Clinical trial NCT02703272
Conditions: Lymphoma, Non-Hodgkin
Keywords: Lymphoma, Non-Hodgkin Ibrutinib JNJ-54179060
Sponsor: Janssen Research & Development, LLC
Start date: 2016-07-01; Completion date: 2021-06-11
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to confirm that the pharmacokinetics of ibrutinib in pediatric participants is consistent with that in adults (part 1) and to assess efficacy (event-free survival \[EFS\]) of ibrutinib in combination with rituximab, ifosfamide, carboplatin, and etoposide (RICE) or rituximab, vincristine, ifosfamide, carboplatin, and idarubicin (RVICI) background therapy compared to RICE or RVICI background therapy alone (part 2).

Detailed description:
This is a Phase 3, randomized (study medication assigned to participants by chance), open-label (identity of study drug will be known to participant and study staff), controlled study which consists of two parts: Part 1 and Part 2. The Part 1 is a pharmacokinetic run-in part, which will be conducted before starting the randomized part (Part 2) of the study and Part 2 is a randomized and open-label study. Part 1 and Part 2 of the study will be conducted in 3 phases: a Pretreatment (Screening) Phase (Up to 14 days before administration of study drug), a Treatment Phase, and a Posttreatment Phase. The Treatment Phase will extend from enrollment (in Part 1) or randomization (in Part 2) until 1 of the following: 1) completion of 3 cycles of therapy, 2) transplantation, if clinically indicated, or 3) progressive disease (PD), whichever comes first. The Posttreatment Phase will continue until death, loss to follow up, consent withdrawal, or study end, whichever occurs first. The end of study is defined as when approximately 60 event-free survival (EFS) events have occurred in Part 2 (death, disease progression, or lack of complete response \[CR\] or partial response \[PR\] after 3 cycles of treatment based on blinded independent event review), or the sponsor terminates the study, whichever comes first. Participants in Part 1 will be 1 to less than (\<) 18 years old. Participants in Part 2 will be 1 to 30 years old. Participants will be primarily evaluated for pharmacokinetics in part 1 and efficacy (EFS) of ibrutinib in combination with RICE or RVICI background therapy compared to RICE or RVICI background therapy alone in part 2. Participants' safety will be monitored throughout the study.

Arms: arm 1: The first 2 participants enrolled in each age group (1-5 years, 6-11 years and 12-17 years) will receive starting dose of Ibrutinib 240 milligram per square meter (mg/m\^2) for the first cycle, followed by dose escalation at the start of Cycle 2 as long as all pharmacokinetic assessments are within the expected range and there are no safety concerns. For participants being treated at 240 mg/m\^2 dose level during the first cycle, the maximum dose should not exceed a total of 420 mg/day. All participants will receive rituximab, ifosfamide, carboplatin, etoposide and dexamethasone (RICE) or ituximab, vincristine, ifosfamide, carboplatin, idarubicin and dexamethasone (RVICI) background therapy (investigator's choice), during treatment phase. Participants with PR or better only will receive Ibrutinib for 3 cycles or until PD, unacceptable toxicity or until initiating antilymphoma therapy or a conditioning regimen for stem cell transplantation during post-treatment phase. arm 2: Participants will either receive ibrutinib and RICE/RVICI background therapy or RICE/RVICI background therapy alone, until 3 cycles are completed or until PD or unacceptable toxicity during the treatment phase. Participants who received ibrutinib and RICE/RVICI background therapy and with PR or better only will receive ibrutinib alone for 3 cycles during post-treatment phase.
Interventions: intervention 1: Ibrutinib intervention 2: Rituximab intervention 3: Ifosfamide intervention 4: Carboplatin intervention 5: Etoposide intervention 6: Vincristine intervention 7: Idarubicin intervention 8: Dexamethasone
Intervention descriptions: intervention 1: Participants will receive Ibrutinib (dose 240 mg/m\^2 /329 mg/m\^2 per day) during part 1 and part 2. intervention 2: Participants will receive a cumulative dose of rituximab 750 mg/m\^2 as a part of RICE/RVICI regimen in part 1 and part 2 per cycle. intervention 3: Participants will receive a cumulative dose of Ifosfamide 9 g/m\^2 and 10 g/m\^2 as a part of RICE and RVICI regimen respectively in part 1 and part 2 per cycle. intervention 4: Participants will receive a cumulative dose of carboplatin 635 mg/m\^2 and 800 mg/m\^2 as a part of RICE and RVICI regimen respectively in part 1 and part 2 per cycle. intervention 5: Participants will receive a cumulative dose of etoposide 300 mg/m\^2 in part 1 and part 2 as a part of RICE regimen per cycle. intervention 6: Participants will receive a cumulative dose of vincristine 1.6 mg/m\^2 in part 1 and part 2 as a part of RVICI regimen per cycle. intervention 7: Participants will receive a cumulative dose of idarubicin 20 mg/m\^2 in part 1 and part 2 as a part of RVICI regimen per cycle. intervention 8: Participants will receive a cumulative dose of dexamethasone 100 mg/m\^2 in part 1 and part 2 as a part of RICE/RVICI regimen per cycle.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 15 September 2020
Janssen Research & Development *
Clinical Protocol
A Randomized, Open-label, Safety and Efficacy Study of Ibrutinib in Pediatric and Young 
Adult Patients With Relapsed or Refractory Mature B-cell non-Hodgkin Lymphoma
Protocol 54179060LYM3003; Phase 3
Amendment 6
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.
This compound is being investigated in Phase 1, 2 and 3 clinical studies.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR Part 312).
EudraCT NUMBER:  2016-000259-28 
Status:
Approved
Date:
15 September 2020
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-ERI-111646582:8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT02703272


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 6
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 28
TIME AND EVENTS SCHEDULE .............................................................................................................. 33
ABBREVIATIONS ...................................................................................................................................... 44
1.
INTRODUCTION................................................................................................................................ 46
1.1.
Mature B-cell Non-Hodgkin Lymphoma......................................................................................... 46
1.2.
Current Methods of Treatment of Previously-Treated Mature B-cell Non-Hodgkin 
Lymphoma ..................................................................................................................................... 46
1.3.
Ibrutinib........................................................................................................................................... 47
1.3.1.
Nonclinical Studies ..................................................................................................................... 47
1.3.2.
Clinical Studies ........................................................................................................................... 48
1.3.2.1.
Human Pharmacokinetics........................................................................................................ 48
1.3.2.2.
Efficacy/Safety Studies............................................................................................................ 50
1.4.
Background Chemoimmunotherapy .............................................................................................. 54
1.5.
Rationale for the Study................................................................................................................... 54
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 56
2.1.
Objectives and Endpoints .............................................................................................................. 56
2.1.1.
Run-in Part (Part 1)..................................................................................................................... 56
2.1.2.
Randomized Part (Part 2)........................................................................................................... 57
2.2.
Hypothesis ..................................................................................................................................... 57
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 58
3.1.
Overview of Study Design.............................................................................................................. 58
3.2.
Study Design Rationale.................................................................................................................. 63
3.2.1.
Study Population......................................................................................................................... 63
3.2.2.
Study Treatments ....................................................................................................................... 63
3.2.3.
Study Assessments .................................................................................................................... 64
3.2.4.
Pharmacodynamic Analysis ....................................................................................................... 64
3.2.5.
Pharmacokinetic Analysis........................................................................................................... 64
3.2.6.
Biomarker Collection................................................................................................................... 64
4.
SUBJECT POPULATION.................................................................................................................. 65
4.1.
Inclusion Criteria ............................................................................................................................ 65
4.2.
Exclusion Criteria ........................................................................................................................... 68
4.3.
Prohibitions and Restrictions ......................................................................................................... 70
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 71
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 71
6.1.
Study Treatment............................................................................................................................. 72
6.1.1.
RICE/RVICI Administration......................................................................................................... 73
6.1.2.
Ibrutinib Administration ............................................................................................................... 73
6.2.
Dose Modifications and Dose Delay.............................................................................................. 74
6.2.1.
RICE/RVICI................................................................................................................................. 74
6.2.2.
Ibrutinib ....................................................................................................................................... 74


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7.
TREATMENT COMPLIANCE............................................................................................................ 75
7.1.
Ibrutinib Compliance ...................................................................................................................... 76
7.2.
RICE/RVICI Compliance................................................................................................................ 76
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 76
8.1.
Permitted Medications and Supportive Therapies ......................................................................... 77
8.1.1.
Medications Permitted Prior to Study Treatment........................................................................ 77
8.1.2.
Medications Permitted During Treatment................................................................................... 77
8.2.
Prohibited Medications................................................................................................................... 78
8.3.
Concomitant Medications to be Avoided or to be Used with Caution............................................ 78
8.3.1.
Radiation Therapy ...................................................................................................................... 78
8.4.
Subsequent Antilymphoma Therapies........................................................................................... 79
9.
STUDY EVALUATIONS .................................................................................................................... 79
9.1.
Study Procedures........................................................................................................................... 79
9.1.1.
Overview..................................................................................................................................... 79
9.1.2.
Pretreatment (Screening) Phase ................................................................................................ 79
9.1.3.
Treatment Phase ........................................................................................................................ 80
9.1.4.
Posttreatment Phase (Follow-Up) .............................................................................................. 81
9.1.5.
Clinical Cutoffs............................................................................................................................ 82
9.2.
Efficacy Evaluations....................................................................................................................... 82
9.2.1.
Imaging Assessments................................................................................................................. 82
9.2.2.
Bone Marrow/ Lymph Node Assessment ................................................................................... 83
9.2.3.
Lumbar Puncture ........................................................................................................................ 83
9.2.4.
Physical Examination.................................................................................................................. 83
9.2.5.
Efficacy Criteria........................................................................................................................... 83
9.2.5.1.
Evaluation of Measurable Disease.......................................................................................... 84
9.2.5.2.
Response Categories .............................................................................................................. 84
9.3.
Pharmacokinetics........................................................................................................................... 86
9.3.1.
Evaluations ................................................................................................................................. 86
9.3.2.
Analytical Procedures................................................................................................................. 87
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 87
9.4.
Pharmacodynamic Evaluations...................................................................................................... 88
9.5.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 88
9.6.
Biomarkers ..................................................................................................................................... 88
9.7.
Palatability Assessment ................................................................................................................. 89
9.8.
Safety Evaluations ......................................................................................................................... 89
9.9.
Sample Collection and Handling.................................................................................................... 92
10.
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY ........................................................................................................................... 92
10.1.
Completion ..................................................................................................................................... 92
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study ................................................... 92
10.3.
Withdrawal From the Use of Research Samples........................................................................... 93
11.
STATISTICAL METHODS................................................................................................................. 94
11.1.
Subject Information ........................................................................................................................ 94
11.2.
Sample Size Determination ........................................................................................................... 94
11.3.
Efficacy Analyses ........................................................................................................................... 95
11.3.1.
Primary Endpoint ........................................................................................................................ 95
11.3.2.
Secondary Endpoints.................................................................................................................. 95
11.4.
Pharmacokinetic Analyses............................................................................................................. 96
11.5.
Pharmacodynamic Analyses and Biomarker Analyses ................................................................. 96
11.6.
Pharmacokinetic-Pharmacodynamic Analysis............................................................................... 96
11.7.
Safety Analyses ............................................................................................................................. 97
11.8.
Independent Data Monitoring Committee ...................................................................................... 98
11.9.
Interim Analysis.............................................................................................................................. 98
11.9.1.
Outcome of IDMC review on 20 July 2020................................................................................. 99


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11.10.
Study Evaluation Team (SET) ....................................................................................................... 99
12.
ADVERSE EVENT REPORTING ...................................................................................................... 99
12.1.
Definitions ...................................................................................................................................... 99
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 99
12.1.2.
Attribution Definitions................................................................................................................ 100
12.1.3.
Severity Criteria ........................................................................................................................ 101
12.2.
Special Reporting Situations........................................................................................................ 101
12.3.
Procedures................................................................................................................................... 102
12.3.1.
All Adverse Events.................................................................................................................... 102
12.3.2.
Serious Adverse Events ........................................................................................................... 103
12.3.3.
Adverse Events of Special Interest........................................................................................... 104
12.3.4.
Other Malignancies................................................................................................................... 104
12.3.5.
Pregnancy................................................................................................................................. 104
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 105
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 105
13.1.
Procedures................................................................................................................................... 105
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 105
14.
STUDY DRUG INFORMATION....................................................................................................... 105
14.1.
Study Drug - Ibrutinib ................................................................................................................... 105
14.1.1.
Physical Description ................................................................................................................. 105
14.1.2.
Packaging ................................................................................................................................. 106
14.1.3.
Labeling .................................................................................................................................... 106
14.1.4.
Preparation, Handling, and Storage ......................................................................................... 106
14.2.
Background Therapy (RICE or RVICI)......................................................................................... 107
14.3.
Drug Accountability ...................................................................................................................... 107
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 107
16.
ETHICAL ASPECTS ....................................................................................................................... 108
16.1.
Study-Specific Design Considerations......................................................................................... 108
16.2.
Regulatory Ethics Compliance..................................................................................................... 109
16.2.1.
Investigator Responsibilities ..................................................................................................... 109
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 109
16.2.3.
Informed Consent and Assent Form......................................................................................... 110
16.2.4.
Privacy of Personal Data .......................................................................................................... 112
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 112
16.2.6.
Country Selection ..................................................................................................................... 112
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 113
17.1.
Protocol Amendments.................................................................................................................. 113
17.2.
Regulatory Documentation .......................................................................................................... 113
17.2.1.
Regulatory Approval/Notification .............................................................................................. 113
17.2.2.
Required Prestudy Documentation........................................................................................... 113
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 114
17.4.
Source Documentation................................................................................................................. 114
17.5.
Case Report Form Completion .................................................................................................... 115
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 116
17.7.
Record Retention ......................................................................................................................... 116
17.8.
Monitoring .................................................................................................................................... 117
17.9.
Study Completion/Termination..................................................................................................... 117
17.9.1.
Study Completion/End of Study................................................................................................ 117
17.9.2.
Study Termination..................................................................................................................... 117
17.10.
On-Site Audits .............................................................................................................................. 118
17.11.
Use of Information and Publication.............................................................................................. 118
REFERENCES.......................................................................................................................................... 120


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INVESTIGATOR AGREEMENT ............................................................................................................... 140


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LIST OF ATTACHMENTS
Attachment 1:
Ibrutinib Dosing Guides ............................................................................................ 123
Attachment 2:
Lansky-Karnofsky Performance Status .................................................................... 132
Attachment 3:
Body Surface Area Calculation ................................................................................ 133
Attachment 4:
Instruction for Concomitant Medications to be Used With Precaution ..................... 134
Attachment 5:
Inhibitors and Inducers of CYP3A ............................................................................ 136
Attachment 6:
Intrathecal Drug Doses by Age ................................................................................ 137
Attachment 7:
Blood Volume Tables ............................................................................................... 138
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Time and Events Schedule (Part 1 Only) ................................................................................. 33
Table 2:
Time and Events Schedule (Part 2).......................................................................................... 36
Table 3:
Time and Events Schedule: Posttreatment Phase for Subjects Continuing on Ibrutinib 
Monotherapy............................................................................................................................. 39
Table 4:
Time and Events Schedule: Posttreatment Phase for Subjects not Receiving Ibrutinib 
Monotherapy............................................................................................................................. 41
Table 5:
Dose and Administration Table: RICE With or Without Ibrutinib .............................................. 42
Table 6:
Dose and Administration Table: RVICI With or Without Ibrutinib ............................................. 43
Table 7:
Completed Efficacy Studies of Ibrutinib in DLBCL ................................................................... 51
Table 8:
Ibrutinib Dose Modifications...................................................................................................... 75
Table 9:
International Pediatric NHL Response Criteria......................................................................... 85
Table 10:
Supporting International Pediatric NHL Response Criteria Data.............................................. 86
Table 11:
Stopping Boundaries (N=72 subjects, 2 Analyses) .................................................................. 98
FIGURES
Figure 1:
Schematic Overview of the Study (Part 1; Run-in Part) ........................................................... 61
Figure 2:
Schematic Overview of the Study (Part 2; Randomized Part).................................................. 62


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Status: Approved, Date: 15 September 2020
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
12 February 2016
Amendment 1
21 June 2016
Amendment 2
24 April 2017
Amendment 3
7 July 2017
Amendment 4
13 April 2018
Amendment 5
19 December 2019
Amendment 6
15 September 2020
Amendments are listed beginning with the most recent amendment.
Amendment 6 (15 September 2020) 
The overall reasons for the amendment: To report the outcome of the pre-planned interim analysis and clarify 
impact on further study conduct, including stopping new subject enrollment.  
Applicable Section(s)
Description of Change(s)
Rationale: To report the outcome and recommendations from the independent data monitoring committee 
(IDMC) following the interim analysis
Synopsis, Overview 
of Study Design
Early stopping rules clarified
Rationale: To report survival follow up duration for subjects without progressive disease (PD)
Synopsis, Efficacy 
Evaluations/ 
Endpoints
Survival follow up duration for subjects without PD clarified
Rationale: To report results of the interim analysis
Synopsis, Statistical 
Methods
New text added to report the outcome of the pre-planned interim analysis.  The IDMC 
recommended stopping new subject enrollment.  
Rationale: Editorial amendment
Synopsis, Table 2
Typographic error updated in Table 2, Time and Event Schedule.  Check box added for 
pregnancy test at Cycle 1, Day 1. New footnote ‘l’ added; subsequent footnotes 
reordered.
Rationale: Editorial amendment 
Section 3.1 Overview 
of Study Design, 
Figure 1
Survival follow up duration for subjects without PD clarified
Rationale: Clarification of follow up duration for subjects with or without PD ≥ 3 years
Section 9.1.4
Posttreatment Phase 
(Follow-Up)
Added requirement to follow up subjects without PD for survival status after the last 
efficacy assessment at 3 years.  For subjects with PD after 3 years, the reason for 
progression will be entered in the case report form (CRF).
Rationale: To report results of the interim analysis 
Section 11.9.1
Results of IDMC 
review on 20 July 
2020
New section added to report results of the pre-planned interim analysis.  The IDMC 
recommended stopping new subject enrollment.  
Rationale: To report results of the interim analysis


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Section 17.9.1 Study 
Completion/End of 
Study 
New text added to report results of the pre-planned interim analysis.
Rationale: Minor editorial changes implemented across the protocol
Amendment 5 (19 December 2019) 
The overall reasons 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 that assessment of pulse/heart rate and blood pressure is expected 
until end of treatment
Applicable Section(s)
Description of Change(s)
Rationale: To update the safety for ibrutinib, including information on cerebrovascular accidents
1.3.2.2 
Efficacy/Safety 
Studies
Safety information on ibrutinib updated to align with the current IB
Rationale: To clarify that regular monitoring of pulse/heart rate and blood pressure is expected until end of 
treatment
Table 2 and Table 3 
Time and Events 
Schedules (row for 
“Heart rate and blood 
pressure” added; 
footnote added); 
Pulse/heart rate and blood pressure assessments added
Footnote d (Table 2) and footnote c (Table 3) added to clarify that vital sign assessments 
should be recorded in source documents but will not be routinely collected in the eCRF
9.8 Safety 
Evaluations
Vital signs description added to specify pulse/heart rate and blood pressure evaluation 
methods and timings, ie, at every protocol-specified visit until end of treatment
Rationale: To add an external link for examples of CYP3A inhibitors and inducers; to add additional dose 
reduction information for CYP3A co-administration
Attachment 4 
Instruction for 
Concomitant 
Medications to be 
Used With 
Precaution, 
Attachment 5 
Inhibitors and 
Inducers of CYP3A
Inserted an additional link to FDA classification of CYP3A inhibitors and inducers in 
Attachment 4 and Attachment 5
Updated dose reduction description in Attachment 4
Attachment 1 
Ibrutinib Dosing 
Guides, Attachment 2 
Potential Dose for 
Younger Subjects
Added dosing tables for 330 mg/m2, 220 mg/m2, and 110 mg/m2 (ie, dose reductions in 
patients starting at 440 mg/m2)
Moved dosing table for 440 mg/m2 to Attachment 1; Attachment 2 deleted
Rationale: To improve clarity and accuracy throughout the protocol
Table 1 and Table 2 
Time and Events 
Schedules
Added a separate Time and Events Schedule for Part 2 of the study (Table 2); removed 
references to Part 2 as appropriate


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Table 1, Table 3, 
Table 4, Table 5 
Time and Events 
Schedules, 
Attachment 7 Blood 
Volume Tables
Added and/or edited headings and footnotes for clarity
3.1 Overview of 
Study Design
Clarified pharmacokinetic sampling to be obtained only for subjects receiving ibrutinib 
in combination with background therapy in Part 2
3.1 Overview of 
Study Design,
6.1 Study Treatment, 
9.1.4 Posttreatment 
Phase (Follow-up)
Clarified subjects must have completed 3 cycles of treatment to be eligible to receive 
ibrutinib monotherapy
Figure 2 Schematic 
Overview of the 
Study (Part 2; 
Randomized Part), 
4.1 Inclusion Criteria
Eligibility criteria updated to specify subjects were to have received only 1 prior line of 
therapy for inclusion in Part 2 of the study
6 Dosage and 
Administration
Added reference to Investigational Product Preparation Instruction for subjects requiring 
dosing through a feeding tube
6.1.2 Ibrutinib 
Administration
Clarified methods for dispensing ibrutinib by cycle
9.2.3 Lumbar 
Puncture
Provided additional information for lumbar puncture and cerebral spinal fluid collection 
Table 9 International 
Pediatric non-
Hodgkin lymphomas 
(NHL) Response 
Criteria
Updated to align with guidance
11.9 Interim Analysis
Replaced “external” with “independent” as a descriptor for the Data Monitoring 
Committee for consistency within the document.
14.3 Drug 
Accountability
Specified documentation on the drug accountability form applicable for study drug 
dispensed from central supply
15 Study-specific 
Materials
Revised bullet “Visual analog scale for palatability” to read “Visual analog for 
palatability and acceptability”
17.4 Source 
Documentation
Deleted bullet referencing history of nicotine use to be recorded into the CRF, as this 
was not collected for the study 
Rationale: Minor editorial changes implemented across the protocol
Amendment 4 (13 April 2018)
The overall reason for the amendment: To amend the study population to subjects in first relapse only, to include 
the 70 mg/mL multi-dose formulation, to make the protocol consistent with updated safety information in the 
Investigator’s Brochure (IB; version 11, November 2017) by including ventricular arrhythmias and Hepatitis B 
reactivation as potential risks along with guidance for their management, and to clarify procedures/requirements for 
the concomitant administration of CYP-mediated medications and pharmacokinetic sampling in subjects who are 
not receiving ibrutinib.


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Applicable Section(s)
Description of Change(s)
Rationale: Upon review of Part 1 data, subjects with >1 relapse were noted to have very short survival duration 
partially due to the nature of the disease but also due to toxicity of multiagent CIT. These high-risk subjects are 
heavily pretreated making them suboptimal candidates for intensive CIT and unable to achieve any meaningful 
exposure to ibrutinib therapy.
Synopsis: Subject 
Population;
Figure 1: Eligibility;
Figure 2: Eligibility;
4.1. Inclusion Criteria; 
Criterion 3 
Clarified that subjects must be in first recurrence or have disease that is primarily 
refractory to conventional therapy. Text indicating “or late(r)” recurrence deleted.
Rationale: To include information on the new 70 mg/mL multi-dose formulation.
14.1.1. Physical 
Description;
14.1.4. Preparation, 
Handling, and Storage
Included information regarding the 70 mg/mL multi-dose suspension.
14.1.2. Packaging
Packaging details were added.
14.3. Drug 
Accountability 
Used bottles added to list of potentially hazardous materials.
Rationale: To make the protocol consistent with updated safety information in the IB (Version 11, November 
2017) and to align with company core data sheet (CCDS) updates.
Table 1: Time and 
Events Schedule (Part 1 
and Part 2), footnote 
“m”; 
9.8. Safety Evaluations 
Provided more specific guidance related to testing and monitoring of subjects with 
evidence of Hepatitis B core antibody positivity, and suggested consideration of 
prophylactic therapy consistent with local practice. 
1.3.2.2. Efficacy/Safety 
Studies, Cardiac 
Arrhythmias 
Updated background on cardiac arrhythmias to align with CCDS; as well as to add
ventricular arrhythmias as a potential risk.
Rationale: To clarify the administration of CYP-mediated medications in subjects who are NOT receiving 
ibrutinib.
6.1.2. Ibrutinib 
Administration; 
6.2.2. Ibrutinib;
8.1. Permitted 
Medications and 
Supportive Therapies;
8.3. Concomitant 
Medications to be 
Avoided or to be Used 
with Caution   
Text clarified to indicate restrictions for subjects receiving ibrutinib. There is no 
restriction in the administration of concomitant medications classified as CYP3A 
inhibitors/inducers in patients NOT receiving ibrutinib as there is no anticipated 
interaction.
Rationale: To minimize enrollment of subjects who may not derive clinical benefit from retreatment with 
ibrutinib after initial failure.
4.2 Exclusion Criteria; 
Criterion 15 
New exclusion criterion added to exclude subjects with previous exposure to 
ibrutinib.
Rationale: To align IV hydration requirements with accepted standard practice.


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Applicable Section(s)
Description of Change(s)
Table 4: Dose and 
Administration Table: 
RICE With or Without 
Ibrutinib
IV hydration requirements of 3,000 mL/m2/day were clarified (ie, required on Days 1 
through 5 of each treatment cycle).
Rationale: To understand the impact of ibrutinib on stem cell collection.
Table 1: Time and 
Events Schedule (Part 1 
and Part 2), Laboratory 
Assessments;
Table 2: Time and 
Events Schedule: 
Posttreatment Phase for 
Subjects Continuing on 
Ibrutinib Monotherapy, 
Laboratory 
Assessments;
Table 3: Time and 
Events Schedule: 
Posttreatment Phase for 
Subjects not Receiving 
Ibrutinib Monotherapy, 
Laboratory 
Assessments;
9.1.1. Overview
Text added to include cell count from stem collection for transplant, if applicable.


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Applicable Section(s)
Description of Change(s)
Rationale: To avoid the use of language that may not translate as intended.
Synopsis, Dosage and 
Administration; Table 1: 
Time and Events 
Schedule (Part 1 and 
Part 2), footnotes “f” 
and “n”; 
1.3.2.2. Efficacy/Safety 
Studies;
4.3. Prohibitions and 
Restrictions: Criterion 1 
and Criterion 4; 
6.2.1. RICE/RVICI;
6.2.2. Ibrutinib;
Table 7, Ibrutinib Dose 
Modifications;
8.3.1. Radiation 
Therapy; 
9.3.1. Evaluations; 
11.10. Study Evaluation 
Team (SET);
Attachment 5
Text that previously read “hold or “held” has been revised to “temporarily stop” or 
“temporarily stopped”
Rationale: To increase clarity throughout the protocol.
Synopsis, Dosage 
Administration;
Table 4: Dose and 
Administration Table: 
RICE With or Without 
Ibrutinib, footnote “e”
Table 5: Dose and 
Administration Table: 
RVICI With or Without 
Ibrutinib, footnote “d”
1.4. Background 
Chemoimmunotherapy
6.1. Study Treatment 
Corticosteroids administered as part of the intrathecal (IT) regimen are not limited to 
hydrocortisone and prednisolone. Text identifying IT corticosteroid as hydrocortisone 
or prednisolone deleted.
Attachment 7 
Footnote added to clarify that other corticosteroids may be administered as per local 
supply provided that the steroid equivalent dose is equal to the prednisolone dose. 
Table 1: Time and 
Events Schedule (Part 1 
and Part 2), Procedures: 
BSA
Table 2: Time and 
Events Schedule: 
Posttreatment Phase for 
Subjects Continuing on 
Ibrutinib Monotherapy,
Procedures: BSA, 
Weight
Footnote “d” added to clarify that BSA and dose should only be recalculated at Cycle 
2 Day 1 and Cycle 3 Day 1 if there is >10% weight change from the weight used in 
the previous BSA calculation.
Footnote “b” modified to clarify that BSA and dose should only be recalculated at 
Day 1 in Cycles 1-3 if there is >10% weight change from the weight used in the 
previous BSA calculation. Weight will continue to be obtained prior to dosing on Day 
1 for each cycle of monotherapy.


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Applicable Section(s)
Description of Change(s)
Table 1: Time and 
Events Schedule (Part 1 
and Part 2), Procedures: 
Pathology and footnote 
“b”; 
4.1 Inclusion Criteria; 
Criterion 2 
9.1.2. Pretreatment 
(Screening) Phase
Clarified that the pathology report from the original NHL diagnosis or the pathology 
report at relapse, if available, is acceptable for the confirmation of diagnosis at study 
entry.
Table 1: Time and 
Events Schedule (Part 1 
and Part 2), footnote “c”
Clarified that for biomarker studies no tumor tissue sample is required at the End of 
Treatment in the absence of progressive disease. 
Table 1: Time and 
Events Schedule (Part 1 
and Part 2), footnote “a”
Clarified which standard of care assessments can be used for the study if performed 
within 5 days of signing the ICF.
Table 1: Time and 
Events Schedule (Part 1 
and Part 2), footnote “o” 
For Part 2, clarified that assessments taken at 4 hour postdose are applicable for 
subjects receiving ibrutinib only. Instruction provided for sample collection in the 
event of post lumbar puncture bleeding.
Table 1, Time and 
Events Schedule, 
footnote “j”; 
9.2.2. Bone 
Marrow/Lymph Node 
Assessment 
Clarified that morphology and IHC or flow cytometry of the bone marrow aspirate 
and/or biopsy are required at screening for all subjects. If a subject has negative bone 
marrow results at screening, subsequent assessments at disease evaluation visits must 
include morphologic assessment of the bone marrow, while immunophenotyping is 
optional.
Table 4: RICE Dose and 
Administration footnote 
“d” 
Table 5: RVICI Dose 
and Administration 
footnote “c”
In Tables 4 and 5, clarified that the instruction for shortened infusion and stopping 
criteria for Mesna administration only applies to subjects who are receiving ibrutinib. 
In Table 5, clarified that the mesna and ifosfamide infusion may be given as per 
standard of care for subjects not receiving ibrutinib.
6.1. Study Treatment; 
7.1. Ibrutinib 
Compliance 
Text added to clarify that dietary intake should be reported on PK days.
8.1.2. Medications 
Permitted During 
Treatment
Clarified that a single dose of corticosteroid premedication is allowed prior to 
rituximab infusion and/or in response to infusion-related reactions. 
Clarified that non-azole antifungal prophylaxis is allowed for subjects on ibrutinib. 
Azole antifungals are allowed for subjects randomized to background therapy only
9.1.4. Posttreatment 
Phase (Follow-Up) 
Text referring to Tables 2 and 3 added to clarify follow-up visit intervals.  
9.2.1. Imaging 
Assessments
Clarified that all anatomical regions should be scanned at each timepoint irrespective 
of the site of disease. 
9.3.1. Evaluations 
Clarified that subjects must take ibrutinib for a minimum of 3 days prior to all 
pharmacokinetics timepoints after Cycle 1 Day 1. If ibrutinib is temporarily stopped 
on any pharmacokinetics sampling days, or within 3 days prior to pharmacokinetics 
sampling, the medical monitor should be contacted for guidance.
9.7. Palatability
Assessment
Clarified that palatability refers to palatability of ibrutinib.


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Applicable Section(s)
Description of Change(s)
Rationale: Alignment of text with recent protocol template changes.
17.3. Subject 
Identification
Added ‘(as allowed by local regulations)’ following 2 instances of ‘date of birth’.
17.4. Source 
Documentation
Added sentence relating to source documentation in e-Source system. 
17.11. Use of 
Information and 
Publication
Added the text in bold: ‘key assessment parameters of the study will be used to 
determine a coordinating investigator for the study’.
Revised the text beginning ‘Authorship of publications...’
Rationale: Minor corrections and errors were addressed.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Table 4: Dose and 
Administration Table: 
RICE With or Without 
Ibrutinib, Table Title 
and footnote “d” 
Table 5: Dose and 
Administration Table: 
RVICI With or Without 
Ibrutinib, Table Title 
and footnote “c”
Title of tables revised to indicate that background therapies (RICE or RVICI) can be 
administered with or without ibrutinib. 
New text added in table and footnotes indicating that shortened infusion for mesna 
(RICE) and mesna and ifosfamide (RVICI) are for subjects receiving ibrutinib.
6.1.2. Ibrutinib 
Administration
Redundant statement “Ibrutinib is to be taken around the same time each day” 
removed from second paragraph.


