dose intensity 
 
Relative dose intensity 
 
Time on Study 
Dose withholding (any dose skip with 7 days or more) and dose reduction will be summarized 
for the number of subjects with any dose withholding (at least one reported dose withholding), 
any dose reduction (at least one reported dose reduction), and any dose modification (at least one 
dose withholding or dose reduction), as well as the frequency and reason of dose withholding 
and dose reduction. 
4.4. 
Protocol Deviations 
In general, protocol violations/deviations will be reviewed by the study team during the study, 
and important protocol deviations will be determined based on the review. The information of 
important protocol deviations will be generated based on the review outcome for all subjects. 
Important protocol deviations will be summarized by center. A corresponding listing is also 
generated. COVID-19 related protocol deviations will be provided in a separate listing. 
4.5. 
Medical History 
Medical history collected at baseline or screening visit will be summarized by system-organ 
class and preferred term for all treated analysis set. Transplant history and underlying disease will 
be summarized and listed. 


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4.6. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). Prior medications are defined as any therapy used before the first dose of the study 
agent. Concomitant medications are defined as any therapy used on or after the same day as the 
first dose of study agent, including those that started before and continue on after the first dose of 
study agent. 
Summaries of concomitant medications will be presented by therapeutic class and preferred term. 
In addition, summary of usage of CYP3A inhibitors as well CYP3A inducers will be provided 
separately. A list of common CYP3A inhibitors and inducers is provided in Attachment 1. The 
summary of usage of anticoagulants and antiplatelets will also be provided. 
Prior and subsequent cGVHD therapies after the start of study drug will be summarized and 
listed separately. Concomitant use of additional immunosuppressants will be summarized and 
listed. 
5. 
EFFICACY 
5.1. 
Analysis Specifications 
5.1.1. 
Level of Significance 
All tests will be 1-sided. The primary efficacy endpoint will be tested at the overall significance 
level of 0.025. For result presentation purpose, a 2-sided 95% confidence interval will be used. 
5.1.2. 
Data Handling Rules 
Unless specified otherwise, missing values will not be imputed and partial dates are described in 
Section 2.10. 
5.2. 
Primary Efficacy Endpoint(s) 
The overall response rate (ie, the proportion of responders [CR or PR]). 
5.2.1. 
Definition 
Response will be defined by the NIH Consensus Development Project Criteria (2014) and must 
occur: 
 
In the absence of new therapy for cGVHD 
 
In the absence of progression of the underlying disease that was the indication for transplant 
(or posttransplant lymphoproliferative disease [PTLD]), or death. 
5.2.2. 
Analysis Methods 
The all treated analysis set will be used for primary endpoint. The response evaluable analysis set 
will be used for sensitivity analysis. 


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The primary analysis for primary endpoint will be conducted at the time when the last subject 
has completed the efficacy assessment at Week 37 or has discontinued treatment before Week 37. 
Final analysis will be conducted at the study end. 
The overall cGVHD response rate (CR + PR) and its 95% confidence interval will be calculated 
with the exact test for binomial distribution in the all treated population. The study is considered 
to be positive if the lower limit of the exact 2-sided 95% confidence interval based on binominal 
distribution exceeds the threshold value (0.25). 
5.3. 
Major Secondary Endpoints 
The secondary efficacy endpoints are: 
 
