Clinical trial NCT04042376
Conditions: Waldenstrom Macroglobulinemia
Sponsor: Janssen Research & Development, LLC
Start date: 2019-12-18; Completion date: 2024-03-19
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the efficacy of ibrutinib based on overall response rate (ORR) (partial response \[PR\] or better) by investigator assessment per the modified Consensus Response Criteria from the Sixth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) (NCCN 2019), in Chinese participants with relapsed or refractory waldenstrom's macroglobulinemia.

Detailed description:

Arms: arm 1: Participants will receive ibrutinib 420 mg once daily, continuously starting at Day 1 of Week 1 until disease progression or unacceptable toxicity, whichever occurs first.
Interventions: intervention 1: Ibrutinib
Intervention descriptions: intervention 1: Ibrutinib will be administered orally, once daily, at a dose of 420 mg (140 mg\*3 capsules taken together at one time).

Protocol documents:
Prot_000.pdf: 
1
Status: Approved,  Date: 25 March 2020
Janssen Research & Development *
Clinical Protocol
A Single Arm, Multicenter, Phase 4 Study of the Bruton’s Tyrosine Kinase (BTK) 
Inhibitor, ibrutinib (PCI-32765) in Chinese Subjects with Relapse or Refractory 
Waldenström’s Macroglobulinemia
Protocol 54179060WAL4001; Phase 4
AMENDMENT 1
JNJ-54179060 (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
Status:
Approved
Date:
25 March 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-175314237, 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.
NCT04042376


JNJ-54179060 (ibrutinib)
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Approved, Date: 25 March 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................... 7
TIME AND EVENTS SCHEDULE ................................................................................................................ 9
ABBREVIATIONS ...................................................................................................................................... 13
1.
INTRODUCTION................................................................................................................................ 15
1.1.
Ibrutinib Background ...................................................................................................................... 16
1.1.1.
Ibrutinib ....................................................................................................................................... 16
1.1.2.
Clinical Studies ........................................................................................................................... 16
1.1.2.1.
Human Pharmacokinetics........................................................................................................ 17
1.1.2.2.
Clinical Efficacy of Ibrutinib in Waldenström’s Macroglobulinemia ......................................... 17
1.1.2.2.1.
Study PCYC-04753.............................................................................................................. 17
1.1.2.2.2.
Study PCYC-1118E ............................................................................................................. 17
1.1.2.2.3.
Study PCYC-1127-CA.......................................................................................................... 18
1.1.2.3.
Clinical Safety of Ibrutinib........................................................................................................ 20
1.1.2.3.1.
Non-Hematological Adverse Events .................................................................................... 20
1.1.2.3.2.
Hematological Adverse Events ............................................................................................ 21
1.1.2.3.3.
Long-term safety .................................................................................................................. 22
1.2.
Overall Rationale for the Study...................................................................................................... 22
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESISES ...................................................................... 23
2.1.
Objectives and Endpoints .............................................................................................................. 23
2.1.1.
Objectives ................................................................................................................................... 23
2.1.2.
Endpoints.................................................................................................................................... 23
2.2.
Hypothesis ..................................................................................................................................... 24
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 24
3.1.
Overview of Study Design.............................................................................................................. 24
3.2.
Study Design Rationale.................................................................................................................. 25
3.2.1.
Rationale for Ibrutinib Dose ........................................................................................................ 25
3.2.2.
Rationale for Efficacy Endpoints................................................................................................. 25
4.
SUBJECT POPULATION.................................................................................................................. 26
4.1.
Inclusion Criteria ............................................................................................................................ 26
4.2.
Exclusion Criteria ........................................................................................................................... 28
4.3.
Prohibitions and Restrictions ......................................................................................................... 30
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 30
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 30
6.1.
Formulation/Packaging/Storage..................................................................................................... 31
6.2.
Overdose........................................................................................................................................ 31
6.3.
Dose Hold, Reduction or Discontinuation of Study Drug............................................................... 32
6.4.
Dose Modification of Study Drug ................................................................................................... 32
6.5.
Dose Modification for Hepatic Impaired Subjects .......................................................................... 33


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7.
TREATMENT COMPLIANCE............................................................................................................ 33
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 33
8.1.
Permitted Concomitant Medications .............................................................................................. 34
8.2.
Medications to be Used with Caution............................................................................................. 34
8.2.1.
CYP3A Inhibitors/Inducers.......................................................................................................... 34
8.2.2.
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib.................................. 35
8.2.3.
Concomitant Use of Antiplatelet Agents and Anticoagulants ..................................................... 35
8.3.
Prohibited Concomitant Medications ............................................................................................. 35
8.4.
Procedures..................................................................................................................................... 35
8.4.1.
Minor Surgical Procedures ......................................................................................................... 36
8.4.2.
Major Surgical Procedures ......................................................................................................... 36
8.4.3.
Emergency Procedures .............................................................................................................. 36
8.5.
Plasmapheresis.............................................................................................................................. 36
9.
STUDY EVALUATIONS .................................................................................................................... 36
9.1.
Study Procedures........................................................................................................................... 36
9.1.1.
Overview..................................................................................................................................... 36
9.1.2.
Screening Phase ........................................................................................................................ 37
9.1.3.
Treatment Phase ........................................................................................................................ 37
9.1.4.
Follow-up Phase......................................................................................................................... 38
9.1.4.1.
Post-treatment Pre-disease Progression Phase ..................................................................... 38
9.1.4.2.
Post-disease Progression Phase ............................................................................................ 38
9.1.5.
Clinical Cut-offs........................................................................................................................... 38
9.2.
Efficacy Evaluations....................................................................................................................... 38
9.2.1.
Quantitative Serum Immunoglobulin .......................................................................................... 39
9.2.2.
Serum Protein Electrophoresis (SPEP)...................................................................................... 39
9.2.3.
Serum Free Light Chain Assay................................................................................................... 39
9.2.4.
Serum Immunofixation................................................................................................................ 40
9.2.5.
Radiographic Imaging................................................................................................................. 40
9.2.5.1.
Radiographic Assessment....................................................................................................... 40
9.2.6.
Bone Marrow Assessment and Pathological diagnosis.............................................................. 41
9.3.
Pharmacokinetics........................................................................................................................... 41
9.3.1.
Evaluations ................................................................................................................................. 41
9.3.2.
Analytical Procedures................................................................................................................. 42
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 42
9.4.
Safety Evaluations ......................................................................................................................... 42
9.4.1.
Adverse Events........................................................................................................................... 42
9.4.2.
Clinical Laboratory Tests ............................................................................................................ 42
9.4.3.
Electrocardiogram (ECG) ........................................................................................................... 43
9.4.4.
Vital Signs and ECOG Performance Status ............................................................................... 44
9.4.5.
Physical Examination.................................................................................................................. 44
9.4.6.
Eye-related symptom assessment ............................................................................................. 44
9.5.
Sample Collection and Handling.................................................................................................... 44
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 44
10.1.
Completion ..................................................................................................................................... 44
10.2.
Discontinuation of Study treatment................................................................................................ 45
10.3.
Withdrawal From the Study............................................................................................................ 45
11.
STATISTICAL METHODS................................................................................................................. 46
11.1.
Subject Information ........................................................................................................................ 46
11.2.
Sample Size Determination ........................................................................................................... 46
11.3.
Efficacy Analyses ........................................................................................................................... 46
11.3.1.
Primary Efficacy Endpoint........................................................................................................... 47
11.3.2.
Secondary Efficacy Endpoints.................................................................................................... 47
11.3.2.1.
Clinical Response Rate ........................................................................................................... 47


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11.3.2.2.
VGPR or Better Rate ............................................................................................................... 47
11.3.2.3.
Duration of Response.............................................................................................................. 47
11.3.2.4.
Time to Response ................................................................................................................... 47
11.3.2.5.
Progression Free Survival ....................................................................................................... 47
11.3.2.6.
Overall Survival ....................................................................................................................... 47
11.4.
Pharmacokinetic Analyses............................................................................................................. 48
11.5.
Safety Analyses ............................................................................................................................. 48
12.
ADVERSE EVENT REPORTING ...................................................................................................... 49
12.1.
Definitions ...................................................................................................................................... 49
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 49
12.1.2.
Attribution Definitions.................................................................................................................. 50
12.1.3.
Severity Criteria .......................................................................................................................... 51
12.1.4.
Adverse Events of Special Interest............................................................................................. 51
12.1.4.1.
Major Hemorrhage................................................................................................................... 51
12.1.5.
Other Malignancies..................................................................................................................... 52
12.1.6.
Eye-related Adverse Events ....................................................................................................... 52
12.2.
Special Reporting Situations.......................................................................................................... 52
12.3.
Procedures..................................................................................................................................... 52
12.3.1.
All Adverse Events...................................................................................................................... 52
12.3.2.
Serious Adverse Events ............................................................................................................. 53
12.3.3.
Pregnancy................................................................................................................................... 54
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 55
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 55
13.1.
Procedures..................................................................................................................................... 55
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 55
14.
STUDY DRUG INFORMATION......................................................................................................... 55
14.1.
Physical Description of Study Drug................................................................................................ 55
14.2.
Packaging ...................................................................................................................................... 56
14.3.
Labeling.......................................................................................................................................... 56
14.4.
Preparation, Handling, and Storage............................................................................................... 56
14.5.
Drug Accountability ........................................................................................................................ 56
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 57
16.
ETHICAL ASPECTS ......................................................................................................................... 57
16.1.
Study-Specific Design Considerations........................................................................................... 57
16.2.
Regulatory Ethics Compliance....................................................................................................... 57
16.2.1.
Investigator Responsibilities ....................................................................................................... 57
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 58
16.2.3.
Informed Consent ....................................................................................................................... 59
16.2.4.
Privacy of Personal Data ............................................................................................................ 60
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 60
17.1.
Protocol Amendments.................................................................................................................... 60
17.2.
Regulatory Documentation ............................................................................................................ 61
17.2.1.
Regulatory Approval/Notification ................................................................................................ 61
17.2.2.
Required Prestudy Documentation............................................................................................. 61
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 62
17.4.
Source Documentation................................................................................................................... 62
17.5.
Case Report Form Completion ...................................................................................................... 63
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 63
17.7.
Record Retention ........................................................................................................................... 64
17.8.
Monitoring ...................................................................................................................................... 64
17.9.
Study Completion/Termination....................................................................................................... 65
17.9.1.
Study Completion/End of Study.................................................................................................. 65
17.9.2.
Study Termination....................................................................................................................... 65


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17.10.
On-Site Audits ................................................................................................................................ 65
17.11.
Use of Information and Publication................................................................................................ 65
REFERENCES............................................................................................................................................ 68
INVESTIGATOR AGREEMENT ................................................................................................................. 77
LIST OF ATTACHMENTS
Attachment 1:
Modified 6th WM Response Criteria (NCCN 2019) for Investigator 
Assessment ................................................................................................................ 70
Attachment 2:
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale .............. 71
Attachment 3:
Inhibitors and Inducers of CYP3A .............................................................................. 72
Attachment 4:
Child-Pugh Score ....................................................................................................... 73
Attachment 5:
Recommended Dose Modifications of Ibrutinib for Use with CYP3A Inhibitors......... 74
Attachment 6:
Calculated Creatinine Clearance................................................................................ 75
Attachment 7:
New York Heart Association Functional Classification............................................... 76
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Efficacy Results with Ibrutinib in subjects with WM.................................................................. 19
Table 2:
Study Drug Dose Modifications ............................................................................................... 33
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 25


JNJ-54179060 (ibrutinib)
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PROTOCOL AMENDMENTS
Protocol Version 
Date
Original Protocol
16 May 2019
Amendment 1
25 March 2020
Amendments below are listed beginning with the most recent amendment.
Amendment 1 (25 March 2020)
The overall reason for the amendment: To update safety information to align with the ibrutinib Investigator’s 
Brochure (IB) to include information regarding cerebrovascular accidents as a new safety observation identified 
from the post-marketing setting, and to clarify procedures and collection of data, eg, monitoring of vital signs and 
blood volume, and to capture editorial changes.
Applicable Section(s)
Description of Change(s)
Rationale: To update the safety information on ibrutinib, including information regarding cerebrovascular 
accidents.
1.1.2.3. Clinical 
Safety of Ibrutinib
Safety information on ibrutinib updated to align with the latest Investigator’s Brochure 
(IB) including information regarding cerebrovascular accidents as a new safety 
observation identified from the post-marketing setting.
Rationale: To update the information based on latest IB Edition 13.
1.1.1. Ibrutinib; 1.1.2. 
Clinical Studies
Background information about ibrutinib (IMBRUVICA®) approval and number of 
completed and ongoing studies updated as of clinical cut-off date of IB Edition 13 
(12 November 2019).
Rationale: To enhance the monitoring of vital signs between Weeks 5-16.
Time and Events 
Schedule (row “Vital 
signs” and footnote 
“p”)
Added “X” in Weeks 5-16 column of the Treatment Phase.
Footnote “p” added:
“Vital sign assessments should be recorded in source documents but will not be routinely 
collected in the eCRF. Clinically significant abnormalities should be recorded as adverse 
events and reported in the eCRF.”
Rationale: To update the total blood volume which was overestimated in the protocol.
9.1.1. Overview
The total blood volume to be collected at each visit is updated.
Rationale: To clarify that clinically significant abnormalities of physical examination will be recorded as adverse 
events and included in the analysis of TEAE.
11.5. Safety Analyses 
Added text in bold and deleted text in strikethrough:
Physical Examination
All clinically significant abnormalities of physical examination will be recorded as 
AEs and included in the analysis of TEAE. Descriptive statistics of changes from 
baseline will be summarized at each scheduled time point.
Rationale: Minor editorial changes implemented as needed to correct typographical errors, clarify text, or address 
inconsistencies.
Throughout protocol
Minor grammatical, formatting, or spelling changes were made. Abbreviations and 
references were updated.


JNJ-54179060 (ibrutinib)
Clinical Protocol 54179060WAL4001 Amendment 1
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Approved, Date: 25 March 2020
SYNOPSIS
Protocol Number: 54179060WAL4001, Phase 4
A Single Arm, Multicenter, Phase 4 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, ibrutinib 
(PCI-32765) in Chinese Subjects with Relapse or Refractory Waldenström’s Macroglobulinemia
Study Drug: Ibrutinib (PCI-32765; JNJ-54179060, IMBRUVICA™) is a first-in-class, potent, 
orally -administered, covalent inhibitor of Bruton’s tyrosine kinase (BTK) and is currently being 
co-developed by Janssen Research & Development, LLC (JRD) and Pharmacyclics, Inc. (PCYC) for a 
variety of B-cell malignancies (including Waldenström’s Macroglobulinemia [WM]), and chronic graft 
versus host disease.
OBJECTIVES, ENDPOINTS, AND HYPOTHESES
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of ibrutinib based on overall response rate
(ORR) (partial response [PR] or better) by investigator assessment per the modified Consensus Response 
Criteria from the VIth International Workshop on WM (IWWM) (NCCN 2019), in Chinese subjects with 
relapsed or refractory WM.
Secondary Objectives
Secondary objectives are to evaluate: clinical response rate (minor response [MR] or better) by 
investigator assessment according to the modified VIth IWWM (NCCN 2019) criteria, Very Good PR
(VGPR) or better by investigator assessment according to the modified VIth IWWM (NCCN 2019)
criteria; duration of response (DOR) by investigator assessment; time to response (TTR) by investigator 
assessment; progression-free survival (PFS) by investigator assessment; overall survival (OS); safety and 
PK of ibrutinib in Chinese subjects with relapsed or refractory WM.
Endpoints
Primary Endpoint
The primary efficacy endpoint is ORR by investigator assessment. ORR is defined as the proportion of 
subjects who achieve PR or better per the modified Consensus Response Criteria from the VIth IWWM
(NCCN 2019).
Secondary Endpoints
Efficacy 

Clinical response rate (CRR, ≥MR)

Rate of VGPR or better

DOR

TTR

PFS

OS


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Pharmacokinetics

To evaluate pharmacokinetics (PK) of ibrutinib in Chinese subjects with relapsed or 
refractory WM
Safety

To assess the safety and tolerability of ibrutinib in Chinese subjects with symptomatic relapsed or 
refractory WM
Hypothesis
The primary hypothesis for this study is that ibrutinib is an effective agent as measured by ORR (with a 
point estimate approximately 70% and the lower bound of the 90% confidence interval [CI] is greater 
than 32%) in Chinese subjects with relapsed or refractory WM.
OVERVIEW OF STUDY DESIGN
This is a single-arm multicenter, Phase 4 study to evaluate the efficacy and safety of ibrutinib 
administered orally, once daily, at a dose of 420 mg in Chinese subjects with relapsed or refractory WM 
with symptomatic disease meeting according to at least 1 of the criteria for treatment in the second 
IWWM. Approximately 17 eligible subjects will be enrolled into the study. Patients will receive ibrutinib 
420 mg daily until disease progression or unacceptable toxicity, whichever occurs first. 
SUBJECT POPULATION
Key eligibility criteria include the following: men and women ≥18 years of age; Eastern Cooperative 
Oncology Group (ECOG) performance status of 0-2; centrally confirmed clinicopathological diagnosis of 
WM in accordance with the consensus panel of the Second IWWM; subjects must have received at least 
one prior therapy for WM and have had either documented disease progression or had no response (stable 
disease) to the most recent treatment regimen; symptomatic disease meeting at least 1 of the 
recommendations from the Second IWWM for requiring treatment; measurable disease defined as serum 
monoclonal immunoglobulin M (IgM) >0.5 g/dL.
EFFICACY EVALUATIONS
Response assessments will be performed using the modified consensus criteria adapted from the VIth
IWWM (NCCN 2019). Progression of nodal and extranodal disease should be evaluated based on the 
revised criteria for malignant lymphoma described in the revised International Working Group for 
non-Hodgkin B Lymphomas (NHL).22
PHARMACOKINETIC EVALUATIONS
Pharmacokinetic samples will be collected prior to the first dose and predose at Weeks 5 and 9 to 
determine plasma concentrations of ibrutinib and metabolite PCI-45227.
SAFETY EVALUATIONS
Safety will be assessed by adverse events, clinical laboratory test results (hematology and chemistry), 
physical examination findings, and vital signs measurements.
STATISTICAL METHODS
Assuming the ORR (PR or better) by investigator is 69.8% in the study population, which is the same as 
global pivotal study (PCYC-1118E) result, approximately 17 subjects will be required to obtain at least 
85% power to declare the ORR is 32% (the minimum clinically meaningful ORR) or higher at the 1-sided 
significance level of 0.05.