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Amendment 3 (7 July 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To amend the total number of pediatric subjects allowed to be enrolled in 
Part 1 from 12 subjects to approximately 24 subjects. The ibrutinib exposures have been lower than expected in the 
initial subjects enrolled in the 2 younger age groups (ages 1-5 and 6-11), and so additional data are required for more 
certainty surrounding dose confirmation in the younger subjects before opening Part 2 to these 2 younger age 
groups. There were no unexpected safety findings identified by the Study Evaluation Team (SET) who perform 
ongoing review of subjects treated with RVICI or RICE in combination with ibrutinib. Furthermore, dose 
escalations were performed as planned per protocol.
Applicable Section(s)
Description of Change(s)
Rationale: Ibrutinib exposures have been lower than expected in the 2 younger age groups (ages 1-5 and 6-11). 
Enrolling more subjects into Part 1 will allow for more confidence around the dosing in these younger subjects 
before opening Part 2 to these 2 younger age groups.
Synopsis (Overview of Study 
Design); 3.1 Overview of Study 
Design; 3.2.2 Study Treatments; 
5 Treatment Allocation and 
Blinding; 6.1 Study Treatment; 
11.10 Study Evaluation Team 
(SET); Attachment 8 (Blood 
Volume Tables)
Revised the number of subjects to be enrolled into Part 1 (ie, from 12 to up to 
approximately 24 subjects). Clarified that at a minimum, the first 2 subjects in 
each age group will enroll into Part 1 before recruitment of children in that age 
group will begin in Part 2. 
Rationale: To clarify testing procedures.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2])
Added footnote “e” to clarify timing of drug acceptability and palatability 
assessment.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2] 
footnote “a”)
Clarified standard of care tests now include comorbidities documentation, and 
include viral serologies in baseline disease documentation.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2] 
footnote “m”)
Clarified that if ibrutinib is held on any PK sampling days, or within 3 days 
prior to PK sampling, the medical monitor should be contacted for guidance.
Removed the footnote “m” from individual time points and moved it to the 
assessment column to include the entire row of assessment.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2] 
footnote “n” and corresponding 
table row)
Clarified timing of Part 2 biomarker blood samples for phospho-protein and 
molecular characterization, and BTK occupancy evaluations.
Table 2 (Time and Events 
Schedule: Posttreatment Phase 
for Subjects Continuing on 
Ibrutinib Monotherapy; footnote 
“h”)
Clarified that whole blood samples for phospho-protein and molecular 
characterization should be obtained at the End-of-Monotherapy Visit and at PD, 
and samples for BTK occupancy should be obtained if PD occurs during 
Cycles 1-3 of monotherapy or and the End-of-Monotherapy Visit.


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Attachment 8 (Blood Volume 
Tables)
Added footnotes “f” and “g” for Part 1 and Part 2 respectively to indicate that 
subjects who enter monotherapy will have a tetanus and pneumococcal titer 
sample taken at End-of-Monotherapy Visit.
Added footnotes “g” and “h” for Part 1 and Part 2 respectively to indicate that 
for the approximate total blood volume, an additional biomarker sample may be 
taken if PD occurs during a follow-up visit.
Clarified footnote “f” for Part 2 to state that pharmacodynamic and biomarker 
samples may be collected in Cycle 2 or Cycle 3.
Rationale: To clarify timing of adverse event reporting or concomitant medication collection.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2]); 
8 Prestudy and Concomitant 
Therapy; 9.8 Safety Evaluations; 
12.3.1 All Adverse Events
Text was amended to indicate that adverse events and concomitant medication 
use will be collected for 30 days after the last dose, or until the start of 
subsequent antilymphoma therapy, whichever is earlier, unless related to study 
treatment.
Rationale: To clarify exclusion criteria for subjects who are pregnant, or breastfeeding, or planning to become 
pregnant while enrolled in this study.
4.2 Exclusion Criteria 9
Added text to clarify that subjects who are pregnant, or breastfeeding, or 
planning to become pregnant while enrolled in this study or within at least 
3 months after the last dose of ibrutinib or 1 year after the last dose of the 
background CIT, whichever is later, are to be excluded from the study.
Rationale: To clarify background chemotherapy doses.
Synopsis (Dosage and 
Administration)
Added text to clarify that background chemoimmunotherapy dose values were 
cumulative.
Rationale: Corrected errors in Amendment 2.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2] 
plasma samples row, biomarker 
row and footnote “n”)
Corrected timing of PK, protein binding, and biomarker assessments by adding 
an assessment at Cycle 1 Day 14.
Table 2 (Time and Events 
Schedule: Posttreatment Phase 
for Subjects Continuing on 
Ibrutinib Monotherapy)
Timing of limited physical exams was revised to align with the timing of 
disease evaluations for subjects in the Post-Treatment phase receiving 
monotherapy with ibrutinib. Assessments were added at 12, 24, and 36 months 
after Cycle 1 Day 1.
Section 15 Study-Specific 
Materials
Removed text “Diagnosis and subtyping report form”, as this form is not 
applicable to the study.
Rationale: To clarify ibrutinib target dose and dose adjustment based on exposure data.
Synopsis (Dosage and 
Administration); 3.2.2 Study 
Treatments; 6.1 Study Treatment
Added text to clarify target ibrutinib dose and dose adjustment are based on 
exposure data.
Rationale:  To outline a higher dosing option in the event that drug exposures in the additional subjects enrolled 
into Part 1 prove to be too low.
Attachment 2 (Potential Dose for 
Younger Subjects)
An additional table for suspension and capsule dosing in younger subjects under 
12 years of age at 440 mg/m2 was added.


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Rationale: To provide sufficient blood sample for pharmacodynamic evaluation.
9.1.1 Overview; Attachment 8 
(Blood Volume Tables)
Increased blood volumes for pharmacodynamic samples for Part 1 and Part 2 
from 4.0 mL to a range of 4.0 – 6.0 mL, and aligned blood sampling with the 
Time and Events Schedule.
Added a new PK and biomarker sample at the End-of-Monotherapy Visit for 
Parts 1 and 2. These changes increased the approximate total blood volume in 
Parts 1 and 2 to a min/max of 139-230.5 mL and 131.4-222.9 mL, respectively.
Rationale: To comply with Janssen company standards.
Title Page
Added Janssen Pharmaceutica NV to list of legal entities
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 2 (24 April 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: The overall reason for the amendment is to incorporate changes requested 
during Health Authority review.
Applicable Section(s)
Description of Change(s)
Rationale: Per a request received from a Health Authority, contraception language was changed to clarify length of 
time subjects should avoid pregnancy after the last dose of any study drug.
Section 4.1 Inclusion Criteria 
(#10)
Clarified that study participants of childbearing potential must agree to remain 
on a highly effective birth control method from 1 year after the last dose of the 
background chemoimmunotherapy (instead of rituximab).
Also added that women of child bearing potential must use highly effective 
contraceptive measures while taking IMBRUVICA. Those using hormonal 
methods of birth control must add a barrier method (eg, condom with 
spermicidal foam/gel/film/cream/suppository).
Section 4.2 Exclusion Criteria
(#9)
The exclusion criteria were updated to clarify the minimum amount of time a 
subject should avoid becoming pregnant or breast feeding following the last 
dose of study drug. 
Rationale: To align with the most recent ibrutinib protocol template language.
Section 1.3.2.2 Efficacy/Safety 
Studies
The risks associated with ibrutinib use were updated; modified the following 
sections (Hematological and non-Hematological Adverse Events): cytopenias, 
lymphocytosis and leukostasis (sections are now separate), bleeding-related 
events, atrial fibrillation, diarrhea, infections, rash, tumor lysis syndrome, 
interstitial lung disease; and hypertension and non-melanoma skin cancer (new 
text added). 


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Attachment 4 (Instruction for 
Concomitant Medications to be 
Used With Precaution); 
Attachment 5 (Inhibitors and 
Inducers of CYP3A)
The web link for classification of commonly used inhibitors and inducers of 
CYP3A enzymes was corrected.
Attachment 5 (Inhibitors and 
Inducers of CYP3A)
The attachment was updated to reflect recent changes per the website.
Rationale: To exclude subjects with post-transplant lymphoproliferative disease since the pathogenesis of the 
disease is different from other mature B-cell non-Hodgkin lymphomas (NHLs).
Section 4.2 Exclusion Criteria 
(added criterion #13) 
Added exclusion criterion for subjects with a diagnosis of post-transplant 
lymphoproliferative disease (PTLD).
Rationale: To implement the Study Evaluation Team recommendation.
Section 4.2 Exclusion Criteria 
(added criterion #14)
Added exclusion criterion for subjects who received an allogeneic bone marrow 
transplant within 6 months.
Rationale: To define the short axis diameter of an involved lymph node that enables a subject to be enrolled.
Synopsis (Subject Population); 
Section 4.1 Inclusion Criteria 
(#4);
Section 9.2.5.1 Evaluation of 
Measurable Disease
Subjects must have at least 1 site of measurable disease defined as >1 cm in the 
longest diameter and >1 cm in the shortest diameter by radiological imaging, 
bone marrow involvement, or cerebrospinal fluid with blasts present. 
Rationale: Clarified follow-up visit requirement to ensure consistency with the study endpoint.
Synopsis (Efficacy 
Evaluations/Endpoints); Table 1 
(Time and Events Schedule [Part 
1 and Part 2]) footnote “f”); 
Figure 1 (Schematic Overview of 
the Study [Part 1; Run-in Part]); 
Figure 2 (Schematic Overview of 
the Study [Part 2: Randomized 
Part]); Section 3.1 Overview of 
Study Design; Section 9.1.4 
Posttreatment Phase (Follow-up)
Changed statement: Follow-up visits to assess disease progression will be 
required if study treatment is discontinued prior to PD (including subjects who 
go on to transplant) and will be completed as per Table 2 and Table 3 until PD, 
the clinical cutoff for the primary endpoint, or for up to 3 years after the date of 
Cycle 1 Day 1, whichever occurs first.
Rationale: To clarify Posttreatment Phase evaluations.
Table 2 (Time and Events 
Schedule [Posttreatment Phase 
for Subjects Continuing on 
Ibrutinib Monotherapy]); Table 3 
(Time and Events Schedule
[Posttreatment Phase for Subjects 
not Receiving Ibrutinib 
Monotherapy])
Table 2 and Table 3 were added to the protocol.
The Posttreatment Phase was deleted from Table 1.
Figure 1 (Schematic Overview of 
the Study [Part 1; Run-in Part]); 
Figure 2 (Schematic Overview of 
the Study [Part 2: Randomized 
Part]) 
Text was clarified in the figures to align with updated protocol text.


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Rationale:  To monitor concomitant steroid dosing.
Section 8.2 Prohibited 
Medications
Clarified that the medical monitor should be contacted if stress dose steroids are 
required.
Rationale: To recommend antimicrobial prophylaxis for subjects at risk for opportunistic infections and guide 
choice of antifungal prophylaxis.
Section 8.1 Permitted 
Medications and Supportive 
Therapies; Section 8.1.2 
Medications Permitted During 
Treatment
Added recommendation for antimicrobial prophylaxis in accordance with 
standard practice in subjects who are at increased risk for opportunistic 
infections. Added recommendation for use of non-azole antifungal prophylaxis 
with coverage for aspergillosis (eg, amphotericin B or echinocandins).
Rationale: Clarified language around mesna dosing in subjects without hematuria.
Table 4 (Dose and 
Administration Table: RICE 
With Ibrutinib)
Removed “shortened infusion” from the dosing instructions for mesna in 
subjects without hematuria in footnote “d”.
Rationale:  Concomitant GCSF was added to the RVICI regimen as prophylaxis against neutropenia commonly 
associated with this regimen.
Table 5 (Dose and 
Administration Table: RVICI 
With Ibrutinib [footnote “e”
added); Section 8.1 Permitted 
Medications and Supportive 
Therapies
Added GCSF to Dose and Administration table with guidance on timing of 
administration (GCSF should be administered beginning on Day 12 and 
continued until ANC ≥500/µL on 2 occasions post-nadir).
Rationale: Changed ifosfamide infusion timing to align with mesna infusion timing.
Table 5 (Dose and 
Administration Table: RVICI 
With Ibrutinib)
Text was changed: Ifosfamide 2 g/m2/24 hr over 5 days (administer as a 
shortened infusion per instructions in the footnote)c  (continuous infusion 
was removed).
Rationale: To clarify treatment modification guidelines for potential ibrutinib-drug related toxicity.
Synopsis (Dosage and 
Administration); Section 6.2.2 
Ibrutinib
Hematologic toxicities are expected with the background CIT therapies (RICE 
and RVICI). Therefore, clarified that treatment with ibrutinib should be held for 
any unmanageable, potentially study drug-related toxicity that is Grade ≥3 in 
severity.
Table 7 (Ibrutinib Dose 
Modifications)
Dose modifications were clarified.
Rationale: Blood volumes were aligned with the Time and Events Schedule (Table 1).
Section 9.1.1 Overview; 
Attachment 7 (Blood Volume 
Tables) 
Updated blood volumes for Cycle 1 (protein binding) in Attachment 7. The 
estimated maximum total volume of blood was also updated in Section 9.1.1.
Rationale:  To indicate that bone marrow on Cycle 2 Day 1 is only to be obtained if clinically indicated.
Synopsis (Efficacy 
Evaluations/Endpoints); Table 1 
(Time and Events Schedule [Part 1 
and Part 2] footnote “h”); Section 
9.2.5 Efficacy Evaluations
Clarified timing of imaging, bone marrow assessments and CSF evaluations. 
Added instruction that bone marrow on Cycle 2 Day 1 is only to be obtained if 
clinically indicated.


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Rationale:  To add flow cytometry as an option to evaluate bone marrow specimens.
Table 1 (Time and Events Schedule 
[Part 1 and Part 2] footnote “h”)
Clarified that morphological examination and IHC or flow cytometry is 
required of all bone marrow specimens.
Rationale: To avoid the need for repeated imaging and radiation exposure if imaging was recently performed.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2] 
footnote “a”); Section 9.2.1 
Imaging Assessments
Added: Imaging performed for standard of care up to 5 days prior to signing 
ICF may be used as baseline evaluations if they are of sufficient quality.
Rationale: To allow flexibility in the timing of procedures.
Table 4 (Dose and 
Administration Table: RICE 
With Ibrutinib [footnote “e”]); 
Table 5 (Dose and 
Administration Table: RVICI 
With Ibrutinib [footnote “d”])
Clarified that intrathecal therapy may be administered not more than 24 hours 
before Day 1 of each cycle.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2] 
footnotes “g” and “h”); 
Section 9.2.2 Bone 
Marrow/Lymph Node 
Assessment; Section 9.2.3 
Lumbar Puncture
Clarified that lumbar puncture and bone marrow procedures may be performed 
the day prior to the start of a treatment cycle for logistical reasons as needed.
Rationale: To highlight that imaging performed on Cycle 1 Day 14 is exploratory and requires clinician discretion 
to determine if response assessment is consistent with PD.
Section 9.1.3 Treatment Phase; 
Section 9.2.5 Efficacy Criteria
Clarified that imaging evaluations performed on Cycle 1 Day 14 are 
exploratory; if PD is indicated based on these scans, investigator discretion 
should be used to determine if the clinical evaluation is consistent with PD. If 
not, the subject may continue with study treatment until confirmation of PD or 
the subject meets other criteria for withdrawal.
Rationale: To require documentation of lymph node size on physical exam.
Section 9.2.4 Physical 
Examination
Clarified that approximate measurement of palpable lymph nodes or masses 
should be provided.
Rationale: Clarification was provided regarding disease assessments in subjects with bone marrow only disease.
Section 9.2.5 Efficacy Criteria
Clarified that for subjects with bone marrow disease and no nodal involvement, 
imaging is only required at screening.
Rationale: Missing laboratory evaluations (lymphoblasts, urea, serology panel, and tetanus and pneumococcal 
testing) were added in this section for consistency with the Time and Events Schedules.
Section 9.8 Safety Evaluations
Lymphoblasts were added to the Hematology Panel, urea was added to the 
Serum Chemistry Panel, a Viral Serology Panel was added, and tetanus and 
pneumococcal antibody titers were added to the safety evaluations section of the 
protocol.
Rationale: Storage conditions for capsules and oral suspension were updated according to the most recent ibrutinib 
Investigator’s Brochure (IB; Edition 10.2).
Section 14.1.4 Preparation, 
Handling, and Storage
The storage conditions for ibrutinib 70 mg and 140 mg capsules, and oral 
suspension were updated for consistency with the current IB.


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Rationale: Clarified the results of a recent drug-drug interaction (DDI) study of ibrutinib in combination with 
moderate CYP3A inhibitors.
Attachment 4 (Instruction for 
Concomitant Medications to be 
Used With Precaution)
A DDI study in patients with B-cell malignancies (PCI-32765LYM1003) found 
that co-administration of ibrutinib with the moderate CYP3A inhibitors 
erythromycin and voriconazole, increased Cmax by 3.4-fold and 6.7-fold and 
increased AUC by 3.0-fold and 5.7-fold, respectively.
Rationale: Clarifications or corrections were made to the protocol.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2])
Footnotes were clarified.
Table 1 (Time and Events 
Schedule [Part 1 and Part 2]); 
Section 3.2.6 Biomarker 
Collection
Timing of biomarker samples was specified.
Table 4 (Dose and 
Administration Table: RICE 
With Ibrutinib); Table 5 (Dose 
and Administration Table: 
RVICI With Ibrutinib)
The formulations of dexamethasone (IV or PO) were clarified.
Section 3.2.2 Study Treatments; 
Section 5 Treatment Allocation 
and Blinding; Section 6.1 Study 
Treatment
Text was clarified to indicate that for subjects being treated at the lower starting 
dose of 240 mg/m2 during the first cycle, the maximum dose should not exceed 
a 420 mg/day equivalent dose. If the pharmacokinetic data are within the 
expected range and there are no safety concerns, at Cycle 2, dose escalation 
may not exceed a 560 mg/day equivalent dose.
Section 6.2.1 RICE/RVICI
Text was clarified to indicate hematologic parameters to be met before initiation 
of Cycles 2 and 3 due to a treatment delay.
Section 8.3.1 Radiation Therapy
Subjects should have (removed “other”) sites of measurable disease, other than 
those that were irradiated, that can be followed for response.
Reference 19 
Citation corrected (authors and title were correct).
Attachment 1 (Ibrutinib Dosing 
Guides)
Column added to provide additional detail on actual dose to be administered for 
suspension formulation.


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Status: Approved, Date: 15 September 2020
Amendment 1 (21 June 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment:  The overall reason for the amendment is to incorporate changes requested 
during Health Authority review.
Applicable Section(s)
Description of Change(s)
Rationale: As requested by a Health Authority, enrollment will begin in the 2 older age groups (6-11 years, 
12-17 years) before allowing enrollment of children in the youngest age group (1-5 years) to ensure adequate safety 
and pharmacokinetic data are available and it is deemed safe by the Study Evaluations Team (SET) to proceed in 
children 1-5 years of age.
Synopsis (Overview of
Study Design and Dosage 
and Administration); 
1.5 Rationale for the Study; 
3.1 Overview of Study 
Design; 
3.2.2. Study Treatments; 
5. Treatment Allocation and 
Blinding; 
6.1. Study Treatment; 
11.10 Study Evaluation 
Team
Clarified that subjects in the 2 older age groups (6-11 years, 12-17 years) will be 
enrolled and treated prior to opening enrollment to subjects in the younger age 
group (1-5 years). The SET will meet to decide on any changes to the starting dose 
for each age group and when enrollment may begin for the youngest age group.
Rationale: Clarification of screening requirements for subjects who enter the study with only bone marrow disease.
Table 1 (Time and Events 
Schedule; footnote ‘f’); 
9.2.2. Bone Marrow/ Lymph 
Node Assessment
Subjects will be followed by bone marrow biopsy and aspirate. Radiographic 
images are required at screening but if no nodal disease is identified, subsequent 
imaging is not required.
Rationale: Clarification of procedures performed in follow-up phase.
Table 1 (Time and Events 
Schedule; footnote ‘h’, ‘i’)
Added lumbar puncture and bone marrow aspirate and biopsy to follow-up phase, 
but qualified in footnotes “obtain if clinically indicated”.
Rationale: Mesna will be administered as a shortened infusion rather than a bolus to allow the longest infusion time 
while still separating it from the ibrutinib dosing to avoid drug-drug interactions.
Table 2 (Time and Events 
Schedule); Table 3 (Time 
and Events Schedule)
Revised mesna infusion to a “shortened infusion” instead of a “bolus”.
Added to footnotes ‘c’ and ‘d’ (Table 2) and footnote ‘c’ (Table 3) that mesna 
infusion should be stopped 3 hours prior to administering ibrutinib and should not 
be started for 6 hours after administering ibrutinib.


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Status: Approved, Date: 15 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Correction made to pharmacokinetic sampling after Cycle 1. Windows were added to provide guidance 
for pharmacokinetic sample collection and whole blood sample collection for pharmacodynamics. 
Table 1 (Time and Events 
Schedule; footnotes ‘l’ and 
‘m’); 9.3.1. Evaluations
In Part 1, added that ‘Subsequent samples will be collected predose and 1, 2, 4, and 
6 hours postdose on Day 1 of Cycle 2 or Cycle 3 (not both). In Part 2 samples will 
be collected either on Day 7 or 8 of Cycle 1 (preferred), but if unable to be obtained 
during Cycle 1, can collect on Day 7 or 8 if Cycle 2 or 3. Collection windows 
provided for all postdose pharmacokinetic sample collection times in footnote ‘l’.
Collection window provided for 4-hour postdose collection of whole blood sample 
for pharmacodynamics analysis in footnote ‘m’.
Rationale: Additions made to provide serologic evidence to support the exclusion criteria.
Table 1 (Time and Events 
Schedule)
Added collection of HIV serologies and Hepatitis B and C serologies to be 
performed at screening to provide support for exclusion criterion #4.
Added footnote ‘q’: A patient without a known history of these viral infections may 
be randomized if the serology results are not available at the time of the 
randomization. However, if the serology results return as positive, the medical 
monitor should be contacted immediately.
Rationale: Baseline assessment added to aid in interpretation of the same assessments collected during study 
follow-up.
Table 1 (Time and Events 
Schedule)
Added tetanus and pneumococcal antibody titers at screening.
Rationale: Clarification on the timing for collection of sample for protein binding
Table 1 (Time and Events 
Schedule, footnote ‘l’)
Sample for protein binding will be taken on Cycle 1 Day 1 (Part 1 only) and must be 
obtained prior to any ibrutinib exposure.
Rationale: Correction to number of cycles subjects will receive ibrutinib monotherapy in Posttreatment Phase
Synopsis (Overview of 
Study Design); 
Table 1 (Time and Events 
Schedule); 
6.1.2. Ibrutinib 
Administration
During the Posttreatment Phase subjects on ibrutinib with a response of PR or better 
will continue on ibrutinib monotherapy for up to three 28-day cycles.
Rationale: Clarification of the definitions of RICE and RVICI.
Synopsis (Objectives, 
Endpoints, and Hypothesis); 
List of Abbreviations; 
1.4. Background 
Chemotherapy
In this study RICE is defined as: rituximab, ifosfamide, carboplatin, etoposide and 
dexamethasone; and RVICI is defined as: rituximab, vincristine, ifosfamide, 
carboplatin, idarubicin, and dexamethasone. For clarity, statements to indicate this 
have been added to the protocol.
Rationale: Added description of results from a recent study of ibrutinib in combination with RICE
1.3.2.2 Efficacy/Safety 
Studies
Results from a Phase 1 combination study of ibrutinib with RICE in subjects with 
relapsed or refractory DLBCL were summarized.


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Status: Approved, Date: 15 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Definition of the term ‘evaluable patient’ was provided for clarity.
3.1. Overview of Study 
Design
Subjects in Part 1 will be considered ‘evaluable’ if PK samples are obtained 
appropriately and lead to interpretable results.
Rationale: Revised language providing age at which a subject can provide informed consent, as this age varies by 
country.
4.1. Inclusion Criteria; 9.1.2. 
Pretreatment (Screening) 
Phase
In inclusion criterion #8 ‘children <18’ was deleted. Reference to <18 years of age 
changed to ‘legal age of consent’.
Rationale: Clarification of biopsy requirements at screening.
Table 1 (Time and Events 
Schedule; footnote ‘o’)
Clarified that the pathology report for the original NHL diagnosis should be sent to 
Janssen immediately after signing the ICF, and if that prior pathology report is not 
available, results of a fresh biopsy will be required for study entry.
4.1. Inclusion Criteria; 9.1.2. 
Pretreatment (Screening) 
Phase
Added to criterion #2 that if the pathology report for the original NHL diagnosis is 
not available, results of a fresh biopsy will be required for enrollment into the study.
Rationale: Change made as safety precaution to take into account the rituximab-half-life and 3-month cycle of 
sperm regeneration.
4.1. Inclusion Criteria
In criterion #10, replaced last dose of ‘study drug’ with ‘at least 3 months after the 
last dose of ibrutinib and 1 year after the last dose of rituximab, whichever is later’.
Rationale: Guidance for dosing of ibrutinib around the time of lumbar procedures added due to risk of bleeding.
4.3. Prohibitions and 
Restrictions
For lumbar punctures, ibrutinib should be held for 24 hours before the procedure. If 
there is evidence of bleeding at the time of the lumbar puncture (ie, a “bloody tap”) 
defined as > 500 RBC/L on cell count, a platelet transfusion should be given. 
Consider giving a platelet transfusion if there is any other clinical sign of bleeding. 
If bleeding does occur, ibrutinib should be held and the medical monitor should be 
contacted. If there is no evidence of bleeding during or post-procedure, ibrutinib 
may be resumed.
Table 1 (Time and Events 
Schedule; footnote ‘l’); 
9.3.1. Evaluations
Added ‘If a subject experiences bleeding with an lumbar puncture and needs to 
delay the dose of ibrutinib on Day 1 of the cycle, the Day 1 pharmacokinetic should 
be done after administration of CIT is complete (on Day 7 or 8) instead. If this 
occurs during Cycle 1, the Day 1 pharmacokinetic will be skipped altogether.’
Rationale: Change made for consistency with recent PIP modification.
6.1.2. Ibrutinib 
Administration
Added recommendation to take ibrutinib within 2 hours after a meal.
Rationale: Change made to allow subjects to switch between capsule and suspension formulations as complications 
of treatment may lead to difficulty in swallowing capsules.
6.1.2. Ibrutinib 
Administration
Changed statement that subjects cannot switch between formulations ‘during the 
study’ to ‘on days when pharmacokinetic will be drawn’.


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Status: Approved, Date: 15 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Change made for consistency with other studies in the ibrutinib program.
8.2. Prohibited Medications; 
8.3. Concomitant 
Medications to be Avoided 
or to be Used with Caution
Strong and moderate CYP3A inhibitors or inducers moved from prohibited 
medications to concomitant medications to be avoided or to be used with caution.
Rationale: Clarification of what is required to be centrally reviewed before a subject is removed from study 
therapy.
8.4. Subsequent 
Antilymphoma Therapies
Text (indicated in bold type) added to the following sentence: Note that the medical 
monitor must be notified of the subject’s suspected PD and all imaging, bone 
marrow, and CSF analyses are required to be centrally reviewed before a subject 
is removed from the study.
Rationale: Clarification of preferences for scanning options for imaging assessments provided.
9.2.1. Imaging Assessments 
Added a list of scanning options in decreasing order of preference.
Rationale: Clarification added regarding when CSF sampling should occur.
9.2.3. Lumbar Puncture
Added ‘Subsequent sampling in subjects with CNS-positive disease should occur 
every 4 days +/- 1 day until CSF is cleared of lymphoma cells. For all subjects, 
CSF should be obtained at the start of each cycle and following completion of 
CIT.’
Rationale: Clarification of tissues that can be used for biomarker analysis.
Synopsis 
(Pharmacodynamic and 
Biomarker Evaluations);
Table 1 (Time and Events 
Schedule, footnote ‘b’); 
9.6. Biomarkers
Added that if archived tissue is unavailable and a fresh lymph node biopsy cannot be 
obtained, bone marrow biopsy slides (when positive for disease) can be submitted.
Added ‘In the event that no archived tissue is available, the subject is too unstable to 
undergo a fresh biopsy, but it is expected that the biopsy may be feasible after 
beginning chemotherapy, a fresh lymph node biopsy is recommended to be obtained 
after debulking with the study treatment regimen in subjects with DLBCL only (cell 
of origin studies will not be affected by initiation of therapy).’
Rationale: To provide a lower acceptable age for subjects providing a palatability assessment
9.7. Palatability Assessment
Children as young as 4 years old should have the capacity to assess palatability with 
the given scale. Clarified that the scale is a 5 point visual analog scale.
Rationale: Corrections made to protocol
9.2.5.1 Evaluation of 
Measurable Disease
Deleted ‘In addition, if more than 6 sites of disease are measurable, then these other 
sites of measurable disease may be included as assessable disease.’
9.8. Safety Evaluations
Clarified that pregnancy testing needs to be performed within 24 hours prior to the 
start of treatment.
Table 1 (Time and Events 
Schedule)
Lumbar puncture/CSF cytologic evaluation assessment added at Early withdrawal/ 
End of Treatment Visit.


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Status: Approved, Date: 15 September 2020
Applicable Section(s)
Description of Change(s)
Rationale: Ibrutinib dosing guides revised to accommodate addition of a lower dose. 
Attachment 1 Ibrutinib 
Dosing Guides
Table added for suspension and capsule dosing at 120 mg/m2.
Rationale: Blood volumes were updated in response to changes made to the protocol.
9.1.1. Overview
Updated blood volumes in Attachment 7. Title changed to ‘Estimated Maximum
Volume of Blood…’.
Rationale: Clarification on discontinuation of study treatment
9.1.3. Treatment Phase
If a subject shows signs of progression on physical examination or laboratory 
assessment, the subject may continue study treatment until PD is confirmed by the 
central IRC progression is confirmed by centrally assessed computed tomography 
(CT) scan. 
Rationale: Clarification to efficacy criteria
9.2.5. Efficacy Criteria
Added ‘Imaging, bone marrow assessments and CSF evaluations are required at 
each disease assessment.’
Rationale: Clarification regarding when hematology and chemistry samples should be drawn.
Table 1 (Time and Events 
Schedule; footnote ‘j’)
Change made to ensure blood samples are in accordance with the label and as per 
standard of care in this patient population.
Rationale: Minor clarifications were made in the protocol.
Table 1 (Time and Events 
Schedule; footnote ‘c’)
Clarified that height is collected during disease evaluation visits in the Treatment 
and Post-treatment phases.
Table 1 (Time and Events
Schedule; footnote ‘h’); 
9.2.3. Lumbar Puncture
Clarified that the lumbar puncture on Cycle 1 Day 1 can be used as the screening 
lumbar puncture only if collected prior to the administration of ibrutinib or 
background therapy.
Table 1 (Time and Events 
Schedule; footnote ‘k’)
Clarified that timing of serum or urine -hCG will occur prior to treatment on Cycle 
1 Day 1.
Table 1 (Time and Events 
Schedule; footnote ‘m’)
Clarified that whole blood samples for flow cytometry and molecular 
characterization will be collected during Part 1 and Part 2.
Table 1 (Time and Events 
Schedule; footnote ‘n’)
Clarified that testing performed per standard of care can be used for the study if 
performed within 5 days of signing the ICF.
Table 1 (Time and Events 
Schedule; footnote ‘p’)
Added that ‘Subjects with hematology and chemistry laboratory results from End of 
Treatment do not need repeat hematology and chemistry testing on monotherapy 
Cycle 1 Day 1 if testing was performed within 1 week.’
3.2.6. Biomarker Collection
Added that analysis will be performed ‘based on availability of tumor samples.’ 
6. Dosage and 
Administration
Added that the medical monitor should be contacted for advice on subjects who 
require dosing through a feeding tube.
6.1. Study Treatment
Clarified that ibrutinib will be supplied as capsules or as a suspension.
6.1.2. Ibrutinib 
Administration
Clarified that the volume of water that should be taken with the ibrutinib capsules or 
suspension is 10 mL/kg with a maximum of 240 mL.
9.2.2. Bone Marrow/ Lymph 
Node Assessment
Removed reference to samples for biomarkers as it is redundant to information in 
Section 9.6.


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Status: Approved, Date: 15 September 2020
Applicable Section(s)
Description of Change(s)
10.2 Discontinuation of 
Study Treatment
Clarified statement on study treatment discontinuation to be more definitive (ie, 
changed “should” to “will”).
Attachment 7 (new)
Blood volume tables moved from body of the protocol into new attachment 
(Attachment 7).
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


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Status: Approved, Date: 15 September 2020
SYNOPSIS
A Randomized, Open-label, Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Patients 
With Relapsed or Refractory Mature B-cell non-Hodgkin Lymphoma
Ibrutinib (IMBRUVICA®; PCI-32765; JNJ-54179060) is an orally-administered, covalently-binding 
small molecule Bruton’s tyrosine kinase (BTK) inhibitor currently being co-developed by Janssen 
Research & Development, LLC and Pharmacyclics LLC for the treatment of B-cell malignancies. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Run-in Part (Part 1):
Objectives
Endpoints
Primary

Confirm that the pharmacokinetics in pediatric 
subjects is consistent with that in adults 

Exposure (area under the plasma concentration-time 
curve [AUC])

Apparent (oral) plasma clearance (CL/F), apparent (oral) 
volume of distribution (Vd/F), and derived measures of 
exposure such as maximum observed plasma 
concentration (Cmax)

Relationship between pharmacokinetic parameters and 
age or measure of body size
Secondary

Evaluate the safety and tolerability of ibrutinib 
in combination with rituximab, ifosfamide, 
carboplatin, etoposide, and dexamethasone 
(RICE) or rituximab, vincristine, ifosfamide, 
carboplatin, idarubicin, and dexamethasone 
(RVICI) background therapy in pediatric 
subjects with B-cell malignancies

Safety parameters, including gastrointestinal effects, 
immune function, intensified cardiac monitoring (in 
particular, after previous anthracycline exposure)

Assess anti-tumor activity of ibrutinib as 
add-on to RICE or RVICI regimens

Overall response (complete response [CR], including CR 
biopsy-negative [CRb] and unconfirmed CR [CRu]) and 
partial response [PR])

Assess disease-specific biomarkers

Phospho-BTK, as well as SYK, STAT3, caspase-3, 
BCL-xL, and cIAP1 expression at baseline and during 
treatment

B-cell receptor (BCR)/CD79B, CARD11, and MYD 
mutations

c-MYC, immunoglobulin, and T-cell receptor gene 
rearrangements at baseline

Assess the pharmacodynamic response

BTK occupancy

Acceptability and palatability assessment of all 
ibrutinib formulations

Visual analog scale score for palatability
Exploratory

Evaluate other response biomarkers

Other biomarkers, as applicable

Explore the exposure-response relationships

Potential relationships between systemic exposure and 
response


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Randomized Part (Part 2):
Objectives
Endpoints
Primary

Assess efficacy (event-free survival [EFS]) of 
ibrutinib in combination with RICE or RVICI 
background therapy compared to RICE or RVICI 
background therapy alone

Difference in EFS between the 2 treatment groups (an 
event is defined as the time from randomization to 
death, disease progression, or lack of CR or PR after 
3 cycles of treatment based on blinded independent 
event review)
Secondary

Evaluate the safety and tolerability of ibrutinib in 
combination with RICE or RVICI background 
therapy in pediatric subjects and young adults with 
B-cell malignancies

Safety parameters, including gastrointestinal effects, 
immune function, intensified cardiac monitoring (in 
particular, after previous anthracycline exposure)

Determine the overall response rate (ORR) 

The proportion of subjects who achieve CR, 
(including CRb and CRu) and PR 

Evaluate tumor volume reduction at Day 14

Percent decrease in the sum of the products of the 
lesion diameters at Day 14

Determine the number and proportion of subjects 
who proceed to stem cell transplantation

Number and proportion of subjects who proceed to 
stem cell transplantation

Evaluate the time to response

The time interval from the first dose of ibrutinib to 
the first documented response for those subjects who 
respond

Measure the duration of response

Duration calculated from the date of initial 
documentation of a response (CR or PR) to the date 
of first documented evidence of progressive disease 
(PD) or death

Evaluate long-term survival (EFS at 2 and 3 years)

Proportion of subjects with EFS at 2 and 3 years

Evaluate overall survival

The duration from the date of randomization to the 
date of the subject’s death

Assess disease-specific biomarkers

Phospho-BTK, as well as SYK, STAT3, caspase-3, 
BCL-xL, and cIAP1 expression at baseline and 
during treatment 

BCR/CD79B, CARD11, and MYD mutations

c-MYC, immunoglobulin, and T-cell receptor gene 
rearrangements at baseline

Assess the pharmacodynamic response, if deemed 
appropriate based on Part 1 results

BTK occupancy

Assess the population pharmacokinetics of 
ibrutinib in pediatric subjects and young adults 

Population pharmacokinetic parameters and derived 
systemic exposure to ibrutinib such as AUC

Relationship between pharmacokinetic parameters 
and age or measure of body size

Acceptability and palatability assessment of all 
ibrutinib formulations

Visual analog scale score for palatability
Exploratory

Evaluate other response biomarkers

Other biomarkers, as applicable

Explore the exposure-response relationships

Potential relationships between systemic exposure 
and response
Hypothesis: The addition of ibrutinib to a salvage chemoimmunotherapy (CIT) regimen will extend EFS 
compared to CIT alone in pediatric and young adult subjects with relapsed or refractory mature B-cell 
non-Hodgkin lymphoma (NHL).