Rate of sustained response for at least 20 weeks  
 
Duration of response 
 
cGVHD response rate at each timepoint 
 
Corticosteroid requirement changes over time 
 
Change in symptom burden measured by the Lee cGVHD Symptom Scale 
5.3.1. 
Definition 
Sustained Response: 
Sustained response is defined as NIH-defined response that sustain continuously for at least 20 
weeks (140 days). Considering 7 days at maximum visit window allowed by protocol, the bound 
of sustained response is defined as 133 days. Intermittent SD assessment between response 
assessments is allowed. 
Duration of Response: 
Duration of Response (DOR) is defined as the interval between the date of initial documentation 
of a response (CR or PR), and the date of first documented evidence of progressive disease, 
death, or date of censoring if applicable, for responders only. DOR will be right censored based 
on Table 2 for all responders: 
Table 2: Date of Event or Censoring for Duration of Response 
Situation 
Date of DOR Event or Censoring 
Outcome 
Death or disease progression occurred on or 
before the start date of subsequent cGVHD 
treatment documented at scheduled disease 
assessments or between two scheduled disease 
assessments. 
Earliest date of adequate disease assessment 
documenting disease progression or date of death, 
whichever occurs first. 
Event 
New subsequent cGVHD treatment before 
disease progression 
Date of last adequate disease assessment prior to 
or on start date of the new subsequent cGVHD 
treatment 
Censored 
Not known to have progressed or died at the data 
analysis cutoff date (this includes subjects who 
were known to have progressed or died after the 
data analysis cutoff date) 
Date of last adequate disease assessment showing 
no evidence of disease progression. 
Censored 


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For subjects who met more than one censoring condition, DOR will be censored according to the 
earliest censoring condition/date. For subjects who have incomplete date for initiation of 
subsequent cGVHD treatment, the partial date will be imputed as the earliest possible date that 
incorporates the available information from the partial date and does not contradict last dose date 
of study drug. 
Corticosteroid Requirement Changes over Time: 
Systemic corticosteroid therapy for cGVHD will be monitored throughout the study. The 
corticosteroid dose level will be measured by the daily dose amount versus the weight of subject 
(mg/kg/day). For the days without weight measurement, the last observed weight measurement 
will be used. Considering the frequency of corticosteroid use might not be once daily, we use 
weekly average daily dose instead of the actual daily dose. The average corticosteroid dose level 
in each week is calculated by  
 
Sum of total corticosteroid dose used in this week / 7 
If a subject terminated the study drug in the middle of the week, the average corticosteroid dose 
level in that week will be calculated by 
Sum of total corticosteroid dose used in the week before the study drug termination / actual days 
in the week up to the last dose of study drug. 
Change in Lee cGVHD Symptom Scale: 
Subject-reported improvement in symptom burden will be evaluated.  The symptom burden is 
measured according to the Lee cGVHD Symptom Scale.1 There are 7 domains, and each has 
several items (refer to Table 3). 
Table 3: Lee cGVHD Symptom Scale 
Subscale 
Related Items 
Maximum No. of Missing Items to 
Get a Valid Score 
Skin 
1, 2, 3, 4, 5 
2 
Energy 
14, 21, 22, 23, 24, 25, 26 
3 
Lung 
12, 13, 15, 16, 27 
2 
Eye 
6, 7, 8 
1 
Nutrition 
11, 17, 18, 19, 20 
2 
Mouth 
9, 10 
1 
Psychological 
28, 29, 30 
1 
A score is calculated for each subscale by taking the mean of all items completed if more than 
50% were answered and normalizing to a 0 to 100 scale. A total summary score is calculated as 
the average of these 7 subscales if at least 4 subscales have valid scores.  
A change in ≥7 points on the Lee cGVHD Symptom Scale will be considered significant and 
relates to improvement in quality of life.2 
5.3.2. 
Analysis Methods 
The all treated population will be used for all secondary efficacy endpoints.  


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Rate of sustained response for at least 20 weeks will be calculated with the exact 2-sided 95% 
confidence interval based on binominal distribution.  
The DOR for responders will be calculated by the Kaplan-Meier method descriptively. Median 
DOR and the corresponding 95% confidence interval will be provided if estimable with Kaplan-
Meier plot. 
The overall cGVHD response rate at each timepoint of efficacy evaluation will be summarized 
by descriptive statistics. 
Corticosteroid requirement changes over time will be summarized by descriptive statistics by 
responder (CR or PR) and non-responder. 
Change in symptom burden measured by the Lee cGVHD Symptom Scale will be summarized 
by descriptive statistics. A summary of total scores as well as each subscale scores for Lee 
cGVHD symptom scale will be performed throughout the study. A summary of the proportion of 
subjects who have decreases of at least 7 points in Lee cGVHD symptom scale during the study 
will be performed. 
5.4. 
Other Efficacy Variable(s) 
The exploratory efficacy endpoints are: 
 
Failure free survival (FFS) 
 