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TIME AND EVENTS SCHEDULE 
Screening 
Phase
Treatment Phase
Post-Treatment/ Follow-Up 
Phase
Study Weeks
1
5-16 
q4 weeks
17
21
25+ 
q8 weeks
Suspected 
PD Visit
End-of-
Treatment 
Visita
Post-treatment 
Pre-disease 
Progression 
Phase 
q12 weeks
Post-disease 
Progression 
Phase
q12 weeks
Study Day of 
the Study Week
1
1
1
1
1
Study Windows
-30 days
± 3 days
± 3 days
± 3 days
Anytime
± 7 days
± 7 days
± 7 days
Study Drug Administration
ibrutinib 420 mg 
PO
Continuous dosing until PD or unacceptable toxicity
Dispense Study 
Drug (ibrutinib)
X
X
X
X
X
Administrative Procedures
Informed 
consentb
X
Confirm 
eligibility
X
X
Medical history 
and 
Demographics
X
Safety Assessments
Physical exam 
(height at 
Screening only)
Xc
Xc
Xd
Xd
Xd
Xd
Xc
Xc
Xc
Eye-related 
symptom 
assessment
X
X
X
X
X
X
X
X
X
ECOG status
X
X
X
X
X
X
X
X
Vital signs
X
X
Xp
X
X
X
X
X
X
ECG
X
Additional assessments may be performed if clinically indicated during the course of the study.


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Screenin
g Phase
Treatment Phase
Post-Treatment/ Follow-Up 
Phase
Study Weeks
1
5-16 
q4 weeks
17
21
25+ 
q8 weeks
Suspected 
PD Visit
End-of-
Treatment 
Visita
Post-treatment 
Pre-disease 
Progression 
Phase 
q12 weeks
Post-disease 
Progression 
Phase
q12 weeks
Study Day of the 
Study Week
1
1
1
1
1
Study Windows
-30 days
± 3 days
± 3 days
± 3 days
Anytime
± 7 days
± 7 days
± 7 days
Clinical Laboratory Assessments
Hematology
X
Xn
X
X
X
X
X
X
X
Serum chemistry
X
Xn
X
X
X
X
X
X
Coagulation (PT, 
INR, and aPTT)
X
X
X
Pregnancy teste
X
Hepatitis 
serologies
Xo
Serum viscosity
(optional)f
X
β2-microglobulin
X
Efficacy Assessments
Serum 
immunofixationg
X
Serum protein 
electrophoresis 
(SPEP)
X
X
X
X
X
X
X
X
X
Quantitative 
serum 
immunoglobulins 
(IgA, IgG and 
IgM)
X
X
X
X
X
X
X
X
X
Serum free light 
chain assay
X
Weeks 49 and 
97
X
Bone marrow 
aspirate and 
biopsyl
X
Weeks 49 and 
97 (± 2 weeks)
X
X


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Screenin
g Phase
Treatment Phase
Post-Treatment/ Follow-Up 
Phase
Study Weeks
1
5-16 
q4 weeks
17
21
25+ 
q8 weeks
Suspected 
PD Visit
End-of-
Treatment 
Visita
Post-treatment 
Pre-disease 
Progression 
Phase 
q12 weeks
Post-disease 
Progression 
Phase
q12 weeks
Study Day of the 
Study Week
1
1
1
1
1
Study Windows
-30 days
± 3 days
± 3 days
± 3 days
Anytime
± 7 days
± 7 days
± 7 days
CT Scans
Xi
Xj
Xj
Xk
Xj
Overall disease 
assessment
X
X
X
X
X
X
X
Survival status, 
new anticancer 
therapy and 
occurrence of 
other malignancym
X
X
PK sampling
PKh
X
Weeks 5
and 9
Ongoing Subject Assessments
Concomitant 
medications
X
Continuous from Informed Consent to 30 days after last dose of study drug
Adverse events
X
Continuous from Informed Consent to 30 days after last dose of study drug
Abbreviations: aPTT=activated partial thromboplastin time; CR= complete response; CT=computed tomography; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report form; EOT=end-of-treatment; ICF=informed consent form; 
IEC=Independent Ethics Committee; INR=international normalized ration; IRB=Institutional Review Board; PCR=polymerase chain reaction; PD=progressive 
disease; PK=pharmacokinetic(s); PO=orally; PT=prothrombin time; q4 weeks=every 4 weeks; q8 weeks=every 8 weeks; q12 weeks=every 12 weeks; REB=research 
ethics board.
a.
Thirty (30) days from last dose of study drug or prior to the start of a new anticancer treatment.
b.
All subjects must first read, understand, sign and date the IRB/REB/IEC-approved ICF before any study-specific screening procedures are performed.
c.
Physical Examination includes: general appearance of subject, height (screening only) and weight and examination of skin, eyes, ears, nose, throat, lungs, heart, 
abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.
d.
Only a limited symptom-directed physical examination and the change in status of lymph nodes, tumor masses, liver and spleen will be required. Review of 
symptoms should include inquiry of ocular symptoms; subjects should be referred to an ophthalmologist for a formal examination if any Grade ≥2 symptoms are 
reported.
e.
Women of reproductive potential only. Serum pregnancy test required at Screening. During the trial, if the subject is suspected of pregnancy, pregnancy test must 
be performed. Pregnancy test will be done by the local laboratory.


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f.
Serum viscosity at Screening is optional. Subsequent serum viscosity (after Screening) should be performed at the discretion of the treating physician in any 
subject with signs and symptoms suggesting a hyperviscosity syndrome.
g.
Repetitive serum immunofixation on study is only required to confirm CR (conducted on the first observation that the subject has no detectable monoclonal 
protein) and then repeat every time until disease progression.
h.
Predose PK samples will be drawn for all subjects according to the schedule in Section 9.3.1.
i.
CT scans of the neck, chest, abdomen, and pelvis should be obtained during Screening (up to 42 days before first dose) for each subject.
j.
Follow-Up CT scans will be required at Weeks 17, 33, 49 65, 81, 97 and thereafter every 24 weeks until PD is confirmed for all subjects with measurable
nodal/extranodal disease during Screening. Additional assessments may be performed if clinically indicated during the course of the study at any time.
k.
CT scan at Suspected PD visit may be performed if clinically indicated as a reason for progression.
l.
Bone marrow aspirate and biopsy required at Screening, Weeks 49 and 97 (± 2 weeks) to confirm paraprotein changes, and at any time as determined necessary or 
to confirm a complete response if the subject has no detectable monoclonal protein, and if clinically indicated at disease progression or EOT visit. 
m.
The assessments can be performed via a clinical visit or a telephone contact.
n.
To be done predose, unless otherwise specified. Hematology and serum chemistry tests do not need to be repeated if the screening tests were performed within 5
days of the first dose of study drug.
o.
For subjects with Anti-HBc+ (DNA – at baseline), during study treatment and for at least 12 months following the last dose of treatment, regular monitoring of 
Hepatitis B PCR and liver enzymes and prophylactic antiviral medication should be considered per published guidelines.
p.
Vital sign assessments should be recorded in source documents but will not be routinely collected in the eCRF. Clinically significant abnormalities should be 
recorded as adverse events and reported in the eCRF.


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ABBREVIATIONS
ALT
alanine transaminase
ASCO
American Society of Clinical Oncology
AST
aspartate transaminase
BCR
B-cell antigen receptor
BCRP
breast cancer resistance protein
BID
twice daily
BTK
Bruton’s tyrosine kinase
CCO
clinical cutoff
cGVHD
chronic graft-versus-host disease
CI
confidence interval
CLL
chronic lymphocytic leukemia
CR
complete response
CRF
case report form(s) (paper or electronic as appropriate for this study)
CRR
clinical response rate
CT
computed tomography
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ERK
extracellular-signal-regulated kinase
EOT
end-of-treatment
eDC
electronic data capture
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HR
hazard ratio
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
INR
international normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IV
Intravenous
IWWM
International Workshop on WM
MCL
mantle cell lymphoma
NMPA
National Medical Product Administration
MR
minor response
MRI
magnetic resonance imaging
MZL
marginal zone lymphoma
NHL
non-Hodgkin B Lymphomas
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PO
orally
PQC
product quality complaint
PR
partial response
PT
prothrombin time
SLL
small lymphocytic lymphoma
SPD
sum of product
SPEP
serum protein electrophoresis
SUSAR
suspected unexpected serious adverse reaction


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SVR
sustained virologic response
TTR
time to response
VGPR
very good PR
WHO
World Health Organization
WM
Waldenström’s Macroglobulinemia


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1.
INTRODUCTION
Waldenström’s macroglobulinemia (WM) is a lymphoproliferative B-cell disorder characterized 
by infiltration of lymphoplasmacytic cells into the bone marrow along with demonstration of an 
immunoglobulin (IgM)
monoclonal gammopathy in the serum. It is a subtype of 
lymphoplasmacytic lymphoma (LPL) belonging to the category of non-Hodgkin B lymphomas 
(NHL) as defined by the World Health Organization (WHO) classification systems1 with an 
indolent course. 
The clinical presentation of WM is extremely heterogeneous. While some signs and symptoms 
are secondary to organ infiltration by clonal cells, including anaemia, lymphoadenopathy and 
splenomegaly, others, such as neuropathy, hyperviscosity, and cryoglobulinemia are due to 
specific immunological and physiochemical features of monoclonal IgM.
WM is an orphan indication accounting for 1-2% of hematologic malignancies. The overall 
incidence of WM is 3 per million persons per year with approximately 1500 new cases 
diagnosed in the United States (US) each year. Currently there is no epidemiology data of WM 
incidence in China.
Existing Therapies in WM
Treatment for WM is recommended only for symptomatic disease. Currently in China, WM is 
treated most often with rituximab as a monotherapy or in combination with chemotherapy. These 
regimens have shown activity, however, none of these options is curative and a standard of care 
has not been established. Short-term- and long-term toxicities caused by traditional therapeutic 
agents (such as chemotherapy or chemoimmunotherapy) make these treatments challenging for 
patients with WM who are generally aged 65 years and older and often have comorbidities. 
Furthermore, present treatment approaches for relapsed WM provide a modest progression-free 
survival of 16–24 months in the second-line and third-line settings.2 More effective therapeutic 
options therefore are needed to provide long-term- disease control with reduced toxicity. 
Ibrutinib is an orally administered, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). 
Unlike traditional therapeutic agents, it can trigger apoptosis of WM cells with MYD88
(Leu265Pro) which is present in more than 90% of WM patients.3, 4 Additionally, ibrutinib 
inhibits HCK, an SRC family member that is transactivated by mutated MYD88 and triggers 
both AKT and extracellular-signal-regulated kinase (ERK) prosurvival signaling in WM cells.5
Studies PCYC-1118E and PCYC-1127-CA demonstrated clinical benefit as well as a favorable 
safety profile of ibrutinib in subjects with WM. Based on the results of these two studies, China 
National Medical Product Administration (NMPA) conditionally approved ibrutinib in WM in
November 2018, making ibrutinib the first drug specifically approved for the treatment of this 
rare disease in China.


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1.1.
Ibrutinib Background
1.1.1.
Ibrutinib
The generation and maintenance of normal and malignant B-cells is controlled by biochemical 
signals transmitted by the B-cell antigen receptor (BCR). BTK is an enzyme required for BCR 
signaling. Selective BTK inhibition is a novel approach to target diseases driven by BCR 
activation. Inhibition of BTK blocks downstream BCR signaling pathways and thus prevents 
B-cell 
proliferation. 
Ibrutinib, 
currently 
under 
development 
for 
the 
treatment 
of 
B-cell- malignancies, is a first-in-class, potent, orally-administered, covalent inhibitor of BTK. 
Clinical studies of ibrutinib in B-cell malignancies demonstrate modest toxicity and significant 
single-agent activity in a variety of B-cell malignancies, including WM. Ibrutinib, PCI-32765, 
and JNJ-54179060 refer to the same molecule; hereafter, “ibrutinib” will be used. 
Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo [3, 4 d] pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis). 
Ibrutinib is a white to off-white solid. It has a single chiral center and is the R-enantiomer. The 
investigational drug product, ibrutinib, is an oral capsule formulation containing micronized 
ibrutinib.
Ibrutinib is being co-developed by Janssen Research & Development, LLC (JRD) and 
Pharmacyclics, Inc. (PCYC). As of 12 November 2019, ibrutinib (IMBRUVICA®) has been 
approved in approximately 100 countries for 1 or more of the following indications: for the 
treatment of adult patients with mantle cell lymphoma (MCL) who have received at least 1 prior 
therapy, chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), CLL/SLL 
with the presence of 17p deletion, WM, marginal zone lymphoma (MZL) who require systemic 
therapy and have received at least 1 prior anti-CD20-based therapy, and chronic graft-versus-
host disease (cGVHD) after failure of 1 or more lines of systemic therapy. Ibrutinib continues in 
late-stage development for patients with B-cell malignancies, cGVHD, and solid tumors. In 
China, ibrutinib was approved as a single-agent for the treatment of 1) MCL in patients who 
have received at least one prior therapy; 2) CLL/SLL; 3) WM in patients who have received at 
least one prior therapy, or in first line treatment for patients unsuitable for chemo 
immunotherapy and in combination with rituximab for the treatment of patients with WM.
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.
For the most comprehensive nonclinical and clinical information regarding the efficacy and 
safety of ibrutinib, refer to the latest version of the Investigator’s Brochure (IB).
1.1.2.
Clinical Studies
As of 12 November 2019, 53 studies have completed their primary or final analysis, and 
17 studies
are ongoing. These studies have investigated the safety, efficacy and/or
pharmacokinetics (PK) of ibrutinib in humans as a single agent and in combination with 
chemotherapy and immunotherapy. Ongoing and completed company-sponsored clinical studies 
of ibrutinib are summarized in the latest version of IB.