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OVERVIEW OF STUDY DESIGN
This is a 2-part, multicenter study. A safety and pharmacokinetic run-in part (Part 1) will be conducted 
before starting the randomized part (Part 2) of the study. Part 2 is a randomized, open-label, Phase 3 study 
to compare the safety and efficacy of ibrutinib in combination with CIT (RICE or RVICI) versus CIT 
alone in children and young adult subjects with relapsed or refractory mature B-cell NHL. All subjects in
Part 1 will receive ibrutinib in combination with CIT (investigator choice of RICE or RVICI); 6 to 
approximately 24 pediatric subjects (1 to <18 years) will be enrolled to allow confirmation of the dose 
regimen. Enrollment will begin with children in the 2 older age groups (6-11, 12-17 years) to assess 
pharmacokinetic and safety data before allowing enrollment of children in the youngest age group 
(1-5 years). The SET will meet to decide on any changes to the starting dose for each age group, and 
when enrollment may begin for the youngest age group. At a minimum, the first 2 subjects in each age 
group will enroll into Part 1 before recruitment of children in that age group will begin in Part 2. In Part 2, 
approximately 72 additional subjects will be randomized in a 2:1 ratio to receive ibrutinib in combination 
with CIT (investigator choice of RICE or RVICI) or CIT alone; at least 40 subjects are targeted to be of 
age 1 to <18 years and at least 10 of the 40 subjects are targeted to be age <11 years. Subjects will be 
stratified by histology (Burkitt lymphoma [BL]/Burkitt leukemia [B-AL] versus other) and by 
background therapy (RICE versus RVICI). Pharmacokinetic samples will be obtained during Part 2 of the 
study to characterize the pharmacokinetics in pediatric subjects. 
Part 1 and Part 2 of the study will be conducted in 3 phases: a Pretreatment (Screening) Phase, a 
Treatment 
Phase, 
and 
a 
Posttreatment 
Phase. 
The 
Treatment 
Phase 
will 
extend 
from 
enrollment/randomization until 1 of the following: 1) completion of 3 cycles of therapy, 
2) transplantation, if clinically indicated, or 3) disease progression, whichever comes first. Subjects will 
begin the Posttreatment Phase after completion of combination therapy. During the Posttreatment Phase, 
subjects on ibrutinib with a response of PR or better and have completed 3 cycles of combination 
treatment will continue on ibrutinib monotherapy for three 28-day cycles as described below (see Dosage 
and Administration). All subjects will be followed to assess disease progression as described below 
(see Efficacy Evaluations/Endpoints). The Posttreatment Phase will continue until death, loss to follow 
up, consent withdrawal, or study end, whichever occurs first. The end of study is defined as when 
approximately 60 EFS events have occurred in Part 2 (death, disease progression, or lack of CR or PR 
after 3 cycles of treatment based on blinded independent event review), or the sponsor terminates the 
study, whichever comes first. Study enrollment may be stopped upon recommendation from the IDMC at 
the interim analysis based on early stopping rules. 
SUBJECT POPULATION
The study population will include subjects with relapsed/refractory BL, Burkitt-like lymphoma, B-AL, 
diffuse large B-cell lymphoma (DLBCL), DLBCL not otherwise specified, or other pediatric mature 
B-cell NHL. Subjects should be in first recurrence and have received only one prior line of therapy or 
have disease that is primarily refractory to conventional therapy. Subjects in Part 1 will be 1 to <18 years 
old. Subjects in Part 2 will be 1 to 30 years old, inclusive, who had an initial diagnosis of mature B-cell 
NHL at <18 years of age. Subjects must have at least 1 site of measurable disease defined as >1 cm in the 
longest diameter and >1 cm in the shortest diameter by radiological imaging, bone marrow involvement, 
or cerebrospinal fluid with blasts present. Subjects will have a Lansky-Karnofsky score of ≥50. 
DOSAGE AND ADMINISTRATION
Ibrutinib at a target dose of 329 mg/m2 per day (estimated equivalent to the maximum fixed dose of 
560 mg per day in adults) is being evaluated as add-on therapy to RICE or RVICI. The first 2 subjects in 
each of the older groups (6-11 years and 12-17 years) will be started on the estimated 420-mg equivalent 
dose (240 mg/m2). The first 2 subjects in the younger age group (1-5 years) will be started on the 420-mg 
equivalent dose (240 mg/m2) or lower, as deemed appropriate by the SET following assessment of 
pharmacokinetic and safety in the 2 older age groups. If there are no safety concerns and exposure (AUC) 
in Cycle 1 does not exceed the target range, the dose will be increased from Cycle 2 onward for these 


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2 subjects and for all subsequently enrolled subjects in that age group. However, if exposure (AUC) in the 
first 2 subjects in a given age group at the 420-mg equivalent is lower than or exceeds the target range set, 
the dose for these subjects and other subjects in that age group may be adjusted as appropriate based on 
available exposure data.
Subjects in Part 1 will receive ibrutinib in combination with background CIT (investigator choice of 
RICE or RVICI) for 3 treatment cycles. Subjects in Part 2 will be randomized in a 2:1 ratio to receive 
either ibrutinib in combination with CIT (RICE or RVICI) or CIT alone, for 3 treatment cycles. The RICE 
regimen is comprised of cumulative doses as follows: rituximab 750 mg/m2, ifosfamide 9 g/m2, 
carboplatin 635 mg/m2, etoposide 300 mg/m2, and dexamethasone 100 mg/m2. The RVICI regimen is 
comprised 
of 
cumulative 
doses 
as 
follows: 
rituximab 
750 mg/m2, 
vincristine 
1.6 mg/m2, 
idarubicin 20 mg/m2, carboplatin 800 mg/m2, ifosfamide 10 g/m2, and dexamethasone 100 mg/m2
(all doses represented as total administered in 1 cycle). For both regimens, triple intrathecal therapy 
consisting of methotrexate, corticosteroid, and cytarabine will be administered for central nervous system 
prophylaxis in age-appropriate dosing. Subjects with central nervous system disease will receive 
additional doses of triple intrathecal therapy. Cycles will be 28 days long, but may be shortened to 
21 days. Study treatment will continue for 3 cycles, unless the subject experiences unacceptable toxicity 
or disease progression. Upon completion of 3 cycles of combination therapy, subjects randomized to 
ibrutinib having a response of PR or better will continue on ibrutinib monotherapy at the same daily dose 
for three 28-day cycles or until disease progression or unacceptable toxicity, or up until initiating 
subsequent antilymphoma therapy or a conditioning regimen for stem cell transplantation, whichever 
comes first. 
Subjects who discontinue any component of CIT without disease progression will continue ibrutinib and 
remaining CIT components until 3 cycles are completed. If ibrutinib is discontinued for any reason, any 
remaining study treatment (RICE/RVICI) may continue. Ibrutinib should be temporarily stopped for any 
unmanageable, potentially study drug-related toxicity that is Grade ≥3 in severity until recovery to Grade 
≤1 or baseline.
EFFICACY EVALUATIONS/ENDPOINTS
Assessment of tumor response and disease progression will be according to the International Pediatric 
NHL Response Criteria. Disease evaluations (imaging, CSF, and bone marrow evaluations) will be 
performed at baseline, Cycle 1 Day 14 (imaging only), beginning of Cycle 2 (CSF evaluation; only 
perform bone marrow if clinically indicated), beginning of Cycle 3 (imaging, CSF and bone marrow), and 
the End-of-Treatment visit (imaging, CSF and bone marrow). During the Posttreatment Phase, all subjects 
who are without PD including those subjects who discontinue study treatment prior to PD will have 
efficacy assessments until PD, the clinical cutoff for the primary endpoint, or for up to 3 years after the 
date of Cycle 1 Day 1, whichever occurs first. After that, evaluations may be performed as clinically 
indicated (at the discretion of the investigator). Subjects who have not progressed by the last efficacy 
assessment at 3 years should continue to be followed up for survival status. If PD is assessed after 3 years,
the date and reason for progression will be entered in the CRF.
PHARMACOKINETIC EVALUATIONS
Population pharmacokinetics will be performed during Part 1 using a sparse sampling approach. 
Additional sparse pharmacokinetic samples will be collected during Part 2 to expand the pediatric 
pharmacokinetic dataset. Pharmacokinetic parameters and exposure information of ibrutinib will be 
derived using population pharmacokinetic modeling. Individual- as well as population-predicted 
pharmacokinetic parameters will include CL/F, Vd/F, and metrics of systemic exposure such as AUC and 
Cmax, as the data allow. The relationships between pharmacokinetics and response (pharmacodynamics, 
clinical, or safety endpoints) will also be explored as the data allow. The impact of age or body size on the
pharmacokinetic parameters will also be investigated.


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PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
Biomarkers will be assessed to characterize the pharmacodynamic profile and to identify markers of 
response to ibrutinib. Biomarkers will be analyzed in tumor tissue or bone marrow biopsy (if positive for 
disease), and blood samples.
SAFETY EVALUATIONS
Regular periodic medical evaluations will be conducted including adverse event monitoring, physical 
examination, weight evolution, vital signs, concomitant medication usage, and performance status 
evaluation. Hematology and serum chemistry tests will be performed at regular intervals. A baseline and 
end-of-treatment electrocardiogram (ECG) and left ventricular ejection fraction measurement by 
multiple-gated acquisition scan (MUGA) or echocardiography is required in all subjects. Further 
echocardiography/MUGA and ECG are required after each cycle in the RVICI treatment group only. Data 
will also be collected on new malignant tumors occurring during study treatment and during any 
protocol-specified follow-up periods.
STATISTICAL METHODS
Approximately 72 subjects will be randomized in Part 2. The sample size calculation for the randomized 
part (Part 2) is based on the assumption of 100% improvement (hazard ratio = 0.5) in median EFS in 
subjects receiving ibrutinib plus CIT (RICE or RVICI) compared with CIT (RICE or RVICI) (10 months 
versus 5 months). Utilizing a 2:1 randomization, Part 2 will enroll approximately 72 subjects 
(approximately 48 subjects treated with ibrutinib [and RICE or RVICI background therapy]). Based on 
60 events for the 2 treatment groups, this study will have at least 80% power, given a 1-sided alpha of 
0.05. An accrual rate of 1.44 subjects per month will result in a study duration of approximately 4.2 years. 
One interim analysis will be conducted when approximately 30 EFS events are reached in Part 2 
(expected to be 32 months after the first subject is randomized). An independent Data Monitoring 
Committee will review safety data periodically and the data from the interim analysis.
Outcome of IDMC review on 20 July 2020
The pre-planned interim analysis was conducted to determine the appropriateness for early stopping using 
the nonbinding stopping rules, in addition to a review of the efficacy and safety of patients in Part 2 of 
this study. As the futility boundary for early stopping was reached (31 of 60 EFS events), the IDMC 
recommended stopping enrollment. Consequently, new patient enrollment has ceased.  No new safety 
concerns were identified. Follow-up of the ongoing patients will continue until the sponsor decides to 
stop the study.
The primary efficacy endpoint is EFS, which is defined as the time interval from randomization to death, 
disease progression, or lack of CR or PR after 3 cycles of treatment based on blinded independent event
review by an Independent Review Committee, whichever occurs first. The efficacy analysis will be based 
on the intent-to-treat population, which is defined as all subjects randomized in Part 2 who will be 
analyzed as randomized. For the primary efficacy analysis, EFS will be compared between treatment 
groups using a non-stratified log-rank test. The estimate of the hazard ratio between the 2 treatment 
groups and its associated 90% confidence interval will be computed based on the non-stratified Cox 
proportional hazards model.


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TIME AND EVENTS SCHEDULE
Table 1:
Time and Events Schedule (Part 1 Only)
Pretreatment 
Phase
Treatment Phase
Screeninga
Up to 14 days 
before 
administration of 
study drug
Cycle 1, 
Day 1
Cycle 1, 
Day 7 or 8
Cycle 1, 
Day 14 
(±1 day)
Cycle 2, 
Day 1
Cycle 3, 
Day 1
Early withdrawal/ 
End-of-Treatment visit
Procedures
Informed consent
X
Pathology report from original NHL 
diagnosis or at relapse, if availableb
X
Formalin-fixed, paraffin-embedded 
archival biopsy tissue, or fresh lymph 
node biopsy or bone marrow slides for 
biomarker studiesc
X
Xc
Inclusion/Exclusion criteria 
confirmed/met
X
Demographics/Medical history
X
Complete physical examination 
including lymph node measurements
X
X
Limited physical examination including 
lymph node measurements with 
lymphoma symptoms reviewed
X
X
X
X
Age-appropriate performance status
X
X
Weight
X
X
X
X
X
Height
X
X
X
X
X
BSA (See Attachment 3)
X
Xd
Xd
ECG
X
Xe
Xe
X
Echocardiogram or MUGA
X
Xe
Xe
X
Concomitant medications/procedures
Adverse events and concomitant medications to be collected from signing of the ICF and up until 30 days after the last dose of study treatment 
or until the start of subsequent antilymphoma therapy, if earlier.
Adverse events
Drug acceptability and palatability 
assessment (Visual analog scale); for 
subjects on ibrutinib onlyf
X
X
Disease Evaluations
Disease evaluation (CT/MRI)g
(see Section 9.2.1)
X
X
Xh
Xh
Lumbar puncture/CSF cytologic 
evaluation
X
Xi
Xi
Xi
Xi
Bone marrow aspirate and/or biopsy
Xj
Xj
Xj
Xj


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Status: Approved, Date: 15 September 2020
Pretreatment 
Phase
Treatment Phase
Screeninga
Up to 14 days 
before 
administration of 
study drug
Cycle 1, 
Day 1
Cycle 1, 
Day 7 or 8
Cycle 1, 
Day 14 
(±1 day)
Cycle 2, 
Day 1
Cycle 3, 
Day 1
Early withdrawal/ 
End-of-Treatment visit
Laboratory Assessments
Hematology (see Section 9.8)
Xk
Xk
Xk
Xk
Xk
Xk
X
Clinical chemistry (see Section 9.8)
Xk
Xk
Xk
Xk
Xk
Xk
X
Serum or urine -hCG pregnancy test 
(for young women with childbearing 
potential)
X
Xl
X
X
HIV serologies, Hepatitis B and C 
serologiesm
X
Tetanus and pneumococcal antibody 
titers
X
Plasma samples for PK and protein 
binding (subjects on ibrutinib only)n
X
X
X
X
X
Biomarker blood samples for phospho-
protein and molecular characterization 
and BTK occupancy evaluations o
X
X
X
X
X
X
Cell count from stem cell collection for 
transplant (if applicable; See 
Section 9.1.1.)
----------------------X ----------------------------
-hCG=beta-human chorionic gonadotropin; BM=bone marrow; BSA=body surface area; BTK=Bruton’s tyrosine kinase; CIT=chemoimmunotherapy; CNS=central 
nervous system; CSF=cerebrospinal fluid; CT=computed tomography; ECG=electrocardiogram; h=hour(s); HIV=human immunodeficiency virus; ICF=informed 
consent form; IHC=immunohistochemistry; MRI=magnetic resonance imaging; MUGA=multiple-gated acquisition scan; NHL=non-Hodgkin lymphoma; 
PD=progressive disease; PK=pharmacokinetics; RVICI=rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone; yrs=years.
a.
Standard of care testing to document comorbidities and baseline disease, with the exception of tetanus and pneumococcal titers, hematology, and chemistry, can be 
counted as screening assessments for the study if performed within 5 days of signing ICF. Procedures must have been performed according to protocol requirements 
and imaging must meet the Imaging Acquisition Guidelines standards.
b.
Pathology report for the original NHL diagnosis or at relapse, if available, should be sent to the Janssen medical monitor immediately after signing the ICF. If the 
prior pathology report is not available, then a pathology report from a fresh biopsy will be required for study entry.
c.
Formalin-fixed paraffin-embedded tumor tissue (mandatory at Screening) collected for biomarker studies only. A fresh lymph node biopsy should be collected at 
Screening or prior to Cycle 1 and at the time of PD (even if not previously collected), if feasible, where local regulations/shipping logistics permit. If archival tissue 
is unavailable and a fresh lymph node biopsy cannot be obtained, bone marrow slides (when positive for disease) can be submitted at screening and at the time of 
PD. No tumor tissue is required at the end of treatment in the absence of progressive disease.
d.
BSA and dose should only be recalculated if there is >10% weight change from the weight used in the previous BSA calculation.
e.
Echocardiography/MUGA and ECG required at the end of each cycle (within 3 days prior to the next cycle) in RVICI treatment group only; otherwise, obtain at 
Screening and End-of-Treatment only.


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Status: Approved, Date: 15 September 2020
f.
If ibrutinib is temporarily stopped on C1D1 or C3D1, the assessment should be taken with the first dose of ibrutinib in each respective cycle.
g.
Positron emission tomography scan at baseline recommended but not mandatory. Subjects entering study with only BM disease should be followed by BM biopsy 
and/or aspirate. In these subjects, radiographic images are required at screening but if no nodal disease is identified, subsequent imaging is not required.
h.
Scans may be performed up to 3 days prior to Cycle 3 Day 1. Scans may be done ± 3 days of End-of-Treatment visit. Disease evaluations that show PD can be used 
as end-of-treatment evaluations. Additional disease evaluations may be obtained at discretion of investigator to confirm clinical response or PD.
i.
Lumbar puncture in conjunction with triple intrathecal therapy for CNS treatment per the Dosage and Administration tables (Table 5 and Table 6) may be performed 
the day prior to the start of a treatment cycle for logistical reasons. Lumbar puncture on Cycle 1 Day 1 can be used as the screening lumbar puncture only if collected 
prior to the administration of any ibrutinib or background therapy. Disease evaluations that show PD can be used as end-of-treatment evaluations.  
j.
Bone marrow at Cycle 2 Day 1 only if clinically indicated. Morphological examination and IHC or flow cytometry is required of all bone marrow specimens at 
screening for all subjects. If bone marrow results at screening are negative, subsequent assessments must include morphologic assessment of the bone marrow, while 
immunophenotyping is optional. Procedure may be performed 1 day prior to the start of a treatment cycle for logistical reasons. If marrow is empty (lack of count 
recovery), repeat marrow should be obtained prior to initiating next cycle. Refer to protocol Section 9.2.2 for details regarding bone marrow testing. Disease 
evaluations that show PD can be used as end-of-treatment evaluations.  
k.
Must be taken on day of or day prior to dosing, provided results are available before study drug is given. Hematology and chemistry should be done at Screening and 
on Cycle 1 Day 1 and weekly thereafter in Cycle 1. For Cycle 2 and Cycle 3, hematology and chemistry should be done on Day 1 and between Days 14 to 21. 
l.
Required within 24 hours prior to treatment on Cycle 1 Day 1.
m. Hepatitis B serologic testing should include HBsAg, HBcAb, and HBsAb. A subject without a known history of these viral infections may be randomized if the 
serology results are not available at the time of the randomization. However, if the serology results return as positive, the medical monitor should be contacted 
immediately, and the guidance provided in Section 9.8 should be followed.
n.
On days of PK sample collection, ibrutinib should be taken within 2 hours after a meal. If ibrutinib is temporarily stopped on any PK sampling days, or within 3 days 
prior to PK sampling, the medical monitor should be contacted for guidance. 
In Cycle 1, samples collected predose and at 1 (window 45-75 minutes), 2 (window 1.5-2.5 hours), 4 (window 3.5-5 hours), and 6 hours (window 5-8 hours) 
postdose on Day 1 and on Day 7 or 8 (per investigator choice). Subsequent samples will be collected predose and 1, 2, 4, and 6 hours postdose on Day 1 of Cycle 2 
or Cycle 3 (not both). If a subject experiences bleeding with a lumbar puncture and needs to delay the dose of ibrutinib on Day 1 of the cycle, the Day 1 PK should 
be done after administration of CIT is complete (on Day 7 or 8) instead. If this occurs during Cycle 1, the Day 1 PK will be skipped altogether. The sample for 
protein binding will be taken on Cycle 1 Day 1 and must be obtained prior to any ibrutinib exposure.
o.
Whole blood sample taken predose and at 4 hours postdose (window 3.5-6h, to coincide with the 4h PK sample) on Day 1 and Day 7 or 8 of Cycle 1 (same day and 
time as PK samples), predose on Cycle 2 Day 1 or Cycle 3 Day 1, and at PD or the End-of-Treatment visit. If a subject experiences bleeding with a lumbar puncture 
and needs to delay the dose of ibrutinib on Day 1 of the cycle, a predose and 4h sample should be done after administration of CIT is complete (on Day 7 or 8) 
instead (same as PK samples). If this occurs during Cycle 1, a predose sample must also be obtained prior to any treatment on Day 1 and prior to ibrutinib exposure.


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Status: Approved, Date: 15 September 2020
Table 2:
Time and Events Schedule (Part 2)
Pretreatment Phase
Treatment Phase
Screeninga
Up to 14 days 
before 
administration of 
study drug
Cycle 1, 
Day 1
Cycle 1, 
Day 14 
(±1 day)
Cycle 2, 
Day 1
Cycle 3, 
Day 1
Early withdrawal/ 
End-of-Treatment visit
Procedures
Informed consent
X
Pathology report from original NHL diagnosis 
or at relapse, if availableb
X
Formalin-fixed, paraffin-embedded archival 
biopsy tissue, or fresh lymph node biopsy or 
bone marrow biopsy slides for biomarker 
studiesc
X
Xc
Inclusion/Exclusion criteria confirmed/met
Xa
Demographics/Medical history
Xa
Complete physical examination 
including lymph node measurements
Xa
X
Limited physical examination including lymph 
node measurements with lymphoma symptoms 
reviewed
X
X
X
X
Age-appropriate performance status
Xa
X
Weight
Xa
X
X
X
X
Height
Xa
X
X
X
X
Vital signsd
Pulse/heart rate and blood pressure are expected in all protocol-specified visits 
BSA (See Attachment 3)
X
Xe
Xe
ECG
Xa
Xf
Xf
X
Echocardiogram or MUGA
Xa
Xf
Xf
X
Concomitant medications/procedures
Adverse events and concomitant medications to be collected from signing of the ICF and up until 30 days after the last dose of study 
treatment or until the start of subsequent antilymphoma therapy, if earlier.
Adverse events
Drug acceptability and palatability assessment 
(Visual analog scale); for subjects on ibrutinib 
onlyg
X
X
Disease Evaluations
Disease evaluation (CT/MRI)h
(see Section 9.2.1)
Xa
X
Xi
Xi
Lumbar puncture/CSF cytologic evaluation
Xa
Xj
Xj
Xj
Xj
Bone marrow aspirate and/or biopsy
Xk
Xk
Xk
Xk


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Status: Approved, Date: 15 September 2020
Pretreatment Phase
Treatment Phase
Screeninga
Up to 14 days 
before 
administration of 
study drug
Cycle 1, 
Day 1
Cycle 1, 
Day 14 
(±1 day)
Cycle 2, 
Day 1
Cycle 3, 
Day 1
Early withdrawal/ 
End-of-Treatment visit
Laboratory Assessments
Hematology (see Section 9.8)
Xm
-----------------Xm-------------------
Clinical chemistry (see Section 9.8)
Xm
-----------------Xm -------------------
Serum or urine -hCG pregnancy test (for 
young women with childbearing potential)
Xa
Xl
Xn
Xn
HIV serologies, Hepatitis B and C serologieso
Xa
Tetanus and pneumococcal antibody titers
Xa
Plasma samples for PK and protein binding 
(subjects on ibrutinib only)p
Xp
Biomarker blood samples for phospho-protein 
and molecular characterization and BTK 
occupancy evaluationsq
X
Xq
X
X
Cell count from stem cell collection for 
transplant (if applicable; See Section 9.1.1.)
----------------X ---------------------
-hCG=beta-human chorionic gonadotropin; BM=bone marrow; BSA=body surface area; BTK=Bruton’s tyrosine kinase; CIT=chemoimmunotherapy; CNS=central 
nervous system; CSF=cerebrospinal fluid; CT=computed tomography; ECG=electrocardiogram; h=hour(s); HIV=human immunodeficiency virus; ICF=informed 
consent form; IHC=immunohistochemistry; MRI=magnetic resonance imaging; MUGA=multiple-gated acquisition scan; NHL=non-Hodgkin lymphoma; 
PD=progressive disease; PK=pharmacokinetics; RVICI=rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone; yrs=years.
a.
Standard of care testing to document comorbidities and baseline disease, with the exception of tetanus and pneumococcal titers, hematology, and chemistry, can be 
counted as screening assessments for the study if performed within 5 days of signing ICF. Procedures must have been performed according to protocol requirements 
and imaging must meet the Imaging Acquisition Guidelines standards.
b.
Pathology report for the original NHL diagnosis or at relapse, if available, should be sent to the Janssen medical monitor immediately after signing the ICF. If the 
prior pathology report is not available, then a pathology report from a fresh biopsy will be required for study entry.
c.
Formalin-fixed paraffin-embedded tumor tissue (mandatory at Screening) collected for biomarker studies only. A fresh lymph node biopsy should be collected at 
Screening or prior to Cycle 1 and at the time of PD (even if not previously collected), if feasible, where local regulations/shipping logistics permit. If archival tissue 
is unavailable and a fresh lymph node biopsy cannot be obtained, bone marrow slides (when positive for disease) can be submitted at screening and at the time of 
PD. No tumor tissue is required at the end of treatment in the absence of progressive disease.
d.
These 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.
e.
BSA and dose should only be recalculated if there is >10% weight change from the weight used in the previous BSA calculation.
f.
Echocardiography/MUGA and ECG required at the end of each cycle (within 3 days prior to the next cycle) in RVICI treatment group only; otherwise, obtain at 
Screening and End-of-Treatment only.
g.
If ibrutinib is temporarily stopped on C1D1 or C3D1, the assessment should be taken with the first dose of ibrutinib in each respective cycle.


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Status: Approved, Date: 15 September 2020
h.
Positron emission tomography scan at baseline recommended but not mandatory. Subjects entering study with only BM disease should be followed by BM biopsy 
and/or aspirate. In these subjects, radiographic images are required at screening but if no nodal disease is identified, subsequent imaging is not required.
i.
Scans may be performed up to 3 days prior to Cycle 3 Day 1. Scans may be done ± 3 days of End-of-Treatment visit. Disease evaluations that show PD can be used 
as end-of-treatment evaluations. Additional disease evaluations may be obtained at discretion of investigator to confirm clinical response or PD.
j.
Lumbar puncture in conjunction with triple intrathecal therapy for CNS treatment per the Dosage and Administration tables (Table 5 and Table 6) may be performed 
the day prior to the start of a treatment cycle for logistical reasons. Lumbar puncture on Cycle 1 Day 1 can be used as the screening lumbar puncture only if collected 
prior to the administration of any ibrutinib or background therapy. Disease evaluations that show PD can be used as end-of-treatment evaluations.  
k.
Bone marrow at Cycle 2 Day 1 only if clinically indicated. Morphological examination and IHC or flow cytometry is required of all bone marrow specimens at 
screening for all subjects. If bone marrow results at screening are negative, subsequent assessments must include morphologic assessment of the bone marrow, while 
immunophenotyping is optional. Procedure may be performed 1 day prior to the start of a treatment cycle for logistical reasons. If marrow is empty (lack of count 
recovery), repeat marrow should be obtained prior to initiating next cycle. Refer to protocol Section 9.2.2 for details regarding bone marrow testing. Disease 
evaluations that show PD can be used as end-of-treatment evaluations.  
l.
Required within 24 hours prior to treatment on Cycle 1 Day 1
m. Must be taken on day of or day prior to dosing, provided results are available before ibrutinib or background therapy is given. Hematology and chemistry should be 
done at Screening and on Cycle 1 Day 1 and weekly thereafter in Cycle 1. For Cycle 2 and Cycle 3, hematology and chemistry should be done on Day 1 and between 
Days 14 to 21. 
n.
Required within 24 hours prior to treatment on Cycle 2 Day 1 and Cycle 3 Day 1.
o.
Hepatitis B serologic testing should include HBsAg, HBcAb, and HBsAb. A subject without a known history of these viral infections may be randomized if the 
serology results are not available at the time of the randomization. However, if the serology results return as positive, the medical monitor should be contacted 
immediately, and the guidance provided in Section 9.8 should be followed.
p.
PK Sampling: On day of PK sample collection, ibrutinib should be taken within 2 hours after a meal. If ibrutinib is temporarily stopped on any PK sampling days, or 
within 3 days prior to PK sampling, the medical monitor should be contacted for guidance. PK samples are only collected from subjects randomized to ibrutinib with 
background CIT.  If randomized to background CIT only, no PK samples are required to be collected.  
Subjects randomized to ibrutinib and background CIT:  4 samples collected from each subject. Samples collected either at C1D14 (preference) or at C2D1, not both 
timepoints. Sample collected at predose; 1 (window 45-75 minutes), 2 (window 1.5-2.5 hours), and 4 hours (window 3.5-6 hours) postdose.  If sample unable to be 
obtained at C1D14 (eg, due to a temporary stop of ibrutinib) sample can be collected on C2D1. 
q.
Biomarker Samples: Whole blood sample must be taken C1D1 predose and at 4 hours postdose (window 3.5-6 hours), and at C1D14 OR C2D1 (same day as the PK 
samples) predose and 4 hours postdose (samples collected either at C1D14 [preference] or at C2D1, not both timepoints).  Note: The 4-hour postdose samples are 
only required for patients randomized to take ibrutinib.  Whole blood sample taken also at predose on C3D1, and at PD or the End-of-Treatment visit. If a 
subject experiences bleeding with a lumbar puncture and needs to delay the dose of ibrutinib on Day 1 of the cycle, a predose and 4h sample should be done after 
administration of CIT is complete (on Day 14) instead. If this occurs during Cycle 1, a predose sample must also be obtained prior to any treatment on Day 1 and 
prior to ibrutinib exposure.


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Status: Approved, Date: 15 September 2020
Table 3:
Time and Events Schedule: Posttreatment Phase for Subjects Continuing on Ibrutinib Monotherapy
Posttreatment Phase for subjects continuing on ibrutinib monotherapy (randomized to ibrutinib and achieved response of PR or better)
Monotherapy
(Day 1 of 
Cycles 1-3, 
28-day cycles)
End-of-
Mono-
therapy visit 
(±7days)
9 months 
after 
C1D1a
(±7days)
12 
months 
after 
C1D1 a
(±7days)
18 months after C1D1a
(±7days)
24 months 
after C1D1a
(±7days)
30 months
after C1D1a
(±7days)
36 months 
after C1D1a
(±7days)
Procedures
Complete physical examination including lymph 
node measurements
X
Limited physical examination including lymph 
node measurements with lymphoma symptoms 
reviewed
X
X
X
X
X
X
X
Age-appropriate performance status
X
X
Weightb
X
Height
X
X
X
X
X
X
X
Vital signsc
X
X
BSAb
X
ECGd
X
Concomitant medications/procedures
X
Adverse events and concomitant medications will be reported until 30 days following the last dose of 
study treatment.
Adverse events
X
Survival
X (after PD, contact by visit or telephone q4wks) 
Disease Evaluations e
Disease evaluation (CT/MRI)
(see Section 9.2.1)
X
X
X
X
Lumbar puncture/CSF cytologic evaluation
Xf
Xf
Xf
Xf
Bone marrow aspirate and/or biopsy
Xf
Xf
Xf
Xf
Laboratory Assessments
Hematology (see Section 9.8)
Xg
X 
Clinical chemistry (see Section 9.8)
Xg
X
Serum or urine -hCG pregnancy test (for young 
women with childbearing potential)
Xh
Tetanus and pneumococcal antibody titers
X
Biomarker fresh tumor biopsy and blood 
samples for phospho-protein and molecular 
characterization and BTK occupancy
evaluationsi
X
X (at the time of PD) 
Cell count from stem cell collection for 
transplant (if applicable; See Section 9.1.1.)
X 
-hCG=beta-human chorionic gonadotropin; BSA=body surface area, C1D1=Cycle 1 Day 1; CSF=cerebrospinal fluid; CT=computed tomography; 
ECG=electrocardiogram; MRI=magnetic resonance imaging; PD=progressive disease; q4wks=every 4 weeks.