Overall survival (OS) 
 
Number and proportion of subjects with all immunosuppressants withdrawn 
 
Best organ response rate 
5.4.1. 
Definition 
Failure free survival (FFS): 
Failure free survival (FFS) is defined as the duration from the date of initial dose to the date of 
relapse of malignancy, initiation of new immunosuppressive therapy for GVHD or death, 
whichever occurs first. FFS will be right censored based on Table 4. 
Table 4: Date of Event or Censoring for Failure Free Survival 
Situation 
Date of FFS event or Censoring 
Outcome 
Death 
Date of death 
Event 
New subsequent cGVHD treatment  
Date of starting the new subsequent cGVHD 
treatment 
Event 
Relapse of malignancy 
Start date of relapse of malignancy  
Event 
Not known to have event at the data analysis 
cutoff date (this includes subjects who were 
known to have event after the data analysis 
cutoff date) 
Date of last known date (last visit) showing no 
evidence of event. 
Censored 


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Overall survival (OS): 
Overall survival (OS) is defined as the duration from the date of initial dose to the date of the 
subject’s death. OS will be right censored if no death has occurred at the data analysis cutoff date. 
Best organ response rate: 
Best organ response rate is defined as the proportion of responders (CR or PR) in a specific 
organ or site. Skin, mouth, liver, upper CI, lower GI, esophagus, lung, eye, and joint/fascia are 
the organs or sites considered. 
5.4.2. 
Analysis Methods 
The Kaplan-Meier method will be used to descriptively summarize the FFS. Median FFS and the 
corresponding 95% confidence interval will be provided if estimable with Kaplan-Meier plot. 
The OS will be evaluated in the same manner as FFS. 
Number and proportion of subjects with all immunosuppressants withdrawn and organ response 
will be summarized by descriptive statistics. 
6. 
SAFETY 
Unless specified otherwise, all safety analyses will be based on Safety Analysis Set. 
6.1. 
Adverse Events 
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be 
graded by the investigator according the National Cancer Institute common terminology criteria 
for adverse events (CTCAE) Version 4.03. Any AE occurring at or after the initial administration 
of study agent through the day of last dose plus 30 days or initiation of subsequent cGVHD 
therapy is considered to be treatment-emergent. If the event date is recorded as partial or 
completely missing, then the event will be considered to be treatment-emergent unless it is 
known to be prior to the first administration of study agent based on partial onset date or 
resolution date. If the event is study drug-related regardless of the start date of the event, it is 
considered to be treatment-emergent. If an event that is present at baseline but worsens in 
severity or is subsequently considered drug-related by the investigator, then it is considered to be 
treatment-emergent. All reported treatment-emergent adverse events will be included in the 
analysis.  For each adverse event, the number and percentage of subjects who experience at least 
1 occurrence of the given event will be summarized. 
Summary tables will be provided for: 
 
Overall summary of all treatment-emergent AEs(TEAEs) 
 
TEAEs by System Organ Class (SOC), preferred term (PT) and toxicity Grade 3 or higher 
 
TEAE with frequency of at least 10% by SOC, PT and toxicity Grade 3 or higher 
 
Drug-related TEAEs by SOC, PT and toxicity Grade 3 or higher 


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 
Serious TEAEs by SOC, PT and toxicity Grade 3 or higher  
 
TEAEs leading to dose reduction by SOC, PT and toxicity Grade 3 or higher 
 
TEAEs leading to discontinuation of study drug by SOC, PT and toxicity Grade 3 or higher 
 
Fatal TE AEs by SOC and PT 
 
TEAEs by SOC, PT and toxicity by period 
In addition to the summary tables, listings will be provided for subjects who: 
 
Had any AE 
 
Had SAEs 
 
Had TEAEs leading to dose modification  
 
Had TEAEs leading to discontinuation of study drug 
 
Had drug-related TEAEs 
 
Had Fatal TEAEs 
Incidence of treatment-emergent adverse events of special interest will be summarized. 
6.1.1. 
AEs of special interest (AESI) 
Number and percent of subjects with following AESIs will be summarized by preferred terms. 
Major hemorrhage 
Major hemorrhage is defined as: 
 
Treatment-emergent hemorrhagic adverse event of Grade 3 or higher. All hemorrhagic 
events requiring a transfusion of red blood cells should be reported as Grade 3 or higher 
adverse events per NCI-CTCAE. 
 