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1.1.2.1.
Human Pharmacokinetics 
The PK of ibrutinib has been assessed in subjects with B-cell malignancies, cGVHD, as well as 
in healthy subjects. In all studies, both parent ibrutinib and metabolite PCI-45227 were 
quantified. PCI-45227 is a prominent dihydrodiol metabolite observed in laboratory animals and 
humans, with a reversible inhibitory activity towards BTK approximately 15 times lower than 
that of ibrutinib and with plasma concentrations in the same range as parent drug levels. The on
target effects of metabolite PCI-45227 are not considered clinically relevant. The PK of ibrutinib 
does not significantly differ in patients with different B-cell malignancies (CLL, SLL, MCL, 
WM, and MZL). Ibrutinib is absorbed after oral administration with a median Tmax of 1 hour to 
2 hours. The half-life of ibrutinib is 4 to 6 hours. Administration of ibrutinib in a fasted condition 
resulted in approximately 60% of exposure (AUC) as compared to administration either in fed 
condition (30 minutes after a high-fat breakfast), or 2 hours after a meal. Considering the 
approximate doubling in mean systemic exposure when dosed with food and the favorable safety 
profile, ibrutinib can be dosed with or without food. The PK in Chinese CLL/SLL patients is 
similar to those in non-Chinese subjects with various B-cell malignancies.
1.1.2.2.
Clinical Efficacy of Ibrutinib in Waldenström’s Macroglobulinemia
Three clinical studies within the clinical development program have enrolled subjects with WM.
Efficacy results are summarized as below.
1.1.2.2.1.
Study PCYC-04753
Study PCYC-04753 is a Phase 1, dose-escalating study of ibrutinib in subjects with recurrent 
B-cell lymphoma. 
The study enrolled 4 male subjects with relapsed/refractory WM who received a median of 
3 prior systemic regimens and were treated at 2 different dose levels (560 mg/day and 
12.5 mg/kg/day). One out of the 4 subjects achieved disease stabilization according to the 
treating physician but ultimately discontinued ibrutinib due to progressive disease after 
8 months. Three out of the 4 subjects achieved a PR (IgM reduction of at least 50% from 
baseline). The induced responses were durable, and all 3 subjects rolled over onto the extension 
Study PCYC-1103-CA and continue to receive treatment with ibrutinib for more than 4 years. In 
addition to the clinically significant IgM decrease in the 3 responders, all 4 subjects had an 
increase in their hemoglobin and hematocrit over treatment time.  
1.1.2.2.2.
Study PCYC-1118E
Study PCYC-1118E is a Phase 2, single-arm, multi-center study designed to evaluate the safety 
and efficacy of ibrutinib in subjects with WM. Treatment was comprised of ibrutinib 
administered orally at a daily dose of 420 mg and continued for approximately 3 years or until 
disease progression. Sixty-four (64) subjects were enrolled; at the time of the data cutoff,
efficacy data were obtained from 63 subjects. The median time on study was 14.8 months.
The clinical response rate (MR or better) was 87.3% and the response rate (PR or better) was 
69.8%, respectively; the responses were rapid, durable, improved over time, and were associated 
with sustained improvements in hemoglobin. The median progression-free survival (PFS) was 


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not reached. The estimated 18-month landmark PFS rate was 83.2%. The median OS was not 
reached. The estimated 18-month landmark OS rate was 81.7%.
1.1.2.2.3.
Study PCYC-1127-CA
The Phase 3 Study PCYC-1127-CA is a randomized, double-blind, placebo-controlled study to 
evaluate safety and efficacy of ibrutinib in combination with rituximab in subjects with WM. In 
addition, an open-label substudy is included to further investigate the safety and efficacy of 
ibrutinib monotherapy in subjects with WM who were considered refractory to the last prior 
rituximab-containing therapy.
In the randomized study, 150 subjects were randomized in a 1:1 ratio to receive ibrutinib and
rituximab (Ibr+R) or placebo and rituximab (Pbo+R). The median time on study was 
26.5 months at the time of the primary analysis (26.7 months for the Ibr+R arm and 26.0 months 
for the Pbo+R arm). 
Analysis of PFS per the Independent Review Committee [IRC]
demonstrated a statistically significant reduction in the risk of disease progression or death in the 
Ibr+R arm compared to the Pbo+R arm (HR=0.202, p<0.0001). The response rate (PR or better) 
per IRC assessment was significantly higher for the Ibr+R arm (72.0%) than the Pbo+R arm 
(32.0%) (p < 0.0001).
Thirty-one (31) subjects were enrolled in the open-label ibrutinib monotherapy substudy, all of 
whom received ibrutinib and comprised the population used for efficacy analyses. The median 
time on study was 34.4 months. Efficacy results show that ibrutinib 420 mg once daily is highly 
active for subjects with rituximab refractory WM. Median PFS per IRC assessment was not 
reached; the 30-month landmark estimate was 57.5%. The response rate (PR or better) per IRC 
assessment was 71.0%.
A summary of efficacy results for Studies PCYC-1118E and PCYC-1127-CA is provided in
Table 1. 


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Table 1:
Efficacy Results with Ibrutinib in subjects with WM
Study
Description
No. of Subjects
Efficacy Resultsa
PCYC-
1118E
Phase 2, open-label, single-arm, monotherapy, 
multicenter study in subjects with previously 
treated WM
63
Median time on study: 14.8 months
PFS (INV)c: 83.2% (95% CI: 66.3, 92.1) at 19 months, median NR
PFS (IRC): 79.5% (95% CI: 65.8, 88.2)
ORR (INV)b: 87.3% (95% CI: 76.5, 94.4)
ORR (IRC): 82.5% (95% CI: 70.9, 90.9)
Major response rate (INV)c: 69.8% (95% CI: 57.0, 80.8)
Major response rate (IRC): 61.9% (95% CI: 48.8, 73.9)
Median DOR (INV)c: NR
OSc: 81.7% at 18 months, median NR
PCYC-
1127-CA
Phase 3, randomized, double-blind, placebo-
controlled, combination therapy, multicenter 
study in subjects with WM.
Randomized study:
75 ibrutinib +R
75 placebo +R 
Median time on study: 26.7 months Ibr+R
                                     26.0 months Pbo+R
PFS (IRC)b: HR 0.20 (95% CI: 0.11, 0.38), p<0.0001
PFS (INV): HR: 0.22 (95% CI: 0.12, 0.40), p<0.0001
Median PFS (IRC)b: NR ibrutinib+R vs. 20.3 months placebo+R
Median PFS (INV): NR ibrutinib+R vs. 20.3 months placebo+R
ORR (IRC)c: 72.0% ibrutinib+R vs. 32.0% placebo+R
ORR (INV): 77.3% ibrutinib+R vs. 33.3% placebo+R
Median TTnT (IRC): NR ibrutinib+R vs. 18.1 months placebo+R
OSc: 93.7% ibrutinib+R vs. 91.9% placebo+R at 30 months, median 
NR for either arm
Open-label substudy:
31 ibrutinib single 
agent treatment
Median time on study: 34.4 months ibrutinib arm
PFS (IRC): 57.5% (95% CI: 38.2, 72.7) at 30 months, median NR
PFS (INV): 64.4% (95% CI: 44.9, 78.4) at 30 months, median NR
ORR (IRC): 71.0%
ORR (INV): 77.4%
OS: 90.3% at 30 months, median NR
Abbreviations: CI=confidence interval; DOR=duration of response; HR=hazard ratio; IRC= Independent Review Committee; NR= not reached; ORR=overall response
rate; OS=overall survival; PFS=progression-free survival.
a.
Efficacy results are based on the primary analysis for Studies PCYC-1118E and PCYC-1127-CA. 
b.
Primary endpoint
c.
Secondary endpoint.
  


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1.1.2.3.
Clinical Safety of Ibrutinib
As of 12 November 2019, safety data from completed studies (primary or final analysis clinical 
study reports [CSRs] completed) are available for 4,439 subjects. Of these, 2,132 subjects were 
exposed to ibrutinib in monotherapy trials (1,600 subjects with hematologic malignancies, 42 
subjects with cGVHD, 460 healthy volunteers, and 30 subjects in a hepatic impairment study) 
and 2,307 subjects were exposed to ibrutinib in combination therapy trials (1,971 subjects with 
hematologic malignancies, and 336 subjects with solid tumors). A brief overview of the potential 
risks associated with the administration of ibrutinib based on sponsor-initiated clinical studies is 
presented in the ibrutinib Investigator’s Brochure and is outlined below.
1.1.2.3.1.
Non-Hematological Adverse Events
Bleeding-Related Events
There have been reports of bleeding events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor bleeding events such as contusion, epistaxis, 
and petechiae; and major bleeding events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria.
In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen induced platelet 
aggregation were observed. Use of either anticoagulant or antiplatelet agents concomitantly with
ibrutinib increases the risk of major bleeding. A higher risk for major bleeding was observed 
with anticoagulant than with antiplatelet agents. Consider the risks and benefits of anticoagulant 
or antiplatelet therapy when co-administered with ibrutinib. Monitor for signs and symptoms of 
bleeding.
See Section 8.2.3 for guidance on concomitant use of anticoagulants, antiplatelet therapy and/or 
supplements. See Section 8.4 for guidance on ibrutinib management with surgeries or 
procedures.
Infections
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy. Some of these infections have been associated with hospitalization 
and death. Consider prophylaxis according to standard of care in subjects who are at increased 
risk for opportunistic infections. Although causality has not been established, cases of 
progressive multifocal leukoencephalopathy and hepatitis B reactivation have occurred in 
subjects treated with ibrutinib. 
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. 


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Interstitial lung disease 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib.  
Non-melanoma skin cancer
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. 
Tumor lysis syndrome
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. 
Hypertension
Hypertension has been commonly reported in subjects treated with ibrutinib. 
Cerebrovascular Accidents 
Although causality has not been established, cases of cerebrovascular accident, transient 
ischemic attack, and ischemic stroke including fatalities have been reported with the use of 
ibrutinib in the post-marketing setting, with and without concomitant atrial fibrillation and/or 
hypertension.
Diarrhea
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy.  Other frequently reported gastrointestinal events include nausea, vomiting,
and constipation. These events are rarely severe and are generally managed with supportive 
therapies including antidiarrheals and antiemetics. 
Rash
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. In a randomized Phase 3 study (PCYC-1112-CA), rash occurred
at a higher rate in the ibrutinib arm than in the control arm.  Most rashes were mild to moderate in
severity.
Isolated cases of severe cutaneous adverse reactions (SCARs) including 
Stevens-Johnson syndrome (SJS) have been reported in subjects treated with ibrutinib. In 
addition, hypersensitivity-related events of erythema, urticaria, angioedema have been reported.
1.1.2.3.2.
Hematological Adverse Events
Cytopenias
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were
reported in subjects treated with ibrutinib.
Leukostasis
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high number 
of circulating lymphocytes (>400,000/mcL) may confer increased risk. Consider temporarily 
holding ibrutinib. 


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Lymphocytosis 
Upon initiation of single agent treatment with ibrutinib, a reversible increase in lymphocyte 
counts (ie, ≥50% increase from baseline and an absolute count >5,000/mcL), often associated 
with reduction of lymphadenopathy, has been observed in most subjects (66%) with CLL/SLL.
This effect has also been observed in some subjects (35%) with MCL treated with ibrutinib. 
When ibrutinib was administered in combination with BR or with obinutuzumab in subjects with 
CLL/SLL, lymphocytosis was infrequent (7% with ibrutinib + BR versus 6% with placebo + BR 
and 7% with ibrutinib + obinutuzumab versus 1% with chlorambucil + obinutuzumab).
Lymphocytosis was not observed in subjects with WM treated with ibrutinib. 
1.1.2.3.3.
Long-term safety
The long-term safety data over 5 years from 1,178 subjects (treatment naïve CLL/SLL n = 162, 
relapsed/refractory CLL/SLL n = 646, and relapsed/refractory MCL n = 370) treated with 
ibrutinib were analyzed. The median duration of treatment for CLL/SLL was 51 months (range, 
0.2 to 98 months) with 70% and 52% of subjects receiving treatment for more than 2 years and 
4 years, respectively. The median duration of treatment for MCL was 11 months (range, 0 to 
87 months) with 31% and 17% of subjects receiving treatment for more than 2 years and 4 years, 
respectively. The overall known safety profile of ibrutinib-exposed subjects remained consistent, 
other than an increasing prevalence of hypertension, with no new safety concerns identified. The 
prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2-3), 
9% (year 3-4), and 9% (year 4-5). The incidence for the 5-year period was 11%.
1.2.
Overall Rationale for the Study
WM is a malignant B-cell lymphoma that is associated with an accumulation of clonal 
lymphoplasmacytic cells and monoclonal IgM secretion.12 Although treatments such as 
chemotherapy or chemoimmunotherapy has shown some activity in subjects with WM, more 
effective therapeutic options still need to provide long term disease control with reduced toxicity 
especially for those who do not respond to rituximab-based treatment.
Ibrutinib is an orally administered, small-molecule inhibitor of BTK. In contrast to the traditional 
therapeutic agents, it can trigger apoptosis of WM cells with MYD88L265P which present in 
more than 90% of subjects. Studies PCYC-1118E and PCYC-1127-CA demonstrated that 
ibrutinib is highly effective and has a favorable safety profile for the treatment of WM, which 
leads to the conditional approval of ibrutinib in WM in China. Since no Chinese subjects were 
enrolled in the global pivotal studies, this single arm, multicenter, Phase 4 study is to evaluate 
the efficacy and safety of ibrutinib monotherapy in Chinese subjects with relapsed or refractory 
WM. As agreed upon with the China NMPA, data from this study will be used to support the full 
approval for ibrutinib in WM in China.


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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESISES
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of ibrutinib based on overall 
response rate (ORR [PR or better]) by investigator assessment per the modified Consensus 
Response Criteria from the VIth International Workshop on WM (IWWM) (NCCN 2019), in 
Chinese subjects with relapsed or refractory WM.19,20
Secondary Objectives
Secondary objectives are to evaluate: clinical response rate (minor response [MR] or better) by 
investigator assessment according to the modified VIth IWWM (NCCN 2019) criteria, Very 
Good PR (VGPR) or better by investigator assessment according to the modified VIth IWWM 
(NCCN 2019) criteria; duration of response (DOR) by investigator assessment; time to response
(TTR) by investigator assessment; PFS by investigator assessment; overall survival (OS); safety 
and PK of ibrutinib in Chinese patients with relapsed or refractory WM.
2.1.2.
Endpoints
Primary Endpoint
The primary efficacy endpoint is ORR by investigator assessment. ORR is defined as the 
proportion of subjects who achieve PR or better per the modified Consensus Response Criteria 
from the VIth IWWM (NCCN 2019).19,20
Secondary Endpoints
Efficacy 

Clinical response rate (CRR, ≥MR)

VGPR or better rate

DOR

TTR

PFS

OS
Pharmacokinetics

To evaluate PK of ibrutinib in Chinese subjects with relapsed or refractory WM
Safety

To assess the safety and tolerability of ibrutinib in Chinese symptomatic relapsed or 
refractory WM subjects
Refer to Section 9, Study Evaluations for evaluations related to endpoints.


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2.2.
Hypothesis
The primary hypothesis for this study is that ibrutinib is an effective agent as measured by ORR 
(with a point estimate approximately 70% and the lower bound of the 90% confidence interval
[CI] is greater than 32%) in Chinese subjects with relapsed/refractory WM.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a single-arm multicenter, Phase 4 study to evaluate the efficacy and safety of ibrutinib in 
Chinese subjects with relapsed or refractory WM with symptomatic disease meeting at least 1 of 
the recommendations from the Second IWWM for requiring treatment. 
Approximately 17 subjects will be enrolled into the study. Subjects will receive ibrutinib 420 mg 
daily until disease progression or unacceptable toxicity, whichever occurs first. Ibrutinib will be 
supplied as hard gelatin capsules for oral administration.
The study will include a Screening Phase, a Treatment Phase and a Follow-Up Phase.
The Screening Phase assessments will be performed within 30 days prior to study treatment and 
will begin on the day the subject signs informed consent. During the Screening Phase, the 
subjects’ eligibility will be determined.
The Treatment Phase will extend from first dose of study drug until study drug discontinuation.
The Follow-up Phase will consist of the Post-treatment pre-disease progression Phase and a 
Post-disease Progression Phase. The Post-treatment pre-disease progression Phase will extend 
from the discontinuation of treatment (for reasons other than disease progression) until the 
subject has progressive disease, at which point the Post-disease Progression Phase will begin. 
Subjects who progress on treatment will transition directly to the post disease progression phase. 
In this latter phase, subsequent anticancer therapy, occurrence of any other malignancy and 
survival status will be recorded until death, lost to follow-up, consent withdrawal, or study 
closure.
The study is planned to be completed 3 years after the last subject receives first dose. 
Clinical cutoffs (CCOs) planned for this study are:

CCO for the primary analysis is estimated to be performed approximately 12 months after the last 
subject receives first dose. Alternative appropriate cutoffs will be considered based on regulatory 
requirement.