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a.
C1D1 of original combination treatment phase.
b.
Weight is required prior to dosing on Day 1 for each cycle of monotherapy. BSA and dose should only be recalculated if there is >10% weight change from the 
weight used in the previous BSA calculation.
c.
These assessments should be recorded in source documents but will not be routinely collected in the eCRF. Clinically significant abnormalities should be recorded as AEs and reported 
in the eCRF.
d.
To be performed at End-of-Monotherapy Visit only if not performed within previous 30 days.
e.
Disease assessments may be repeated as clinically indicated to confirm response or progression.
f.
Obtain only if clinically indicated. 
g.
Laboratory results from End-of-Treatment do not need to be repeated on monotherapy Cycle 1 Day 1 if testing was performed within 1 week.
h.
Required within 24 hours prior to treatment on monotherapy Cycle 1 Day 1 and monthly thereafter.
i.
Whole blood samples for phospho- protein and molecular characterization should be obtained at the End-of-Monotherapy Visit and at PD. Whole blood sample for 
pharmacodynamic analysis (BTK occupancy) should be obtained if PD occurs during Cycles 1-3 of monotherapy or at the End-of-Monotherapy Visit. A fresh 
lymph node biopsy should be collected at PD (even if not previously collected), if feasible, where local regulations/shipping logistics permit. If a fresh lymph node 
biopsy cannot be obtained, bone marrow slides (when positive for disease at PD) can be submitted.


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Table 4:
Time and Events Schedule: Posttreatment Phase for Subjects not Receiving Ibrutinib Monotherapy
Posttreatment Phase for subjects NOT receiving ibrutinib monotherapy
6 months after 
C1D1a
(±7days)
9 months after 
C1D1a
(±7days)
12 months after 
C1D1a
(±7days)
18 months after 
C1D1 a
(±7days)
24 months after 
C1D1a
(±7days)
30 months after 
C1D1 a
(±7days)
36 months after 
C1D1a
(±7days)
Procedures
Limited physical examination including 
lymph node measurements with 
lymphoma symptoms reviewed
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
Survival
X (after PD, contact by visit or telephone q4wks) 
Disease Evaluations b
Disease evaluation (CT/MRI)
(see Section 9.2.1)
X
X
X
X
Lumbar puncture/CSF cytologic 
evaluation
Xc
Xc
Xc
Xc
Bone marrow aspirate and/or biopsy
Xc
Xc
Xc
Xc
Laboratory Assessments
Tetanus and pneumococcal antibody 
titers
X
Fresh tumor biopsy and blood samples 
for biomarker evaluationsd
X (at the time of PD) 
Cell count from stem cell collection for 
transplant (if applicable; See 
Section 9.1.1.)
X 
C1D1=Cycle 1 Day 1; CSF=cerebrospinal fluid; CT=computed tomography; ECG=electrocardiogram; MRI=magnetic resonance imaging; PD=progressive disease; 
q4wks=every 4 weeks.
a.
C1D1 of treatment phase.
b.
Disease assessments may be repeated as clinically indicated to confirm response or progression.
c.
Obtain only if clinically indicated.
d.
Whole blood samples for phospho- protein and molecular characterization should be obtained at PD. A fresh lymph node biopsy should be collected at PD (even if 
not previously collected), if feasible, where local regulations/shipping logistics permit. If a fresh lymph node biopsy cannot be obtained, bone marrow slides (when 
positive for disease at PD) can be submitted.


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Table 5:
Dose and Administration Table: RICE With or Without Ibrutinib
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Days10-28a
Ibrutinib 329 mg/m2  b
X c
X
X
X
X
X
X
X
X
X
Rituximab 375 mg/m2
X
X
Ifosfamide 3 g/m2 over 2 hrsc
X
X
X
Carboplatin 635 mg/m2 over 1 hr
X
Etoposide 100 mg/m2 over 1 hr
X
X
X
Mesna 600 mg/m2 with ifosfamide and at 3, 6, 
9, and 12 hrs after the start of each dosec
X
X
X
Mesna 3,000 mg/m2/day (administer as a 
shortened infusion per instructions in footnote 
for subjects receiving ibrutinib) d
X
X
X
X
X
X
X
Dexamethasone 20 mg/m2/day in 3 divided 
doses (IV or PO)
X
X
X
X
X
IV hydration 3,000 mL/m2/day 
X
X
X
X
X
Triple intrathecal therapy e  
X
Xe
Xe
CNS=central nervous system; hr(s)=hour(s); IV=intravenous; PO=orally; RICE=rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone.
Note: See Pharmacy Manual/study Site Investigational Product Manual for calculation of ibrutinib dose.
a.
If count recovery occurs quickly, cycles can be shortened to a minimum of 21 days.
b.
Up to a maximum dose of 560 mg per day. See Attachment 1 for ibrutinib dosing guides.
c. 
Ibrutinib to be administered early in the day. To avoid a drug-drug interaction, mesna infusion should be stopped 3 hours prior to administering ibrutinib and not 
started for 6 hours after administering ibrutinib. Since mesna is given first with ifosfamide, ifosfamide dosing should also be separated accordingly from ibrutinib.
d.
Administer mesna as a continuous infusion instead of intermittent dosing only in subjects with hematuria. For subjects receiving ibrutinib, to avoid a drug-drug 
interaction, mesna infusion should be stopped 3 hours prior to administering ibrutinib and not started for 6 hours after administering ibrutinib.
e.
If CNS-negative, triple intrathecal therapy (methotrexate, corticosteroid, and cytarabine) should be administered on the first day of each cycle. If CNS-positive, 
administer every 4 ± 1 days until cerebrospinal fluid is cleared of blasts. Intrathecal rituximab is not permitted. Intrathecal therapy may be administered not more 
than 24 hours before Day 1 of each cycle.


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Table 6:
Dose and Administration Table: RVICI With or Without Ibrutinib
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Days 10-28a
Ibrutinib 329 mg/m2  b
X c
X
X
X
X
X
X
X
X
X
Rituximab 375 mg/m2
X
X
Vincristine 0.4 mg/m2/24 hr 
continuous infusion over 4 days
X
X
X
X
Idarubicin 10 mg/m2 over 4 hrs
X
X
Carboplatin 200 mg/m2/24 hr 
continuous infusion over 4 days
X
X
X
X
Ifosfamide 2 g/m2/24 hr over 5 days 
(administer as a shortened infusion 
per instructions in the footnote for 
subjects receiving ibrutinib) c
X
X
X
X
X
Mesna 500 mg/m2 bolus 
X
Mesna 3,000 mg/m2/day (administer 
as a shortened infusion per 
instructions in the footnote for 
subjects receiving ibrutinib) c
X
X
X
X
X
X
X
Dexamethasone 20 mg/m2/day in 
3 divided doses (IV or PO)
X
X
X
X
X
IV hydration 3,000 mL/m2/day 
X
X
X
X
X
X
X
X
X
Triple intrathecal therapy d
X
X
X
GCSF
X e
ANC=absolute neutrophil count; CNS=central nervous system; hr(s)=hour(s); GCSF=granulocyte colony-stimulating factor; IV=intravenous; PO=orally; 
RVICI=rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone.
Note: See Pharmacy Manual/study Site Investigational Product Manual for calculation of ibrutinib dose.
a.
If count recovery occurs quickly, cycles can be shortened to a minimum of 21 days.
b.
Up to a maximum dose of 560 mg per day. See Attachment 1 for ibrutinib dosing guides.
c.
Ibrutinib to be administered early in the day. For subjects receiving ibrutinib, to avoid a drug-drug interaction, mesna infusion should be stopped 3 hours prior to 
administering ibrutinib and not started for 6 hours after administering the dose. Since mesna is given first with ifosfamide, ifosfamide dosing should also be 
separated accordingly from ibrutinib. For subjects not receiving ibrutinib, the mesna and ifosfamide infusion may be given as per standard of care.
d.
If CNS-negative, triple intrathecal therapy (methotrexate, corticosteroid, and cytarabine) should be administered on the first day of each cycle. Intrathecal therapy 
may be administered not more than 24 hours before Day 1 of each cycle. If CNS-positive, administer every 4 ± 1 days until cerebrospinal fluid is cleared of blasts. 
Intrathecal rituximab is not permitted.
e.
GCSF should be administered beginning Day 12 and continued until ANC ≥500/L on 2 occasions post-nadir.


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ABBREVIATIONS
ANC
absolute neutrophil count
AUC
area under the plasma concentration-time curve
B-AL
Burkitt leukemia
B-ALL
B-cell acute lymphoblastic leukemia
BCR
B-cell receptor
β-hCG
beta-human chorionic gonadotropin
BL
Burkitt lymphoma
BLL
Burkitt-like lymphoma
BSA
body surface area
BTK
Bruton’s tyrosine kinase
CIT
chemoimmunotherapy
CL/F
apparent (oral) plasma clearance
CLL
chronic lymphocytic leukemia
Cmax
maximum observed plasma concentration
CNS
central nervous system
CR
complete response
CRb
complete response biopsy-negative 
CRF
case report form 
CRu
unconfirmed complete response
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eDC
electronic data capture
EFS
event-free survival
EICNHL
European Intergroup Collaboration for Childhood non-Hodgkin Lymphoma
EMA
European Medicines Agency
GCB
germinal center B-cell like
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
ILD
interstitial lung disease
IRB
Institutional Review Board
IRC
Independent Review Committee
ITT
intent-to-treat
IWRS
interactive web response system
LVEF
left ventricular ejection fraction
MCL
mantle cell lymphoma
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition (scan)
NCI
National Cancer Institute 
NHL
non-Hodgkin lymphoma
ORR
overall response rate
PBPK
physiologically-based pharmacokinetic
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
P-gp
P-glycoprotein
PQC
Product Quality Complaint
PR
partial response
PTLD
post-transplant lymphoproliferative disease


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RICE
rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone
RVICI
rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone
SET
Study Evaluation Team
SF
shortening fraction
SJS
Stevens-Johnson Syndrome
SLL
small lymphocytic lymphoma
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
Vd/F
apparent (oral) volume of distribution


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1.
INTRODUCTION
Ibrutinib 
(IMBRUVICA®; 
PCI-32765; 
JNJ-54179060) 
is 
an 
orally-administered, 
covalently-binding, small molecule Bruton’s tyrosine kinase (BTK) inhibitor currently 
co-developed by Janssen Research & Development, LLC and Pharmacyclics LLC for the 
treatment of B-cell malignancies. For the most comprehensive nonclinical and clinical 
information regarding ibrutinib, refer to the latest version of the Investigator's Brochure and 
Addenda for ibrutinib and the ibrutinib package insert. The term "sponsor" used throughout this 
document refers to the entities listed in the Contact Information page(s), which will be provided 
as a separate document.
1.1.
Mature B-cell Non-Hodgkin Lymphoma
In children, mature B-cell non-Hodgkin lymphomas (NHLs) occur rarely; the most common 
types are Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).24,29 Although 
these are aggressive lymphomas that are fatal in weeks to months if untreated,8 the cure rate in 
children with BL and DLBCL is between 85% to 90% after initial treatment.25,33 Given this high 
cure rate, the incidence of relapsed or refractory BL and DLBCL within the broader pediatric 
population of NHL is very small.2,4,6,13,31,35,41 Relapse of pediatric BL most commonly occurs 
within 6 months of the end of treatment and has a poor prognosis.26 A review of children with 
mature B-cell NHL who relapsed or progressed following treatment with frontline pediatric 
B-cell NHL protocols had survival rates of less than 20%; however, these data were not 
summarized by the individual subtypes of BL or DLBCL.3,7,34 Despite the reported overall 
response rate (ORR) of over 50% in most of these series, the overall mortality of this population 
is high and the 1- and 2-year event-free survival (EFS) rates are approximately 40% and 20%, 
respectively. Long-term survival beyond 2 years is poor, with only 10% to 20% of these patients 
surviving,3,13,15,18 underscoring the unmet medical need in this patient population.
1.2.
Current Methods of Treatment of Previously-Treated Mature B-cell 
Non-Hodgkin Lymphoma
Due to the low number of pediatric patients who relapse and the aggressive nature of the disease 
at the time of relapse, few studies have been conducted that have established a standard of care 
regimen in the relapsed or refractory setting. In both pediatric and adult patients in the relapsed 
and refractory setting, therapy may include a stem cell transplantation.1,5,14,40
The most recent study in relapsed or refractory BL and DLBCL was a pilot Phase 2 study 
(Study ANHL0121) conducted by the Children’s Oncology Group that assessed the toxicity and 
efficacy of ifosfamide, carboplatin, and etoposide (ICE) combined with rituximab in children and 
adolescents with recurrent or refractory B-cell (CD20+) NHL and mature B-cell acute 
lymphoblastic leukemia ALL (B-ALL).15 In this study, rituximab, ifosfamide, carboplatin, and 
etoposide (RICE) was established as an acceptable salvage induction regimen for patients who 
had been previously treated with a risk-adapted dose-intense chemotherapy regimen. An ORR of 
60% was achieved (14 BL/mature B-ALL, 6 DLBCL evaluable subjects). The complete response 
(CR) rate was 64% and 50% among subjects with BL/B-ALL and DLBCL, respectively.


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Similar to other salvage regimens, almost all subjects treated with the RICE regimen had severe 
myelosuppression that was reversible. Infections were frequently seen, but clinically 
manageable. No subjects died from infection. Rituximab-related infusion reactions occurred 15% 
of the time infusions were administered. Following completion of therapy, 6 subjects were able 
to proceed to consolidation with high-dose therapy and stem cell rescue. However, despite the 
60% ORR, 40% (8/20) of subjects failed therapy and had a poor outcome (median survival of 
2.5 months from study entry); among the subjects who responded, long-term survival 
(>24 months) was 15% (ie, 2/14 BL/B-ALL and 1/6 DLBCL). The high mortality rate in the 
relapsed/refractory population supports the unmet medical need to develop new and effective 
therapies for this pediatric population.3,13,15,16,18,19,32
Historically, RICE has been the most commonly used treatment regimen for DLBCL and BL in 
the relapsed/refractory pediatric population. However, among members of the European 
Intergroup Collaboration for Childhood non-Hodgkin Lymphoma (EICNHL), an alternative 
treatment regimen (the rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and 
dexamethasone [RVICI] regimen) is being increasingly used in BL patients.15,42
1.3.
Ibrutinib 
1.3.1.
Nonclinical Studies
Pharmacologic Profile
In vitro studies have shown that ibrutinib binds covalently to a cysteine residue (Cys-481) in the 
BTK active site, leading to potent and irreversible inhibition of BTK enzymatic activity.30
Ibrutinib inhibited the proliferation of cell lines derived from patients with DLBCL, with a 
median effective concentration of 1 or 2 nM.
Toxicology 
General toxicity studies in rats and dogs have identified lymphoid tissues (lymphoid depletion) 
and the gastrointestinal tract (soft feces/diarrhea, with or without inflammation) as the target 
organs with potential relevance to human safety. Results from an immunotoxicity assessment of 
ibrutinib in rats were consistent with the expected pharmacology of the drug and included 
dose-associated decreases in B-lymphocyte numbers, lymphoid depletion in the white pulp of the 
spleen and decreased immunoglobulin responses to keyhole limpet hemocyanin immunization. 
Cardiovascular assessments in dog safety pharmacology and toxicity studies identified decreased 
heart rate and prolonged PR intervals related to ibrutinib administration as a relevant finding.
Pharmacokinetics and Metabolism 
After oral administration, ibrutinib showed rapid absorption and high plasma clearance in 
nonclinical species. Excretion of ibrutinib-related radioactivity occurred principally via feces. In 
human plasma, 97.3% of ibrutinib and 91.0% of the major dihydrodiol metabolite PCI-45227 
was bound to protein. 


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In vitro nonclinical data show that ibrutinib is metabolized primarily by cytochrome P450 
(CYP)3A. Ibrutinib is a weak reversible inhibitor toward CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A4/5 and does not display time-dependent CYP450 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. 
1.3.2.
Clinical Studies
1.3.2.1.
Human Pharmacokinetics
The pharmacokinetics of ibrutinib has been assessed in subjects with B-cell malignancies as well 
as in healthy subjects. Pharmacokinetic assessments in subjects with B-cell malignancies were 
typically done in elderly subjects (median 67 years; range, 30-87). In all studies, both parent 
ibrutinib and metabolite PCI-45227 were quantified. The on-target effects of metabolite 
PCI-45227 are not considered clinically relevant. The pharmacokinetic profile of ibrutinib does 
not significantly differ for patients with different B-cell malignancies.
Extensive pharmacokinetic sampling and evaluation have been performed in approximately 
250 subjects receiving ibrutinib across 5 clinical studies: PCYC-04753, PCYC-1102-CA, 
PCYC-1104-CA, PCYC-1106-CA, and PCYC-1109-CA. Results are briefly summarized below:
Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day, area 
under the plasma concentration-time curve (AUC) values for ibrutinib increased with increasing 
dose, but with considerable overlap in values. The coefficient of variation for the AUC ranged 
from 60% to 107% across 3 studies (Studies PCYC-04753, PCYC-1102-CA, and 
PCYC-1109-CA). The mean half-life of ibrutinib across 4 clinical studies ranged from 4.3 to 
8.9 hours, with a median time of maximum concentration of 2 hours. Ibrutinib pharmacokinetics 
in adults could be accurately predicted using a physiologically-based pharmacokinetic (PBPK) 
model, which was also successfully used to predict the magnitude of interactions with CYP3A 
inhibitors and inducers.
A population pharmacokinetics model was developed based on the data of 9 clinical Phase 1 to 
3 studies in subjects with hematological malignancies (N=1,202, mainly chronic lymphocytic 
leukemia [CLL] and mantle cell lymphoma [MCL]). The population pharmacokinetics model 
was a linear 2-compartment pharmacokinetics model with sequential zero to first order 
absorption and first order elimination. Ibrutinib pharmacokinetics were dose-proportional and 
time-independent, absorption was rapid, apparent oral plasma clearance (CL/F) and oral volume 
of distribution at steady-state were approximately 1,100 L/h and 9,000 L, respectively. The 
pharmacokinetics model included a significant effect of food on relative bioavailability (F1, 
decreased when ibrutinib was given in overnight fasting condition versus the meal condition 
used in the clinical studies [ibrutinib taken at least 30 minutes before eating or at least 2 hours 
after a meal] and after a high-fat meal) and duration of the zero order absorption process (D1, 
increased when ibrutinib was given after a high-fat meal). The model also included the effect of 
the co-administration of moderate and strong CYP3A inhibitors, which caused a significant 
increase of F1 (and thus, of the systemic exposure to ibrutinib). Also, increasing age was 


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associated with a significant, though minor, increase in ibrutinib systemic exposure. None of the 
other examined covariates (including sex, subject pretreatment, and clinical chemistry data, such 
as calculated creatinine clearance, baseline liver enzymes, and total bilirubin) had a significant 
effect on pharmacokinetic parameters.
In a food effect study (Study PCI-32765CLL1001), AUC of ibrutinib approximately doubled 
when 420 mg was given 30 minutes before, 30 minutes after, or 2 hours after a high-fat 
breakfast, in comparison with the fasted condition. The effect on maximum observed plasma 
concentration (Cmax) ranged from 2- to 4-fold, with the maximal effect observed when ibrutinib 
was administered 2 hours after the meal. This latter condition was chosen to determine the effect 
of food on the suspension formulation developed for administration to pediatric patients 
(Study PCI-32765CLL1015). Preliminary data showed a similar food effect as for the capsule 
formulation. The relative bioavailability of the suspension in comparison with the capsule 
(560 mg) was similar for AUC and was approximately 35% lower for Cmax.
In a mass-balance study (Study PCI-32765CLL1004) in 6 men administered ibrutinib as a 
140-mg solution admixed with 14C-ibrutinib, approximately 90% of radioactivity was excreted 
within 168 hours after administration, with less than 10% accounted for in urine and the 
remainder in feces. A negligible fraction was excreted as unchanged drug.
Pharmacokinetic and Pharmacodynamic Relationships
Ibrutinib binds covalently and irreversibly to Cys-481 near the BTK active site and inhibits the 
enzymatic activity of purified BTK with a half maximal inhibitory concentration of 0.39 nM. In 
Study PCYC-04753, the BTK active-site occupancy by ibrutinib was measured. Bruton’s 
tyrosine kinase remained fully occupied by ibrutinib (≥90% occupancy) for at least 24 hours in 
all subjects receiving 2.5 to 12.5 mg/kg/day and for the 560 mg continuous dosing cohorts. 
Although ibrutinib is rapidly eliminated from the plasma after oral administration, once daily 
dosing with ibrutinib is adequate to sustain maximal pharmacodynamic activity for 24 hours 
post-dosing.
Based on the available data, ibrutinib exposures were not significantly related to tumor response. 
This may be due to the limited number of subjects exposed to low doses of ibrutinib; only few of 
the examined subjects showed ibrutinib exposures lower than the AUC required for providing 
90% BTK engagement. The mean steady-state AUC in the adult population after a daily dose of 
560 mg (953 ng.h/mL) is on the flat part of the exposure-response curve and deemed sufficient to 
achieve >90% BTK engagement in the large majority of subjects. The occurrence of bleeding 
and infections (irrespective of the severity and causal relationship to the ibrutinib treatment) did 
not highlight a significant or meaningful relationship with ibrutinib systemic exposure.


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Drug-drug Interaction Study
Study PCI-32765CLL1002 was an open-label study with a drug-drug interaction cohort of 
18 healthy men, in which ibrutinib was administered alone at a 120 mg dose or in combination 
with ketoconazole at a 40 mg dose. Results demonstrated that ketoconazole, a strong CYP3A 
inhibitor, increased ibrutinib exposure by 29- and 24-fold, respectively. Guidance on 
concomitant use of ibrutinib with CYP3A inhibitors or inducers is provided in Attachment 4. 
1.3.2.2.
Efficacy/Safety Studies
Burkitt Lymphoma
No clinical data on the use of ibrutinib in BL are available. Burkitt cell line experiments 
demonstrate that ibrutinib significantly induces a dose-dependent decrease in cell proliferation in 
both rituximab-sensitive and rituximab-resistant cell lines. In addition, a significant decrease in 
phospho-BTK expression was demonstrated in the presence of ibrutinib when compared to 
control. When cells lines were exposed to a combination of ibrutinib and dexamethasone, cell 
proliferation decreased significantly following 5 days of treatment.28
In BL xenografted mice, a significant decrease in tumor burden was observed at Days 20 and 25 
compared to control. Additionally, ibrutinib-treated mice demonstrated prolonged survival when 
compared to control mice with a median survival post-ibrutinib therapy of 31.5, 37.5, and 
22.5 days, respectively, when compared to control (24 days). These results indicate that ibrutinib 
may serve as an adjuvant therapy for BL.21
Diffuse Large B-cell Lymphoma
Three early phase studies have been completed and a Phase 3 registration study in adults is 
ongoing. The 3 completed studies are summarized in Table 7. Efficacy results from 
Studies PCYC-04753 and PCYC-1106-CA demonstrate that ibrutinib has robust activity as a 
single agent in subjects with relapsed or refractory DLBCL, with possible lower response rates in 
subjects with the germinal center B-cell (GCB) subtype.


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Table 7:
Completed Efficacy Studies of Ibrutinib in DLBCL
Study Number/Design
Study Population
Ibrutinib Dosing 
Schedule
Outcome
PCYC-04753: 
First-in-human, 
open-label, 
nonrandomized, 
multicenter, dose 
escalation study
Recurrent NHL
1.25-12.5 mg/kg for 
28 consecutive days 
in a 35-day cycle; 
or 8.3 mg/kg/day 
(continuous); 
or 560 mg/day 
(continuous)

Full BTK occupancy (>95%) achieved 
at doses ≥2.5 mg/kg/day 
(12.5 mg/kg/day highest dose cohort 
evaluated). MTD not established.

5/15 (33%) subjects with DLBCL had 
objective responses (2 CRs, 3 PRs).

Median time on treatment: 8 weeks 
(range: 2 to 98 weeks).

Median PFS: 2.5 months (range: 0.7 to 
4.6 months).

Median follow-up: 3.5 months (range: 
0.8 to 22.5 months).
PCYC-1106-CA: 
Open-label, 
parallel-cohort, 
nonrandomized, 
multicenter study
Relapsed or 
refractory DLBCL
560 mg/day 
(continuous)

ORR: 24% (60 subjects).

Median time on study: 3.9 months.

ABC subtype, ORR: 41% 
(10/25 subjects; CR: 17%, PR: 24%).

GCB subtype, ORR: 5%.

Ibrutinib showed preferential activity 
in the non-GCB DLBCL subtype.
PCI-32765DBL1002: 
Open-label, 
nonrandomized, 
multicenter, 
dose-escalation study
Newly diagnosed 
CD20-positive 
B-cell NHL 
including DLBCL, 
FL, and MCL
280, 420, or 
560 mg/day 
(continuous), 
+ R-CHOP 

Demonstrated tolerability and efficacy 
of ibrutinib (560 mg) in combination 
with R-CHOP.

ORR (DLBCL, MCL, and FL): 85.7%, 
100.0%, 95.2%, and 93.8% in the 
280 mg, 420 mg, 560 mg, and 
combined dose cohorts.

18 subjects (7 GCB, 2 non-GCB) with 
DLBCL at 560 mg 
ibrutinib+R-CHOP: 100.0% ORR 
(15 CRs, 3 PRs).
ABC=activated B-cell like DLBCL; BTK=Bruton’s tyrosine kinase; CR=complete response; DLBCL=diffuse large 
B-cell lymphoma; FL=follicular lymphoma; GCB=germinal center B-cell like; MCL=mantle cell lymphoma; 
MTD=maximum tolerated dose; NHL=non-Hodgkin lymphoma; non-GCB=non-germinal center B-cell like; 
ORR=overall response rate; PFS=progression-free survival; PR=partial response; R-CHOP=rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone.
A Phase 1 study was conducted to evaluate ibrutinib in combination with RICE in adult subjects 
with relapsed or refractory DLBCL. A standard 3 + 3 dose escalation schedule for ibrutinib, 
420 mg, 560 mg, and 840 mg, was administered on Days 1 to 21 with RICE for 3 cycles. There 
were no dose limiting toxicities observed up to 840 mg daily in combination with RICE. 
Per computed tomography (CT), 1 CR, 6 PRs, and 4 subjects with stable disease were reported. 
Per positron emission tomography (PET), 4 subjects achieved a CR and 7 remained PET avid at 
the end of treatment.37
Clinical Safety of Ibrutinib 
For the most comprehensive clinical safety information, please refer to the latest version of the 
ibrutinib Investigator’s Brochure and Addenda.


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Hematological Adverse Events
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Monitor complete blood counts monthly.
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/small 
lymphocytic lymphoma (SLL). This effect has also been observed in some subjects (35%) with 
MCL treated with ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and 
should not be considered progressive disease (PD) in the absence of other clinical findings. In 
both disease types, lymphocytosis typically occurs during the first month of ibrutinib therapy and 
typically resolves within a median of 8 weeks in subjects with MCL and 14 weeks in subjects 
with CLL/SLL (range, 0.1 to 104 weeks). This pharmacodynamic effect was less prominent or 
not observed in other indications.
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. These subjects 
should be closely monitored. Administer supportive care including hydration and/or 
cytoreduction as indicated. Ibrutinib may be temporarily stopped, and medical monitor should be 
contacted.
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. See Attachment 4 for guidance on 
concomitant use of anticoagulants, antiplatelet therapy, and/or supplements. See Section 4.3 for 
guidance on ibrutinib management with surgeries or procedures.
Subjects with congenital bleeding diathesis have not been studied. 
Subjects in the current study will be monitored closely for bleeding (see Section 12.3.3).


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Cardiac Arrhythmias 
Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia including some fatal 
events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac 
risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmia. 
Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic 
symptoms (eg, palpitations, lightheadedness, syncope, chest discomfort or new onset of dyspnea) 
should be evaluated clinically and, if indicated, have an electrocardiogram (ECG) performed. For 
cardiac arrhythmias which persist, consider the risks and benefits of ibrutinib treatment and 
follow the dose modification guidelines.
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. Regular monitoring and appropriate treatment of conditions that can contribute to 
the occurrence of these events is recommended.
Diarrhea
Diarrhea is the most frequently reported non-hematologic adverse event with ibrutinib 
monotherapy and combination therapy. Other frequently reported gastrointestinal events include 
nausea, vomiting, and constipation. These events are rarely severe and are generally managed 
with supportive therapies including antidiarrheals and antiemetics. Subjects should be monitored 
carefully for gastrointestinal adverse events and cautioned to maintain fluid intake to avoid 
dehydration. Medical evaluation should be made to rule out other etiologies such as 
Clostridium difficile or other infectious agents. Should symptoms be severe or prolonged, follow 
the protocol dose modification guidelines. Refer to Section 6.2.
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 (see Section 8.1). Although causality has not been established, 
cases of progressive multifocal leukoencephalopathy and Hepatitis B reactivation have occurred 
in subjects treated with ibrutinib. Subjects should be monitored for signs and symptoms (fever, 
chills, weakness, confusion, vomiting, and jaundice) and appropriate therapy should be instituted
as indicated.
Rash
Rash has been commonly reported in subjects treated with either single-agent ibrutinib or in 
combination with chemotherapy. Rash occurred at a higher rate in the ibrutinib arm than in the 
ofatumumab arm in Study 1112. Most rashes were mild to moderate in severity. Isolated cases of 
severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have 
been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs 


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and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate. In addition, hypersensitivity-related events erythema, urticaria, angioedema 
have been reported.
Hypertension
Hypertension has occurred in subjects treated with ibrutinib. Regularly monitor blood pressure in 
subjects treated with ibrutinib and initiate or adjust antihypertensive medication throughout 
treatment with ibrutinib as appropriate. 
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions.
Interstitial Lung Disease 
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, follow the 
protocol dose modification guidelines (see Section 6.2.2). If symptoms persist, consider the risks 
and benefits of ibrutinib treatment and follow the dose modification guidelines (see 
Section 6.2.2).
Non-melanoma Skin Cancer
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer.
1.4.
Background Chemoimmunotherapy
Ibrutinib is being evaluated as add-on therapy to RICE or RVICI (see Table 5 and Table 6, 
respectively, for doses). In this study, dexamethasone was added to RICE to align with the 
dexamethasone given as part of RVICI. In a Children’s Oncology Group study of children with 
NHL in the relapsed/refractory setting, RICE led to a 60% ORR.15 The RVICI regimen has 
demonstrated a 63% 4-year survival.42 For both regimens, triple intrathecal therapy consisting of 
methotrexate, corticosteroid, and cytarabine will be administered for central nervous system 
(CNS) prophylaxis in age-appropriate dosing (see Attachment 6). Subjects with CNS disease will 
receive additional doses of triple intrathecal therapy as per the Time and Events Schedule 
(Table 5 and Table 6). For further information regarding background therapy, please refer to the 
local prescribing information.
1.5.
Rationale for the Study
As described above, long-term survival for patients with relapsed or refractory BL and DLBCL 
is poor, with only 10% to 20% of these patients surviving beyond 2 years,3,13,15,18 underscoring 
the unmet medical need in this patient population. Ibrutinib is an oral agent with an acceptable 
safety profile and novel mechanism of action. The drug inhibits the B-cell receptor pathway via 


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BTK inhibition, thereby overcoming the B-cell receptor (BCR) and chemokine-controlled 
retention of malignant B cells in their supportive microenvironments. It has been shown to 
disrupt the pathogenesis of several B-cell malignancies. Therefore, the addition of ibrutinib to a 
salvage regimen like RICE/RVICI may provide some advantages for the pediatric population 
given its non-overlapping mechanism of action and toxicity profile. Although there is no clinical 
pediatric experience with ibrutinib, translational models demonstrate activity of ibrutinib in BL 
and DLBCL. Clinical data also demonstrate the safety and activity of ibrutinib in adult subjects 
with relapsed DLBCL. No effect of the R-CHOP regimen (rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone) on ibrutinib pharmacokinetics was observed, nor did 
ibrutinib affect the pharmacokinetics of vincristine, also a CYP3A substrate. Therefore, an 
open-label study of ibrutinib in combination with RICE/RVICI in pediatric subjects with 
relapsed or refractory BL or DLBCL is planned. The available safety and pharmacokinetic 
information combined with the unmet medical need support foregoing a stepwise approach and 
support starting treatment using the body surface area (BSA)-derived equivalent of the 560 mg 
ibrutinib dose used in adults with lymphomas. In the 2 older age groups (6-11 years, 
12-17 years), the first 2 evaluable subjects in each age group will start treatment with the 
equivalent of 420 mg, followed by up-titration to the 560-mg equivalent guided by safety and 
pharmacokinetic evaluation. In the youngest age group (1-5 years), the first 2 evaluable subjects 
will start treatment with the equivalent of 420 mg or lower as deemed appropriate by the Study 
Evaluation Team (SET) following assessment of pharmacokinetic and safety in the 2 older age 
groups.