Treatment-emergent SAE of Hemorrhagic event of any grade 
 
Treatment-emergent central nervous system hemorrhage/hematoma of any grade 
Hemorrhagic event 
Hemorrhagic events will be identified by hemorrhage Standardized MedDRA Query [SMQ] 
excluding laboratory terms. 
Cardiac arrhythmia 
Cardiac arrhythmia will be determined based on Cardiac arrhythmias (SMQ, broad and narrow). 
Interstitial Lung Disease 
Interstitial Lung Disease (ILD) will be determined based on Interstitial lung disease (SMQ, 
narrow). All treatment emergent ILD events will be summarized by preferred terms. 


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Severe Cutaneous Adverse Reaction 
Severe Cutaneous Adverse Reaction (SCAR) will be determined based on Severe cutaneous 
adverse reactions (SMQ, narrow). 
Hypertension 
Hypertension will be determined based on Hypertension (SMQ, narrow). 
Other Malignancies 
Treatment-emergent Neoplasms benign, malignant and unspecified (incl cysts and polyps) of any 
grade (SOC). Relapse of underlying malignancy will not be considered as other malignancies. 
Hypersensitivity 
This definition will be specified in DPS, separatory. 
CNS Hemorrhage 
CNS hemorrhage is a subset of CNS related PTs in the hemorrhage SMQ. 
Ischemic stroke 
Ischemic stroke is determined based on Ischemic central nervous system vascular conditions 
(SMQ). 
Cardiac failure 
Cardiac failure is determined based on Cardiac failure SMQ (narrow). 
6.2. 
Death 
Subjects who died during the study will be listed. 
6.3. 
Clinical Laboratory Tests 
All clinical laboratory tests will be displayed for the subjects included in the safety analysis set. 
Laboratory data for hematology and serum chemistry tests will be reported in SI units. 
Applicable laboratory results will be graded according to NCI-CTCAE Version 4.03. 
The following laboratory tests will be analyzed:  
 
Hematology: hemoglobin, platelet count, white blood cell (WBC) count, absolute neutrophil 
count (ANC), absolute lymphocyte count, and absolute eosinophil count 
 
Chemistry: sodium, potassium, glucose, total bilirubin, blood urea nitrogen (BUN), 
creatinine, total protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase, lactic acid dehydrogenase (LDH), uric acid and albumin. 
 
Donor/host chimerism, serum immunoglobulin levels (IgG, IgM, IgA) 
Descriptive statistics and change from baseline will be presented for all laboratory tests with 
continues values at scheduled time points. 


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Frequency tabulations of the changes from baseline results will be presented in pre versus 
postintervention cross-tabulations (with classes for Low, Normal, and High). Frequency 
tabulations of the abnormalities will be made. A listing of subjects with laboratory results will be 
provided. A listing of subjects with liver function abnormality will also be provided. Parameters 
with predefined NCI-CTCAE toxicity grades will be summarized. Change from baseline to the 
worst adverse event grade experienced by the subject during the study will be provided as shift 
tables. 
6.4. 
Vital Signs and Physical Examination Findings 
Continuous vital sign parameters including temperature, respiratory rate, weight, pulse and blood 
pressure (systolic and diastolic) will be summarized at each assessment time point. A listing will 
also be provided. 
6.5. 
Death 
Subjects who died in the study will be listed. 
6.6. 
Other Safety Parameters 
Descriptive summary will be provided for following parameters: 
 