CCO for the final analysis is estimated to occur 3 years after last subject receives first dose.
A diagram of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview of the Study
3.2.
Study Design Rationale
3.2.1.
Rationale for Ibrutinib Dose
The proposed dose for ibrutinib is 420 mg per day (3 × 140-mg capsules) administered once
daily without interruption. In Study1118E and Study 1127, the 420 mg dose administered once 
daily appeared safe and favorable responses were seen in subjects with previously treated WM as 
outlined in Section 1.1.2.2.
3.2.2.
Rationale for Efficacy Endpoints
The proposed study uses ORR as the primary endpoint, since it has already served as the basis 
for regulatory approvals in WM. Key secondary endpoints such as DOR are also recommended 
endpoints for the clinical study evaluation of new treatments for WM.18


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4.
SUBJECT POPULATION
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Men and women ≥18 years of age.
2.
Eastern Cooperative Oncology Group (ECOG) performance status grade of ≤2.
3.
Subjects must have received at least one prior therapy for WM and have had either 
documented disease progression or had no response (stable disease) to the most recent 
treatment regimen.
4.
Centrally confirmed clinicopathological diagnosis of WM in accordance with the consensus 
panel of the Second IWWM.
Note: Bone marrow aspirate and biopsy should be performed for all subjects at screening 
and should be completed within 30 days of first dose administration. Samples will be sent to 
the central laboratory to confirm clinicopathological diagnosis of WM.
5.
Measurable disease defined as serum monoclonal IgM >0.5 g/dL.
6.
Symptomatic disease meeting at least 1 of the criteria from the Second IWWM for requiring 
treatment.21
a.
Constitutional symptoms documented in the subject’s chart with supportive objective 
measures, as appropriate, defined as one or more of the following disease-related 
symptoms or signs:
i.
Unintentional weight loss ≥10% within the previous 6 months prior to Screening
ii.
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks prior to Screening 
without evidence of infection
iii.
Night sweats for more than 1 month prior to Screening without evidence of 
infection
b. Clinically relevant fatigue which is not relieved by rest due to WM
c.
Symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises (or in 
equivalent units)  
d. Lymphadenopathy which is either symptomatic or bulky (≥5 cm in maximum diameter)
e.
Symptomatic hepatomegaly and/or splenomegaly and/or organ tissue infiltration
f.
Peripheral neuropathy due to WM


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g. Symptomatic cryoglobulinemia
h. Cold agglutinin anemia
i.
IgM related immune hemolytic anemia and/or thrombocytopenia
j.
Nephropathy related to WM
k. Amyloidosis related to WM
l.
Hemoglobin ≤10 g/dL
m. Platelet count <100 × 109/L
n. Serum monoclonal protein >6 g/dL, with or without overt clinical symptoms
7.
Meet the following laboratory parameters:
a.
Absolute neutrophil count >750 cells/mm3 (0.75 × 109/L) independent of growth factor 
support within 7 days of the laboratory testing 
b. Platelet count >50,000 cells/mm3 (50 × 109/L) without transfusion support within 7 days 
of the laboratory testing 
c.
Hemoglobin ≥7 g/dL without transfusion or growth factor support within 7 days of the 
laboratory testing 
d. Serum aspartate transaminase (AST) or alanine transaminase (ALT) <3.0 × upper limit of 
normal (ULN).
e.
Estimated Creatinine Clearance using Cockcroft Gault ≥30 mL/min (see Attachment 6).
f.
Total bilirubin ≤1.5 × ULN (unless bilirubin rise is due to Gilbert’s syndrome or of 
nonhepatic origin).
g. Prothrombin time (PT)/international normalized ratio (INR) ≤1.5 × ULN and PTT (aPTT)
≤1.5 × ULN unless abnormality is unrelated to a coagulopathy or bleeding disorder.
8.
Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening and agree to use highly effective methods of contraception while taking study 
drug. Those using hormonal methods of birth control must add a barrier method. Female 
subjects of childbearing potential should avoid becoming pregnant while taking ibrutinib and 
for up to 1 month after the last dose of study drug. 
9.
Male subjects must use an effective barrier method of contraception during the study and for 
3 months following the last dose of ibrutinib if sexually active with a female of childbearing 
potential.


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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. Involvement of the central nervous system by WM.
2. Evidence of disease transformation.
3. Prior exposure to ibrutinib or other BTK inhibitors.
4. Known hypersensitivity reaction (eg. Anaphylactic and anaphylactoid reactions) to 
ibrutinib or to the excipients in its formulation. Refer to the IB for a list of excipients.
5. Received any WM-related therapy (eg, chemotherapy, immunotherapy, investigational 
drug) ≤30 days prior to first administration of study treatment.
6. Received a prior allogeneic hematopoietic stem cell transplant. 
7. Plasmapheresis <35 days prior to the initiation of study drug, except when at least one 
serum IgM central assessment was performed during the screening period and was 
>35 days from the most recent plasmapheresis procedure.

Subjects with high IgM values or viscosity symptoms during screening may 
receive plasmapheresis prior to initiating study drug (refer to Section 8.5) if the 
previous plasmapheresis was performed >35 days before the plasmapheresis 
performed during screening (in order to obtain a true baseline IgM value for 
efficacy evaluations).
8. History of other malignancies, except:

Malignancy treated with curative intent and with no known active disease present 
for ≥2 years before the first dose of study drug and felt to be at low risk for 
recurrence by treating physician.

Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease.

Adequately treated carcinoma in situ without evidence of disease.
9. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
10. Infection requiring systemic treatment that was completed ≤14 days before the first dose 
of study drug.
11. Bleeding disorders (eg, von Willebrand’s disease) or hemophilia.
12. Stroke or intracranial hemorrhage within 6 months prior to enrollment.


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13. Infection with human immunodeficiency virus (HIV).
14. Active infection with hepatitis B or hepatitis C. 

Note: If Hepatitis B surface antigen (HBsAg) is positive, the subject is excluded. 
Hepatitis B DNA polymerase chain reaction (PCR) needs to be confirmed 
negative prior to first study agent administration in subjects who are Hepatitis B 
core antibody positive. If Hepatitis C antibody is positive, RNA PCR needs to be 
performed and confirmed negative prior to the first study agent administration.
Patient with history of Hepatitis C virus infection should have documented 24wks 
of sustained virologic response (SVR) in order to be eligible for the study.
15. Major surgery (as defined in Section 8.4.2) within 4 weeks of first dose of study drug.
16. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes 
at undue risk.
17. Currently active, clinically significant hepatic impairment Child-Pugh Class B or C 
according to the Child Pugh classification (see Attachment 4).
18. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification (Attachment 7); or a history of myocardial 
infarction, unstable angina, or acute coronary syndrome within 6 months prior to first
dose.
19. Requires or receiving anticoagulation with warfarin or other Vitamin K antagonists (eg, 
phenprocoumon).
20. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel 
obstruction.
21. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see 
Attachment 3).
22. Lactating or pregnant.
23. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information (in 
accordance with national and local subject privacy regulations).


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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 drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria. Subjects who fail to meet the inclusion
and exclusion criteria (ie, screen failures) may be rescreened once if their condition changes. 
Rescreening must be discussed with and approved by the sponsor on a case-by-case basis. 
Subjects who are determined to be eligible for rescreening must sign a new ICF and then will be 
assigned a new Screening number.
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 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).
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.
TREATMENT ALLOCATION AND BLINDING
Randomization will not be used in this study. Subjects will be enrolled to receive study treatment 
after eligibility is confirmed. As this is an open study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
Ibrutinib will be administered orally, once daily, at a dose of 420 mg (140 mg × 3 capsules taken 
together at one time). Protocol-specified dose modifications of ibrutinib will be made as 


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necessary. Study drug (3 capsules) is administered orally once daily with approximately 8 ounces 
(240 mL) of water. The capsules should be swallowed whole and should not be opened, broken, 
or chewed. The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges 
should be avoided for the duration of the study (Section 8.2 and Attachment 3).
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. Missed doses of study drug will not be made up.
The first dose will be administered in the clinic on Day 1 of Week 1, after which study drug will 
be self-administered daily by the subjects on an outpatient basis. Study drug will be dispensed to 
subjects in bottles. Unused study drug dispensed during previous visits must be returned to the 
site and drug accountability records (Section 14.5) updated at each visit. Returned capsules must 
not be re-dispensed to anyone. 
Study drug dosing is continuous (without interruptions) throughout the Treatment Phase. 
6.1.
Formulation/Packaging/Storage
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib. All 
formulation excipients are compendial and are commonly used in oral formulations. Refer to the 
ibrutinib IB for a list of excipients.
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies. All study 
drugs will be dispensed in child-resistant packaging. Refer to the pharmacy manual/site 
investigational product manual for additional guidance on study drug storage, preparation and 
handling. Study drug labels will contain information to meet the applicable regulatory 
requirements.
6.2.
Overdose
Any dose of study drug administered in excess of that specified in this protocol is considered to 
be an overdose. Signs and symptoms of an overdose that meet any Serious Adverse Event 
criterion must be reported as a Serious Adverse Event in the appropriate time frame and 
documented as clinical sequelae to an overdose.
There is no specific experience in the management of ibrutinib overdose in patients. No 
maximum tolerated dose was reached in the Phase 1 study in which subjects received up to 
12.5 mg/kg/day (1,400 mg/day). Healthy subjects were exposed up to single dose of 1,680 mg. 
One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) 
after a dose of 1,680 mg. Subjects who ingested more than the recommended dosage should be 
closely monitored and given appropriate supportive treatment. Refer to Section 12 for further 
information regarding AE reporting (refer to Section 12.3.2 for Special Reporting Situations).


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6.3.
Dose Hold, Reduction or Discontinuation of Study Drug
Treatment with study drug should be withheld for any unmanageable, potentially study 
drug-related non-hematological toxicity that is Grade 3 or higher in severity and any hematologic 
toxicity meeting the criteria in Section 6.4. Subjects who require full-dose of anticoagulant 
treatment (eg, heparin) should have study drug held until stable on anticoagulant therapy 
(Section 8.2.3). Subjects that require an invasive procedure or surgery must have study drug 
withheld according to the guidance in Section 6.2. Any other clinically important events where 
dose delays may be considered appropriate by the Investigator must be discussed with the 
Medical Monitor.
Study drug may be withheld for a maximum of 28 consecutive days for toxicity. Study drug 
should be discontinued in the event of a toxicity lasting more than 28 days, unless reviewed and
approved by the Medical Monitor.
6.4.
Dose Modification of Study Drug
The dose of study drug should be modified according to the dose modification guidance in 
Table 2 if any of the following drug-related toxicities occur:
•
Grade 3 or greater neutropenia with infection or fever
•
Grade 4 ANC (<500/μL) for more than 7 days. The use of neutrophil growth factors is 
permitted per American Society of Clinical Oncology (ASCO) guidelines and must be 
recorded in the electronic case report form (eCRF). Refer to Section 8 for instruction 
regarding the use of growth factor support.
•
Grade 3 thrombocytopenia (platelets <50,000/μL) in the presence of Grade ≥2 bleeding
events.
•
Grade 4 thrombocytopenia (platelets <25,000/μL).
•
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal anti-emetic
and/or anti-diarrheal therapy.
•
Any other Grade 4 or unmanageable Grade 3 toxicity attributed to study drug.
For Grade 3 or 4 atrial fibrillation or persistent atrial fibrillation of any grade, consider the risks 
and benefits of ibrutinib treatment. If clinically indicated, the use of anticoagulants or antiplatelet 
agents may be considered for the thromboprophylaxis of atrial fibrillation (Section 8.2.3).


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Table 2:
Study Drug Dose Modifications
Occurrence 
Action
First
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at original 
dose level
Second 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose 
level lower (ie, 280 mg/day/2 capsules)
Third 
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose 
level lower (ie, 140 mg/day/1 capsule)
Fourth 
Discontinue ibrutiniba
a. If the oral study drug is discontinued for toxicity, subject will end the Treatment Phase of the study.
Please see Section 8.2.1 for guidelines for management of study drug in subjects who require 
treatment with a strong CYP3A inhibitor.
Once there has been a dose reduction of ibrutinib, there will be no dose re-escalations. No dose 
escalation of ibrutinib (above 420 mg) is allowed in this study.
6.5.
Dose Modification for Hepatic Impaired Subjects
Ibrutinib is metabolized in the liver. For subjects with mild liver impairment (Child-Pugh class 
A), the recommended dose for ibrutinib is 140 mg daily (one capsule). Subjects with moderate or 
severe hepatic impairment (Child-Pugh class B or C) should avoid using ibrutinib. Monitor 
subjects for signs of toxicity and follow dose modification guidance as needed.
7.
TREATMENT COMPLIANCE
The investigator or designated study personnel will maintain a log of all study drug dispensed 
and returned. Drug supplies for each subject will be inventoried and accounted for throughout 
the study. 
The study drug is to be prescribed only by the principal investigator or a qualified physician 
listed as a sub-investigator. Records should be kept on the study drug accountability form 
provided by the sponsor or its designee (any alternative forms must be preapproved by the 
sponsor). Administration of the study drug must be recorded in the subject’s source 
documentation. The study drug may not be used for any purpose other than that outlined in this 
protocol, including other human studies, animal investigations, or in vitro testing.  
8.
PRESTUDY AND CONCOMITANT THERAPY
All prestudy antineoplastic therapies, including those since diagnosis of WM, must be recorded 
at screening. Concomitant therapies will include only clinically significant prescription therapies,
“significant” will be any medications which the investigator thinks important and are prescribed 
for AE. They must be recorded throughout the study beginning with the time of written informed 
consent to 30 days after the last dose of study drug. All concomitant therapies (prescription, 
nonprescription, herbal) being taken at the time of an SAE will be collected. The use of these 
medications/transfusions must be recorded in the eCRF.


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All other therapies (over-the-counter medications except fish oil, vitamin E preparations; non-
pharmacologic therapies such as electrical stimulation, acupuncture, special diets, exercise 
regimens) are not required to be recorded in the eCRF.
8.1.
Permitted Concomitant Medications
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted. Use of granulocyte colony-stimulating factors or erythropoietin growth factors is 
permitted per institutional policy and in accordance with the ASCO guidelines (Smith 2006). 
Transfusions may be given in accordance with institutional policy.
Short courses (≤14 days) of steroid treatment for non-WM related medical reasons (eg, joint 
inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at doses that do 
not exceed 100 mg per day of prednisone or equivalent are permitted. In addition, for subjects 
with chronic medical conditions, continuous administration of up to 20 mg per day of prednisone 
or equivalent is permitted for the treatment of this medical condition where no acceptable 
therapeutic alternative is available.
8.2.
Medications to be Used with Caution
8.2.1.
CYP3A Inhibitors/Inducers
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong CYP3A4 
inhibitors (eg, ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, 
telithromycin, itraconazole, nefazadone, and cobicistat) and consider alternative agents with less 
CYP3A inhibition. If the benefit outweighs the risk and a strong CYP3A inhibitor must be used: 
a) for voriconazole and posaconazole (at doses less than or equal to suspension 200 mg twice 
daily [BID]), reduce ibrutinib to 140 mg once daily; b) for posaconazole at higher doses
(suspension 200 mg three times daily or 400 mg BID, IV injection 300 mg once daily, delayed-
release tablets 300 mg once daily) or other strong CYP3A4 inhibitors used short-term (such as 
anti-infectives for seven days or less), interrupt ibrutinib. If a moderate CYP3A inhibitor (eg, 
fluconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, 
diltiazem, fosamprenavir, imatinib, verapamil, amiodarone, and dronedarone) must be used, 
reduce ibrutinib to 280 mg for the duration of the inhibitor use. No dose adjustment is required in 
combination with mild inhibitors. Subjects should be monitored for signs of ibrutinib toxicity. 
Avoid grapefruit and Seville oranges during ibrutinib treatment, as these contain strong or 
moderate inhibitors of CYP3A (see Section 6). Recommended dose modifications for ibrutinib 
when co-administered with CYP3A inhibitors are summarized in Attachment 5.
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort).
A list of
CYP3A inhibitors and inducers can be found in Attachment 3
and at 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. This website is continually revised and 
should be checked frequently for updates. For the most comprehensive effect of CYP3A 
inhibitors or inducers on ibrutinib exposure, please refer to the current version of the IB.


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8.2.2.
Drugs That May Have Their Plasma Concentrations Altered by 
Ibrutinib
In vitro studies indicated that ibrutinib is a weak reversible inhibitor toward CYP2B6, CYP2C8 
CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 and does not display time-dependent CYP 
inhibition. The dihydrodiol metabolite of ibrutinib is a weak inhibitor toward CYP2B6, 
CYP2C8, CYP2C9, and CYP2D6. Both ibrutinib and the dihydrodiol metabolite are at most 
weak inducers of CYP450 isoenzymes in vitro. Therefore, it is unlikely that ibrutinib has any 
clinically relevant drug-drug interactions with drugs that may be metabolized by the CYP450 
enzymes.
Ibrutinib is a mild inhibitor of P-gp and breast cancer resistance protein (BCRP). 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 are no clinical 
data available. To minimize the 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.
Ibrutinib may also inhibit BCRP systemically and increase the exposure of drugs that undergo 
BCRP-mediated hepatic efflux, such as rosuvastatin.
8.2.3.
Concomitant Use of Antiplatelet Agents and Anticoagulants
Warfarin or other vitamin K antagonists as well as supplements such as fish oil and vitamin E 
preparations should be avoided. Use ibrutinib with caution in subjects requiring anticoagulants or 
medications that inhibit platelet function. Subjects with congenital bleeding diathesis have not 
been studied. Ibrutinib should be held at least 3 to 7 days pre- and post-surgery depending upon 
the type of surgery and the risk of bleeding (see Section 8.4).
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment. If therapeutic anticoagulation is 
clinically indicated, treatment with ibrutinib should be held and not be restarted until the subject 
is clinically stable and has no signs of bleeding. No dose reduction is required when study drug is 
restarted. Subjects should be observed closely for signs and symptoms of bleeding.
8.3.
Prohibited Concomitant Medications
Any other chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy are 
prohibited while the subject is receiving study drug.
Corticosteroids for the treatment of the underlying disease are prohibited. Please refer to 
Section 8.1 for corticosteroid use in other medical situations.
The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which use of prohibited therapies are considered.
8.4.
Procedures
The following guidance should be applied during the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving study drug.