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2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Run-in Part (Part 1)
Objectives
Endpoints
Primary

Confirm that the pharmacokinetics in pediatric 
subjects is consistent with that in adults 

Exposure (AUC) 

CL/F, apparent (oral) volume of distribution (Vd/F), and 
derived measures of exposure such as Cmax

Relationship between pharmacokinetic parameters and 
age or measure of body size 
Secondary

Evaluate the safety and tolerability of ibrutinib 
in combination with RICE or RVICI 
background therapy in pediatric subjects with 
B-cell malignancies

Safety parameters, including gastrointestinal effects, 
immune function, intensified cardiac monitoring (in 
particular, after previous anthracycline exposure)

Assess anti-tumor activity of ibrutinib as 
add-on to RICE or RVICI regimens

Overall response (CR, including CR biopsy-negative 
[CRb] and unconfirmed CR [CRu]) and partial response 
[PR])

Assess disease-specific biomarkers

Phospho-BTK, as well as SYK, STAT3, caspase-3, 
BCL-xL, and cIAP1 expression at baseline and during 
treatment

BCR/CD79B, CARD11, and MYD mutations

c-MYC, immunoglobulin, and T-cell receptor gene 
rearrangements at baseline

Assess the pharmacodynamic response

BTK occupancy

Acceptability and palatability assessment of all 
ibrutinib formulations

Visual analog scale score for palatability
Exploratory

Evaluate other response biomarkers

Other biomarkers, as applicable

Explore the exposure-response relationships

Potential relationships between systemic exposure and 
response


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2.1.2.
Randomized Part (Part 2)
Objectives
Endpoints
Primary

Assess efficacy (EFS) of ibrutinib in combination 
with RICE or RVICI background therapy 
compared to RICE or RVICI background therapy 
alone

Difference in EFS between the 2 treatment groups (an 
event is defined as the time from randomization to 
death, disease progression, or lack of CR or PR after 
3 cycles of treatment based on blinded independent 
event review)
Secondary

Evaluate the safety and tolerability of ibrutinib in 
combination with RICE or RVICI background 
therapy in pediatric subjects and young adults with 
B-cell malignancies

Safety parameters, including gastrointestinal effects, 
immune function, intensified cardiac monitoring (in 
particular, after previous anthracycline exposure)

Determine the ORR 

The proportion of subjects who achieve CR, 
(including CRb and CRu) and PR 

Evaluate tumor volume reduction at Day 14

Percent decrease in the sum of the products of the 
lesion diameters at Day 14

Determine the number and proportion of subjects 
who proceed to stem cell transplantation

Number and proportion of subjects who proceed to 
stem cell transplantation

Evaluate the time to response

The time interval from the first dose of ibrutinib to 
the first documented response for those subjects who 
respond

Measure the duration of response

Duration calculated from the date of initial 
documentation of a response (CR or PR) to the date 
of first documented evidence of PD or death

Evaluate long-term survival (EFS at 2 and 3 years)

Proportion of subjects with EFS at 2 and 3 years

Evaluate overall survival

The duration from the date of randomization to the 
date of the subject’s death

Assess disease-specific biomarkers

Phosphor-BTK, as well as SYK, STAT3, caspase-3, 
BCL-xL, and cIAP1 expression at baseline and 
during treatment 

BCR/CD79B, CARD11, and MYD mutations

c-MYC, immunoglobulin, and T-cell receptor gene 
rearrangements at baseline

Assess the pharmacodynamic response, if deemed 
appropriate based on Part 1 results

BTK occupancy

Assess the population pharmacokinetics of 
ibrutinib in pediatric subjects and young adults 

Population pharmacokinetic parameters and derived 
systemic exposure to ibrutinib such as AUC 

Relationship between pharmacokinetic parameters 
and age or measure of body size

Acceptability and palatability assessment of all 
ibrutinib formulations

Visual analog scale score for palatability
Exploratory

Evaluate other response biomarkers

Other biomarkers, as applicable

Explore the exposure-response relationships

Potential relationships between systemic exposure 
and response
Refer to Section 9, Study Evaluations, for evaluations related to endpoints.
2.2.
Hypothesis
The addition of ibrutinib to a salvage chemoimmunotherapy (CIT) regimen will extend EFS 
compared to CIT alone in pediatric and young adult subjects with relapsed or refractory mature 
B-cell NHL. 


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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a 2-part multicenter study. A safety and pharmacokinetic run-in part (Part 1) will be 
conducted before starting the randomized part (Part 2) of the study. Part 2 is a randomized, 
open-label, Phase 3 study to compare the safety and efficacy of ibrutinib in combination with 
CIT (RICE or RVICI) versus CIT alone in children and young adult subjects with relapsed or 
refractory mature B-cell NHL. Subjects who are 1 to 30 years old at the time of relapse (but with 
primary NHL diagnosis at age of <18 years old) will be eligible. 
Due to the expected similarity among subjects in each cohort in pharmacokinetics, the rarity of 
the patient population, and expected tolerability of ibrutinib, a safety and pharmacokinetic run-in 
part (Part 1) will be conducted before starting the randomized part (Part 2) of the study. The 
safety and tolerability of the ibrutinib dose initially proposed based on modeling and simulation 
will be confirmed clinically during the run-in part (Part 1) of the study. The data generated 
during Part 1 will be used to confirm or adapt the dose prior to starting Part 2, by taking into 
account observed exposures in combination with the predicted exposures using the PBPK 
modeling. Interim pharmacokinetic and, if feasible, pharmacodynamic assessments will be 
conducted in order to monitor if predictions are correct (ie, ensure drug exposure is consistent 
with the equivalent adult dose of 560 mg). If exposure is within the approximate range observed 
in adult subjects treated at 560 mg/day adult steady-state exposure (median, 830 ng.h/mL; range, 
250 to 1,500 ng.h/mL), then no dose adjustment will be required, provided there are no safety 
concerns. If exposure is not within the adult steady-state exposure range, then dose adjustments 
will be considered. A SET will review safety and pharmacokinetic data during the SET meetings 
(see Section 11.10). Safety will be assessed by evaluating the number of dose reductions and 
dose interruptions among the subjects treated in Part 1. Enrollment will begin with children in 
the 2 older age groups (6-11, 12-17 years) to assess pharmacokinetic and safety data before 
allowing enrollment of children in the youngest age group (1-5 years). The SET will meet to 
decide on any changes to the starting dose for each age group, and when enrollment may begin 
for the youngest age group. If dose adjustment requires a higher dose to be evaluated in the 
run-in part (Part 1), then the highest adult dose of 560 mg once daily will not be exceeded in 
children. 
In Part 1, a minimum of 6 and up to approximately 24 pediatric subjects (1 to <18 years) 
evaluable for pharmacokinetic assessment will be enrolled. Subjects in Part 1 will be considered 
“evaluable” if pharmacokinetic samples are obtained appropriately and lead to interpretable 
results. Based on the disease characteristics, it is expected that a range of ages will be 
represented. Safety and tolerability of ibrutinib in combination with RICE or RVICI will be 
assessed. If dose adjustment is required due to pharmacokinetic assessments or safety concerns, 
enrollment will be expanded to include additional subjects until dose adjustments are no longer 
needed for any age group. At a minimum, the first 2 subjects in each age group will enroll into 
Part 1 before recruitment of children in that age group will begin in Part 2. For each of the CIT 
regimens (RICE or RVICI), at least 3 subjects must receive that regimen in Part 1 with no 
toxicities of concern identified before randomization on that regimen can begin in Part 2.


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In Part 2, approximately 72 subjects will be randomized in a 2:1 ratio to receive ibrutinib in 
combination with CIT (investigator choice of RICE or RVICI) or CIT alone. Among the 
approximately 72 subjects enrolled in Part 2, at least 40 subjects are targeted to be age 
1 to <18 years, and at least 10 of the 40 subjects are targeted to be age <11 years. Subjects will 
be stratified by histology (BL/Burkitt leukemia [B-AL] versus “other”) and by background 
therapy (RICE versus RVICI). Pharmacokinetic samples will be obtained from those subjects 
randomized to ibrutinib in combination with RICE or RVICI during Part 2 of the study to 
characterize the pharmacokinetics in pediatric subjects. 
Part 1 and Part 2 of the study will be conducted in 3 phases: a Pretreatment (Screening) Phase, a 
Treatment Phase, and a Posttreatment Phase. Before any study-related procedure can be 
performed, each subject or his/her legally-acceptable representative must sign an informed 
consent form (ICF). In addition, an assent form must be signed by children capable of 
understanding the nature of the study, if applicable according to local regulations. The Screening 
Phase will occur within 14 days before administration of study drug, during which the subject’s 
eligibility and baseline characteristics will be determined. 
The Treatment Phase will extend from enrollment (in Part 1) or randomization (in Part 2) until 
1 of the following: 1) completion of 3 cycles of therapy, 2) transplantation, if clinically indicated, 
or 3) PD, whichever comes first. Cycles will be 28 days long; however, if count recovery occurs 
quickly and the investigator deems a subject ready to proceed with the next cycle of therapy, 
cycles can be shortened to as few as 21 days. As long as there is no disease progression after 
Cycle 1 or 2, a second and third cycle of therapy will be given, respectively. All subjects will 
receive background therapy with RICE or RVICI during the Treatment Phase. 
The investigator will evaluate sites of disease by radiological imaging, physical examination, or 
other procedures as necessary, including but not limited to review of hematology, clinical 
chemistry, and lumbar puncture results. Assessment of tumor response and progression will be 
according to the International Pediatric NHL Response Criteria. The primary efficacy analysis of 
EFS will be based on assessment by an Independent Review Committee (IRC). At each site visit, 
subjects will undergo safety evaluations. Safety evaluations will include adverse event 
monitoring, physical examinations, concomitant medication usage, and clinical laboratory 
parameters. Population pharmacokinetics will be performed during Part 1 using a sparse 
sampling approach. Additional sparse pharmacokinetic samples will be collected during Part 2 to 
expand the pediatric pharmacokinetic dataset. Blood samples will be obtained for 
pharmacodynamic assessments (BTK occupancy) and for protein binding (Part 1 only).
Subjects will begin the Posttreatment Phase after completion of combination therapy. During the 
Posttreatment Phase, subjects on ibrutinib having a response of PR or better and have completed 
3 cycles of combination treatment will continue on ibrutinib monotherapy at the same daily dose 
for three 28-day cycles, or until disease progression or unacceptable toxicity, or up until 
initiating subsequent antilymphoma therapy or a conditioning regimen for stem cell 
transplantation, whichever comes first. Follow-up visits to assess disease progression will be 
required if study treatment is discontinued prior to PD (including subjects who go on to 
transplant) and will be completed as per Table 3 and Table 4 until PD, the clinical cutoff for the 


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primary endpoint, or for up to 3 years after the date of Cycle 1 Day 1, whichever occurs first. 
After that, evaluations may be performed as clinically indicated at the discretion of the 
investigator. Subjects who have not progressed by the last efficacy assessment at 3 years should 
continue to be followed for survival status. Subjects who discontinue study treatment for reasons 
other than disease progression must continue to have disease evaluations according to the Time 
and Events Schedules (Table 1, Table 2, Table 3, and Table 4). The Posttreatment Phase will 
continue until death, loss to follow-up, consent withdrawal, or study end, whichever occurs first. 
The end of study is defined as when approximately 60 EFS events have occurred in Part 2 (death, 
disease progression, or lack of CR or PR after 3 cycles of treatment based on blinded 
independent event review), or the sponsor terminates the study, whichever comes first.  Study 
enrollment may be stopped early upon recommendation from the IDMC at the interim analysis 
based on early stopping rules.
During the randomized part of the study, an independent Data Monitoring Committee (DMC) 
will convene for ongoing, real-time review of safety and make recommendations (refer to 
Section 11.8, Independent Data Monitoring Committee, for details). One interim analysis will be 
conducted when approximately 30 EFS events are reached (approximately 32 months after the 
first subject is enrolled). The DMC will determine the appropriateness for early stopping using 
the nonbinding stopping rules as well as other efficacy and safety endpoints (see Section 11.8). A 
diagram of the study design for Part 1 and Part 2 is provided in Figure 1 and Figure 2, 
respectively.


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Figure 1:
Schematic Overview of the Study (Part 1; Run-in Part)
SCREENING
Eligibility:

Male or female age 1 to <18 years old.

Relapsed/refractory BL, BLL, Burkitt leukemia (ie, B-AL), DLBCL, DLBCL NOS, or other pediatric 
mature B-cell NHL. No diagnosis of PTLD. 

No allogeneic bone marrow transplant within 6 months of treatment start. 

In first recurrence or have disease that is primarily refractory to conventional therapy.

Lansky-Karnofsky score of ≥50.

No ongoing anticoagulation with Vitamin K antagonists and no inherited or acquired bleeding disorders.

No clinically significant arrhythmia, complex congenital heart disease, or LVEF <50% or SF ≤28%.
                                                              
↓
TREATMENT PHASE
Treatment:
Combination therapy: Ibrutinib + CIT (RICE or RVICI) until 3 cycles are completed, transplantation is 
indicated, or until PD or unacceptable toxicity
Response Assessment: 
Response assessments will be done at Disease Evaluation 1 which includes Cycle 1 Day 14 (imaging only) 
and start of Cycle 2 BM (if clinically indicated) and CSF, Disease Evaluation 2 beginning of Cycle 3 and at 
Disease Evaluation 3 at the EoT.
                                                             ↓
POSTTREATMENT PHASE
Treatment:
Monotherapy (subjects with PR or better only): Ibrutinib for 3 cycles, or until PD, unacceptable toxicity, or 
up until initiating subsequent antilymphoma therapy or a conditioning regimen for stem cell transplantation
Response Assessment:
Response assessed by CT, MRI and/or PET, CSF and BM evaluations.
For subjects on ibrutinib monotherapy: evaluations per Table 3 until PD, the clinical cutoff for the primary 
endpoint, or for up to 3 years after date of Cycle 1 Day 1, whichever occurs first.
Survival Follow-up:
The Posttreatment Phase will continue until death, loss to follow-up, consent withdrawal, or study end, 
whichever occurs first.
B-AL=mature B-cell acute lymphoblastic leukemia; BL=Burkitt lymphoma; BLL=Burkitt-like lymphoma; 
BM=bone marrow; CIT=chemoimmunotherapy; CSF=cerebrospinal fluid; CT=computed tomography; 
DLBCL=diffuse large B-cell lymphoma; EoT =End of Therapy; LVEF=left ventricular ejection fraction; 
MRI=magnetic resonance imaging; NHL=non-Hodgkin lymphoma; NOS=not otherwise specified; 
PD=progressive disease; PET=positron emission tomography; PR=partial response; PTLD=post-transplant 
lymphoproliferative disease; RICE=rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone; 
RVICI=rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone; SF=shortening fraction. 


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Figure 2:
Schematic Overview of the Study (Part 2; Randomized Part)
SCREENING
Eligibility:

Male or female age 1 to 30 years old.

Relapsed/refractory BL, BLL, Burkitt leukemia (ie, B-AL), DLBCL, DLBCL NOS, or other pediatric 
mature B-cell NHL. No diagnosis of PTLD. 

No allogeneic bone marrow transplant within 6 months of treatment start.

In first recurrence and have received only one prior line of therapy or have disease that is primarily 
refractory to conventional therapy.

Lansky-Karnofsky score of ≥50.

No ongoing anticoagulation with Vitamin K antagonists and no inherited or acquired bleeding disorders.

No clinically significant arrhythmia, complex congenital heart disease, or LVEF <50% or SF ≤28%.
                                                                           ↓
Randomization 2:1 ratio
Stratified by histology and background CIT regimen
                              ↓
       ↓
TREATMENT PHASE
Treatment: 
Combination therapy: ibrutinib + CIT (RICE or 
RVICI) until 3 cycles are completed, transplantation 
is indicated, or until PD or unacceptable toxicity
Response Assessment:
Response assessments will be done at 
Disease Evaluation 1 which includes Cycle 1 
Day 14 (imaging only) and start of Cycle 2 BM (if 
clinically indicated) and CSF, Disease Evaluation 2
beginning of Cycle 3 and at Disease Evaluation 3 at 
the EoT.
TREATMENT PHASE
Treatment: 
Combination therapy: CIT (RICE or RVICI) until 
3 cycles are completed, transplantation is indicated, or 
until PD or unacceptable toxicity
Response Assessment:
Response assessments will be done at 
Disease Evaluation 1 which includes Cycle 1 Day 14 
(imaging only) and start of Cycle 2 BM (if clinically 
indicated) and CSF, Disease Evaluation 2 beginning of 
Cycle 3 and at Disease Evaluation 3 at the EoT.
↓
↓
POSTTREATMENT PHASE
Treatment: 
Monotherapy (subjects with PR or better only): 
Ibrutinib for up to 3 cycles. or until PD, 
unacceptable toxicity, or up until initiating 
subsequent antilymphoma therapy or a conditioning 
regimen for stem cell transplantation.
Response Assessment:
Response assessed per Table 3 until PD, the clinical 
cutoff for the primary endpoint, or for up to 3 years 
after date of Cycle 1 Day 1, whichever occurs first.
POSTTREATMENT PHASE
Treatment: 
None.
Response Assessment:
Response assessed per Table 4 until PD, the clinical 
cutoff for the primary endpoint, or for up to 3 years 
after date of Cycle 1 Day 1, whichever occurs first.
B-AL=mature B-cell acute lymphoblastic leukemia; BL=Burkitt lymphoma; BLL=Burkitt-like lymphoma; 
BM=bone marrow; CIT=chemoimmunotherapy; CSF=cerebrospinal fluid; DLBCL=diffuse large B-cell lymphoma; 
EoT=End of Therapy; LVEF=left ventricular ejection fraction; NHL=non-Hodgkin lymphoma; NOS=not otherwise 
specified; PD=progressive disease; RICE=rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone; 
PTLD=post-transplant lymphoproliferative disease; RVICI=rituximab, vincristine, ifosfamide, carboplatin, 
idarubicin, and dexamethasone; SF=shortening fraction. 


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3.2.
Study Design Rationale
This is a Phase 3, randomized, open-label, controlled study evaluating the addition of ibrutinib to 
the standard of care for children and young adults with relapsed/refractory mature B-cell NHL. 
This is a registration study designed to support global regulatory applications. The study will 
recruit subjects globally and is adequately powered to demonstrate improved efficacy of the 
addition of ibrutinib to the standard of care treatment. 
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons between treatment groups. Subjects will be stratified by histology and 
background therapy. The study is not blinded; however, the determination of response by the 
IRC is blinded.
3.2.1.
Study Population
Although there is no clinical pediatric experience with ibrutinib, translational models 
demonstrate activity of ibrutinib in BL and DLBCL. Clinical data also demonstrate the safety 
and activity of ibrutinib in adult subjects with relapsed DLBCL.
Enrollment will be targeted toward children aged 1 to <18 years. However, for sites that treat 
young adult populations, subjects between 18 and 30 years of age may be enrolled if the initial 
diagnosis of NHL occurred before 18 years of age.
3.2.2.
Study Treatments
The target dose of 329 mg/m2 daily dose of ibrutinib (up to a maximum of 560 mg per day) was 
selected as the recommended dose based on normalization per BSA relative to a 1.7 m2 adult. 
Enrollment will begin with children in the 2 older age groups (6-11 years, 12-17 years) to assess 
pharmacokinetics and safety data before allowing enrollment of children in the youngest age 
group (1-5 years). For the first 2 subjects enrolled per age group (1-5 years, 6-11 years, and 
12-17 years) in the study, a lower starting dose of 240 mg/m2 for the first cycle (up to a 
maximum of 420 mg per day), which is equivalent to the lower therapeutic dose of ibrutinib 
(adult dose of 420 mg normalized per 1.7 m2, rounded down from 247 mg/m2), was selected to 
confirm exposure and safety, particularly in the younger age groups (see Section 6.1 for dose 
escalation details). Metabolic clearance of ibrutinib is almost exclusively mediated by CYP3A, 
which is known to reach adult expression levels at around 1 year of age,9 and characterized by 
blood flow limited clearance and high first pass metabolism, resulting in low oral bioavailability. 
Exposure predictions across the range of pediatric ages have been performed by adapting the 
adult PBPK model for ibrutinib. Based on the adult dose of 560 mg, the BSA-derived equivalent 
dose of 329 mg/m2 with a maximum dose of 560 mg per day is expected to result in comparable 
systemic exposures (within 1.4-fold [40% higher] using either the adapted adult PBPK model or 
allometric scaling) in children aged 6 years and older, but higher exposures in children 1 to 
5 years of age (up to approximately 2.3-fold at 12 months of age using the adapted adult PBPK 
model). Given the safety margins with ibrutinib, the starting dose of 240 mg/m2 in pediatric 


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subjects and the intra-subject escalation is considered adequate for Phase 1. Dose escalation will 
occur at the start of Cycle 2 as long as all pharmacokinetic assessments are within the expected 
range and there are no safety concerns. This approach to dosing will occur for the first 2 subjects 
in each age group during Part 1, and the age cohorts will only be allowed to enroll into Part 2 
after approval by the SET. The intensified pharmacokinetic schedule will occur for all subjects in 
Part 1. Dosing confirmation will be performed as a Phase 1b run-in. Data from the run-in will be 
used to verify that exposure is equivalent to that in adults. However, if exposure (AUC) in the 
first 2 subjects in a given age group at the 420-mg equivalent dose is below or exceeds the target 
range set, the dose for these subjects and all other subjects in that age group will be adjusted as 
appropriate based on available exposure data. 
The comparator in this study, CIT, is the standard of care for DLBCL and BL in children. 
Historically, RICE has been the most commonly used treatment regimen for DLBCL and BL in 
the relapsed/refractory population. However, among members of the EICNHL, an alternative 
treatment regimen (RVICI) is being increasingly used in BL patients.42
3.2.3.
Study Assessments
The primary endpoint, EFS, has served as the basis for regulatory approval in DLBCL and 
represents a clinically meaningful improvement attributable to treatment in this subject 
population.
3.2.4.
Pharmacodynamic Analysis
The pharmacodynamic activity of ibrutinib in the presence of CIT (RICE or RVICI) may be assessed 
by determining the percentage of probe occupancy of the BTK receptor at the timepoints listed in the 
Time and Events Schedule (Table 1, Table 2, and Table 3), according to the conditions specified 
in Section 9.4. Previous studies of single-agent ibrutinib have shown that greater than 90% receptor 
occupancy occurs within 4 hours of treatment; however, in combination with other agents the time of 
full occupancy may be different, and this will be compared to the previous studies. Therefore, 
monitoring for pharmacodynamic effects following combination treatment could provide an estimate 
of target engagement (BTK occupancy).
3.2.5.
Pharmacokinetic Analysis
The assessment of pharmacokinetics is important to extrapolate both safety and efficacy from 
adults to this patient population. The study includes a sparse pharmacokinetic sampling strategy 
for population pharmacokinetic purposes, which will serve as a means to derive the individual 
subject’s ibrutinib exposure. In addition to determination of subject-covariates that influence the 
pharmacokinetics of the drug, this may provide supportive evidence for the efficacy and safety 
analyses, help in deriving dosing regimens not directly studied in clinical studies, and identify 
at-risk subjects who require a dose-adaptation.
3.2.6.
Biomarker Collection
As a part of the biomarker collection, tumor (from archived tumor tissue or biopsies collected 
during Screening) and blood will be evaluated to identify markers predictive of response to 
ibrutinib. Analyses for mechanistic features including expression of certain characteristic genes, 


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and also for identification of cell of origin subtype (non-GCB or GCB; for DLBCL subjects 
only) will be performed based on availability of tumor samples. Tumor response in the non-GCB 
cohort 
will 
be 
compared 
to 
that 
observed 
in 
other 
studies 
in 
DLBCL 
(Study PCI-32765DBL3001). If feasible, tumor samples obtained at progression may be 
subjected to sequence analysis and compared to identify novel mutations/genetic lesions that 
correlate with primary resistance or response, or with acquired resistance during therapy. 
Subjects with resistant mutations can be excluded or targeted for other combination therapy in 
future biomarker-driven studies. Regional or local regulations could sometimes limit sample 
availability for somatic genome analysis. However, if regions allow, samples from other cells, 
such as T-cells, will be banked and analyzed later as sequencing controls and to evaluate T-cell 
receptor gene rearrangements. Other proteomic assays to confirm drug mechanism of action will 
be performed in these samples. Secreted proteins may be analyzed in these samples to examine 
the effects of treatment on protein expression. The volume and frequency of blood samples will 
be limited to minimize undue stress to the children in this pediatric study.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 14 days before administration of the 
study drug. The inclusion and exclusion criteria for enrolling subjects in this study are described 
in the following 2 subsections. If there is a question about the inclusion or exclusion criteria 
below, the investigator must consult with the medical monitor and resolve any issues before 
enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination. The last assessment/evaluation or laboratory result obtained prior to 
randomization will be used to determine eligibility.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
1 to <18 years of age (Part 1 only), or 1 to 30 years of age, inclusive, if initial 
diagnosis of mature B-cell NHL occurred at <18 years of age (Part 2 only)
2.
Criterion modified per amendment 1
2.1
Criterion modified per amendment 4
2.2
Relapsed/refractory BL, Burkitt-like lymphoma (BLL), Burkitt leukemia 
(ie, B-AL) with FAB3 morphology or presence of surface immunoglobulin by flow 
cytometry, DLBCL, DLBCL not otherwise specified (NOS), or other pediatric 
mature B-cell NHL
NOTE: Must have pathology report for the original NHL diagnosis or from the time 
of relapse (if available). If these pathology reports are not available, the pathology 
results of a fresh biopsy will be required for enrollment into the study.


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3.
Criterion modified per amendment 4
3.1
Criterion modified per amendment 5
3.2
Must be in first recurrence and have received only one prior line of therapy 
or have disease that is primarily refractory to conventional therapy 
4.
Criterion modified per amendment 2 
4.1
Must have at least 1 of the following:
a) 1 site of measurable disease >1 cm in the longest diameter and >1 cm in the 
shortest diameter by radiological imaging
b) bone marrow involvement 
c) cerebrospinal fluid with blasts present
5.
Lansky-Karnofsky score of ≥50
6. 
Adequate organ function defined as follows:
a) Absolute neutrophil count (ANC) 500 cells/µL. Growth factor support per 
institutional guidelines is permitted during the Screening and Treatment 
phases.
b) Platelets 50,000 cells/µL. Subjects with thrombocytopenia due to bone 
marrow infiltration are eligible if platelets are 25,000 cells/µL. Transfusion 
support is permitted during the Screening and Treatment phases.
c) Alanine aminotransferase 3 x upper limit of normal (ULN)
d) Aspartate aminotransferase 3 x ULN
e) Total bilirubin <1.5 x ULN, except in subjects with Gilbert syndrome or in 
subjects in whom the bilirubin rise is of non-hepatic origin
f)
Serum creatinine <2 x ULN for age or glomerular filtration rate 
>30 mL/min/1.73 m2 by the CKiD Schwartz equation38
7.
Must have recovered from the acute toxic effects of prior chemotherapy, 
immunotherapy, or radiotherapy, in the opinion of the investigator, prior to entering 
this study; and hematologic toxicities must meet the above criteria
8.
Criterion modified per amendment 1
8.1
ICF must be signed by legally authorized representative or by the subject if 
at legal age of consent indicating understanding of the purpose of, and procedures 
required for, the study and willingness to participate in the study. Assent is also 
required of children capable of understanding the nature of the study per 
country-specific or site-specific standards as described in Section 16.2.3, Informed 
Consent and Assent Form.


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9.
Adolescent women/young women of childbearing potential must have a negative 
highly sensitive serum or urine -human chorionic gonadotropin (-hCG) pregnancy 
test at Screening before enrollment/randomization. Adolescent/young women who 
are pregnant or breastfeeding are ineligible for this study. 
10.
Criterion modified per amendment 1
10.1
Criterion modified per amendment 2
10.2
Adolescents/young women of childbearing potential must be practicing a 
highly effective method of contraception (failure rate of <1% per year when used 
consistently and correctly) and agree to remain on a highly effective method 
throughout the study and for at least 3 months after the last dose of ibrutinib and 
1 year after the last dose of the background CIT, whichever is later.
Examples of highly effective contraceptives include
- user-independent methods: 
implantable progestogen-only hormone contraception associated with 
inhibition of ovulation; intrauterine device (IUD); intrauterine 
hormone-releasing 
system 
(IUS); 
vasectomized 
partner; 
sexual 
abstinence (sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the subject).
- user-dependent methods:
combined 
(estrogen-
and 
progestogen-containing) 
hormonal 
contraception associated with inhibition of ovulation: oral, intravaginal, 
and transdermal; progestogen-only hormone contraception associated 
with inhibition of ovulation: oral and injectable; a barrier method of 
contraception 
(eg, 
condom 
with 
spermicidal 
foam/gel/film/cream/suppository).
Typical use failure rates may differ from those when used consistently and 
correctly. Use should be consistent with local regulations regarding the use 
of contraceptive methods for subjects participating in clinical studies. 
Hormonal contraception may be susceptible to interaction with the study 
drug, which may reduce the efficacy of the contraceptive method.
Women of child bearing potential must use highly effective contraceptive 
measures while taking IMBRUVICA. Those using hormonal methods of 
birth control must add a barrier method (eg, condom with spermicidal 
foam/gel/film/cream/suppository).


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Note: If the childbearing potential changes after start of the study (eg, a 
premenarchal woman experiences menarche) or the risk of pregnancy 
changes (eg, a woman who is not heterosexually active becomes active,) a 
woman must begin a highly effective method of contraception, as described 
throughout the inclusion criteria.
11.
During the study and for a minimum of 1 spermatogenesis cycle (defined as 
approximately 90 days) after receiving the last dose of study drug, in addition to the 
user-independent highly effective method of contraception, a man 

who is sexually active with a woman of childbearing potential must agree to 
use a barrier method of contraception (eg, condom with spermicidal 
foam/gel/film/cream/suppository)

who is sexually active with a woman who is pregnant must use a condom

must agree not to donate sperm
12.
Must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Ongoing anticoagulation treatment with warfarin or equivalent vitamin K antagonists (eg, 
phenprocoumon), or ongoing treatment with agents known to be strong CYP3A4/5 
inhibitors, or has taken any disallowed therapies as noted in Section 8.2, Prohibited 
Medications, before the planned first dose of study drug
2.
Inherited or acquired bleeding disorders
3.
Clinically significant arrhythmias, complex congenital heart disease, or left ventricular 
ejection fraction (LVEF) <50% or shortening fraction (SF) ≤28%
4.
Known history of human immunodeficiency virus (HIV) or active Hepatitis B or C virus
5.
Any condition that could interfere with the absorption or metabolism of ibrutinib 
including malabsorption syndrome, disease significantly affecting gastrointestinal 
function, or resection of the stomach or small bowel
6.
Known allergies, hypersensitivity, or intolerance to ibrutinib or its excipients (refer to 
Investigator's Brochure)


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7.
Known allergy, hypersensitivity, or intolerance to any of the backbone CIT 
8.
Received an investigational drug (including investigational vaccines) or used an invasive 
investigational medical device within 30 days before the planned first dose of study drug, 
or is currently being treated in an investigational study
9.
Criterion modified per amendment 2:
9.1
Criterion modified per amendment 3
9.2
Pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study or 
within at least 3 months after the last dose of ibrutinib or 1 year after the last dose of the 
background CIT, whichever is later
10.
Plans to father a child while enrolled in this study or within 3 months after the last dose of 
study drug
11.
Any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the subject (eg, compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments
12.
Had major surgery (eg, requiring general anesthesia) within 4 weeks before 
enrollment/randomization, or has not fully recovered from surgery, or has surgery planned 
during the time the subject is expected to participate in the study or within 4 weeks after 
the last dose of study drug administration. Lumbar puncture, bone marrow 
aspiration/biopsy, or placement of central venous access device are not considered major 
procedures.
13.
Criterion added per amendment 2:
13.1
A diagnosis of post-transplant lymphoproliferative disease (PTLD)
14.
Criterion added per amendment 2:
14.1
Patients who are within 6 months of an allogeneic bone marrow transplant
15.
Criterion added per amendment 4
15.1
Subjects who have had prior exposure to ibrutinib
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.


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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.
Criterion modified per amendment 4
1.1
Concurrent radiation with ibrutinib is prohibited. Ibrutinib must be temporarily 
stopped for 3 days post-radiation
2.
Refer to Section 8, Prestudy And Concomitant Therapy, for details regarding 
prohibited and restricted therapy during the study
3.
Agree to follow the contraceptive requirements as noted in the inclusion criteria
4.
Criterion modified per amendment 4
4.1
The following guidance should be applied during the perioperative period for 
subjects who require surgical intervention or an invasive procedure while receiving 
ibrutinib:

For any surgery or invasive procedure requiring sutures or staples for closure, 
ibrutinib should be temporarily stopped at least 7 days prior to the intervention 
and should be temporarily stopped 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 procedures such as a central line placement, needle biopsy, thoracentesis, 
or paracentesis ibrutinib should be temporarily stopped for at least 3 days prior 
to the procedure and should not be restarted for at least 3 days after the 
procedure. For bone marrow biopsies that are performed while the subject is 
on ibrutinib, it is not necessary to temporarily stop ibrutinib.

For lumbar punctures, ibrutinib should be temporarily stopped for 24 hours 
before the procedure. If there is evidence of bleeding at the time of the lumbar 
puncture (ie, a “bloody tap”) defined as > 500 RBC/L on cell count, a platelet 
transfusion should be given. Consider giving a platelet transfusion if there is 
any other clinical sign of bleeding. If bleeding does occur, ibrutinib should be 
temporarily stopped and the medical monitor should be contacted. If there is 
no evidence of bleeding during or post-procedure, ibrutinib may be resumed.
For emergency procedures, ibrutinib should be temporarily stopped after the 
procedure until the surgical site is reasonably healed, for at least 7 days after the 
urgent surgical procedure.