Karnofsky/Lansky Performance Scale 
 
Forced expiratory volume in 1 second (FEV1). 
Corresponding listings will also be provided. 
7. 
PHARMACOKINETICS/PHARMACODYNAMICS 
7.1. 
Pharmacokinetics 
Pharmacokinetic evaluable analysis set will be used for PK analyses. The individual plasma 
concentration data of ibrutinib and PCI-45227 will be listed and graphically displayed (normal 
scale and semilog scale). Concentrations below the lowest quantifiable concentration or missing 
data will be labeled as such in the concentration data presentation. The data will be summarized 
at each timepoint using descriptive statistics (mean, standard deviation [SD], coefficient of 
variation, median, minimum and maximum) and mean (±SD) concentration-time profile will be 
graphically displayed (normal scale and semilog scale). Concentration data below the lowest 
quantifiable concentration will be treated as zero in the summary statistics. Subgroup analysis by 
concomitant CYP3A inhibitors will be performed. Additional analyses may be performed as 
deemed necessary. 
For concentration summary, applying the following rules. 
 
When more than half (>50%) of concentration data are BQL at each scheduled time point, 
mean and median will be reported as ‘BQL’; SD and %CV are reported as ‘NC’; maximum 
and minimum will be reported as observed (including BQL). 


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 
When number of concentration data are equal to or less than 2, SD, %CV, median, minimum 
and maximum will be shown as ‘NC’ regardless of the proportion of BQL. 
The individual PK parameters (Cmax, tmax, t1/2, tlast, CL/F, Vdz/F, AUClast, AUC24, AUC∞ and λZ) 
of ibrutinib and PCI-45227 will be calculated using noncompartmental analysis based on actual 
sampling times. Accumulation ratios based on Cmax and AUC24 for Week 2 is derived for both 
ibrutinib and PCI-45227. Metabolite-to-parent ratio (MPR) based on Cmax, AUClast, AUC24 and 
AUC∞ will be generated. Dose-normalized Cmax, AUClast, and AUC24 will be calculated to a 
420 mg ibrutinib dose. Individual values (Cmax, tmax, t1/2, tlast, CL/F, Vdz/F, AUClast, AUC24, 
AUC∞, λZ, dose-normalized Cmax, AUClast, and AUC24, accumulation ratios based on Cmax, 
accumulation ratio based on AUC24, MPR based on Cmax, MPR based on AUClast, MPR based on 
AUC24 and MPR based on AUC∞) will be listed and summarized for ibrutinib and PCI-45227 
using descriptive statistics (mean, SD, coefficient of variation [CV], geometric mean, median, 
minimum and maximum [SD, CV, geometric mean are not needed for tmax and tlast]).  
Subgroup analysis by ibrutinib dose and concomitant CYP3A inhibitors will be performed on the 
individual PK parameters of ibrutinib and PCI-45227 (Cmax, tmax, t1/2, tlast, AUClast, AUC24, AUC∞ 
and λZ). Only strong/moderate CYP3A inhibitors taken on the PK assessment days (Week 1, Day 
1 and Week 2, Day 1) will be considered. The subgroups will be defined based on the name of 
the inhibitors (eg, fluconazole [ibrutinib dose: 420 mg]). Summary tables will be provided to 
present the summary statistics derived for each subgroup. In addition, individual and mean 
values of selected PK parameters (eg, Cmax, AUClast) will be graphically presented to visually 
compare the values between each subgroup.  The graphical presentation will be performed for 
dose-normalized PK parameters (eg, dose-normalized Cmax, AUClast) regardless of ibrutinib dose. 
Additional analyses may be performed as deemed necessary. 
For PK parameter summary, applying the following rules. 
 
In the case following criteria are not met, t1/2, AUC∞, CL/F, Vdz/F, λz, and MPR based on 
AUC∞ will be reported with annotation as such and excluded from the descriptive statistics. 
 
At least 3 data points are used in calculation for λz; 
 
r2adj for the regression of λz ≥0.90; 
 
%AUC∞,ex is ≤20%. 
Data or subjects will be excluded from the analysis if the data do not allow for accurate 
assessment of the PK. All subjects and samples excluded from the analysis will be clearly 
documented in the study report. 
7.2. 
Pharmacodynamics 
Pharmacodynamic evaluable analysis set will be used for PD analyses. The BTK and ITK 
binding site occupancy will be tabulated and summarized at each timepoint using descriptive 
statistics (mean, SD, coefficient of variation, median, minimum and maximum). Box plots of 
individual data at each time point will be presented in one panel. Additional analyses (eg, 


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subgroup analyses by ibrutinib dose or concomitant CYP3A inhibitors) may be performed as 
deemed necessary. 