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8.4.1.
Minor Surgical Procedures
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture [other 
than shunt reservoir access] thoracentesis, or paracentesis) study drug 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 drug, it is not 
necessary to hold study drug.
8.4.2.
Major Surgical Procedures
For any surgery or invasive procedure requiring sutures or staples for closure, study drug 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.
8.4.3.
Emergency Procedures
For emergency procedures, study drug should be held after the procedure for at least 7 days after 
the urgent surgical procedure.
8.5.
Plasmapheresis
Management of hyperviscosity in WM patients may include plasmapheresis before and during 
treatment with study drug. Modifications to the dosing of study drug are not required.
In the event that a subject requires plasmapheresis prior to study treatment, the IgM level 
obtained prior to plasmapheresis should be considered as the baseline value and study drug
should be initiated shortly thereafter (not more than 7 days) after last plasmapheresis. IgM level 
obtained within five half-lives (ie, ≤35 days) after the last plasmapheresis should not be 
considered for response evaluation. An IgM level obtained more than 35 days after 
plasmapheresis can be used in response determination. The IgM level prior to and after each 
plasmapheresis during the screening phase and during the study should be collected centrally and 
will be recorded in the eCRF.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The study is divided into a Screening Phase, a Treatment Phase, and a Follow-up Phase. The 
TIME AND EVENTS SCHEDULE summarizes the frequency and timing of efficacy, PK, and 
safety measurements applicable to this study. All subjects enrolled will undergo the same study 
procedures throughout the study unless otherwise noted.
The total blood volume to be collected estimated is approximately 30 mL for the Screening 
Phase, 72 mL from Week 1 to Week 24, 12 mL every 8 weeks from Week 25, 15 mL at the 
suspected PD visit, 15 mL at the End-of-Treatment (EOT) Visit, and 7 mL every 12 weeks for 
the Post-treatment Pre-disease Progression Phase. Repeat or unscheduled samples may be taken 


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for safety reasons or for technical issues with the samples. The volume of blood to be drawn is 
considered to be normal and acceptable for subjects participating in a cancer clinical study and is 
deemed reasonable over the time frame of the study.
9.1.2.
Screening Phase
Screening procedures will be performed up to 30 days prior to Day 1 of Week 1, unless 
otherwise specified. All subjects must first read, understand, sign and date the ICF before any 
study-specific screening procedures are performed. Clinicopathological diagnosis of WM must
be confirmed by a central laboratory for all subjects before enrollment.   
Unless specified otherwise, all study tests and procedures should be performed at the study 
center at which the subject was enrolled and will be receiving treatment. After signing the ICF, 
screening, and being deemed eligible for entry, subjects will be enrolled in the study. Refer to the 
TIME AND EVENTS SCHEDULE for a complete list of procedures to be performed at 
Screening.
9.1.3.
Treatment Phase
Details of the procedures performed during the treatment phase are outlined in the
TIME AND EVENTS SCHEDULE. The latest measurements taken on Day 1 of Week 1 before 
administration of study drugs or at screening will be defined as the baseline values. Clinical 
evaluations and laboratory studies may be repeated more frequently, if clinically indicated. If a 
subject shows signs of progression on physical examination or laboratory assessment, a 
suspected PD visit should be scheduled and the subject may continue study treatment until 
progression is confirmed. If progressive disease is diagnosed, the subject will discontinue study 
drug, complete the EOT Visit and enter the Follow-up Phase.
Suspected PD Visit
The Suspected PD visit should be performed at any time during the study, if based on clinical 
and/or laboratory evaluation, the investigator suspects progressive disease (PD), or if the subject
discontinues treatment for any other reason. If possible, the visit should be performed within 
24 hours after the subject’s previous dose. 
End of Treatment Visits
Unless a subject withdraws consent for study participation, died, or is lost to follow-up, the EOT
visit should occur 30 days (± 7 days) from the last dose of study drug or prior to the start of a 
new anticancer treatment. If the subject starts a new anticancer treatment less than 7 days after 
the Suspected PD visit, only those procedures not conducted at the Suspected PD visit should be 
performed at the EOT visit. Refer to TIME AND EVENTS SCHEDULE for procedures to be 
performed at the EOT visit.
Every effort should be made to conduct the EOT visit before the subject starts subsequent 
treatment. If a subject is unable to return to the site for the EOT visit, then the subject should be 
contacted to collect information on adverse events that occur up to 30 days after the last dose of 


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study treatment. Additional information on reporting of adverse events is presented in 
Section 12.
9.1.4.
Follow-up Phase
The Follow-up Phase will consist of 2 phases: a Post-treatment Pre-disease Progression Phase 
and a Post-disease Progression Phase. 
9.1.4.1.
Post-treatment Pre-disease Progression Phase
Subjects who discontinue the treatment for reasons other than PD will be followed every 
12 weeks (±7 days) by clinic visit until disease progression is confirmed, regardless of initiation 
of subsequent anticancer treatment. Procedures performed during this period are outlined in 
TIME AND EVENTS SCHEDULE.
9.1.4.2.
Post-disease Progression Phase
After investigator confirmed disease progression, subjects will be contacted to assess survival 
status, the use of alternative antineoplastic therapy and occurrence of any other malignancy 
approximately every 12 weeks (±7 days) by clinic visit or telephone until death, withdrawal by 
subject, lost to follow-up, or study terminated by Sponsor, whichever comes first. At the time of 
the primary analysis and at study closure, a survival sweep will be conducted. All subjects who 
are on study and not known to have died prior to the survival sweep will be contacted at that 
time.
9.1.5.
Clinical Cut-offs
Clinical cutoffs (CCOs) planned for this study are:
•
CCO for the primary analysis is estimated to be performed approximately 12 months 
after the last subject receives first dose. Alternative appropriate cutoffs will be considered 
based on regulatory requirement.
•
CCO for the final analysis is estimated to occur 3 years after last subject receives first 
dose.
9.2.
Efficacy Evaluations
Efficacy evaluations will be conducted as outlined in the TIME AND EVENTS SCHEDULE. 
Response assessments will be performed using the modified consensus criteria adapted from the 
VIth IWWM (NCCN 2019) (Attachment 1).
Progression of nodal and extranodal disease should be evaluated based on the revised criteria for 
malignant lymphoma described in the revised International Working Group for NHL.22
Efficacy evaluation will include the following components:

Hematologic parameters by complete blood count (CBC)

Quantitative IgM serum immunoglobulins


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
Quantitative serum-M protein (serum protein electrophoresis [SPEP])

Serum free light chain assay

Qualitative serum immunofixation, if applicable

Radiographic evaluation, if applicable

Bone marrow aspirate and biopsy, if applicable
Sequential changes in IgM levels used for assessing responses can be determined either by SPEP 
or by quantitative IgM serum immunoglobulins. It is crucial that for each subject, sequential 
response assessments are performed using the same methodology which is prespecified by site.
In the event a subject required plasmapheresis prior study treatment, the IgM level obtained prior 
plasmapheresis will be considered as the baseline value and study treatment should be initiated 
shortly thereafter (not more than 7 days) after last plasmapheresis. IgM level obtained within five 
half-lives (ie, ≤35 days) after plasmapheresis should not be considered as nadir on therapy or for 
response evaluation. IgM levels obtained more than 35 days after plasmapheresis can be used in 
response determination.
Any suspected case of disease progression should be reported to the Sponsor within 24 hours of 
awareness. If disease progression is suspected solely based on the results of a single examination 
or a single laboratory parameter (eg, IgM), this finding should be confirmed by a subsequent 
evaluation at least within 4 weeks from the first finding. Additional hematologic parameters, 
radiographic evaluation and bone marrow aspirate and biopsy should be performed at the 
discretion of the treating physician to confirm progressive disease if indicated.
In general, subjects should continue study treatment until progression is confirmed by a serial 
examination within 4 weeks from the first finding. When disease progression has been 
confirmed, study treatment should be withheld. Once disease progression has been confirmed, 
subjects should continue to adhere to all other study-related procedures. Whenever possible, 
subsequent anticancer therapy should be withheld until disease progression is confirmed.
If at any time complete response (CR) is suspected (serum IgM values in normal range and 
disappearance of the SPEP), all assessments including serum immunofixation, bone marrow 
assessment and radiographic evaluation (if nodal/extranodal disease is present at baseline) must 
be performed according to the IWWM response assessment guidelines.
9.2.1.
Quantitative Serum Immunoglobulin
Testing for IgA, IgG and IgM levels will be performed by a central laboratory.
9.2.2.
Serum Protein Electrophoresis (SPEP)
Sample(s) will be sent to a central laboratory to quantify the serum-M protein.
9.2.3.
Serum Free Light Chain Assay
Sample(s) will be sent to a central laboratory for measurement of immunoglobulin-free light 
chains in serum.


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9.2.4.
Serum Immunofixation
Samples will be collected and sent to a central laboratory. Repetitive immunofixation on study is 
only required to confirm CR (conducted on the first observation that the subject has no 
detectable monoclonal protein) and then repeated every study visit until disease progression.
9.2.5.
Radiographic Imaging
Pretreatment tumor assessment will be performed up to 42 days before the first dose of study 
drug. Lesions that have been irradiated cannot be included in the tumor assessment unless 
unequivocal tumor progression has been documented in these lesions after radiation therapy.
A computed tomography (CT) scan (with contrast unless contraindicated) of the neck, chest, 
abdomen, and pelvis must be performed. Information on extranodal involvement will also be 
recorded.
Magnetic resonance imaging (MRI) is only allowed to evaluate sites of disease that cannot be 
adequately imaged using CT or in the case where CT with contrast is contraindicated (in cases 
where MRI is desirable, the MRI must be obtained at baseline and at all subsequent response 
evaluations). If MRI is required for any other reason, this must be discussed with the study 
medical monitor first.
The same imaging method should be used for a given subject throughout the study. The same 
equipment should be utilized for all scans whenever possible. The same radiologist should be 
assigned to read all the scans for a given patient throughout the study as much as possible.
All subjects with presence of nodal and/or extranodal disease at Screening will require follow up 
CT scans of the neck, chest, abdomen, and pelvis every 16 weeks for the first 2 years and 
thereafter every 24 weeks, until disease progression is confirmed (regardless of whether or not 
the subject remains on treatment). In the event disease progression is suspected due to physical 
examination or laboratory test, a CT scan should be performed to evaluate nodal or extranodal 
progression regardless if the subject had nodal/extranodal disease at Screening.
9.2.5.1.
Radiographic Assessment
Progression of nodal and extranodal disease should be evaluated based on the revised criteria for
malignant lymphoma described in the revised International Working Group for NHL.22 The 
spleen is considered nodal disease.
Up to 6 measurable lymph nodes should be considered as target lesions if the long axis is more 
than 1.5 cm regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it
should only be considered abnormal if its short axis is more than 1.0 cm. Lymph nodes ≤1.0 cm 
× ≤1.0 cm will not be considered as abnormal for relapse or progressive disease. In addition, 
target lesions should be clearly measurable in at least 2 perpendicular dimensions and, if 
possible, they should be from disparate regions of the body when these areas are significantly 
involved. If additional lesions are present but are not included in the target lesion assessment, 
they can be added as non-target lesions followed throughout the study.


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The longest cranial-caudal measurement of the spleen will be assessed at Screening and all 
subsequent timepoints (if applicable). Splenomegaly is present when the cranial to caudal 
measurement of the spleen is >130 mm.
Nodal progression by imaging is defined as one of the following:

Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size.

At least a 50% increase from nadir in the sum of product (SPD) of any previously involved 
nodes, or in a single involved node. To be considered progressive disease, a lymph node 
with a diameter of the short axis of less than 1.0 cm must increase by ≥50% and to a size of 
1.5 × 1.5 cm or more than 1.5 cm in the long axis.

At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cm in its short axis.
9.2.6.
Bone Marrow Assessment and Pathological diagnosis
Bone marrow aspirate and biopsy is required at Screening. Inclusion of the subject in the trial 
will be based on central pathological assessment and histopathological confirmation of 
lymphoplasmacytic lymphoma (LPL), which is the underlying histology of WM. 
Additional Bone Marrow assessment should be obtained:

to confirm CR at any time

predose at Weeks 49 and 97 to assess bone marrow/tissue response

at time of progression or at suspected PD due to progressive cytopenia without any other 
evidence of PD
Standard clinical Bone Marrow assessment will all be performed at the central laboratory.
9.3.
Pharmacokinetics 
9.3.1.
Evaluations
Venous blood samples of approximately 2 mL will be collected from all subjects for 
measurement of plasma concentrations of ibrutinib and metabolite PCI-45227 before dosing 
ibrutinib capsules on Day 1 of Weeks 1, 5, and 9 (see TIME AND EVENTS SCHEDULE).
Subjects should refrain from taking the study drug on the morning of study visits designated for 
PK sampling. After PK sampling, the study drug will be self-administered by the subjects on an 
outpatient basis, except for Day 1 of Week 1, when the study drug will be administered in the 
clinic. The exact dose, dates and times for the doses administered 1 day preceding and actual PK 
sampling dates and times must be recorded. Additional information about the collection, 
handling, and shipment of biological samples can be found in the Laboratory Manual.
Samples collected for PK analyses may additionally be used to evaluate safety or efficacy 
aspects that address concerns arising during or after the study period.


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9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of ibrutinib and metabolite 
PCI-45227 using a validated, specific, and sensitive quantitative method by or under the 
supervision of the sponsor. 
9.3.3.
Pharmacokinetic Parameters 
Plasma concentrations of ibrutinib and metabolite PCI-45227 will be summarized using 
descriptive statistics. Based on the individual plasma concentration-time data, using the actual 
dose taken and the actual sampling times, PK parameters and exposure information of ibrutinib 
may be derived using population PK modelling, if it is deemed appropriate and if data allow.
9.4.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the TIME AND EVENTS SCHEDULE. Any clinically significant 
abnormalities persisting at the end of the treatment will be followed by the investigator until 
resolution, until a clinically stable endpoint is reached, or until the end of the study.
9.4.1.
Adverse Events
All adverse events will be reported from the time a signed and dated ICF is obtained until 
30 days following the last dose of study drug. Adverse events will be reported by the subject (or, 
when appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative) for 
the duration of the study. Adverse events will be followed by the investigator as specified in 
Section 12.
9.4.2.
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. See TIME AND EVENTS SCHEDULE for exact time 
points of these and other assessments.

Hematology Panel (local laboratory)
-hemoglobin
-platelet count
-hematocrit
-total white blood cell (WBC) count
-absolute neutrophil count
-absolute lymphocyte count

Serum Chemistry Panel (local laboratory)
-albumin
-alkaline phosphatase
-ALT
-AST
-calcium
-blood urea nitrogen (BUN)
-creatinine
-glucose
- lactic acid dehydrogenase (LDH)
-potassium


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-phosphate
-total bilirubin
-sodium
-uric acid
-total protein

Coagulation (central laboratory)
-PT/INR
-activated partial thromboplastin time

Serum immunoglobulin (central laboratory)
-IgG
-IgA
-IgM

β2 -microglobulin (central laboratory)
Samples will be collected at Screening.

Serum Viscosity (local laboratory) 
Serum viscosity at Screening is optional. After Screening, it should be performed at the 
discretion of the treating physician in any subject with signs and symptoms suggesting a 
hyperviscosity syndrome.

Hepatitis B Screening (local laboratory)
- HBsAg
- Hepatitis B core antibody
If HBsAg is positive, the subject will be excluded. Hepatitis B DNA needs to be performed if 
Hepatitis B core antibody is positive. DNA PCR needs to be confirmed negative prior to first 
dose of administration in subjects who are Hepatitis B core Ab positive. During study treatment 
and for at least 12 months following the last dose of treatment, regular monitoring of Hepatitis B 
PCR and liver enzymes and prophylactic antiviral medication should be considered per published 
guidelines.16,17

Hepatitis C Screening (local laboratory)
-Hepatitis C antibody
If Hepatitis C antibody is positive, RNA PCR needs to be performed and confirmed negative 
prior to first dose administration. Patient with History of Hepatitis C virus infection should have 
documented 24 weeks of sustained virologic response (SVR) in order to be eligible for the study.