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5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Enrollment in Part 1
All subjects enrolled in Part 1 will receive ibrutinib and RICE or RVICI background therapy. A 
minimum of 6 subjects are needed in order to proceed to the randomized portion of the study. 
Three subjects are required in the RICE group and 3 in the RVICI group. If 6 subjects are 
enrolled and the majority receives RICE, Part 2 randomization will be opened for RICE only and 
RVICI randomization will only open after 3 subjects have completed Part 1 with this background 
therapy. If dose adjustments are required based on pharmacokinetic analyses, enrollment will be 
expanded before proceeding to the randomized portion of the study. The first 2 subjects enrolled 
in each age group (1-5 years, 6-11 years, and 12-17 years) will be treated at a lower starting dose 
of 240 mg/m2 (not to exceed 420 mg) for the first cycle (older children [6-17 years] will be 
enrolled first before enrolling younger children [1-5 years]), followed by dose escalation at the 
start of Cycle 2 as long as all pharmacokinetic assessments are within the expected range and 
there are no safety concerns.
Procedures for Randomization and Stratification (Part 2 Only)
Central randomization will be implemented in Part 2 of this study. Subjects will be randomly 
assigned to 1 of 2 treatment groups based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified by histology and background 
therapy, then randomized in a 2:1 ratio to either Treatment Arm A (ibrutinib and RICE or RVICI 
background therapy) or Treatment Arm B (RICE or RVICI background therapy only). The 
interactive web response system (IWRS) will assign a unique treatment code, which will dictate 
the treatment assignment and matching study drug kit for the subject. The requestor must use his 
or her own user identification and personal identification number when contacting the IWRS, 
and will then provide the relevant subject details to uniquely identify the subject.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
For the purposes of this study, ‘study drug’ refers to ibrutinib and ‘study treatment’ refers to 
ibrutinib and CIT. The dosages for background CIT are described in Table 5 and Table 6. A 
dosing guide for ibrutinib is provided in Attachment 1. For subjects who require dosing through 
a feeding tube please refer to the Investigational Product Preparation Instruction (IPPI) for 
information on compatible tubes. All dosing information must be recorded in the Dosage 
Administration page of the case report form (CRF). 


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6.1.
Study Treatment
Ibrutinib will be administered at a target dose of 329 mg/m2 per day (up to a maximum of 
560 mg per day). The first 2 subjects in each age group (1-5 years, 6-11 years, and 12-17 years) 
will be started on the 420-mg equivalent dose (240 mg/m2). For subjects being treated at the 
240 mg/m2 dose level, the maximum dose should not exceed a total of 420 mg per day. If there 
are no safety concerns and exposure (AUC) in Cycle 1 does not exceed the target range, the dose 
will be increased from Cycle 2 onward for these 2 subjects and for all subsequently enrolled 
subjects in that age group. However, if exposure (AUC) in these 2 subjects at the 420-mg 
equivalent is lower than or exceeds the target range set, the dose for these subjects and all other 
subjects in that age group will be adjusted as appropriate based on available exposure data. 
Enrollment will begin with children in the 2 older age groups (6-11, 12-17 years) to assess 
pharmacokinetic and safety data before allowing enrollment of children in the lowest age group 
(1-5 years). The SET will meet to decide on any changes to the starting dose for each age group, 
and when enrollment may begin for the youngest age group. At a minimum, the first 2 subjects in 
each age group will be enrolled into Part 1 before children in that age group will be enrolled into 
Part 2.
This approach to dosing will occur for the first 2 subjects in each age group. The intensified 
pharmacokinetic schedule will occur for all subjects in Part 1 (regardless of age).
All subjects will receive background CIT, which is investigator’s choice of either RICE or 
RVICI. For both regimens, triple intrathecal therapy consisting of methotrexate, corticosteroid, 
and cytarabine will be administered for CNS prophylaxis in age-appropriate dosing (see 
Attachment 6). Subjects with CNS disease will receive additional doses of triple intrathecal 
therapy as per the Time and Events Schedule (Table 5 and Table 6). Dosages and schedule of 
study treatments for RICE and RVICI are described in Table 5 and Table 6, respectively.
Subjects will be randomized in a 2:1 ratio to Treatment Arm A (ibrutinib 329 mg/m2 or other 
dose as determined in Part 1, and RICE or RVICI background therapy) or Treatment Arm B 
(RICE or RVICI background therapy only). Study treatment administration begins on Cycle 1 
Day 1 and ends on the last day of Cycle 3, unless the subject experiences unacceptable toxicity 
or disease progression. Cycles will be 28 days long; however, if count recovery occurs quickly, 
cycles can be truncated to as few as 21 days. As long as there is no disease progression after 
Cycle 1 or 2, a second and third cycle of therapy will be given, respectively. Upon completion of 
3 cycles of combination therapy, subjects randomized to ibrutinib having a response of PR or 
better will continue on ibrutinib monotherapy at the same daily dose for three 28-day cycles or 
until disease progression or unacceptable toxicity, or up until initiating subsequent antilymphoma 
therapy or a conditioning regimen for stem cell transplantation, whichever comes first.
Ibrutinib will be supplied as capsules or as a suspension and will be self-administered at home on 
each day of each cycle. Study-site personnel will instruct subjects on how to store ibrutinib for 
at-home use as indicated for this protocol. Subjects randomized to ibrutinib will be asked to keep 
a log of medication administration and report dietary intake on PK days.


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The amount (in mg) of all study treatment to be administered will be determined by BSA 
(Attachment 3). Dosing guides for capsule and suspension administration are provided in 
Attachment 1. If a subject experiences a >10% change in weight from the weight used in the 
previous BSA calculation, then the BSA and dose should be recalculated.
6.1.1.
RICE/RVICI Administration
Investigators should refer to the local prescribing information for storage and handling, and 
detailed instructions on the administration of rituximab, ifosfamide, carboplatin, etoposide, 
vincristine, idarubicin, and dexamethasone. Rituximab biosimilar drugs are not permitted in this 
study. All intravenous drugs should be administered at the dosages and schedule outlined in 
Table 5 and Table 6. Refer also to the Pharmacy Manual/study Site Investigational Product 
Manual.
6.1.2.
Ibrutinib Administration
Subjects will be instructed to take ibrutinib orally once daily, starting at Cycle 1, Day 1. Study 
medication will be taken around the same time each day. It is recommended to take ibrutinib 
within 2 hours after a meal.
Subjects may receive ibrutinib in either a capsule (70 mg or 140 mg) or suspension formulation 
(see Section 14.1 for a description of the study drug and Attachment 1 for ibrutinib dosing 
guides). Subjects may not switch between formulations on days when pharmacokinetics will be 
drawn (ie, for each subject, the same formulation given on the first day pharmacokinetic samples 
are taken [capsule or suspension] should be given on all days when pharmacokinetic samples 
will be drawn thereafter). Further instructions regarding the administration of study medication 
are provided in the Pharmacy Manual/study Site Investigational Product Manual. Capsules and 
suspension should be taken with approximately 10 mL/kg with a maximum of 240 mL of water. 
The capsules should be swallowed whole and should not be opened, broken, or chewed.
Subjects taking ibrutinib should avoid consuming food and beverages containing grapefruit or 
Seville oranges for the duration of the study due to CYP3A inhibition. Subjects taking ibrutinib 
should refrain from taking the study drug on the morning of study visits designated for 
pharmacokinetic sampling until seen at the site (see Section 9.3.1). On days of pharmacokinetic 
sample collection (see Table 1 and Table 2), ibrutinib should be taken within 2 hours after a 
meal.
If a dose of study drug is missed, 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 doses to make 
up the missed dose.
Ibrutinib (capsules or suspension) will be dispensed on Day 1 of each treatment cycle, with
sufficient study drug to cover dosing for the entire cycle. Regardless of remaining capsules or 
suspension at the end of a treatment cycle, a new IWRS dispensing transaction should occur at 
the start of each new cycle and new bottle(s) of ibrutinib capsules or suspension dispensed for 
the subject’s new cycle.


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During the Posttreatment Phase, for subjects continuing on monotherapy, ibrutinib will be 
dispensed per cycle for three 28-day cycles. Unused study drug dispensed during previous visits 
must be returned and drug accountability records will be updated. Returned study drug must be 
discarded and may not be re-used in this study or outside the study. Study staff will instruct 
subjects on how to store study drug for at-home use as indicated for this protocol. Storage 
instructions are provided in the study Site Investigational Product Manual.
6.2.
Dose Modifications and Dose Delay
6.2.1.
RICE/RVICI
Management of toxicities and any dose modifications with rituximab, ifosfamide, carboplatin, 
etoposide, vincristine, idarubicin, and dexamethasone should be done in accordance with the 
respective product labels or institutional guidance. Refer to the product labels and institutional 
guidance for complete details on expected adverse events for each component of RICE/RVICI.
The start of a new cycle may be delayed on a weekly basis until recovery of toxicity to a level 
allowing continuation of therapy. A subject whose cycle is delayed should be assessed at least 
weekly for resolution of toxicity. If toxicity persists after a 2-week cycle delay that is related to 
1 specific drug (eg, vincristine, carboplatin, etc.), the responsible drug should continue to be 
temporarily stopped and the new cycle should be started with the remaining drugs. If 
RICE/RVICI chemotherapy is delayed, treatment with ibrutinib should be continued during the 
delay phase.
Subjects who discontinue any component of RICE/RVICI chemotherapy without disease 
progression may continue the remaining components and ibrutinib until 3 cycles are completed, 
disease progression, or unacceptable toxicity, whichever occurs first. If there is a delay in the 
start of a new cycle of more than 3 weeks due to insufficient recovery from toxicity (with all 
drugs temporarily stopped), the case should be discussed with the medical monitor before 
reinitiating therapy. However, the start of a new cycle after more than a 3-week delay (with all 
drugs temporarily stopped) may occur if there is clear clinical benefit and only after approval by 
the sponsor. Cycles 2 and 3 may be initiated, at the discretion of the investigator, after the 
following parameters are met:

Platelet count ≥50,000 cells/µL (prior platelet transfusion is allowed)

Hemoglobin ≥8 g/dL (≥4.96 mmol/L) (prior red blood cell transfusion or recombinant 
human erythropoietin use is allowed)

ANC ≥500 cells/µL (growth factor use is allowed, eg, granulocyte colony-stimulating factor 
or granulocyte-macrophage colony-stimulating factor)
6.2.2.
Ibrutinib
Treatment with ibrutinib should be temporarily stopped for any unmanageable, potentially study 
drug-related toxicity that is Grade ≥3 in severity. Hematologic toxicities are expected with RICE 
and RVICI and it may not be feasible to determine any relationship to ibrutinib. If the 
hematologic toxicities are not manageable, ibrutinib should be temporarily stopped, however, if 


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the cytopenias can be managed with transfusion and/or growth factor support and there are no 
unmanageable secondary complications from these cytopenias (eg, serious infection, significant 
bleeding) ibrutinib may be continued, at the discretion of the investigator. Ibrutinib may be 
temporarily stopped for a maximum of 21 consecutive days unless reviewed and approved by the 
sponsor. Ibrutinib should be discontinued permanently in the event of a toxicity lasting more 
than 21 days. If ibrutinib is delayed or temporarily stopped, any remaining study treatment (ie, 
rituximab, ifosfamide, carboplatin, etoposide, vincristine, idarubicin, and dexamethasone) may 
be continued.
The actions in Table 8 below should be taken for the following drug-related toxicities. Changes 
must be recorded in the Drug Accountability Records and Dosage Administration page of the 
electronic CRF.

Grade 3 or greater febrile neutropenia

Grade 4 neutropenia (ANC <0.5 x 109/L [ie, <500/mm3]) for >14 days (after completion of 
CIT)

Grade 3 thrombocytopenia (platelets <50 x 109/L [ie, <50,000/mm3]) in the presence of 
significant bleeding (ie, ≥Grade 2 bleeding)

Grade 4 thrombocytopenia (platelets <25 x 109/L [ie, <25,000/mm3])

Grade 3 or greater non-hematological toxicity
Table 8:
Ibrutinib Dose Modifications
Occurrence of the 
Same Adverse Event
Action
First
Temporarily stop study drug until recovery to Grade ≤1 or baseline; may restart at original 
dose level
Second
Temporarily stop study drug until recovery to Grade ≤1 or baseline; restart at 25% 
decrease in dose (ie, 1 dose level lower)a
Third
Temporarily stop study drug until recovery to Grade ≤1 or baseline; restart at 50% 
decrease in dose (ie, 1 dose level lower)a
Fourth
Discontinue study drug
a. Consult the sponsor for calculation of the reduced dose to be administered, if needed.
Refer to Attachment 1 for BSA-based dosing/rounding. Refer to Attachment 4 for instructions on 
dose modifications or temporary stop during concomitant administration of CYP3A inhibitors or 
inducers for subjects taking ibrutinib. Refer to Section 4.3 for guidance on dose delays during the 
perioperative period for subjects who require surgical intervention or an invasive procedure 
while receiving study drug.
7.
TREATMENT COMPLIANCE
Upon termination of the study, or at the request of the sponsor or its designee, the pharmacist 
must return the study drug to the sponsor or its designee, after all drug supplies have been 
accounted for, unless it is destroyed at the site as agreed upon by both the sponsor and the site. 


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Instructions regarding accountability for study drug are provided in the study Site Investigational 
Product Manual.
7.1.
Ibrutinib Compliance
The study drug (ibrutinib) is to be prescribed only by the principal investigator or a qualified 
physician listed as a subinvestigator on required forms. Records should be kept on the study drug 
accountability record provided by the sponsor or its designee. Dispensing of the study drug 
(ibrutinib) must be recorded in the subject’s source documents. Ibrutinib may not be used for any 
purpose other than that outlined in this protocol, including other human studies, animal 
investigations, or in vitro testing.
The IWRS will be used to assign centrally supplied study treatment kits for each subject. The 
investigator or the site pharmacist will maintain a log of all ibrutinib dispensed and returned. 
Drug supplies for each subject will be inventoried and accounted for throughout the study. 
Subjects/caregivers will be provided with a diary card to record intake at home. Site personnel 
are to instruct the subject to bring the diary card and any unused ibrutinib to the site at the 
beginning of each treatment cycle to check ibrutinib dosing compliance.
Instructions for proper self-administration and ibrutinib storage conditions will be provided. 
Precautions associated with the use of ibrutinib and prohibited concomitant medications will be 
reviewed. Site staff will provide additional instruction to re-educate any subject who is not 
compliant with the ibrutinib schedule. Subjects will be asked to keep a log of ibrutinib 
administration and report dietary intake on PK days.
7.2.
RICE/RVICI Compliance
Background therapy with RICE/RVICI will be provided by qualified study-site personnel and 
each administration will be recorded in the electronic CRF. The site pharmacist will maintain a 
log of all drug vials prepared for infusion and administration. Drug supplies, if provided by the 
sponsor, for each subject will be inventoried and accounted for throughout the study. The
infusion will be administered according to the approved prescribing information or approved 
institutional guidelines.
8.
PRESTUDY AND CONCOMITANT THERAPY
Systemic use of the following concomitant medications will be collected in the electronic CRF 
and recorded in the source documents beginning with signing of the ICF to 30 days after the last 
dose of the last study treatment or until the start of subsequent antilymphoma therapy (whichever 
is earlier): growth factors, transfusions, anti-infectives (antibacterials, antivirals, and 
antimycotics), steroids, anti-arrhythmics and other cardiac supportive therapy, anti-epileptics, 
psychoanaleptics, and any anticancer therapy (including radiation). Concomitant therapies 
administered at the time of, and used in the treatment of a serious adverse event, should be 
recorded. The sponsor must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered.


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8.1.
Permitted Medications and Supportive Therapies
Concomitant medications for medical conditions other than NHL are permitted.  Usage of 
antimicrobial prophylaxis in accordance with standard practice is permitted and should be 
considered in subjects who are at increased risk for opportunistic infections. Non-azole 
antifungal prophylaxis with coverage for aspergillosis is recommended (eg, amphotericin B or 
echinocandins). The use of growth factors is permitted in this study, but should be used 
according to institutional, provincial, or other guidelines (eg, American Society of Clinical 
Oncology) and according to the investigators site standard for use of growth factors during 
treatment of NHL with standard RICE/RVICI chemotherapy. The use of granulocyte colony 
stimulatory factor (GCSF) should be used with the RVICI regimen beginning on Day 12 and 
continued until ANC 500/µL on 2 occasions post-nadir (Table 6). Supportive therapies, other 
than anticancer treatment, needed for the management of subjects enrolled in this study are 
permitted with restrictions for corticosteroids (see Section 8.2).
8.1.1.
Medications Permitted Prior to Study Treatment
Corticosteroids 
to 
control 
symptoms 
of 
lymphoma 
are 
permitted 
prior 
to 
enrollment/randomization (40 mg/m2/day prednisone or equivalent) for a maximum of 10 days. 
If pretreatment corticosteroids exceed 40 mg/m2/day of prednisone or equivalent, please consult 
the medical monitor. If steroids are administered, they should be given after the baseline imaging 
assessment, baseline laboratory assessments, and baseline performance status assessment. 
Steroids must be recorded on the electronic CRF. Treatment with steroids should be discontinued 
upon beginning the Treatment Phase.
8.1.2.
Medications Permitted During Treatment
The following supportive therapies are recommended:

Histamine 2 (H2) blocker or proton pump inhibitors for peptic ulcer prophylaxis

5-HT3 antagonists or equivalent antiemetics

Uric acid-lowering agents: 
Subjects with more than 1 of the factors listed below are considered to be at increased risk of 
tumor lysis syndrome and should be considered for hydration and treatment with a uric 
acid-lowering agent as well as for frequent monitoring of tumor lysis-associated signs and 
symptoms, including blood chemistry. Uric acid-lowering agents may include xanthine 
oxidase inhibitor allopurinol or Uloric® [febuxostat] with or without rasburicase per the drug 
product package inserts.

Serum creatinine ≥1.5 x ULN or calculated creatinine clearance <60 mL/min

Uric acid ≥450 μmol/L or 7.5 mg/dL

Bulky disease (eg, lymph node >10 cm or massive splenomegaly)

Elevated lactic acid dehydrogenase >2 x ULN

Premedication with acetaminophen or equivalent, and diphenhydramine (or an antihistamine 
of investigator’s choice).


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
Loperamide for the treatment of diarrhea, starting at the time of the first watery stool. 
Infectious diarrhea should be ruled out prior to initiation of loperamide. The loperamide 
dose regimen should be according to standard practice.

Blood product transfusions (including but not limited to platelets, red blood cells, and 
immunoglobulins), and growth factors, as required.

Prophylactic treatment for pneumocystis carinii pneumonia, oral candidiasis and Herpes 
simplex virus infections according to local standards.

Non-azole antifungal prophylaxis with coverage for aspergillosis (eg, amphotericin B or 
echinocandins) for subjects on ibrutinib. Azole antifungals are allowed for subjects 
randomized to background therapy only.

A single dose of corticosteroids given as premedication prior to rituximab infusions and/or 
in response to infusion-related reactions.
8.2.
Prohibited Medications
The following medications and supportive therapies are prohibited during the Treatment Phase:

Any anticancer agent other than the outlined CIT regimen

Systemic corticosteroids above that given for CIT chemotherapy and anti-emetic use 
(prednisone not more than 4 to 5 mg/m2/day or its equivalent is allowed for the treatment of 
adrenal insufficiency or other medical reason that is not cancer related). If stress dose 
steroids are required, the medical monitor should be informed.

Any experimental agents other than ibrutinib
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
8.3.
Concomitant Medications to be Avoided or to be Used with Caution 
Attachment 4 provides instructions for medications to be avoided or used with precaution in 
subjects taking ibrutinib, including strong and moderate CYP3A inhibitors or inducers, and a list 
of these medications is provided in Attachment 5. Numerous antibiotics, antivirals, antifungals, 
antiepileptic, and cardiac medications are included in this list. Supplements such as fish oil and 
vitamin E preparations should be avoided.
8.3.1.
Radiation Therapy
Radiation therapy must not be given concurrently with ibrutinib. Ibrutinib should be temporarily 
stopped for 3 days after the last radiation treatment. Subjects should have sites of measurable 
disease, other than those that were irradiated, that can be followed for response. If a subject’s 
disease progresses while on study and the subject requires radiation therapy, disease assessment 
evaluations should be obtained prior to initiating radiation.


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8.4.
Subsequent Antilymphoma Therapies
Administration of subsequent antilymphoma therapy is not allowed until:

Confirmed residual disease after completion of at least 3 cycles of study treatment, or

PD (or relapse after CR) any time during treatment as established according to the criteria 
described in Section 9.2.5.2, Response Categories.
Note that the medical monitor must be notified of the subject’s suspected PD and all imaging, 
bone marrow, and cerebrospinal fluid (CSF) disease analyses are required to be centrally 
reviewed before a subject is removed from study therapy. Subjects who have not progressed 
while on therapy and who receive subsequent therapy for NHL will continue to be followed until 
PD. For any subsequent antilymphoma therapy, the start date, end date, and best response should 
be documented in the appropriate section of the electronic CRF.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The study is divided into 3 phases: a Pretreatment (Screening) Phase, a Treatment Phase, and a 
Posttreatment Phase. The Time and Events Schedule summarizes the frequency and timing of 
efficacy, pharmacokinetic, pharmacodynamic, biomarker, and safety measurements applicable to 
this study (Table 1, Table 2, Table 3, and Table 4).
The estimated maximum blood volume collected from each subject for the entire study duration 
is approximately 139.0 to 230.5 mL in Part 1, and 131.4 to 222.9 mL in Part 2, including samples 
drawn for safety, pharmacokinetics, pharmacodynamics, biomarkers, protein binding (Part 1 
only), and pregnancy testing (when urine is not available for testing; young women of 
childbearing potential only) (see Attachment 7). Blood volumes drawn should not exceed local 
or institutional standards.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples but should not exceed allowable daily blood volume limits per local standards.
If at any time, a subject undergoes stem cell harvest in preparation for a stem cell transplant, the 
total cell count collected should be recorded in the eCRF.
9.1.2.
Pretreatment (Screening) Phase
All subjects, or their legally-acceptable representatives, must sign an ICF prior to the conduct of 
any study-related procedures. Where applicable, subjects below the age of legal consent should 
sign an assent form prior to the conduct of any study-related procedures. During this phase, 
eligibility criteria will be reviewed and a complete clinical evaluation performed as specified in
the Time and Events Schedule (Table 1 and Table 2). The pathology report for the original 
diagnosis of NHL or at the time of relapse, if available, will be used to confirm diagnosis. If that 
pathology report is not available, the results of a fresh biopsy will be required for enrollment into 


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the study. The results of laboratory tests noted in the inclusion criteria must be within the limits 
specified prior to enrollment/randomization; testing may be repeated for this purpose. The last 
result obtained prior to start of study treatment will be used to determine eligibility. Assessments 
performed as part of the subject’s routine clinical evaluation and not specifically for this study 
need not be repeated after signed informed consent has been obtained provided that assessments 
fulfill the study requirements and are performed within the specified timeframe prior to 
randomization (Table 1 and Table 2). Echocardiography or multiple-gated acquisition scan 
(MUGA) is mandatory at Screening, and for subjects treated with RVICI background therapy, it 
is also mandatory after each cycle (before treatment on Day 1 of Cycle 2 and Cycle 3). 
Echocardiography or MUGA may be repeated if clinically indicated during the study (using 
same modality) either at an assessment visit or at an unscheduled visit. 
Retesting for Eligibility
Limited retesting of abnormal Screening values that lead to exclusion are allowed only once 
using an unscheduled visit during the Screening period (to reassess eligibility). If a subject does 
not meet all inclusion and exclusion criteria (is a screen failure) but at some point in the future is 
expected to meet the subject eligibility criteria, the subject may be rescreened on 1 occasion 
only. Subjects who are rescreened will be assigned a new subject number, undergo the informed 
consent process, and then restart a new screening phase.
9.1.3.
Treatment Phase
The Treatment Phase will begin at enrollment (for Part 1) or randomization (for Part 2) and will 
continue until discontinuation of combination study treatment (ie, ibrutinib + CIT or CIT alone) 
due to disease progression, initiation of subsequent antilymphoma therapy, unacceptable toxicity, 
withdrawal, CR, or completion of study treatment after Cycle 3. The last measurements taken on 
Cycle 1 Day 1 before administration of study treatment or at Screening (whichever value was 
last) will be defined as the baseline values for safety assessment and treatment decision. 
Laboratory values obtained prior to Cycle 1 Day 1 should be repeated if they were collected 
more than 5 days prior to the start of ibrutinib treatment. These values should be consistent with 
the values in the inclusion and exclusion criteria (Sections 4.1 and 4.2, respectively) in order for 
the subject to receive treatment.
A symptom-directed physical exam (including lymphoma B-symptoms) and laboratory testing 
will be conducted. Adverse events and changes to concomitant medications will be recorded. 
Subjects will be evaluated throughout this phase for possible toxicities. Dose modifications will 
be made as according to criteria described in the protocol (see Section 6.2).
All subjects will visit the study site on Day 1 of Cycle 1 during the Treatment Phase. Clinical 
evaluations and laboratory studies may be repeated more frequently, if clinically indicated. When 
all evaluations have been completed, and it has been determined that the subject may continue 
treatment, CIT will be administered intravenously and sufficient study drug will be dispensed for 
self-administration. The subject should refrain from taking the study drug on the morning of 
study visits designated for pharmacokinetic sampling until seen at the site. If a subject shows 
signs of progression on physical examination or laboratory assessment, the subject may continue 


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study treatment until PD is confirmed by the central IRC. If PD is diagnosed, then the subject 
will discontinue study treatment, complete the End-of-Treatment visit within 30 days after the 
last dose of the last study treatment, and enter the Posttreatment Phase. Imaging evaluations 
performed on Cycle 1 Day 14 are exploratory; therefore, if PD is indicated based on these scans, 
investigator discretion should be used to determine if the clinical evaluation is consistent with 
PD. If not, the subject may continue with study treatment until confirmation of PD or the subject 
meets other criteria for withdrawal. If CR is confirmed at the end of 2 cycles of treatment, then 
the subject is eligible to proceed to stem cell transplantation.
End-of-Treatment Visit
Subjects who discontinue the last study treatment due to progression, adverse event, or other 
reasons and enter the Posttreatment Phase should have the End-of-Treatment visit completed 
before starting any subsequent antilymphoma therapy. If a subject is unable to return to the site 
for the End-of-Treatment visit, the subject should be contacted to collect adverse events that 
occur within 30 days after the last dose of the last study treatment. Additional information on 
reporting adverse events may be found in Section 12.
If the subject requires subsequent antilymphoma therapy in the interim period following the last 
dose of study treatment and the End-of-Treatment visit, then this visit should be completed 
earlier, ie, just prior to initiation of subsequent antilymphoma therapy. Refer to the Time and 
Events Schedule for a complete list of procedures to be performed (Table 1, Table 2, Table 3, 
and Table 4).
9.1.4.
Posttreatment Phase (Follow-Up)
After the completion of the End-of-Treatment procedures, all subjects will enter a Posttreatment 
Phase. During the Posttreatment Phase, subjects randomized to ibrutinib having a response of PR 
or better after 3 cycles of combination treatment will continue on ibrutinib monotherapy at the 
same daily dose for three 28-day cycles or until disease progression or unacceptable toxicity, or 
up until initiating subsequent antilymphoma therapy or a conditioning regimen for stem cell 
transplantation, whichever occurs first.
For subjects who enter the Posttreatment Phase without disease progression, follow-up visits to 
assess disease progression will be completed as per Table 3 and Table 4 until PD, the clinical 
cutoff for the primary endpoint, or for up to 3 years after the date of Cycle 1 Day 1, whichever 
occurs first. After that, evaluations may be performed as clinically indicated at the discretion of 
the investigator. After the last protocol efficacy assessment at 3 years, subjects without PD will 
be followed for survival status as per the standard routine of care of the investigator site. If PD is 
assessed after 3 years, the date and reason for progression will be entered in the CRF.  
Additionally, if the investigator becomes aware of the subject death, the date of death will be 
entered in the CRF.
The interval between follow-up visits should be maintained as outlined in the Times and Events 
Schedules (Table 3 and Table 4); if a visit occurs earlier or later than the scheduled visit date, 
then the next visit date should be rescheduled to maintain the required interval from the previous 


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visit. At any visit, if there is clinical evidence or suspicion of PD, then appropriate testing must 
be performed to document progression (See Section 9.2.1).
Investigators may re-contact the subject to obtain long-term follow-up information regarding the 
subject's safety or survival status as noted in the ICF (refer to Section 16.2.3, Informed Consent 
and Assent Form). Survival follow-up (physician visit or telephone contact) will be required 
every 4 weeks for all subjects following PD until death or study end, whichever occurs first. The 
interval between post-PD survival follow-up visits should be maintained at 4 weeks; if a visit 
occurs earlier or later than the scheduled visit date, then the next visit date should be rescheduled 
to maintain the required interval from the previous visit.
At the time of PD or if residual disease is present upon completion of 3 cycles, the subject is 
considered eligible to receive subsequent antilymphoma therapy. Subsequent antilymphoma 
therapy will be recorded in the electronic CRF. Subjects with residual disease who receive 
subsequent antilymphoma therapy will be followed until PD, end of the study, or death. 
Investigators should maintain adequate contact with the subject to obtain follow-up information 
on safety and survival status. Where allowed by local law, public records may be used to 
document death. Any new malignancy reported during the posttreatment follow-up phase will be 
recorded in the CRF (Section 12.3.4).
9.1.5.
Clinical Cutoffs
Two clinical cutoffs are planned. The first clinical cutoff will occur when approximately 30 EFS 
events have been observed in Part 2 of the study. The second clinical cutoff will occur when 
approximately 60 EFS events have been observed in Part 2 of the study. The interim analysis and 
final analysis of the primary endpoint EFS will take place at these 2 clinical cutoffs, respectively. 
9.2.
Efficacy Evaluations
9.2.1.
Imaging Assessments
Magnetic resonance imaging (MRI) or CT scan with intravenous contrast of the neck, chest, 
abdomen and pelvis, and, if indicated, CNS, with or without a PET scan, should be used to 
evaluate sites of disease as specified in the Time and Events Schedule (Table 1, Table 2, Table 3, 
and Table 4). Each region is to be scanned regardless of the presence/absence of disease in a 
given area. The same modality used at baseline should be obtained at subsequent disease 
evaluations. Positron emission tomography scan at baseline is recommended but not mandatory. 
If disease is PET avid upon Screening, PET should be repeated at subsequent evaluations. 
Imaging performed for standard of care up to 5 days prior to signing ICF may be used as baseline 
evaluations if they are of sufficient quality. Brain MRI and lumbar puncture may be required in 
subjects with CNS-positive disease, as clinically indicated. Evaluation of other sites of disease 
may be performed by radiological imaging, physical examination, or other procedures as 
necessary, and should be performed throughout the study using the same method of assessment 
per subject.
The following are scanning options in decreasing order of preference: 


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1.
Neck-Chest-Abdomen-Pelvis CT with IV-contrast administration 
2.
Chest CT without IV-contrast administration and Neck-Abdomen-Pelvis MRI with 
gadolinium IV contrast, only if iodine contrast media is medically contraindicated at any 
time during the study 
3.
Neck-Chest-Abdomen-Pelvis MRI with IV contrast, only if CT IV contrast media is 
medically contraindicated at any time during the study and chest CT cannot be performed 
4.
Neck-Chest-Abdomen-Pelvis CT without IV contrast, only under exceptional circumstances 
if MRI cannot be performed
9.2.2.
Bone Marrow/ Lymph Node Assessment
A subject may enter the study with only bone marrow disease. If this happens, then the subject 
will be followed by a bone marrow biopsy and/or aspirate for disease evaluations. Radiographic 
images are required at screening in these subjects but if no nodal disease is identified, subsequent 
imaging is not required. The timepoints for bone marrow evaluations are outlined in Table 1, 
Table 2, Table 3, and Table 4. Morphological examination and IHC or flow cytometry is 
required of all bone marrow specimens at screening for all subjects. If bone marrow results at 
screening are negative, subsequent assessments must include morphologic assessment of the 
bone marrow, while immunophenotyping is optional. Bone marrow procedures may be 
performed the day prior to the start of a treatment cycle for logistical reasons as needed.
9.2.3.
Lumbar Puncture
Cerebral spinal fluid should be obtained at Screening in order to diagnose CNS-status at study 
entry. Lumbar puncture on Cycle 1 Day 1 can be used as the screening lumbar puncture only if 
collected prior to administration of ibrutinib or background therapy. For all subjects, CSF should 
be obtained at the start of each cycle and following completion of study treatment. Lumbar 
punctures may be performed the day prior to the start of a treatment cycle for logistical reasons 
as needed. In addition, CSF sampling in subjects with CNS-positive disease at baseline should 
occur every 4 days ±1 day until CSF is cleared of lymphoma cells.
9.2.4.
Physical Examination
During the Screening, Treatment Phase, and Posttreatment Phase (see Time and Events Schedule 
for procedures, (Table 1, Table 2, Table 3, and Table 4), subjects should have a physical 
examination to evaluate the presence of palpable lymph nodes, tumor masses, or spleen and liver 
enlargement. Approximate measurement of palpable lymph nodes or masses should be provided. 
Symptom-directed questions will be asked to evaluate for the presence of B-symptoms.
9.2.5.
Efficacy Criteria
All efficacy assessments must continue until disease progression (even if subsequent 
antilymphoma therapy is started), withdrawal of consent from study participation, or clinical 
cutoff for the primary analysis. The Sponsor Medical Monitor is to be notified within 24 hours 
for subjects who have disease progression and central assessment will ensue. Imaging, bone 
marrow assessments and CSF evaluations are required at Screening, Cycle 3 Day 1, and at End 
of Treatment. CSF evaluation is also required at Cycle 2 Day 1, but bone marrow is only 


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required at this time point if clinically indicated. Subjects without nodal disease (ie, subjects with 
bone marrow only disease) only require imaging at Screening. Imaging evaluations performed on 
Cycle 1 Day 14 are exploratory; if PD is indicated based on these scans, investigator discretion 
should be used to determine if the clinical evaluation is consistent with progressive disease. If 
not, the subject may continue with study treatment until confirmation of PD or the subject meets 
other criteria for withdrawal.
9.2.5.1.
Evaluation of Measurable Disease
Subjects with nodal disease must have at least 1 measurable lymph node >1 cm in the longest 
diameter and >1 cm in the shortest diameter detected by CT scan or MRI in order to participate 
in this study. Measurable sites of disease are defined as lymph nodes, lymph node masses, or 
extranodal sites of lymphoma/leukemia. In the absence of nodal disease, the presence of blasts in
the cerebrospinal fluid or >25% blasts in the bone marrow will be sufficient for measurable 
disease. 
Up to 6 of the most representative nodal or extranodal masses should be selected for 
measurement in 2 perpendicular dimensions. In addition, the selection of these lesions should be 
from as disparate regions of the body as possible. Additional lesions that are present but not 
included in the assessment should be added as non-target lesions and followed throughout the 
study. The longest diameter of the spleen and liver will be assessed at Screening and at all 
subsequent disease evaluations. 
All other sites of disease will be considered assessable. Assessable disease includes objective 
evidence of disease that is identified by radiological imaging, physical examination, or other 
procedures as necessary including bone marrow aspiration/biopsy or peripheral blood counts. 
Examples of assessable disease include bone lesions; mucosal lesions in the gastrointestinal tract; 
effusions; pleural, peritoneal, or bowel wall thickening; disease limited to bone marrow; and 
groups of lymph nodes that are not measurable but are thought to represent lymphoma. 
9.2.5.2.
Response Categories
Assessment of tumor response and progression will be according to the International Pediatric 
NHL Response Criteria (Table 9 and Table 10).36 Disease response will be evaluated by 
radiological imaging, physical examination, or other procedures as necessary, including but not 
limited to review of hematology, clinical chemistry, and lumbar puncture results. Disease 
evaluations, for the purpose of the study result analyses, will be reviewed by an IRC blinded to 
study treatment information and independent of investigators and personnel who are involved in 
conduct of the study. As part of the central review, radiographic evaluations will be assessed by 
an independent radiologist and relevant clinical data will be assessed by an independent 
oncologist. Detailed procedures will be described in a separate charter.