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REFERENCES 
 
1. 
Lee SJ, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure symptoms of chronic 
graft-versus-host disease. Biologyu of Blood and Marrow Transplantation 2002;8:444-452. 
2. 
Lee SJ, Kim HT, Ho VT, et al. Quality of life associated with acute and chronic graft-versus-host disease. 
Bone Marrow Transplant 2006;38:305-10. 
 
 


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ATTACHMENTS 
ATTACHMENT 1: PLANNED LISTINGS 
The details will be specified in the Data Presentation Specifications. 
Output Title 
Analysis Set 
Subject Information (SI) 
 
Demographics and Baseline Characteristics 
All Treated Analysis Set  
Disease Characteristics 
All Treated Analysis Set 
Transplant History 
All Treated Analysis Set  
Discontinuation of Study Drug 
All Treated Analysis Set  
Terminated from Study 
All Treated Analysis Set  
Subjects Excluded from the Analysis set 
All Treated Analysis Set  
Duration, Cumulative Dose and Dose Intensity 
All Treated Analysis Set  
Study Drug Administration 
All Treated Analysis Set  
Major Protocol Deviation 
All Treated Analysis Set  
Prior cGVHD Therapy 
All Treated Analysis Set  
Concomitant Medications 
All Treated Analysis Set  
Concomitant Use of CYP3A Inhibitors 
All Treated Analysis Set  
Concomitant Use of CYP3A Inducers 
All Treated Analysis Set  
Concomitant Additional Immunosuppressants during Study 
All Treated Analysis Set 
Anti-coagulants 
All Treated Analysis Set  
Anti-platelets 
All Treated Analysis Set 
Potential Hy’s Law Case 
All Treated Analysis Set  
Subsequent cGVHD Therapy 
All Treated Analysis Set 
Medical History 
All Treated Analysis Set 
Underlying Disease 
All Treated Analysis Set 
cGVHD Assessment (NIH) 
All Treated Analysis Set 
Efficacy (EF) 
 
Efficacy Variables 
All Treated Analysis Set 
cGVHD Response 
All Treated Analysis Set 
Corticosteroid requirement 
All Treated Analysis Set 
Symptom burden measured by the Lee cGVHD Symptom Scale 
All Treated Analysis Set 
Safety (SF) 
 
Treatment-emergent Adverse Events 
Safety Analysis Set 
Serious Adverse Events 
Safety Analysis Set 
Treatment-emergent Adverse Events Leading to Death 
Safety Analysis Set 
Treatment-emergent Adverse Events Leading to Discontinuation of Study Drug 
Safety Analysis Set 
Treatment-emergent Adverse Events Leading to Dose Reduction 
Safety Analysis Set 
Death 
Safety Analysis Set 
Laboratory Data 
Safety Analysis Set 
Vital Signs  
Safety Analysis Set 
Karnofsky/Lansky Performance Scale 
Safety Analysis Set 
Chimerism test 
Safety Analysis Set 
Pharmacokinetic (PK) 
 
Individual Plasma Ibrutinib Concentrations 
Pharmacokinetic-
evaluable Population 
Ibrutinib pharmacokinetic parameters on Week 1, Day 1 
Pharmacokinetic-
evaluable Population 
Ibrutinib pharmacokinetic parameters on Week 2, Day 1 
Pharmacokinetic-
evaluable Population 
Individual Plasma PCI-45227 Concentrations 
Pharmacokinetic-
evaluable Population 


JNJ-54179060  (Ibrutinib)  
 
 
 
Statistical Analysis Plan 54179060GVH3001  
25 
Approved, Date: 13 January 2022  
Output Title 
Analysis Set 
PCI-45227 pharmacokinetic parameters on Week 1, Day 1 
Pharmacokinetic-
evaluable Population 
PCI-45227 pharmacokinetic parameters on Week 2, Day 1 
Pharmacokinetic-
evaluable Population 
Other (OT) 
 
Lot Number 
All Treated Analysis Set