Pregnancy Test (local laboratory)
For women of childbearing potential, serum will be drawn at screening for a pregnancy test. 
During the trial, if the subject is suspected of pregnancy, the pregnancy test must be performed. 
The pregnancy test will be done by the local laboratory.
9.4.3.
Electrocardiogram (ECG)
A 12- lead electrocardiogram (ECG) will be performed at screening for all subjects. The subject 
should 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 


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or moving arms or legs. Abnormalities noted at screening should be included in the medical 
history.
ECGs may also be performed at the investigator’s discretion, particularly in subjects with 
arrhythmic symptoms (eg, palpitations, lightheadedness, syncope, chest discomfort or new onset 
of dyspnea).
9.4.4.
Vital Signs and ECOG Performance Status
Vital signs (body temperature, heart rate, respiratory rate, and blood pressure) and ECOG 
Performance Status grade (Attachment 2) will be measured at the timepoints specified in the 
TIME AND EVENTS SCHEDULE.
9.4.5.
Physical Examination
The Screening, Week 1, Suspected PD, EOT and Follow-Up physical examination will include, 
at a minimum, the general appearance of the subject, height (screening only) and weight, and 
examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities,
musculoskeletal system, nervous system, and lymphatic system. Only a limited symptom-
directed physical examination and the change in status of lymph nodes, tumor masses, liver and 
spleen will be required after Week 1 at time points specified in the TIME AND EVENTS 
SCHEDULE.
9.4.6.
Eye-related symptom assessment
The subjects will be asked about eye-related symptoms at time points specified in the 
TIME AND EVENTS SCHEDULE. If there are any eye-related symptoms of severity Grade ≥2 
at Screening or if the subject develops any eye-related symptoms of severity Grade ≥2 while on 
study treatment, an ophthalmologic evaluation/consult must be performed and the outcome must 
be reported on the ophthalmologic eCRF.
9.5.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. Refer to the TIME AND EVENTS SCHEDULE for the timing and frequency 
of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has died before the end of 
the study, has not been lost to follow-up, or has not withdrawn consent before the end of study.


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The study is planned to be completed 3 years after the last subject receives first dose. The study 
drug will be supplied until study completion.  
10.2.
Discontinuation of Study treatment
A subject will not be automatically withdrawn from the study if he or she has to discontinue 
study treatment before the end of the intervention regimen.
Study treatment will be discontinued in the event of any of the following events:

Confirmed progressive disease

Unacceptable toxicity: an intercurrent illness or adverse event that prevents further ibrutinib 
administration

The subject refuses further treatment with the study drug

Investigator decision (such as chronic noncompliance, significant protocol deviation, or best 
interest of the subject)

The subject becomes pregnant 
All subjects, regardless of reason for discontinuation of study treatment will undergo an EOT 
visit and be followed for progression and survival. The Investigator should notify the Sponsor 
within 24 hours if a subject discontinues ibrutinib treatment due to disease progression and 
should provide documentation of disease progression for review by the Sponsor’s Medical 
Monitor. If a subject shows signs of disease progression on physical examination or laboratory 
assessment, the subject may continue study treatment until disease progression is confirmed. 
These subjects should stay in the study to be followed for survival.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study (including all follow-up) for any of the following 
reasons:

Lost to follow-up

Withdrawal of consent

Study termination by Sponsor

Death
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, EOT and posttreatment 


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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 or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
The primary analysis for all efficacy and safety endpoints will be conducted 12 months after last 
subject receives first dose or alternative appropriate cutoff will be considered based on 
regulatory requirement. Final analysis will be conducted at the study end.
Analysis of efficacy will be performed using the All-Treated Population. The 90% CIs for the 
ORR, CRR and rate of VGPR or better will be calculated using exact binomial distribution. 
Exact (Clopper-Pearson) 90% CIs will be presented. Time to-event variables (including DOR, 
PFS and OS) will be described using the Kaplan-Meier method. Time to response will be 
summarized descriptively for responders only. Unless otherwise specified, all continuous 
endpoints will be summarized using descriptive statistics, which will include the number of 
subjects with a valid measurement (n), mean, standard deviation, median, minimum, and 
maximum. All categorical endpoints will be summarized using frequencies and percentages.
11.1.
Subject Information
The following definitions will be used for the efficacy, safety and PK analysis, respectively:
All Treated population: All enrolled subjects who receive at least 1 dose of study drug.
Safety population: All enrolled subjects who receive at least 1 dose of study drug. The safety 
population is identical to All Treated population. 
PK evaluable population: All enrolled subjects who receive at least 1 dose of ibrutinib and have 
at least 1 available PK sample after treatment.
11.2.
Sample Size Determination
Assuming the ORR (PR or better) by investigator is 69.8% in the study population, which is the 
same as global pivotal study (PCYC-1118E) result, approximately 17 subjects will be required to 
obtain at least 85% power to declare the ORR is 32% (the minimum clinically meaningful ORR) 
or higher at the 1-sided significance level of 0.05.
11.3.
Efficacy Analyses 
For continuous variables, number of observations, means, standard deviations, medians, and 
ranges will be included. For categorical variables, frequency and percentage will be summarized. 
For time-to-event variables, Kaplan-Meier estimates will be provided.


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11.3.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is ORR by investigator assessment. ORR is defined as the 
proportion of subjects who achieve PR or better per the modified Consensus Response Criteria 
from the VIth IWWM (NCCN 2019).
The overall response rate (PR or better) and its 90% CI 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 90% CI based on binomial distribution exceeds the threshold 
value (0.32).
11.3.2.
Secondary Efficacy Endpoints
11.3.2.1.
Clinical Response Rate
CRR is defined as the proportion of subjects who achieve MR or better according to the modified 
IVth IWWM (NCCN 2019) criteria as assessed by the investigator. CRR will be analyzed with 
the exact 2-sided 90% CI based on binominal distribution in a similar fashion as ORR.
11.3.2.2.
VGPR or Better Rate
VGPR or better rate is defined as the proportion of subjects who achieve VGPR or better 
according to the modified IVth IWWM (NCCN 2019) criteria as assessed by the investigator. 
VGPR or better rate will be analyzed in a similar fashion as CRR. 
11.3.2.3.
Duration of Response
DOR is defined as duration from the date of initial documentation of a response (PR or better) to 
the date of first documented evidence of progressive disease or death for responders (PR or 
better) as assessed by the investigator. DOR will be evaluated descriptively using Kaplan-Meier 
method. Median DOR and the corresponding 95% CI will be provided if estimable with 
Kaplan-Meier plot.
11.3.2.4.
Time to Response
Time to response (TTR) is defined as the time from the date of first dose to the date of initial 
documentation of a response (PR or better). TTR will be summarized by descriptive statistics.
11.3.2.5.
Progression Free Survival
PFS is defined as duration from the date of first dose to the date of disease progression or death, 
whichever is first reported, assessed according to the modified VIth IWWM (NCCN 2019) 
criteria. PFS will be evaluated descriptively using Kaplan-Meier method. Median PFS and the 
corresponding 95% CI will be provided if estimable with Kaplan-Meier plot. PFS rates at 1-year, 
2-year and 3-year landmarks will also be estimated using Kaplan-Meier.
11.3.2.6.
Overall Survival
OS is measured from the date of first dose to the date of the subject’s death from any cause. The 
OS will be evaluated in a similar fashion as DOR and PFS.


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11.4.
Pharmacokinetic Analyses 
The plasma concentration data for ibrutinib and metabolite PCI-45227 at each timepoint will be 
listed and summarized using descriptive statistics. All concentrations below the lowest 
quantifiable concentration or missing data will be labeled as such in the concentration data 
listing. Concentrations below the lowest quantifiable concentration will be treated as zero for the 
population PK modeling, if needed. All subjects and samples excluded from the analysis will be 
clearly documented in the study report.
If feasible, population PK analysis of ibrutinib may be performed using nonlinear mixed-effects 
modeling (NONMEM). Data may be pooled with other ibrutinib trials if appropriate. Model-
derived exposure parameters may be subjected to further explore correlation between exposure 
and relevant clinical information.
11.5.
Safety Analyses
The safety analysis will be conducted using the safety population. The safety variables to be analyzed 
include adverse events, clinical laboratory test results (hematology and chemistry), physical 
examination findings, and vital signs measurements. Exposure to study drug and reasons for 
discontinuation from study drug will be tabulated. In general, continuous variables will be 
summarized using descriptive statistics (n, mean, median, standard deviation, standard error and 
range). Categorical variables will be summarized using frequencies and percentages.
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). Treatment-emergent adverse 
events are those adverse events occurring after the first dose of study drugs and within 30 days 
following the last dose of study drug or initiation of subsequent antineoplastic treatment, 
whichever occurs earlier; any adverse event that is considered study drug-related regardless of 
the start date of the event; or any adverse event that is present at baseline but worsens after the 
first administration of study drug in severity or is subsequently considered drug-related by the 
investigator. All treatment-emergent adverse events will be included in the analysis. For each 
AE, the number and percentage of subjects who experience at least one occurrence of the given 
event will be summarized. The number and percent of subjects with treatment-emergent adverse 
events will be summarized according to intensity (NCI CTCAE, v4.03) and drug relationship as 
well as categorized by system organ class and preferred term. Summaries, listings, datasets, or 
subject narratives may be provided, as appropriate, for those subjects who die, who discontinue
treatment due to an adverse event, or who experience a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized for hematology and chemistry. 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). 


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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 v4.03 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, heart rate, respiratory rate, and blood pressure (systolic and 
diastolic) values and changes from baseline will be summarized at each scheduled time point. 
The percentage of subjects with values beyond clinically important limits will be summarized.
Physical Examination
All clinically significant abnormalities of physical examination will be recorded as AEs and 
included in the analysis of TEAE.
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.
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 
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).


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Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

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.
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 an investigational product ie, ibrutinib, the 
expectedness of an adverse event will be determined by whether or not it is listed in the IB. 
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.
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.


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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
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 
(CTCAE v4.03) will be used for grading the severity (intensity) of AEs. The CTCAE v4.03 
displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. 
Should a subject experience any AE not listed in the CTCAE v4.03, the following grading 
system should be used to assess severity:

Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, 
and not interfering with the subject’s daily activities

Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures

Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment

Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death

Grade 5 (Death related to AE) – experiences which result in subject death
12.1.4.
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 will be reported to the sponsor within
24 hours of awareness irrespective of seriousness (ie, serious and nonserious adverse events)
following the procedure described above for serious adverse events and will require enhanced
data collection.
12.1.4.1.
Major Hemorrhage
Major hemorrhage is defined as any of the following:
1.
Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher*
2.
Any treatment-emergent serious adverse events of bleeding of any grade
3.
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade


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*All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or 
higher AE per NCI CTCAE.
12.1.5.
Other Malignancies
In addition to all routine AE reporting, all new malignancies, including solid tumors, skin 
malignancies and hematologic malignancies, are to be reported for the duration of study 
treatment and during any protocol-specified follow-up periods including post-progression 
follow-up for overall survival.
12.1.6.
Eye-related Adverse Events
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was
Grade 2 or higher at baseline and worsens should be evaluated by an ophthalmologist, whose
findings should be reported on the ophthalmologic eCRF.
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 drug, unexpected therapeutic benefit,

Accidental or occupational exposure to a sponsor study drug

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 a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All subjects who receive at least one dose of study drug will be considered evaluable for safety 
assessments. 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 completion of the 
subject's last study-related procedure, which may include contact for follow-up of safety. Serious 
adverse events, including those spontaneously reported to the investigator within 30 days after 
the last dose of study drug, 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.
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. The primary cause of death on the 


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autopsy report should be the term reported. Autopsy and postmortem reports must be forwarded 
to the Sponsor, or designee, as outlined above.
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a serious adverse event.
Progressive disease should NOT be reported as an adverse event term, but instead symptoms/ 
clinical signs of disease progression may be reported. Otherwise, all events that meet the
definition of a serious adverse event will be reported as serious adverse events, regardless of 
whether they are protocol-specific assessments.
If study drug is discontinued because of a serious adverse event, this information must be 
included in the serious adverse event report.
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 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.
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 serious adverse events 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.


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Information regarding serious adverse events 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 a serious adverse event should be transmitted electronically or by 
facsimile (fax).
All serious adverse events 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 a 
serious adverse event. 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 a serious 
adverse event, except hospitalizations for the following:

Hospitalizations not intended to treat an adverse event (eg, social reasons such as pending 
placement in long-term care facility)

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 serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.

For convenience the investigator may choose to hospitalize the subject for the duration of 
the intervention period.
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to
Section 12.1.1, Adverse Event Definitions and Classifications).
12.3.3.
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 serious 


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adverse events and must be reported using the Serious Adverse Event Form. Any subject who 
becomes pregnant during the study must be promptly discontinue further study treatment.
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 a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2). 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 DRUG INFORMATION
14.1.
Physical Description of Study Drug
Ibrutinib is provided as hard gelatin capsules containing 140 mg of ibrutinib. 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 capsules are packaged in opaque high-density polyethylene (HDPE) plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies. The drug 
product is manufactured for Pharmacyclics, Inc. by a contract manufacturer.
All study drug will be dispensed in child-resistant packaging.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. The 
investigational product will be labeled and handled as open-label materials.
14.4.
Preparation, Handling, and Storage
The recommended storage condition for ibrutinib capsules is controlled room temperature. 
Formal ICH stability studies are ongoing to determine the shelf-life of the product. Current 
stability data indicate that the capsules will be stable for the duration of the clinical study under 
the labeled storage conditions.
14.5.
Drug 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 must be instructed to return all original containers, whether empty 
or containing ibrutinib.
Ibrutinib 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 ibrutinib 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 ibrutinib, 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 
the same subject. 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.


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15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study protocol

Ibrutinib IB 

Subject study tools (appointment card, emergency ID card, etc., as applicable per country)

Investigator study tools and quick reference cards

Trial Center File, and corresponding site-specific documentation

Pharmacy manual and study site investigational product manual

Laboratory manual and laboratory kits

Study site investigational product and procedures manual

NCI-CTCAE Version 4.03

Electronic data capture (eDC) manual and electronic eCRF completion guidelines

Sample ICF

Subject diaries

Subject Thank You card
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Ibrutinib WM indication was already granted conditional approval in China. Study 1118E and 
Study 1127 have already demonstrated efficacy and safety in patients with relapsed or refractory 
WM, so ibrutinib may also demonstrate clinical benefit for the population of 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.
The total blood volume to be collected is normal and acceptable for subjects participating in a 
cancer clinical study and is deemed reasonable over the time frame of the study.
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.


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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)

IB (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 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


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
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
Each subject 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) that is/are used 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 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 


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confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject 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 subject 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 the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
If the subject 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 is obtained.
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 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 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.
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 non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 


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amendment must be 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 must be submitted to the Center for Drug Evaluation (CDE) after compiling
according to WM new indication approval letter’s requirement. The protocol amendment(s) if 
applicable should be submitted to healthy authority. 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)


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
Completed investigator financial disclosure form from the principal investigator, where 
required

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 age at initial informed consent. In cases where the subject is not enrolled into the study, the 
date seen and age at initial informed consent 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).


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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 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
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.
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 
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 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.


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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.
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.
17.8.
Monitoring
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 
post-initiation 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.