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Table 9:
International Pediatric NHL Response Criteria
Criterion
Definition
CR
Disappearance of all disease (3 designations)
CR
CT or MRI reveals no residual disease or new lesions
Resected residual mass that is pathologically (morphologically) negative for disease (detection 
of disease with more sensitive techniques described as supporting data [Table 10])
BM and CSF morphologically free of disease (detection of disease with more sensitive 
techniques described as supporting data [Table 10]) with no new lesions by imaging 
examination
CRb
Residual mass has no morphologic evidence of disease from limited or core biopsy (detection 
of disease with more sensitive techniques described as supporting data), with no new lesions by 
imaging examination
BM and CSF morphologically free of disease (detection of disease with more sensitive 
techniques described as supporting data [Table 10])
No new or PD elsewhere
CRu
Residual mass is negative by FDG-PET; no new lesions by imaging examination
BM and CSF morphologically free of disease (detection of disease with more sensitive 
techniques described as supporting data [Table 10])
No new or PD elsewhere
PR
50% decrease in SPD on CT or MRI; FDG-PET may be positive (Deauville score or 4 or 5 with 
reduced lesional uptake compared with baseline); no new or PD; morphologic evidence of 
disease may be present in BM or CSF if present at diagnosis (detection of disease with more 
sensitive techniques described as supporting data [Table 10]); however, there should be 50% 
reduction in percentage of lymphoma cells
MR
Decrease in SPD >25% but <50% on CT or MRI; no new or PD; morphologic evidence of 
disease may be present in BM or CSF if present at diagnosis (detection of disease with more 
sensitive techniques described as supporting data [Table 10]); however, there should be 25% to 
50% reduction in percentage of lymphoma cells
NR
For those who do not meet CR, PR, MR, or PD criteria
PD
For those with >25% increase in SPD of residual lesions (calculated from nadir) on CT or MRI, 
Deauville score 4 or 5 on FDG-PET with increase in lesional uptake from baseline, 
documentation of new lesions or development of new morphologic evidence of disease in BM 
or CSF
BM=bone marrow; CR=complete response; CRb=complete response biopsy-negative; CRu=complete response 
unconfirmed; CSF=cerebrospinal fluid; CT=computed tomography; FDG=[18F]fluorodeoxyglucose; MR=minor 
response; MRI=magnetic resonance imaging; NHL=non-Hodgkin lymphoma; NR=no response; PD=progressive 
disease; PET=positron emission tomography; PR=partial response; SPD=sum of the products of the lesion 
diameters.


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Table 10:
Supporting International Pediatric NHL Response Criteria Data
Supporting Information
Definition
BM Involvement
Currently defined by morphologic evidence of lymphoma cells; this applies to any 
histologic subtype; type and degree of BM involvement should be specifieda
BMm
BM positive by morphology (specify percentage of lymphoma cells)
BMi
BM positive by immunophenotypic methods (histochemical or flow cytometric 
analysis; specify percentage of lymphoma cells)
BMc
BM positive by cytogenetic or FISH analysis (specify percentage of lymphoma 
cells)
BMmol
BM positive by molecular techniques
CNS Involvement
CSF status
CSF positivity is based on morphologic evidence of lymphoma cells; CSF should be 
considered positive when any number of blasts is detected; CSF may be unknown; 
as with BM, type of CSF involvement should be described whenever possible
CSFm
CSF positive by morphology (specify No. of blasts/µL)
CSFi
CSF positive by immunophenotype methods (histochemical or flow cytometric 
analysis; specify percentage of lymphoma cells)
CSFc
CSF positive by cytogenetic or FISH analysis (specify percentage of lymphoma 
cells)
CSFmol
CSF positive by molecular techniques
RM
RMm
Tumor detected by standard morphologic evaluation
RMi
Tumor detected by immunophenotypic methods (immunohistochemical or flow 
cytometric analysis)
RMc
Tumor detected by cytogenetic or FISH analysis
RMmol
Tumor detected by molecular techniques
BM=bone marrow; CNS=central nervous system; CSF=cerebrospinal fluid; FISH=fluorescent in situ hybridization; 
NHL=non-Hodgkin lymphoma; PB=peripheral blood; RM=residual mass.
a. Same approach should be used for PB involvement (ie, PBm, PBi, PBc, PBmol).
9.3.
Pharmacokinetics 
Plasma samples will be used to evaluate the pharmacokinetics of ibrutinib. Plasma collected for 
pharmacokinetic analyses may additionally be used to evaluate safety or efficacy aspects that 
address concerns arising during or after the study period. Genetic analyses will not be performed 
on these samples. 
9.3.1.
Evaluations 
During Part 1, venous blood samples of approximately 0.6 mL will be collected for measurement 
of plasma concentrations of ibrutinib and the PCI-45227 metabolite using a sparse sampling 
approach (1 sample predose, and 4 samples at 1, 2, 4, and 6 hours postdose on Day 1 and on 
Day 7 or 8 of Cycle 1). Subsequent samples will be collected predose and 1, 2, 4, and 6 hours 
postdose on Day 1 of Cycle 2 or Cycle 3 (not both). Sample time windows are provided in 
Table 1 (Time and Events Schedule). If a subject experiences bleeding with a lumbar puncture 
and needs to delay the dose of ibrutinib on Day 1 of the cycle, the “Day 1” pharmacokinetic 
sampling should be done after administration of CIT is complete (on Day 7 or 8) instead. If this 
occurs during Cycle 1, the Day 1 pharmacokinetic assessment for that day will be skipped 
altogether.


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During Part 2, sparse pharmacokinetic samples will be collected from subjects randomized to 
receive ibrutinib to expand the pediatric pharmacokinetic dataset. Four samples will be collected 
from each subject. Samples will be collected at the following timepoints: samples collected at 
predose; 1 (window 45-75 minutes), 2 (window 1.5-2.5 hours), and 4 hours (window 3.5-6 
hours) postdose, either on Cycle 1 Day 14 (preferred), but if unable to be obtained during Cycle 
1 (eg, due to a temporary stop of ibrutinib) can be collected on Cycle 2 Day 1. Please note that 
subjects must take ibrutinib for a minimum of 3 days prior to all pharmacokinetics timepoints 
after Cycle 1 Day 1 for pharmacokinetics to be valid. If ibrutinib is temporarily stopped on any 
pharmacokinetics sampling days, or within 3 days prior to pharmacokinetics sampling, the 
medical monitor should be contacted for guidance.
Additional information about the collection, handling, and shipment of biological samples can be 
found in the Laboratory Manual.
Subjects should refrain from taking the study drug on the morning of study visits designated for 
pharmacokinetic sampling until instructed to do so at the site. Subjects should not receive red 
blood cell transfusions during the period of pharmacokinetic sampling, beginning 1 hour before 
the first sample collection. On days of pharmacokinetic sample collection (see Table 1 and 
Table 2), ibrutinib should be taken within 2 hours after a meal. The times of the meals before and 
after dosing, as well as any vomiting up to 4 hours after ibrutinib administration, are to be 
recorded on the laboratory requisition form. The investigator or designee will supervise 
administration of the study treatment and record the exact time of study treatment administration. 
Samples and information on subjects’ feeding state will only be collected from subjects treated 
with ibrutinib.
9.3.2.
Analytical Procedures
Plasma samples will be analyzed to determine concentrations of ibrutinib and the metabolite 
PCI-45227 using a validated, specific, and sensitive liquid chromatography/tandem mass 
spectrometry (LC-MS/MS) method by or under the supervision of the sponsor. If required, some 
plasma samples may be analyzed to document the presence of circulating metabolites using a 
qualified research method.
9.3.3.
Pharmacokinetic Parameters 
Based on the individual plasma concentration-time data obtained in Part 1, using the actual dose 
taken and the actual sampling times, pharmacokinetic parameters and metrics of exposure of 
ibrutinib will be derived using population pharmacokinetic modeling (nonlinear mixed effects 
modeling). The population model developed in adults may be used. Individual as well as 
population-predicted pharmacokinetic parameters will include CL/F and Vd/F. Metrics of 
systemic exposure to ibrutinib (AUC) will also be estimated. The effect of age or body size 
(weight, BSA) on pharmacokinetics parameters will be evaluated. The effect of other baseline 
covariates (eg, creatinine clearance, race) on pharmacokinetic parameters may also be explored, 
as considered relevant.


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Plasma concentration-time data obtained in Part 2 will be used to expand the pediatric 
pharmacokinetic dataset and further refine the model, as required. The details of the 
pharmacokinetic assessments will be described in a dedicated analysis plan. Metabolite data will 
be only summarized using descriptive statistics (not derived using population pharmacokinetic 
modeling).
9.4.
Pharmacodynamic Evaluations 
Blood samples will be collected for pharmacodynamic assessments (BTK occupancy) according 
to the Time and Events Schedule (Table 1, Table 2, and Table 3).
9.5.
Pharmacokinetic/Pharmacodynamic Evaluations
Model-derived exposure parameters may be subjected to further analyses to explore the 
correlations between ibrutinib exposure and relevant clinical or biomarker information. Results 
will be presented in a separate report.
9.6.
Biomarkers 
Archived formalin-fixed paraffin-embedded tumor or fresh lymph node biopsy (if collection is 
feasible and where local regulations and shipping logistics permit) will be used for biomarker 
evaluations at Screening and at the time of disease progression. If archived tissue is unavailable 
and a fresh lymph node biopsy cannot be obtained, bone marrow biopsy slides (when positive for 
disease) can be used. 
In the event that no archived tissue is available, the subject is too unstable to undergo a fresh 
biopsy, but it is expected that the biopsy may be feasible after beginning chemotherapy, a fresh 
lymph node biopsy is recommended to be obtained after debulking with the study treatment 
regimen in subjects with DLBCL only (cell of origin studies will not be affected by initiation of 
therapy). Blood samples for biomarker evaluations, as described in Section 3.2.6, will be 
collected according to the Time and Events Schedule (Table 1, Table 2, Table 3, and Table 4). 
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may 
be deferred or not performed if, during or at the end of the study, it becomes clear that the 
analysis will have no scientific value or if there are not enough samples or responders to allow 
for adequate biomarker evaluation. In the event the study is terminated early or shows poor 
clinical efficacy, completion of biomarker assessments will be based on justification and 
intended utility of the data.
Additional Collections
If it is determined at any time before study completion that additional material is needed from a 
formalin-fixed, paraffin-embedded tumor sample for the successful completion of the 
protocol-specified analyses, the sponsor may request that additional material be retrieved from 
existing samples. Also, based on emerging scientific evidence, the sponsor may request 
additional material from previously collected tumor samples during or after study completion for 


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a retrospective analysis. In this case, such analyses would be specific to research related to the 
study drug or diseases being investigated.
9.7.
Palatability Assessment
Palatability of ibrutinib will be measured using a visual analog scale adapted from published 
literature.22,23,39 The scale is a 5-point visual analog scale incorporating a facial hedonic scale
designed to span pediatric ages and levels of subject comprehension. Children as young as 4 
years should have the developmental capacity to assess palatability using this scale. Assessments 
will be obtained during the study Treatment Phase as specified in the Time and Events Schedule 
(Table 1 and Table 2).
9.8.
Safety Evaluations
All subjects who receive at least 1 dose of treatment will be considered evaluable for safety. The 
SET will monitor subject safety during the dose-confirmation part of the study. Part 2 of the 
study will be monitored by an independent DMC (details are provided in Section 11.8, 
Independent Data Monitoring Committee). Subjects will be assessed by physical examination, 
weight evolution, and performance status evaluation. Hematology and clinical chemistry tests 
will be performed at regular intervals as specified in the Time and Events Schedule. The study 
will include the following evaluations of safety and tolerability according to the timepoints 
provided in the Time and Events Schedule (Table 1, Table 2, Table 3, and Table 4). 
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally-acceptable representative) from the time of signed consent until 30 days 
after the last dose of study drug (including ibrutinib monotherapy) or until the start of a 
subsequent systemic antineoplastic therapy, if earlier, unless the subject has withdrawn consent 
for study participation. Adverse events occurring after 30 days following the last dose of study 
treatment should also be reported if considered related to study treatment. Any clinically relevant 
changes occurring during the study must be recorded on the Adverse Event section of the CRF. 
Any clinically significant abnormalities persisting at the End-of-Treatment visit/early withdrawal 
will be followed by the investigator until resolution or until a clinically stable endpoint is 
reached. All Grade 3 or 4 adverse events considered related to study drug must be followed until 
recovery to ≤Grade 1 or baseline, deemed irreversible, or until end of study.
All adverse events will be recorded with the details of the duration and the severity of each 
episode, action taken with respect to the study drug, investigator’s evaluation of its relationship 
to the study drug (ie, not related, doubtful, possibly, probably, very likely related), and the 
subjects’ outcome. All serious adverse events (life-threatening, results in death, results in or 
prolongs hospitalization, or results in persistent disability/incapacity, congenital anomaly/birth 
defect, suspected transmission of any infectious agent, or medically important) must be reported 
to the sponsor within 24 hours. Progressive disease of NHL should not be reported as an adverse 
event, but instead, the clinical diagnosis that is associated with disease progression is to be 
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Adverse Events of Special Interest
Major hemorrhage has been identified as an adverse event of special interest and will require 
enhanced reporting and data collection (see Section 12.3.3, Adverse Events of Special Interest, 
for details).
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. Samples for required 
laboratory tests may be collected on the day of or day before dosing. For Day 1 Cycle 1 only, 
clinical laboratory tests do not need to be repeated if the Screening tests were performed within 
5 days prior to the first dose of study treatment, with the exception of pregnancy testing which 
needs to be performed within 24 hours prior to the start of treatment per cycle.
The investigator must review the local laboratory results, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event section of the CRF. 
For example, laboratory abnormalities leading to an action regarding any study treatment (dose 
change, temporary stop, delay of the start of a cycle or permanent stop) or the start of 
concomitant therapy should be reported. For each laboratory abnormality reported as an adverse 
event, the following laboratory values should be reported in the laboratory section of the 
electronic CRF: the value indicative of the onset of each toxicity grade; the most abnormal value 
observed during the adverse event, and the value supporting recovery to Grade ≤1 or to baseline 
values. The following tests will be performed by the local laboratory at the timepoints shown in 
the Time and Events Schedule (Table 1, Table 2, Table 3, and Table 4):

Hematology Panel 
-hemoglobin
-platelet count
-white blood cell count
-absolute neutrophil count
-absolute lymphocyte count
-lymphoblasts (also called blasts) if applicable

Serum Chemistry Panel 
-sodium
-alkaline phosphatase
-potassium
-total bilirubin
-blood urea nitrogen or urea
-lactic acid dehydrogenase 
-creatinine
-uric acid
-aspartate aminotransferase 
-alanine aminotransferase 
-albumin

Viral Serology Panel 
-HBsAg
-HBsAb
-HBcAb
-Hepatitis C
-HIV


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If Hepatitis B core antibody is positive, Hepatitis B DNA by polymerase chain reaction 
(PCR) needs to be performed and confirmed as negative to continue with study participation. 
Subjects should be monitored for viral reactivation by liver enzymes and Hepatitis B PCR 
when appropriate and prophylactic antiviral medication should be considered per local 
practice.

Tetanus and pneumococcal antibody titers (central laboratory)

Serum or urine pregnancy testing for young women of childbearing potential only
Electrocardiogram/Echocardiography/MUGA Scan
Baseline LVEF/SF must be assessed by MUGA or echocardiogram and demonstrate LVEF 
≥50% or SF >28% for subjects to be eligible and may be repeated throughout the study, protocol 
directed or when clinically indicated. When the examination is repeated, the same modality 
should be used. Echocardiography/MUGA and 12-lead ECGs will be obtained for all subjects at 
the timepoints specified in the Time and Events Schedule (Table 1, Table 2, and Table 3). 
Additional cardiovascular assessments should be performed as clinically appropriate to ensure 
subject safety.
During the collection of ECGs, subjects 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 or moving arms or legs. If blood sampling 
is scheduled for the same timepoint as ECG recording, the ECG should be performed before the 
blood draw.
Vital Signs
Assessment of pulse/heart rate and blood pressure is expected at every protocol-specified visit 
from screening until end of treatment. Blood pressure and pulse/heart rate measurements should 
be preceded by at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell 
phones). Clinically significant abnormalities should be recorded as adverse events. If an 
abnormal heart rhythm is suspected, further investigation (ECG and/or Holter monitor) is 
required per investigator’s discretion.
Body Surface Area
Calculation of BSA (Attachment 3) at Cycle 1 Day 1 is required for CIT and ibrutinib dosing. 
The BSA should be recalculated if a subject experiences a >10% change in weight from the 
weight used in the most recent BSA calculation. Weight will be collected as specified in the 
Time and Events Schedule (Table 1, Table 2, and Table 3).
Physical Examination
Complete physical examination will be performed at Screening. The Screening physical 
examination will include, at a minimum, the general appearance of the subject, height and 
weight, examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, lymphatic system, and nervous system. Directed physical examination 


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(includes all organ systems that were previously abnormal or involved with disease and 
documentation of any clinically relevant abnormalities in any organ) will be performed at the 
timepoints specified in the Time and Events Schedule (Table 1, Table 2, Table 3, and Table 4). 
Lymphoma symptoms reported at Screening should be reviewed and recorded during the 
directed physical examination.
9.9.
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 (Table 1, Table 2, Table 3, and Table 4). Instructions for the collection, 
handling, storage, and shipment of samples are found in the Laboratory Manual that will be 
provided.
Any volume of blood collected must be consistent with the recommendations of the European 
Medicines Agency (EMA) for study-related blood loss.12 In pediatric populations this should be 
no more than 3% of the total blood volume during a 4-week period and not more than 1% of total 
blood volume at a single timepoint. At a total blood volume estimated at 80 to 90 mL/kg body 
weight this equals 2.4 to 2.7 mL of blood per kilogram of body weight every 4 weeks or 0.8 to 
0.9 mL per kilogram at any one time. It is the responsibility of the investigator to comply with 
these guidelines and to prioritize study blood collection as follows:
1.
Safety laboratory studies (hematology and serum chemistry) that are study-related and not 
part of routine care
2.
Pharmacokinetic samples
3.
Pharmacodynamic samples
4.
Biomarker samples
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.
10.2.
Discontinuation of Study Treatment/Withdrawal from the Study 
Subjects who discontinue any component of CIT without disease progression will continue study 
drug (ibrutinib) and remaining components until 3 cycles are completed followed by ibrutinib 
monotherapy in case of response (PR or better), or until disease progression, or unacceptable 
toxicity, or until initiating subsequent antilymphoma therapy or a conditioning regimen for stem 
cell transplant, or for a maximum of three 28-day cycles, whichever occurs first. If study drug is 
discontinued for any reason, any remaining study treatment (CIT) may continue. Investigators 
are encouraged to keep a subject experiencing clinical benefit (ie, PR, CR, MR, or NR) in the 
study unless significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk. 


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Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if they have to discontinue 
treatment before the end of the treatment regimen. A subject's study treatment will be 
discontinued if:

The subject experiences disease progression or relapse

The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it 
is in the best interest of the subject to discontinue study treatment

The subject becomes pregnant 

The subject or legally authorized representative refuses further treatment

The criteria for discontinuation of study treatment described in Section 6.2 are met

A serious protocol violation has occurred, as determined by the principal investigator or the 
sponsor
If a subject discontinues study treatment for any reason before the end of the Treatment Phase, 
end-of-treatment and posttreatment assessments should be obtained and scheduled assessments 
should be continued.
Withdrawal from the Study 
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Sponsor discontinues the study
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. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study, end-of-treatment and posttreatment assessments should be
obtained, if possible. 
10.3.
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the ICF.


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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. 
All statistical testing will be performed using a 2-sided test at the 10% level of significance, 
unless otherwise noted. Confidence intervals will be presented as 2-sided 90% confidence 
intervals. Summary statistics for continuous variables include mean, standard deviation, median, 
minimum, and maximum unless otherwise specified. Categorical data will be presented as 
frequencies and percentages.
11.1.
Subject Information
The intent-to-treat (ITT) Population will consist of all randomized subjects where subjects will 
be analyzed based on randomization, regardless of study drug received. The ITT population will 
be used for all efficacy analyses. The primary efficacy analysis is based on the ITT population 
for data collected in the Part 2. Efficacy for Part 1 will be provided as a secondary endpoint for 
Part 1.
The Safety population will consist of all subjects who received at least 1 dose of treatment. The 
safety population will be used for all safety analyses and subjects will be analyzed based on 
actual study drug received. 
Summaries (demographics and baseline characteristics, safety) will be presented for Part 1 and 
Part 2 of the study. Analyses of disposition, demographic, baseline disease characteristics, and 
prior and concomitant therapy will be conducted on the ITT population. Analyses on treatment 
compliance and extent of exposure will be conducted on the Safety population. No statistical 
testing is planned.
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. Percentages will be calculated by dividing the 
number of subjects with the characteristic of interest by the number of subjects in the analysis 
population or the evaluable population.
11.2.
Sample Size Determination
Approximately 72 subjects will be randomized in Part 2. The sample size calculation for the 
randomized part (Part 2) is based on the assumption of 100% improvement (hazard ratio = 0.5) 
in median EFS in subjects receiving ibrutinib plus CIT (RICE or RVICI) compared with CIT 
(RICE or RVICI) (10 months versus 5 months). Utilizing a 2:1 randomization, this study will 
enroll approximately 72 subjects (approximately 48 subjects treated with ibrutinib [and RICE or 
RVICI background therapy]) during Part 2. Based on a total of 60 events for the 2 treatment 
groups, this study will have at least 80% power, given a 1-sided alpha of 0.05. An accrual rate of 
1.44 subjects per month will result in a study duration of approximately 4.2 years.


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11.3.
Efficacy Analyses 
Descriptive statistics and subject listings will be used to summarize the data. For continuous 
variables, the number of observations, means, standard deviations, medians, and ranges will be 
used. For discrete variables, frequency will be provided. For time-to-event variables, 
Kaplan-Meier estimates will be provided.
Comparisons between the 2 treatment arms in Part 2 will be performed as follows: for the 
continuous variables representing change from baseline to a particular postbaseline timepoint, 
analysis of variance will be used. For discrete variables, Chi-square test will be used. For 
time-to-event variables, non-stratified log-rank test and non-stratified Cox proportion hazard 
model will be used unless specified otherwise. All tests will be conducted at 2-sided test at the 
10% level of significance and 90% confidence intervals will be provided, unless otherwise 
stated.
11.3.1.
Primary Endpoint
The primary efficacy endpoint is EFS in Part 2, which is defined as the time interval from 
randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment, 
based on blinded independent event review by the IRC, whichever occurs first. The process and 
conventions of the IRC will be detailed in a separate IRC charter.
The analysis of the primary endpoint (EFS) will be based on the ITT population. For the primary 
efficacy analysis, EFS will be compared between treatment groups using a non-stratified 
log-rank test. The Kaplan-Meier method will be used to estimate the distribution functions of 
EFS for each treatment group. The number of events, subjects censored, the estimate of medians, 
and 90% confidence interval for the medians will be presented. The plot of EFS using the 
Kaplan-Meier method will be presented. The estimate of the hazard ratio between the 2 treatment 
groups and its associated 90% confidence interval will be computed based on the non-stratified 
Cox proportional hazards model. 
11.3.2.
Secondary Endpoints
Secondary endpoints in Part 1 (Section 2.1.1) will be provided as listings. In Part 2, tumor 
volume reduction at Day 14, ORR, time to response, duration of response, overall survival, and 
number (%) of subjects who proceed to stem cell transplantation will be summarized. Other 
secondary endpoints will be provided as listings.
Overall survival is defined as the duration from the date of enrollment (in Part 1) or 
randomization (in Part 2) to the date of the subject’s death. Overall survival will be analyzed 
using the non-stratified log-rank test for treatment comparison in Part 2. The overall survival 
distribution and median overall survival with its 90% confidence interval will be estimated using 
the Kaplan-Meier product-limit method. The hazard ratio for ibrutinib+CIT relative to CIT alone 
and its associated 90% confidence interval will be calculated based on the non-stratified Cox 
proportional hazards model. Exploratory analysis using the Cox proportional hazards model with 
and without the covariates, as well as exploratory analysis on the effect of subsequent 
antilymphoma therapy on overall survival, will be performed as appropriate.


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11.4.
Pharmacokinetic Analyses 
Population pharmacokinetic analysis of ibrutinib plasma concentration-time data from sparse 
samplings will be performed using nonlinear mixed effects modeling. All concentrations below 
the lowest quantifiable concentration or missing data will be labeled as such in the concentration 
database. Concentrations below the lower quantifiable concentration will be treated as zero in the 
summary statistics. All subjects and samples excluded from the analysis will be clearly 
documented in the study report.
A cutoff date for pharmacokinetic samples to be analyzed will be defined at the time of interim 
analysis, if required. Samples collected before this date will be analyzed for ibrutinib and 
included in the population pharmacokinetic analysis. Samples collected after the cutoff date will 
be analyzed at a later date, and may be included in a population pharmacokinetic re-analysis 
when they become available after database lock.
Data will be listed for all subjects with available plasma concentrations per treatment group. 
Subjects will be excluded from the pharmacokinetic analysis if their data do not allow for 
accurate assessment of pharmacokinetics (eg, incomplete administration of the study drug; 
missing information of dosing and sampling times; concentration data not sufficient for 
pharmacokinetic parameter calculation). Descriptive statistics, including arithmetic mean, 
standard deviation, coefficient of variation, median, minimum, and maximum will be calculated 
for all individual ibrutinib and the PCI-45227 metabolite concentrations by dose (as applicable) 
and timepoints. 
Pharmacokinetic analysis should allow achievement of, with at least 80% power, a 95% 
confidence interval within 60% and 140% of the geometric mean estimates of CL/F and Vd/F in
the age group from 2 to less than 11 years. Mean or median plasma ibrutinib concentration-time 
profiles will be plotted after the first dose of study drug, and individual plasma 
concentration-time profiles may also be plotted. Details of the analysis will be provided in a 
population pharmacokinetic analysis plan and results of the population pharmacokinetic analysis 
will be presented in a separate report.
11.5.
Pharmacodynamic Analyses and Biomarker Analyses
Biomarker analyses will be conducted on the ITT population. Changes in biomarkers over time 
will be summarized by treatment group. Summary statistics will be provided as appropriate. 
Based on resulting data, additional analyses may be performed. The results of the biomarkers 
analyses will be presented in a separate report.
11.6.
Pharmacokinetic-Pharmacodynamic Analysis
The relationship between ibrutinib metrics of systemic exposure and relevant pharmacological 
(BTK engagement) and clinically (efficacy or safety-related) relevant endpoints will be explored 
graphically.


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11.7.
Safety Analyses
All safety analyses will be based on the safety population and will be performed by the treatment 
actually received. Safety parameters to be evaluated are the incidence, intensity, and type of 
adverse events, clinically significant changes in the subject’s physical examination findings and 
clinical laboratory results by treatment arms. Exposure to investigational product and reasons for 
discontinuation of study treatment will be tabulated.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events 
will be included in the analysis.
Treatment-emergent adverse events are adverse events with onset during the Treatment Phase or 
that are a consequence of a pre-existing condition that has worsened since baseline, and occur 
during treatment or within 30 days following the last dose of study treatment, or any adverse 
event that is considered study treatment-related regardless of the start date of the event. The 
number and percent of subjects with treatment-emergent adverse events will be summarized 
according to intensity using the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) (Version 4.03), drug relationship, and outcome. For each adverse 
event, the percentage of subjects who experience at least 1 occurrence of the given event will be 
summarized by treatment group. In addition, comparisons between treatment groups will be 
provided if appropriate. Summaries, listings, datasets, or subject narratives may be provided, as 
appropriate, for those subjects who die, who discontinue treatment due to an adverse event, or 
who experience a severe or a serious adverse event.
Clinical Laboratory Tests
Laboratory data of hematology, coagulation, and serum chemistry up to 30 days after last dose of 
study treatment or the End-of-Treatment visit date, whichever is later, will be reported in 
International System of Units. Laboratory data will be summarized by type of laboratory test. 
Reference ranges and markedly abnormal results (specified in the Statistical Analysis Plan) will 
be used in the summary of laboratory data. Descriptive statistics will be calculated for each 
laboratory analyte at baseline and for observed values and changes from baseline at each 
scheduled timepoint. Changes from baseline results will be presented in pre- versus 
posttreatment cross-tabulations (with classes for below, within, and above normal ranges). 
Frequency tabulations of the abnormalities will be made. A listing of subjects with any 
laboratory results outside the reference ranges will be provided. A listing of subjects with any 
markedly abnormal laboratory results will also be provided. 
Parameters with predefined NCI-CTCAE toxicity grades will be summarized. Change from 
baseline to the worst adverse event grade experienced by the subject during the study will be 
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Electrocardiogram (ECG)
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations. These tables will include observed values and changes from baseline 
values (the initial ECG will be used as baseline).
Physical Examination
Physical examination findings will be summarized at each scheduled timepoint. Descriptive 
statistics will be calculated at baseline and for observed values and changes from baseline at each 
scheduled timepoint. Frequency tabulations of the abnormalities will be made.
11.8.
Independent Data Monitoring Committee
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study and review the interim analysis results. 
The DMC will consist of at least 2 medical experts in the relevant therapeutic area and at least 
1 statistician. The DMC responsibilities, authorities, and procedures will be documented in its 
charter. 
The committee will meet periodically to review interim data. After the review, the DMC will 
make recommendations regarding the continuation of the study. The details will be provided in a 
separate DMC charter. At the interim analysis, the DMC may recommend stopping the study for 
either futility or efficacy, if the pre-specified stopping boundary is crossed (Section 11.9).
11.9.
Interim Analysis
During Part 2, an independent DMC will be used for ongoing, real-time review of safety and will 
conduct an interim analysis. The pre-planned interim analysis will be conducted when 
approximately 30 EFS events are reached. An independent DMC will determine the 
appropriateness for early stopping using the nonbinding stopping rules (Table 11) as well as 
other efficacy and safety endpoints. The 1-sided p-value required for early stopping for futility is 
≥0.367 and efficacy is ≤0.006 if there are 30 EFS events at the interim analysis. This design 
employs the sequential testing approach as described by O’Brien and Fleming (1979)27 to 
preserve the Type–I error rate. The interim analysis will also include a pharmacokinetic 
assessment using the available data at the time.
Table 11:
Stopping Boundaries (N=72 subjects, 2 Analyses)
Analysis 
Number
EFS 
events 
Approximate 
Time
Number 
of 
Subjects
Cumulative Error
Stopping Boundary
p-value (1-sided)
Observed Hazard 
Ratio
Alpha
Beta
Efficacy
Futility
Efficacy
Futility
Efficacy
Futility
Interim  
30 
(50%)
32 months 
46
0.006
0.07
≤0.006
≥0.367
<0.378
≥0.878
Final 
60 
(100%)
50 months 
72 
0.050
0.2
≤0.048
--------
<0.632
--------
EFS=event-free survival.