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17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed 3 years after the last subject receives the first dose. 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.
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 research data, generated as a result of this study, 
are considered confidential and remain the sole property of the sponsor. The investigator agrees 


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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 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 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 


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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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REFERENCES
1.
Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of 
lymphoid neoplasms. Blood. 2016;127:2375-2390. 
2.
Buske C, Sadullah S, Kastritis E, et al. Treatment and outcome patterns in patients with relapsed 
Waldenström’s macroglobulinemia: development of a large observational Pan-European data platform. The 
21st European Hematology Association Annual Congress; Copenhagen, Denmark; June 9–12, 2016. Abstr 
E1275.
3.
Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N 
Engl J Med. 2012;367:826–833.
4.
Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P)supports the survival of lymphoplasmacytic cells 
by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood. 2013;122:1222–1232.
5.
Yang G, Buhrlage SJ, Tan L, et al. HCK is a survival determinant transactivated by mutated MYD88, and a 
direct target of ibrutinib. Blood. 2016;127:3237–3252.
6.
Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for 
treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 
2011;117:6287-6296.
7.
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell 
activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl Acad. Sci. 
USA. 2010;107:13075-13080..
8.
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. 
ChemMedChem. 2007;2:58–61.
9.
Ponander S, Chen S-S, Buggy J, et al. The Bruton’s tyrosine kinase inhibitor PCI-32765  thwarts chronic 
lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119:1182-1189.
10.
McGreivy J, Zhou C, Salido C, Vintilla-Friedman S, and Irving S. Phase 1 dose-escalation study of Bruton’s 
tyrosine kinase (BTK) inhibitor PCI-32765 in Recurrent B-Cell Lymphoma. Clinical Study Report, 
Pharmacyclics, Inc., 2013.
11.
Advani RH, Buggy JJ, Sharman JP, et al. Burton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant 
activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.
12.
Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenstrom’s macroglobulinemia: 
consensus panel recommendations from the Second International Workshop on Waldenstrom’s 
Macroglobulinemia. Semin Oncol. 2003;30:110-115.
13.
Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenstr.m’s macroglobulinemia. N Engl 
J Med. 2012;367:826-833.
14.
Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized 
by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with 
B-cell lymphomagenesis. Blood. 2014;123:1637-1646.
15.
Yang G, Zhou Y, Liu X, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic 
cells by activation of Bruton tyrosine kinase in Waldenstr.m macroglobulinemia. Blood. 2013;122:1222-1232.
16.
Artz AS, Somerfield MR, Feld JJ, Giusti AF, Kramer BS, Sabichi AL, Zon RT, Wong SL. American Society 
of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients 
receiving cytotoxic chemotherapy for treatment of malignant diseases. J Clin Oncol. 2010; 28(19):3199-3202.
17.
Zhonghua Gan Zang Bing Za Zhi. Consensus on the management of lymphoma in patients with hepatitis B 
virus infection. Clin J hematol, 2013;34 (11):815-820.
18.
Response assessment in Waldenstro¨m macroglobulinaemia: update from the VIth International Workshop
19.
Owen RG, Kyle RA, Stone MJ et al. Response assessment in Waldenstrom macroglobulinaemia: update from 
the VIth International Workshop. Br. J. Haematol. 160(2), 171–176 (2013).


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20.
Clinical Practice Guidelines in Oncology: Waldenstr¨om’s macroglobulinemia/lymphoplasmacytic lymphoma 
version 1.2019. www.nccn.org/professionals/physician gls/pdf /waldenstroms.pdf
21.
Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in Waldenström’s 
macroglobulinemia: consensus panel recommendations from the Second International Workshop on 
Waldenström’s Macroglobulinemia. Semin Oncol 2003;30:116–120.
22.
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 
2007;25:579-586.


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Attachment 1: Modified 6th WM Response Criteria (NCCN 2019) for Investigator Assessment
Modified WM Response Criteria for Investigator Assessment of Response and Progression
Category
Response Criteria
Complete Response
(CR)
•
Serum IgM values in normal range
•
Disappearance of monoclonal protein by immunofixation
Note: Reconfirmation of CR status is required with a second immunofixation at 
any time point
•
No histological evidence of bone marrow involvement

Complete resolution of lymphadenopathy4/splenomegaly if present at baseline
Very Good Partial
Response (VGPR)
•
At least 90% reduction of serum IgM from baseline or serum IgM values in 
normal range
•
Reduction in lymphadenopathy4/splenomegaly if present at baseline
Partial Response (PR)
•
At least 50% reduction of serum IgM from baseline
•
Reduction in lymphadenopathy4/splenomegaly if present at baseline
Minor Response (MR)
•
At least 25% but <50% reduction of serum IgM from baseline
Stable Disease (SD)
•
Not meeting criteria for CR, VGPR, PR, MR, or progressive disease (PD)
Progressive Disease 
(PD)
At least one of the following
•
A ≥25% increase in serum IgM with a total increase of at least 500 mg/dL from 
nadir1
o Confirmation of the initial IgM increase is required when IgM is sole 
criterion for progressive disease.
•
Appearance of a new lymph nodes >1.5 cm in any axis, ≥50% increase from 
nadir in sum of product of diameters (SPD) of more than one node, or ≥ 50% 
increase in longest diameter of a previously identified node >1 cm 
in short axis2
•
Appearance of new splenomegaly or ≥50% increase from nadir in enlargement
of the spleen2
•
Appearance of new extranodal disease 2/3
•
New or recurrent involvement in the bone marrow
•
New symptomatic disease on the basis of malignant pleural effusion, Bing Neel 
(WM CNS disease) syndrome, amyloidosis or light chain deposition disease, or 
other paraprotein mediated disorder.
Abbreviations:  CNS= central nervous system; WM= Waldenström’s macroglobulinemia 
1. Nadir for serum IgM is defined as the lowest serum IgM value obtained at any time from baseline onwards with 
the exception that serum IgM levels post-plasmapheresis will not be considered for up to 35 days.
2. For additional clarification to assess the appearance or progression of existing nodal and extranodal disease 
(Refer to Section 9.2.5)
3. Measurable extranodal disease should be assessed in a manner similar to that for nodal disease.
4. Sum of the products of multiple lymph nodes (as evaluated by CT scans) or the longest diameter of one target 
lymph node.


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Attachment 2: Eastern Cooperative Oncology Group (ECOG) Performance Status Scale
Grade 
Eastern Cooperative Oncology Group Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source:  
1.
Oken MM (1982), Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655.


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Attachment 3: Inhibitors and Inducers of CYP3A
Examples of inhibitors and inducers of CYP3A can be found at the following website: https://drug-
interactions.medicine.iu.edu/Main-Table.aspx. The list below reflects information obtained from the 
website on 20 November 2018.
Inhibitors of CYP3A
Inducers of CYP3A
Strong inhibitors:
Barbiturates 
Boceprevir
Carbamazepine
Clarithromycin
Efavirenz
Cobicistat
Glucocorticoids
Grapefruita
Modafinil
Indinavir
Nevirapine
Itraconazole
Oxcarbazepine
Ketoconazole
Phenobarbital
Mibefradil
Phenytoin
Nefazodone
Pioglitazone
Nelfinavir
Rifabutin
Posaconazole
Rifampin
Ritonavir
St. John’s Wort
Saquinavir
Troglitazone
Suboxone
Telithromycin
Troleandomycin
Voriconazole
Moderate inhibitors:
Amiodarone
Amprenavir
Aprepitant
Atazanavir
Ciprofloxacin
Crizotinib
Darunavir
Diltiazem 
Dronedarone
Erythromycin
Fluconazole
Fosamprenavir
Imatinib 
Seville orange 
Verapamil
Weak inhibitors:
Cimetidine
Fluvoxamine
All other inhibitors:
Chloramphenicol
Delaviridine
Gestodene
Mifepristone
Norfloxacin
Norfluoxetine
Starfruit
a.
Also contains moderate CYP3A inhibitors.


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Attachment 4: Child-Pugh Score
Measure
1 point
2 points
3 points
Total bilirubin, μmol/l
(mg/dl)
<34 (<2)
34-50 (2-3)
>50 (>3)
Serum albumin, g/L (g/dl)
>35 (>3.5)
28-35 (2.8-3.5)
<28 (<2.8)
PT INR
<1.7
1.71-2.30
>2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed
with medication)
Grade III-IV
(or refractory)
Points
Class
5-6
A
7-9
B
10-15
C
Source:
1.
Child CG, Turcotte JG (1964) “Surgery and portal hypertension”. In Child CG. The liver and
portal hypertension. Philadelphia:Saunders. pp. 50-64.
2.
Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R (1973). “Transection of the
oesophagus for bleeding oesophageal varices”. The British journal of surgery, 60 (8): 646-9


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Attachment 5: Recommended Dose Modifications of Ibrutinib for Use with CYP3A Inhibitors
Patient Population
Co-administered Drug
Recommended Ibrutinib Dose for the 
Duration of the Inhibitor Usea
B-Cell Malignancies
Mild CYP3A inhibitors
420 mg or 560 mg once daily per indication. No 
dose adjustment required.
Moderate CYP3A inhibitors
280 mg once daily.
•
Voriconazole
•
Posaconazole at doses less than 
or equal to suspension 200 mg 
BID 
140 mg once daily.
•
Other strong CYP3A inhibitors
•
Posaconazole at higher dosesb 
Avoid concomitant use and consider alternative 
with less CYP3A inhibitory potential
If these inhibitors will be used short-term (such 
as anti-infectives for seven days or less), interrupt 
ibrutinib.
a.
Monitor for adverse reactions to ibrutinib and interrupt or modify dose as recommended.
b.
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, 
posaconazole IV injection 300 mg once daily, posaconazole delayed-release tablets 300 mg once daily).


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Attachment 6: Calculated Creatinine Clearance
Cockcroft-Gault formula:
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault formula:
CrCl = (140 − age [in years]) ×  weight (kg) (×  0.85 for females)/(72 
×  serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, micromol/L), use the 
following formula to convert SI units to conventional (mg/dL) units (Manual of Laboratory & Diagnostic 
Tests, 2004):
serum creatinine (micromol/L) divided by 88.4 = serum creatinine (mg/dL).


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Attachment 7: New York Heart Association Functional Classification
NYHA Class
Symptoms
NYHA Class Symptoms
I
No symptoms and no limitation in ordinary physical activity, eg, shortness of breath
when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during
ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary activity,
eg, walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.


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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 Research & Development 
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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
25Mar2020, 12:53:17 PM, UTC
Document Approval
PPD

SAP_001.pdf: 
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Status: Approved, Date: 22 April 2022
Janssen Research & Development
Statistical Analysis Plan
A Single Arm, Multicenter, Phase 4 Study of the Bruton’s Tyrosine Kinase (BTK) 
Inhibitor, ibrutinib (PCI-32765) in Chinese Subjects with Relapse or Refractory 
Waldenström’s Macroglobulinemia
Protocol 54179060WAL4001; Phase 4
JNJ-54179060  (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
Status:
Approved
Date:
22 April 2022
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-207136398, 2.0
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.
NCT04042376


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Status: Approved, Date: 22 April 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLE ............................................................................................................................ 4
AMENDMENT HISTORY.............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 7
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 8
1.4.
Sample Size Justification ................................................................................................................. 8
1.5.
Randomization and Blinding ............................................................................................................ 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Visit Windows................................................................................................................................... 8
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 8
2.3.
Analysis Sets.................................................................................................................................... 8
2.3.1.
All Treated Analysis Set................................................................................................................ 8
2.3.2.
Safety Analysis Set....................................................................................................................... 8
2.3.3.
Pharmacokinetics Evaluable Analysis Set.................................................................................... 8
2.4.
Study Day and Relative Day ............................................................................................................ 9
2.5.
Baseline ........................................................................................................................................... 9
2.6.
Treatment Duration .......................................................................................................................... 9
2.7.
Time on Study.................................................................................................................................. 9
2.8.
Dose Intensity .................................................................................................................................. 9
2.9.
Relative Dose Intensity .................................................................................................................... 9
2.10.
Imputation Rules for Missing Date................................................................................................... 9
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 11
4.
SUBJECT INFORMATION................................................................................................................ 11
4.1.
Demographics and Baseline Characteristics ................................................................................. 11
4.2.
Disposition Information................................................................................................................... 12
4.3.
Extent of Exposure......................................................................................................................... 13
4.4.
Protocol Deviations ........................................................................................................................ 13
4.5.
Prior and Concomitant Medications ............................................................................................... 13
4.6.
Medical history ............................................................................................................................... 14
5.
EFFICACY ......................................................................................................................................... 14
5.1.
Analysis Specifications................................................................................................................... 14
5.1.1.
Level of Significance................................................................................................................... 14
5.1.2.
Data Handling Rules................................................................................................................... 14
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 14
5.2.1.
Definition..................................................................................................................................... 14
5.2.2.
Analysis Methods........................................................................................................................ 14
5.2.3.
Primary Estimand ....................................................................................................................... 14
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 15
5.3.1.
Definition..................................................................................................................................... 15
5.3.2.
Analysis Methods........................................................................................................................ 16
6.
SAFETY............................................................................................................................................. 17
6.1.
Adverse Events .............................................................................................................................. 17
6.1.1.
AEs of special interest (AESI) .................................................................................................... 18
6.1.2.
AEs of clinical interest................................................................................................................. 18


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Status: Approved, Date: 22 April 2022
6.2.
Clinical Laboratory Tests................................................................................................................ 19
6.3.
Death.............................................................................................................................................. 20
6.4.
Vital Signs and Physical Examination Findings ............................................................................. 20
6.5.
Eye-related symptom assessment................................................................................................. 20
6.6.
Other Safety Parameters ............................................................................................................... 20
7.
PHARMACOKINETICS ..................................................................................................................... 21
REFERENCES............................................................................................................................................ 22


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Status: Approved, Date: 22 April 2022
LIST OF IN-TEXT TABLE
Table 1:
Demographic and Baseline Characteristic Variables ............................................................... 11
Table 2:
Date of Event or Censoring for Duration of Response/Progression Free Survival .................. 16


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Status: Approved, Date: 22 April 2022
AMENDMENT HISTORY
SAP Version History Summary
SAP Version
Approval Date
Major Changes
1
25 September 2020
Not Applicable
2
22 April 2022
Added analysis of primary 
estimand (section 5.2.3).
In section 6.1.1., added Eye 
Disorders and Other 
Malignancies in AEs of special 
interest (AESI).
In section 6.1.2., added 
Cardiac failure, Leukostasis, 
Hepatic Disorders, Cytopenic 
Adverse Events, Infections, 
Tumor Lysis syndrome, 
Ischemic stroke, Rash. And 
Other Malignancies has been 
removed.
In section 7, the wording is 
organized to clarify.
ABBREVIATIONS
AE
adverse event
BQL
below the quantification limit
CCO
clinical cutoff
CI
confidence interval
CR
complete response
CRF
case report form
CRR
clinical response rate
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
IWWM
International Workshop on WM
MedDRA
Medical Dictionary for Regulatory Activities
MR
minor response
ORR
overall response rate
OS
overall survival
PD
progression disease 
PFS
progression-free survival
PI
principal investigator
PK
pharmacokinetic(s)
PR
partial response
PT
preferred term
SAE
serious adverse event


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Status: Approved, Date: 22 April 2022
SAP
Statistical Analysis Plan
SD
standard deviation
SMQs
standardized MedDRA queries
SOC
system organ class
TEAE
treatment-emergent adverse event
TTR
time to response
VGPR
very good partial response
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WM
Waldenström’s Macroglobulinemia


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Status: Approved, Date: 22 April 2022
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) covers Primary Analysis and Final Analysis specified in the 
protocol 54179060WAL4001. It contains definitions of analysis sets, derived variables and 
statistical methods for analyses of efficacy, safety and pharmacokinetic (PK) data of study 
54179060WAL4001.
1.1.
Trial Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of ibrutinib based on overall response 
rate (ORR) (partial response [PR] or better) by investigator assessment per the modified Consensus 
Response Criteria from the VIth International Workshop on Waldenström’s Macroglobulinemia
(IWWM) (NCCN 2019)1,2, in Chinese subjects with relapsed or refractory Waldenström’s
Macroglobulinemia (WM).
Secondary Objectives
Secondary objectives are to evaluate: clinical response rate (minor response [MR] or better) by
investigator assessment according to the modified VIth IWWM (NCCN 2019) criteria, Very Good 
PR (VGPR) or better by investigator assessment according to the modified VIth IWWM (NCCN 
2019) criteria; duration of response (DOR) by investigator assessment; time to response (TTR) by 
investigator assessment; progression-free survival (PFS) by investigator assessment; overall 
survival (OS); safety and PK of ibrutinib in Chinese subjects with relapsed or refractory WM.
1.2.
Trial Design
This is a single-arm multicenter, Phase 4 study to evaluate the efficacy and safety of ibrutinib in 
Chinese subjects with relapsed or refractory WM with symptomatic disease meeting at least 1 of 
the recommendations from the Second IWWM for requiring treatment.
Approximately 17 subjects will be enrolled into the study. Subjects will receive ibrutinib 420 mg 
daily until disease progression or unacceptable toxicity, whichever occurs first. Ibrutinib will be 
supplied as hard gelatin capsules for oral administration.
The study will include a Screening Phase, a Treatment Phase and a Follow-Up Phase. During the 
Screening Phase, the subjects’ eligibility will be determined. The Treatment Phase will extend 
from first dose of study drug until study drug discontinuation. The Follow-up Phase will consist 
of the Post-treatment pre-disease progression Phase and a Post-disease Progression Phase. The 
Post-treatment pre-disease progression Phase will extend from the discontinuation of treatment 
(for reasons other than disease progression) until the subject has progressive disease, at which 
point the Post-disease Progression Phase will begin. Subjects who progress on treatment will 
transition directly to the post disease progression phase. In this latter phase, subsequent anticancer 
therapy, occurrence of any other malignancy and survival status will be recorded until death, lost 
to follow-up, consent withdrawal, or study closure. The study is planned to be completed 3 years 
after the last subject receives first dose.


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Status: Approved, Date: 22 April 2022
Clinical cutoffs (CCOs) planned for this study are:

CCO for the primary analysis is estimated to be performed approximately 12 months after the 
last subject receives first dose. Alternative appropriate cutoffs will be considered based on 
regulatory requirement.

CCO for the final analysis is estimated to occur 3 years after last subject receives first dose.
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis for this study is that ibrutinib is an effective agent as measured by ORR 
(with a point estimate approximately 70% and the lower bound of the 90% confidence interval 
[CI] is greater than 32%) in Chinese subjects with relapsed/refractory WM.
1.4.
Sample Size Justification
Assuming the ORR (PR or better) by investigator is 69.8% in the study population, which is the 
same as global pivotal study (PCYC-1118E) result, approximately 17 subjects will be required to 
obtain at least 85% power to declare the ORR is 32% (the minimum clinically meaningful ORR) 
or higher at the 1-sided significance level of 0.05.
1.5.
Randomization and Blinding
This is an open label study, randomization and blinding procedures are not applicable. 
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
For visit-wise analysis, CRF-recorded visits will be followed.
The visit windows are described in “Time and Events Schedule” of the protocol.
2.2.
Pooling Algorithm for Analysis Centers
Data from all study centers will be pooled for analyses.
2.3.
Analysis Sets
2.3.1.
All Treated Analysis Set
All Treated analysis set is defined as all enrolled subjects who receive at least 1 dose of study drug.
2.3.2.
Safety Analysis Set
Safety analysis set is defined as all enrolled subjects who receive at least 1 dose of study drug. The 
safety population is identical to All Treated population.
2.3.3.
Pharmacokinetics Evaluable Analysis Set
PK evaluable analysis set includes all enrolled subjects who receive at least 1 dose of ibrutinib and 
have at least 1 available PK sample after treatment.


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Status: Approved, Date: 22 April 2022
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 prior to the start of the first study agent 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.
2.8.
Dose Intensity
The dose intensity (mg/day) of study drug is calculated as (sum of total daily dose during the 
treatment phase)/treatment 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 Date
In general, imputation of missing dates will be made for AE onset date, AE resolution date, start 
and end dates of prior and concomitant and subsequent therapies and date of initial diagnosis 
according to the following rules.


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
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 presented 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 
information 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.

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.


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Status: Approved, Date: 22 April 2022

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.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized.
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 Characteristic 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)
Aspartate Aminotransferase (AST) (U/L)
Alanine Aminotransferase (ALT) (U/L)
Total bilirubin (umol/L)
Baseline creatinine (umol/L)
Baseline creatinine clearance rate (mL/min)
Categorical Variables
Age (<=65, and >65 years)
Frequency distribution with the 
number and percentage of subjects 
in each category.
Sex (male, female, undifferentiated)
Baseline creatinine clearance rate (<30mL/min, 30-<60mL/min, 
>=60mL/min)
Baseline liver function based on NCI criteriaa (Normal, Mild, Moderate 
and Severe)


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Status: Approved, Date: 22 April 2022
Table 1:
Demographic and Baseline Characteristic Variables
Continuous Variables:
Summary Type
a: Mild (total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 
1.5×ULN); moderate (1.5×ULN < total bilirubin ≤ 3×ULN); and severe (total 
bilirubin > 3×ULN).
Following baseline disease characteristics information will be summarized for all treated subjects:

Month from initial diagnosis, which is defined as the time period between date of initial WM 
diagnosis and date of first dose of study drug.

ECOG performance grade (0-1, 2)

Number of prior systemic treatment regimens (1-2, >-3)

Serum IgM

Monoclonal protein spike

Beta-2 microglobulin

Extramedullary disease (adenopathy, splenomegaly)

Longest diameter of spleen

Sum of products of diameters - target nodal lesions

Tumor involvement of the bone marrow by: Cellularity

Intertrabecular space (percentage of total bone marrow cells within intertrabecular space)

Cytopenia (hemoglobin <=110 g/L, platelets <=100x10^9/L, absolute neutrophil count 
<=1.5x10^9/L)
4.2.
Disposition Information
The number of subjects in the following disposition categories will be summarized throughout the 
study:

Subjects screened

Subjects received study agent

Subjects who is still on treatment at CCO

Subjects who discontinued study agent

Reasons for discontinuation of study agent, including COVID-19 related reasons

Subjects who terminated study prematurely

Reasons for termination of study
Listings of subjects will be provided for the following categories:

Subjects who discontinued study agent

Subjects who terminated study prematurely


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Status: Approved, Date: 22 April 2022
Subjects who discontinue from treatment or study due to COVID-19 related reasons will be listed.
4.3.
Extent of Exposure
Extent of exposure to study treatment will be summarized and presented based on the safety 
analysis set. Descriptive statistics (N, mean, SD, median, and range [minimum, maximum)) will 
be presented for the following parameters:

Treatment duration (month)

Cumulative total dose (g)

Dose intensity (mg/day)

Relative dose intensity

Time on study (month)
The number (%) of subjects with a study drug modification (dose skip and/or dose reduction) will 
be summarized. Reasons for study drug modifications will also be summarized.
4.4.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ rights, safety or well-being, or the integrity and/or result of the clinical study. Subjects 
with major protocol deviations (including COVID-19 related deviations) will be identified prior 
to database lock and the subjects with major protocol deviations will be summarized by category
for all treated analysis set.

Entered but did not satisfy inclusion/exclusion criteria

Received a disallowed concomitant treatment

Received incorrect dose

Developed withdrawal criteria but not withdrawn

Efficacy assessment deviation

Safety assessment deviation
4.5.
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 
drug. Concomitant medications are defined as any therapy used on or after the same day as the 
first dose of study drug, including those that started before and continue on after the first dose of 
study drug.
Summaries of prior and concomitant medications will be presented by therapeutic class and 
preferred term for all treated analysis set. In addition, the following concomitant medications will 
be summarized separately: growth factors, blood supportive products and immunoglobulin, 


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Status: Approved, Date: 22 April 2022
CYP3A inhibitors (strong, moderate and weak), CYP3A inducers, anticoagulants and/or 
antiplatelets and subsequent antineoplastic therapy.
In addition, concomitant medication for COVID-19 infection will be listed.
4.6.
Medical history
Medical history collected at baseline or screening visit will be summarized by system-organ
class and preferred term for all treated population.
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 0.05. For result presentation purpose, a 2-sided 90% 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 primary efficacy endpoint is ORR by investigator assessment.
5.2.1.
Definition
ORR is defined as the proportion of subjects who achieve PR or better per the modified Consensus 
Response Criteria from the VIth IWWM (NCCN 2019).
5.2.2.
Analysis Methods
The all treated analysis set will be used for primary endpoint.
The primary analysis for primary endpoint will be conducted at the time of approximately 12 
months after the last subject receives first dose. Final analysis will be conducted at the study end, 
which is estimated to occur 3 years after last subject receives first dose.
The overall response rate (PR or better) and its 90% 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 90% confidence interval based on binominal 
distribution exceeds the threshold value (0.32).
5.2.3.
Primary Estimand
Primary Trial Objective: To evaluate the efficacy of ibrutinib in Chinese patients with relapsed 
or refractory WM.


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Primary Estimand Scientific Question of Interest: What is the effect on overall response rate 
of assigning ibrutinib to Chinese relapsed or refractory WM subjects?
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 5 components:
•
Population: Chinese subjects with relapsed or refractory Waldenstrom’s 
Macroglobulinemia who have received at least one prior therapy for Waldenstrom’s 
Macroglobulinemia and have had either documented disease progression or had no 
response (stable disease) to the most recent treatment regimen.
•
Variable: Overall response
•
Treatment: Ibrutinib 420 mg orally, once daily
•
Summary measure: Overall response rate
•
Intercurrent Events (IEs) and Corresponding Strategies: 
Intercurrent Events
Name of Strategy for Addressing Intercurrent Events 
and Its Description
Subsequent anti-cancer therapy
While on Treatment Strategy, targeting a treatment 
effect prior to the initiation of subsequent anti-cancer 
therapy.
Treatment discontinuation
Treatment Policy Strategy, targeting a treatment effect 
regardless of this IE.
5.3.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

Clinical response rate (CRR, i.e. MR or better)

Very good partial response (VGPR) or better rate

Duration of response (DOR)

Time to response (TTR)

Progression-free survival (PFS)

Overall survival (OS)
5.3.1.
Definition
Clinical response rate:
CRR is defined as the proportion of subjects who achieve MR or better according to the modified
IVth IWWM (NCCN 2019) criteria as assessed by the investigator.
Very good partial response (VGPR) or better rate:
VGPR or better rate is defined as the proportion of subjects who achieve VGPR or better according 
to the modified IVth IWWM (NCCN 2019) criteria as assessed by the investigator.


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Duration of response (DOR):
DOR is defined as duration from the date of initial documentation of a response (PR or better) to
the date of first documented evidence of progressive disease, death or date of censoring if 
applicable, for responders (PR or better) as assessed by the investigator. DOR will be right 
censored based on Table 2 for all responders:
Table 2:
Date of Event or Censoring for Duration of Response/Progression Free Survival
Situation
Date of DOR/PFS event or Censoring
Outcome
Death 
or 
disease 
progression 
occurred 
regardless 
of 
the 
use 
of 
subsequent 
antineoplastic therapy prior to documented 
death or disease progression.
Earliest date of adequate disease assessment 
documenting disease progression or date of 
death, whichever occurs first.
Event
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
Time to response:
Time to response is defined as the time from the date of first dose to the date of initial 
documentation of a response (PR or better) for responders.
Progression-free survival (PFS):
PFS is defined as duration from the date of first dose to the date of disease progression or death,
whichever is first reported, assessed according to the modified VIth IWWM (NCCN 2019)
criteria. The same censoring rules for DOR are used for PFS.
Overall survival (OS):
OS is measured from the date of first dose to the date of the subject’s death from any cause. OS 
will be right censored if no death has occurred at the data analysis cutoff date.
5.3.2.
Analysis Methods
The all treated population will be used for all secondary efficacy endpoints.
CRR rate and VGPR or better rate will be analyzed with the exact 2-sided 90% CI 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.
Time to response will be summarized descriptively for responders only.
Progression-free survival will be evaluated descriptively using Kaplan-Meier method. Median PFS 
and the corresponding 95% CI will be provided if estimable with Kaplan-Meier plot. PFS rates at 
1-year, 2-year and 3-year landmarks will also be estimated using Kaplan-Meier.


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OS will be evaluated in a similar fashion as DOR and PFS.
6.
SAFETY
All safety analyses will be based on the safety analysis set and based on actual treatment received, 
unless otherwise specified.
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
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). Treatment-emergent adverse events
(TEAEs) are those adverse events occurring after the first dose of study drugs and within 30 days
following the last dose of study drug or initiation of subsequent antineoplastic treatment,
whichever occurs earlier; any adverse event that is considered study drug-related regardless of the 
start date of the event; or any adverse event that is present at baseline but worsens after the first 
administration of study drug in severity or is subsequently considered drug-related by the
investigator. If the event occurs on the day of the initial administration of study agent, and either 
event time or time of administration are missing, then the event will be assumed 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. 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 treatment-emergent adverse events:

Overall summary of all 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

Serious TEAEs by SOC, PT and toxicity grade 3 or higher

TEAEs leading to dose modification (including dose interruption and 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

TEAEs leading to death by SOC and PT

TEAEs by SOC, PT and toxicity by period

TEAE of interest for COVID-19 infection by PT and toxicity grade

Serious TEAE of interest for COVID-19 infection by PT and toxicity grade


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
TEAE of interest for COVID-19 infection leading to death by PT
In addition to the summary tables, listings will be provided as appropriate.
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 bleeding of any grade

Treatment-emergent central nervous system hemorrhage/hematoma of any grade
Hemorrhagic events will be identified by hemorrhage Standardized MedDRA Query [SMQ] 
excluding laboratory terms.
Eye Disorders
Eye disorders will be obtained from the SOC of “Eye Disorders”.
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.
6.1.2.
AEs of clinical interest
Cardiac arrhythmia
Cardiac arrhythmia will be determined based on Cardiac arrhythmias (SMQ, broad and narrow) 
and Ventricular tachyarrhythmias (SMQ, narrow).
Cardiac failure
Cardiac failure will be determined based on Cardiac failure SMQ (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.
Leukostasis
Leukostasis will be obtained for preferred term of “leukostasis syndrome”.


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Hypertension
Hypertension will be determined based on Hypertension (SMQ, narrow).
Hepatic Disorders
Hepatic disorders will be obtained from the SOC of “Hepatobiliary Disorders”.
Cytopenic Adverse Events
Cytopenic adverse events will be obtained from preferred terms of “neutropenia”,“neutrophil 
count decreased” “febrile neutropenia” , “thrombocytopenia”“ platelet count decreased” and 
“anaemia”.
Infections
Infections will be obtained from the SOC of “Infections and Infestations”.
Tumor Lysis syndrome
Tumor Lysis syndrome will be obtained from preferred term of “tumor lysis syndrome”.
Ischemic stroke
Ischemic central nervous system vascular conditions (SMQ).
Hypersensitivity
This definition will be specified in DPS, separatory.
Rash
All preferred terms containing the word “Rash”.
6.2.
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 hematocrit

Chemistry: calcium, sodium, potassium, glucose, total bilirubin, blood urea nitrogen (BUN),
creatinine, total protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase, phosphate, lactic acid dehydrogenase (LDH), uric acid and albumin.

serum immunoglobulin levels (IgG, IgM, IgA)


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
coagulation
Descriptive statistics and change from baseline will be presented for all laboratory tests with 
continues values at scheduled time points.
For categorical variables, 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.
6.3.
Death
A summary of deaths will be displayed for the safety analysis set. Frequencies for the following 
parameters will be included in the summary table:

Number of subjects who died

Cause of death

If the primary cause of death is an AE, relationship to study agent (yes/no)
A summary of the number of deaths since first administration of study agent until 30 days after 
last study agent administration will also be provided, along with the primary cause of death. A 
listing of subjects who died will be provided.
Deaths due to COVID-19 will be listed separately.
6.4.
Vital Signs and Physical Examination Findings
Descriptive statistics of weight, temperature, heart rate, respiratory rate, and blood pressure 
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled 
time point.
6.5.
Eye-related symptom assessment
Proportion of subjects with abnormal eye-related symptoms will be calculated at each scheduled 
time point. A data listing will be provided for abnormal ophthalmologic exam findings, including 
subject ID, visit, assessment date, ophthalmologic exam, and description of abnormal findings.
6.6.
Other Safety Parameters
Eastern Cooperative Oncology Group (ECOG) status will be summarized by each scheduled 
timepoint. 
In addition, a data listing by subjects will be provided.


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7.
PHARMACOKINETICS
Pharmacokinetic evaluable analysis set will be used for PK analyses. The individual plasma 
concentration data of ibrutinib and its metabolite PCI-45227 will be listed and graphically 
displayed (linear scale and/or semi-log 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 will be graphically displayed
if possible. Concentration data below the lowest quantifiable concentration will be treated as zero 
in the summary statistics. 
Subgroup analysis by ibrutinib dose and concomitant CYP3A inhibitors may be performed on the 
individual pre-dose plasma concentration at Week 5 Day 1 and Week 9 Day 1 of ibrutinib and 
PCI-45227. Necessity of subgroup analysis will be determined based on the actual number of 
subjects who received concomitant CYP3A inhibitors and/or dose reduction till the pre-dose of 
Week 9 Day 1. Summary tables and visual comparisons may be provided to present the summary 
statistics derived for each subgroup, if possible. The visual comparisons graphical presentation 
may also be performed for dose-normalized pre-dose plasma concentration of ibrutinib at Week 5 
Day 1 and Week 9 Day 1 regardless of ibrutinib dose.
Additional analyses may be performed as deemed necessary.
Based on the individual plasma concentration-time data, using the actual dose taken and the actual 
sampling times, PK parameters and exposure information of ibrutinib may be derived using 
population PK modelling, if it is deemed appropriate and if data allow.
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).

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.
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.


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REFERENCES
1.
Owen RG, Kyle RA, Stone MJ et al. Response assessment in Waldenström’s macroglobulinemia: update from
the VIth International Workshop. Br. J. Haematol. 160(2), 171–176 (2013).
2.
Clinical Practice Guidelines in Oncology: Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma
version 1.2019. www.nccn.org/professionals/physician gls/pdf /waldenstroms.pdf