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11.9.1.
Outcome of IDMC review on 20 July 2020
The pre-planned interim analysis was conducted per the specifications outlined in Section 11.9 to 
determine the appropriateness for early stopping using the nonbinding stopping rules, in addition 
to a review of the efficacy and safety of patients in Part 2 of this study. As the futility boundary 
for early stopping was reached (31 of 60 EFS events), the IDMC recommended stopping 
enrollment.  Consequently, new patient enrollment has ceased.  No new safety concerns were 
identified. Follow-up of the ongoing patients will continue per guidance in Section 9.1.3 and 
Section 9.1.4, until the sponsor decides to stop the study.
11.10. Study Evaluation Team (SET)
A SET composed of study investigators and internal sponsor team members will convene (for all 
subjects in Part 1) to evaluate the safety of ibrutinib in combination with CIT to determine if the 
dose is appropriate, and when enrollment may start in the youngest age group. Safety review by 
the SET will include non-hematologic toxicities that required temporarily stopping study 
treatment for more than 10 days or cardiac rhythm abnormalities in those subjects receiving 
RVICI.
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 treatment. 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 European Union Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent 1 of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a serious and unexpected suspected adverse reaction even if it is a component of 
the study endpoint (eg, all-cause mortality), other than PD of NHL. Progressive disease of NHL 
should not be reported as a serious and unexpected adverse event.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For ibrutinib, the expectedness of an adverse 
event will be determined by whether or not it is listed as an expected adverse event in the 
Investigator's Brochure. For background CIT (RICE or RVICI), the expectedness of an adverse 
event will be determined by whether or not it is listed in the package insert for each component 
study treatment drug.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.


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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 drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the NCI-CTCAE, Version 4.03. The 
investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on ibrutinib that may require expedited reporting or safety evaluation 
include, but are not limited to:

Overdose of ibrutinib or any of the components of background CIT

Suspected abuse/misuse of ibrutinib or any of the components of background CIT

Accidental or occupational exposure to ibrutinib or any of the components of background 
CIT

Medication error involving ibrutinib (with or without subject/patient exposure to ibrutinib, 
eg, name confusion) or any of the components of background CIT

Exposure to ibrutinib from breastfeeding

Pregnancy
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.


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12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or nonserious, will be
reported from the time a signed and dated ICF is obtained until 30 days following the last dose of 
study treatment or until the start of a subsequent systemic antineoplastic therapy, if earlier, unless 
the subject has withdrawn consent for study participation. Adverse events reported after 30 days 
following the last dose of study treatment should also be reported if considered related to study 
treatment. All Grade 3 or Grade 4 adverse events considered related to study treatment must be 
followed until recovery to baseline or Grade ≤1 or until no further improvement is expected. 
Cardiac adverse events of Grade 2 or higher will be followed until improvement to baseline or 
Grade ≤1 or no further improvement is expected. Any unresolved events will be followed for a 
maximum of 6 months. 
Serious adverse events, including those spontaneously reported to the investigator during 
treatment or 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 adverse events of 
special interest, as defined in Section 12.3.3, related to bleeding or resulting in bleeding 
complications must be followed until recovery or until there is no further improvement. 
Progressive disease should not be reported as an adverse event, but instead symptoms/clinical 
signs of disease progression may be reported, which then should be attributed to PD. 
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. All records 
will need to capture the details of the duration and the severity of each episode, the action taken 
with respect to the study treatment, investigator’s evaluation of its relationship to the study 
treatment, and the subject outcome. Whenever possible, diagnoses should be given when signs 
and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and 
head congestion should be reported as "upper respiratory infection"). Investigators must record in 
the CRF their opinion concerning the relationship of the adverse event to study therapy. All 
measures required for adverse event management must be recorded in the source document and 
reported according to sponsor instructions.
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


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
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. 
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed 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 made 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 should be reported as a 
serious adverse event (medically important). 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 acute illness or 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 treatment period. A standard procedure for protocol therapy administration will not be 


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reported as a serious adverse event. Hospitalization or prolonged hospitalization for a 
complication of therapy administration will be reported as a serious adverse event. 

The administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable serious adverse 
event.

A procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling, pharmacokinetic, or biomarker blood 
sampling). Hospitalization or prolonged hospitalization for a complication of such 
procedures remains a reportable serious adverse event.

Prolonged hospitalization for technical, practical, or social reasons in the absence of an 
adverse event.
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 should be reported if they fulfill the serious adverse event definition (refer to 
Section 12.1.1, Adverse Event Definitions and Classifications).
12.3.3.
Adverse Events of Special Interest
Specific adverse events or groups of adverse events will be followed as part of standard safety 
monitoring activities by the sponsor. These events should 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.
Major Hemorrhage
Major hemorrhage is defined as:

Any treatment-emergent hemorrhagic adverse event of Grade 3 or higher.*

Any treatment-emergent serious adverse event of bleeding of any grade.

Any treatment-emergent CNS hemorrhage/hematoma of any grade.
*All hemorrhagic adverse events requiring a transfusion of red blood cells should be reported as 
a Grade 3 or higher adverse events per NCI-CTCAE.
12.3.4.
Other Malignancies
In addition to all routine adverse event reporting; all new malignant tumors, including solid 
tumors, skin malignancies, and hematologic malignancies; are to be reported for the duration of 
study treatment and during any protocol-specified follow-up periods including post-progression 
follow-up for overall survival.
12.3.5.
Pregnancy 
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered 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 discontinue further study treatment. Because the effect 
of the study drug on sperm is unknown, pregnancies in partners of male subjects included in the 
study will be reported as noted above. 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, Serious Adverse Events). A sample of the suspected 
product should be maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
For the purposes of this study, ‘study drug’ refers to ibrutinib.
14.1.
Study Drug - Ibrutinib
14.1.1.
Physical Description
The following formulations will be used in this study:

Ibrutinib capsules, 140 mg  

Ibrutinib capsules, 70 mg 


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
Ibrutinib suspension, 70 mg/mL Single Dose

Ibrutinib suspension, 70 mg/mL Multi-Dose
Ibrutinib capsules, 70 mg are hard gelatin capsules that contain 70 mg of ibrutinib. Ibrutinib oral 
suspension is supplied as a 70 mg/mL for use in this study. All excipients in all formulations are 
compendia and are commonly used in oral formulations. Refer to the Investigator's Brochure for 
capsule, single-dose vial, and multi-dose bottle suspension formulations. The 140-mg ibrutinib 
capsule, 70-mg ibrutinib capsule, and 70-mg/mL ibrutinib oral suspension will be dosed to meet 
the different dosing regimens and age groups. The study drug will be manufactured and provided 
under the responsibility of the sponsor. 
14.1.2.
Packaging
Ibrutinib capsules, 140 mg and 70 mg, will be packaged in opaque high-density polyethylene 
bottles with child-resistance closures. Ibrutinib single-dose oral suspension, 70 mg/mL, will be 
packaged in Type I amber glass vials with rubber stopper and aluminum seal. Ibrutinib multi-
dose oral suspension, 70 mg/mL, will be packaged in Type III amber glass bottles with dosing 
adaptor and child resistant screw cap.
All study drugs will be packaged in individual subject kits with labels bearing the appropriate 
label text as required by governing regulatory agencies.
14.1.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. 
14.1.4.
Preparation, Handling, and Storage 
Refer to the Pharmacy Manual/study Site Investigational Product Manual for additional guidance 
on study drug preparation, handling, and storage.
Ibrutinib capsules, 140 mg, should be stored according to the storage conditions indicated on the 
label. The recommended storage condition for ibrutinib capsules is 15°C to 25°C (59°F to 77°F) 
with excursions permitted to 30°C (86°F).
Ibrutinib capsules, 70 mg, should be stored according to the storage conditions indicated on the 
label. The recommended storage condition for this drug product is 15°C to 25°C (59°F to 77°F) 
with excursions permitted to 30°C (86°F). Current stability data indicate that the capsules will be 
stable for the duration of the clinical study under the labeled storage conditions. Study staff will 
instruct subjects on how to store medication for at-home use as indicated for this protocol. 
Ibrutinib oral suspension, 70 mg/mL (both single and multi-dose), should be stored according to 
the storage conditions indicated on the label. The recommended storage condition for this drug 
product is 2°C to 8°C (35.6°F to 46.4°F). Once opened, the multi-dose drug bottle should be 
stored at 15°C to 25°C (59°F to 77°F). Current stability data indicate that the suspension will be 
stable for the duration of the clinical study under the labeled storage conditions. Study staff will 
instruct subjects on how to store medication for at-home use as indicated for this protocol. 


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14.2.
Background Therapy (RICE or RVICI)
Rituximab, ifosfamide, carboplatin, etoposide, Mesna, dexamethasone, vincristine, and 
idarubicin labels will contain information to meet the applicable regulatory requirements. 
Rituximab, ifosfamide, carboplatin, etoposide, Mesna, dexamethasone, vincristine, and 
idarubicin must be prepared in an aseptic manner according to local standards for handling 
cytotoxic/cytostatic drugs. Refer to the rituximab, ifosfamide, carboplatin, etoposide, Mesna, 
dexamethasone, vincristine, and idarubicin local prescribing information or the Pharmacy 
Manual/study Site Investigational Product Manual for further instructions on preparation, 
handling, and storage.
14.3.
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 (ibrutinib) to the subject, 
and the return of study drug from the subject (if applicable), must be documented in the drug 
accountability records. Subjects, or their legally-acceptable representatives where applicable, 
must be instructed to return all original containers, whether empty or containing study drug. For 
study drug supplied centrally, the CIT (RICE or RVICI) administered to the subject must be 
documented on the drug accountability form. All study treatment will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject, must be 
available for verification by the sponsor's study-site monitor during on-site monitoring visits. 
The return to the sponsor of unused study drug, or used returned study drug for destruction, will 
be documented on the drug 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 drug return form. 
Potentially hazardous materials such as used ampules, needles, syringes, bottles, and vials 
containing hazardous liquids, should be disposed of immediately in a safe manner and therefore 
will not be retained for drug 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.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Study protocol

Ibrutinib Investigator's Brochure


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
Ibrutinib study drug diary

International Pediatric NHL Response Criteria36

Pharmacy Manual/study Site Investigational Product Manual

Laboratory Manual

NCI-CTCAE, Version 4.03

Visual analog scale for palatability and acceptability

IWRS Manual and supplies 

Electronic Data Capture (eDC) Manual and electronic CRF Completion Guidelines

Sample ICF

Subject information materials
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is a randomized, open-label, multicenter Phase 3 study to compare the safety and efficacy of 
ibrutinib in combination with CIT (RICE or RVICI) versus CIT alone in subjects with relapsed 
or refractory BL/B-AL and DLBCL, in subjects 1 to 30 years of age at the time of relapse. All 
subjects will receive background therapy with RICE or RVICI, recommended by an advisory 
board of key opinion leaders in pediatric oncology (see Section 3.2.2).
All participating subjects will receive full supportive care and will be followed closely for safety 
and efficacy throughout the study. Efficacy assessments will occur according to the 
internationally accepted International Pediatric NHL Response Criteria.36 Safety assessments 
will occur through regular clinic visits including laboratory analyses. An independent DMC will 
be established to review the safety and efficacy of the treatment combination and make 
recommendations as to the future conduct of the study. 
Potential subjects will be fully informed of the risks and requirements of the study and, during 
the study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may 
be withdrawn at any time with no reason given and without penalty or loss of benefits to which 
they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential adverse events of the study, and provide their consent voluntarily will be 
enrolled.
When referring to the signing of the ICF, the terms legal guardian and legally-acceptable 
representative refer to the legally appointed guardian of the child with authority to authorize 
participation in research. For each subject, his or her parent(s) (preferably both parents, if 
available) or a legally-acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has 
been fully explained and before the performance of any study-related assessments. Assent must 


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be obtained from children (minors) capable of understanding the nature of the study; please refer 
to local regulations. For the purposes of this study, all references to subjects who have provided 
consent (and assent, as applicable) refers to the subjects and his or her parent(s) or the subject's 
legal guardian(s) or legally-acceptable representative(s) who have provided consent according to 
this process. Minors who assent to a study and later withdraw that assent will not be maintained 
in the study against their will, even if their parents still want them to participate.
The volume of blood collected will be consistent the recommendations of the EMA for 
study-related blood loss.12 Sample volumes will be adjusted according to standards for pediatric 
subjects.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements. Good Clinical Practice is an international ethical and scientific 
quality standard for designing, conducting, recording, and reporting studies that involve the 
participation of human subjects. Compliance with this standard provides public assurance that 
the rights, safety, and well-being of study subjects are protected, consistent with the principles 
that originated in the Declaration of Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 


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


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


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subject or legally-acceptable representative must be informed about the study as soon as possible 
and give consent to continue.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. These data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with 
applicable data privacy protection laws and regulations. Appropriate technical and organizational 
measures to protect the personal data against unauthorized disclosures or access, accidental or 
unlawful destruction, or accidental loss or alteration must be put in place. Sponsor personnel 
whose responsibilities require access to personal data agree to keep the identity of subjects 
confidential.
The informed consent/assent obtained from the subject (or his or her legally-acceptable 
representative) includes explicit consent/assent 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/assent 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.
Exploratory biomarker research is not conducted under standards appropriate for the return of 
data to subjects. In addition, the sponsor cannot make decisions as to the significance of any 
findings resulting from exploratory research. Therefore, exploratory research data will not be 
returned to subjects or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand ibrutinib, to 
understand NHL, to understand differential drug responders, and to develop tests/assays related 
to ibrutinib and NHL. The research may begin at any time during the study or the post-study 
storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw consent for sample storage for research 
(refer to Section 10.3).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 


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addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
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 
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 
IRB/IEC (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (listed in the Contact Information page(s), which will be provided as a separate 
document). Except in emergency situations, this contact should be made before implementing 
any departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the CRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 


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applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care, must be available for the 
following: subject identification, eligibility, and study identification; study discussion and date of 
signed informed consent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all adverse events and follow-up of adverse events; concomitant 


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medication; drug receipt/dispensing/return records; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. The author of an entry in the source documents should be identifiable. 
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document). The following data will be recorded directly into the 
CRF and will be considered source data: 

Race

Height and weight 

Details of physical examination
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician, or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents. An e-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 
e-Source is utilized, references made to the CRF in the protocol include the e-Source system but 
information collected through e-Source 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 data relating to the study must be recorded in CRF. 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. Worksheets may be used for the capture of some data to facilitate completion of the 
CRF. Any such worksheets will become part of the subject's source documents. Data must be 
entered into the 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 


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


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17.8.
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote or on-site 
monitoring) to monitor this study. The sponsor will perform on-site monitoring visits as 
frequently as necessary. The monitor will record dates of the visits in a study-site visit log that 
will be kept at the study site. The first 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.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. Central monitoring will take place for data identified by the sponsor as 
requiring central review.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study 
The 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.
On 20 July 2020, the IDMC conducted a pre-planned review of the interim analysis data for 
efficacy and safety.  The IDMC recommended stopping enrollment into the study as ibrutinib in 
combination with CIT did not demonstrate additive efficacy.  No new safety concerns were 
identified.  Consequently, new patient enrollment has ceased.  Ongoing patients may continue 
study treatment, as appropriate according to the investigator’s medical judgement, and will be 
followed up as per time and events schedule Table 2.  Patients who have completed treatment 
will continue to be followed up as per time and events schedule in Table 4 or until the sponsor 
decides to stop the study.
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 


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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 exploratory biomarker research data, generated as 
a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of ibrutinib, and thus may be disclosed as 
required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 


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performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory 
biomarker 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 (ICMJE) 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 12 months of the 
availability of the final data (tables, listings, graphs), 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 the important intellectual content; and given final approval of the 
version to the published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.


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Attachment 1: Ibrutinib Dosing Guides
Suspension and Capsule Dosing 329 mg/m2
(Full Dose Equivalent; 560 mg/1.7 m2)
Body Surface Area
(m2)
Target Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by Capsule 
(mg)
From
To
0.30
0.34
98.8
1.4
98
-
-
0.35
0.39
115.3
1.6
112
-
-
0.40
0.44
131.8
1.9
133
-
-
0.45
0.49
148.2
2.1
147
-
-
0.50
0.54
164.7
2.4
168
-
-
0.55
0.59
181.2
2.6
182
-
-
0.60
0.64
197.6
2.8
196
3
210
0.65
0.69
214.1
3.1
217
3
210
0.70
0.74
230.6
3.3
231
3
210
0.75
0.79
247.1
3.5
245
4
280
0.80
0.84
263.5
3.8
266
4
280
0.85
0.89
280.0
4.0
280
4
280
0.90
0.94
296.5
4.2
294
4
280
0.95
0.99
312.9
4.5
315
4
280
1.00
1.04
329.4
4.7
329
5
350
1.05
1.09
345.9
4.9
343
5
350
1.10
1.14
362.4
5.2
364
5
350
1.15
1.19
378.8
5.4
378
5
350
1.20
1.24
395.3
5.6
392
6
420
1.25
1.29
411.8
5.9
413
6
420
1.30
1.34
428.2
6.1
427
6
420
1.35
1.39
444.7
6.4
448
6
420
1.40
1.44
461.2
6.6
462
7
490
1.45
1.49
477.6
6.8
476
7
490
1.50
1.54
494.1
7.1
497
7
490
1.55
1.59
510.6
7.3
511
7
490
1.60
1.64
527.1
7.5
525
8
560
1.65
1.69
543.5
7.8
546
8
560
1.70 and higher
560.0
8.0
560
8
560
a.
Rounded to nearest 70 mg capsule. 
b.
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


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Suspension and Capsule Dosing for the 240 mg/m2 Dose 
(Full Dose Equivalent; 420 mg/1.7 m2) 
Body Surface Area
(m2)
Target Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by Capsule 
(mg)
From
To
0.30
0.34
72.0
1.0
70
-
-
0.35
0.39
84.0
1.2
84
-
-
0.40
0.44
96.0
1.4
98
-
-
0.45
0.49
108.0
1.5
105
-
-
0.50
0.54
120.0
1.7
119
-
-
0.55
0.59
132.0
1.9
133
-
-
0.60
0.64
144.0
2.1
147
2
140
0.65
0.69
156.0
2.2
154
2
140
0.70
0.74
168.0
2.4
168
2
140
0.75
0.79
180.0
2.6
182
3
210
0.80
0.84
192.0
2.7
189
3
210
0.85
0.89
204.0
2.9
203
3
210
0.90
0.94
216.0
3.1
217
3
210
0.95
0.99
228.0
3.3
231
3
210
1.00
1.04
240.0
3.4
238
3
210
1.05
1.09
252.0
3.6
252
4
280
1.10
1.14
264.0
3.8
266
4
280
1.15
1.19
276.0
3.9
273
4
280
1.20
1.24
288.0
4.1
287
4
280
1.25
1.29
300.0
4.3
301
4
280
1.30
1.34
312.0
4.5
315
4
280
1.35
1.39
324.0
4.6
322
5
350
1.40
1.44
336.0
4.8
336
5
350
1.45
1.49
348.0
5.0
350
5
350
1.50
1.54
360.0
5.1
357
5
350
1.55
1.59
372.0
5.3
371
5
350
1.60
1.64
384.0
5.5
385
5
350
1.65
1.69
396.0
5.7
399
6
420
1.70
1.74
408.0
5.8
406
6
420
1.75 and higher
420.0
6.0
420
6
420
a.
Rounded to nearest 70 mg capsule.
b.
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


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Suspension and Capsule Dosing 160 mg/m2
(Full Dose Equivalent; 280 mg/1.7 m2)
Body Surface Area
(m2)
Target 
Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by 
Capsule (mg)
From
To
0.30
0.34
48.0
0.7
49
-
-
0.35
0.39
56.0
0.8
56
-
-
0.40
0.44
64.0
0.9
63
-
-
0.45
0.49
72.0
1.0
70
-
-
0.50
0.54
80.0
1.1
77
-
-
0.55
0.59
88.0
1.3
91
-
-
0.60
0.64
96.0
1.4
98
-
-
0.65
0.69
104.0
1.5
105
-
-
0.70
0.74
112.0
1.6
112
-
-
0.75
0.79
120.0
1.7
119
2
140
0.80
0.84
128.0
1.8
126
2
140
0.85
0.89
136.0
1.9
133
2
140
0.90
0.94
144.0
2.1
147
2
140
0.95
0.99
152.0
2.2
154
2
140
1.00
1.04
160.0
2.3
161
2
140
1.05
1.09
168.0
2.4
168
2
140
1.10
1.14
176.0
2.5
175
3
210
1.15
1.19
184.0
2.6
182
3
210
1.20
1.24
192.0
2.7
189
3
210
1.25
1.29
200.0
2.9
203
3
210
1.30
1.34
208.0
3.0
210
3
210
1.35
1.39
216.0
3.1
217
3
210
1.40
1.44
224.0
3.2
224
3
210
1.45
1.49
232.0
3.3
231
3
210
1.50
1.54
240.0
3.4
238
3
210
1.55
1.59
248.0
3.5
245
4
280
1.60
1.64
256.0
3.7
259
4
280
1.65
1.69
264.0
3.8
266
4
280
1.70
1.74
272.0
3.9
273
4
280
1.75 or higher
280.0
4.0
280
4
280
a
Rounded to nearest 70 mg capsule. 
b
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
126
Status: Approved, Date: 15 September 2020
Suspension and Capsule Dosing 120 mg/m2
(Full Dose Equivalent; 210 mg/1.7 m2)
Body Surface Area
(m2)
Target 
Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by 
Capsule (mg)
From
To
0.30
0.34
36.0
0.5
35
-
-
0.35
0.39
42.0
0.6
42
-
-
0.40
0.44
48.0
0.7
49
-
-
0.45
0.49
54.0
0.8
56
-
-
0.50
0.54
60.0
0.9
63
-
-
0.55
0.59
66.0
0.9
63
-
-
0.60
0.64
72.0
1.0
70
-
-
0.65
0.69
78.0
1.1
77
-
-
0.70
0.74
84.0
1.2
84
-
-
0.75
0.79
90.0
1.3
91
-
-
0.80
0.84
96.0
1.4
98
-
-
0.85
0.89
102.0
1.5
105
-
-
0.90
0.94
108.0
1.5
105
-
-
0.95
0.99
114.0
1.6
112
-
-
1.00
1.04
120.0
1.7
119
2
140
1.05
1.09
126.0
1.8
126
2
140
1.10
1.14
132.0
1.9
133
2
140
1.15
1.19
138.0
2.0
140
2
140
1.20
1.24
144.0
2.1
147
2
140
1.25
1.29
150.0
2.1
147
2
140
1.30
1.34
156.0
2.2
154
2
140
1.35
1.39
162.0
2.3
161
2
140
1.40
1.44
168.0
2.4
168
2
140
1.45
1.49
174.0
2.5
175
2
140
1.50
1.54
180.0
2.6
182
3
210
1.55
1.59
186.0
2.7
189
3
210
1.60
1.64
192.0
2.7
189
3
210
1.65
1.69
198.0
2.8
196
3
210
1.70
1.74
204.0
2.9
203
3
210
1.75 or higher
210.0
3.0
210
3
210
a.
Rounded to nearest 70 mg capsule. 
b.
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
127
Status: Approved, Date: 15 September 2020
Suspension and Capsule Dosing 80 mg/m2
(Full Dose Equivalent; 140 mg/1.7 m2)
Body Surface Area
(m2)
Target 
Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by 
Capsule (mg)
From
To
0.30
0.34
24.0
0.3
21
-
-
0.35
0.39
28.0
0.4
28
-
-
0.40
0.44
32.0
0.5
35
-
-
0.45
0.49
36.0
0.5
35
-
-
0.50
0.54
40.0
0.6
42
-
-
0.55
0.59
44.0
0.6
42
-
-
0.60
0.64
48.0
0.7
49
-
-
0.65
0.69
52.0
0.7
49
-
-
0.70
0.74
56.0
0.8
56
-
-
0.75
0.79
60.0
0.9
63
-
-
0.80
0.84
64.0
0.9
63
-
-
0.85
0.89
68.0
1.0
70
-
-
0.90
0.94
72.0
1.0
70
-
-
0.95
0.99
76.0
1.1
77
-
-
1.00
1.04
80.0
1.1
77
-
-
1.05
1.09
84.0
1.2
84
-
-
1.10
1.14
88.0
1.3
91
-
-
1.15
1.19
92.0
1.3
91
-
-
1.20
1.24
96.0
1.4
98
-
-
1.25
1.29
100.0
1.4
98
-
-
1.30
1.34
104.0
1.5
105
-
-
1.35
1.39
108.0
1.5
105
-
-
1.40
1.44
112.0
1.6
112
2
140
1.45
1.49
116.0
1.7
119
2
140
1.50
1.54
120.0
1.7
119
2
140
1.55
1.59
124.0
1.8
126
2
140
1.60
1.64
128.0
1.8
126
2
140
1.65
1.69
132.0
1.9
133
2
140
1.70
1.74
136.0
1.9
133
2
140
1.75 and higher
140.0
2.0
140
2
140
a.
Rounded to nearest 70 mg capsule. 
b.
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
128
Status: Approved, Date: 15 September 2020
Suspension and Capsule Ibrutinib Dosing 440 mg/m2
(Full Dose Equivalent; 748 mg/1.7 m2)
NOTE: only to be used in subjects under 12 years of age dose administered will not exceed 
560 mg
Body Surface Area
(m2)
Target Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by Capsule 
(mg)
From
To
0.30
0.34
132
1.9
133
-
-
0.35
0.39
154
2.2
154
-
-
0.40
0.44
176
2.5
175
-
-
0.45
0.49
198
2.8
196
-
-
0.50
0.54
220
3.1
217
-
-
0.55
0.59
242
3.5
245
3
210
0.60
0.64
264
3.8
266
4
280
0.65
0.69
286
4.1
287
4
280
0.70
0.74
308
4.4
308
4
280
0.75
0.79
330
4.7
329
5
350
0.80
0.84
352
5.0
350
5
350
0.85
0.89
374
5.3
371
5
350
0.90
0.94
396
5.7
399
6
420
0.95
0.99
418
6.0
420
6
420
1.00
1.04
440
6.3
441
6
420
1.05
1.09
462
6.6
462
7
490
1.10
1.14
484
6.9
483
7
490
1.15
1.19
506
7.2
504
7
490
1.20
1.24
528
7.5
525
8
560
1.25
1.29
550
7.9
553
8
560
1.30
1.34
560
8.0
560
8
560
1.35
1.39
560
8.0
560
8
560
1.40
1.44
560
8.0
560
8
560
1.45
1.49
560
8.0
560
8
560
1.50
1.54
560
8.0
560
8
560
1.55
1.59
560
8.0
560
8
560
1.60
1.64
560
8.0
560
8
560
1.65
1.69
560
8.0
560
8
560
1.70 and higher
560
8.0
560
8
560
a.
Rounded to nearest 70 mg capsule. 
b.
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
129
Status: Approved, Date: 15 September 2020
Suspension and Capsule Dosing 330 mg/m2
(Full Dose Equivalent; 561 mg/1.7 m2)
Body Surface Area
(m2)
Target Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by Capsule 
(mg)
From
To
0.30
0.34
99.0
1.4
98
-
-
0.35
0.39
115.5
1.7
119
-
-
0.40
0.44
132.0
1.9
133
-
-
0.45
0.49
148.5
2.1
147
-
-
0.50
0.54
165.0
2.4
168
-
-
0.55
0.59
181.5
2.6
182
-
-
0.60
0.64
198.0
2.8
196
3
210
0.65
0.69
214.5
3.1
217
3
210
0.70
0.74
231.0
3.3
231
3
210
0.75
0.79
247.5
3.5
245
3
210
0.80
0.84
264.0
3.8
266
4
280
0.85
0.89
280.5
4.0
280
4
280
0.90
0.94
297.0
4.2
294
4
280
0.95
0.99
313.5
4.5
315
4
280
1.00
1.04
330.0
4.7
329
5
350
1.05
1.09
346.5
5.0
350
5
350
1.10
1.14
363.0
5.2
364
5
350
1.15
1.19
379.5
5.4
378
5
350
1.20
1.24
396.0
5.7
399
6
420
1.25
1.29
412.5
5.9
413
6
420
1.30
1.34
429.0
6.1
427
6
420
1.35
1.39
445.5
6.4
448
6
420
1.40
1.44
462.0
6.6
462
7
490
1.45
1.49
478.5
6.8
476
7
490
1.50
1.54
495.0
7.1
497
7
490
1.55
1.59
511.5
7.3
511
7
490
1.60
1.64
528.0
7.5
525
8
560
1.65
1.69
544.5
7.8
546
8
560
1.70 and higher
560.0
8.0
560
8
560
a.
Rounded to nearest 70 mg capsule. 
b.
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
130
Status: Approved, Date: 15 September 2020
Suspension and Capsule Dosing 220 mg/m2
(Full Dose Equivalent; 374 mg/1.7 m2)
Body Surface Area
(m2)
Target Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by Capsule 
(mg)
From
To
0.30
0.34
66.0
0.9
63
-
-
0.35
0.39
77.0
1.1
77
-
-
0.40
0.44
88.0
1.3
91
-
-
0.45
0.49
99.0
1.4
98
-
-
0.50
0.54
110.0
1.6
112
-
-
0.55
0.59
121.0
1.7
119
-
-
0.60
0.64
132.0
1.9
133
2
140
0.65
0.69
143.0
2.0
140
2
140
0.70
0.74
154.0
2.2
154
2
140
0.75
0.79
165.0
2.4
168
2
140
0.80
0.84
176.0
2.5
175
3
210
0.85
0.89
187.0
2.7
189
3
210
0.90
0.94
198.0
2.8
196
3
210
0.95
0.99
209.0
3.0
210
3
210
1.00
1.04
220.0
3.1
217
3
210
1.05
1.09
231.0
3.3
231
3
210
1.10
1.14
242.0
3.5
245
3
210
1.15
1.19
253.0
3.6
252
4
280
1.20
1.24
264.0
3.8
266
4
280
1.25
1.29
275.0
3.9
273
4
280
1.30
1.34
286.0
4.1
287
4
280
1.35
1.39
297.0
4.2
294
4
280
1.40
1.44
308.0
4.4
308
4
280
1.45
1.49
319.0
4.6
322
5
350
1.50
1.54
330.0
4.7
329
5
350
1.55
1.59
341.0
4.9
343
5
350
1.60
1.64
352.0
5.0
350
5
350
1.65
1.69
363.0
5.2
364
5
350
1.70
1.74
374.0
5.3
371
5
350
1.75 and higher
385.0
5.5
385
6
420
a.
Rounded to nearest 70 mg capsule. 
b.
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
131
Status: Approved, Date: 15 September 2020
Suspension and Capsule Dosing 110 mg/m2
(Full Dose Equivalent; 187 mg/1.7 m2)
Body Surface Area
(m2)
Target Dose
(mg)
Suspension 
(70 mg/mL) 
Volume to be 
Administered 
(mL)
Actual Dose to 
Administer by 
Suspension (mg)
# 70 mg 
Capsulesa,b
Actual Dose to 
Administer by Capsule 
(mg)
From
To
0.30
0.34
33.0
0.5
35
-
-
0.35
0.39
38.5
0.6
42
-
-
0.40
0.44
44.0
0.6
42
-
-
0.45
0.49
49.5
0.7
49
-
-
0.50
0.54
55.0
0.8
56
-
-
0.55
0.59
60.5
0.9
63
-
-
0.60
0.64
66.0
0.9
63
1
70
0.65
0.69
71.5
1.0
70
1
70
0.70
0.74
77.0
1.1
77
1
70
0.75
0.79
82.5
1.2
84
1
70
0.80
0.84
88.0
1.3
91
1
70
0.85
0.89
93.5
1.3
91
1
70
0.90
0.94
99.0
1.4
98
1
70
0.95
0.99
104.5
1.5
105
1
70
1.00
1.04
110.0
1.6
112
2
140
1.05
1.09
115.5
1.7
119
2
140
1.10
1.14
121.0
1.7
119
2
140
1.15
1.19
126.5
1.8
126
2
140
1.20
1.24
132.0
1.9
133
2
140
1.25
1.29
137.5
2.0
140
2
140
1.30
1.34
143.0
2.0
140
2
140
1.35
1.39
148.5
2.1
147
2
140
1.40
1.44
154.0
2.2
154
2
140
1.45
1.49
159.5
2.3
161
2
140
1.50
1.54
165.0
2.4
168
2
140
1.55
1.59
170.5
2.4
168
2
140
1.60
1.64
176.0
2.5
175
3
210
1.65
1.69
181.5
2.6
182
3
210
1.70
1.74
187.0
2.7
189
3
210
1.75 and higher
192.5
2.8
196
3
210
a.
Rounded to nearest 70 mg capsule. 
b.
For older children, one 140-mg capsule may be substituted for each two 70-mg capsules.


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
132
Status: Approved, Date: 15 September 2020
Attachment 2: Lansky-Karnofsky Performance Status
Karnofsky Scalea (recipient age ≥16 years)
Lansky Scaleb (recipient age <16 years)
100: Normal, no complaints, no evidence of disease
100: Fully active, normal
90: Able to carry on normal activity. Minor signs or 
symptoms of disease.
90: Minor restriction with strenuous physical 
activity
80: Normal activity with effort. Some signs or 
symptoms of disease.
80: Active, but gets tired more quickly
70: Cares for self, unable to carry on normal 
activity or to do active work
70: Both greater restrictions of, and less time spent 
in, active play
60: Requires occasional assistance but is able to 
care for most of personal needs
60: Up and around, but minimal active play; keeps 
busy with quieter activities
50: Requires considerable assistance and frequent 
medical care
50: Lying around much of the day, but gets dressed; 
no active play; participates in all quiet play and 
activities
40: Disabled, requires special care and assistance
40: Mostly in bed; participates in quiet activities
30: Severely disabled, hospitalization indicated, 
although death not imminent
30: Stuck in bed; needs help even for quiet play
20: Hospitalization necessary. Very sick, active 
supportive treatment necessary.
20: Often sleeping; play is entirely limited to very 
passive activities
10: Moribund, fatal process progressing rapidly
10: Does not play or get out of bed to play
0: Dead
0: Unresponsive
a. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In Evaluation of 
chemotherapeutic agents. Edited by MacLeod CM. New York: Columbia University Press; 1949:191-205.17
b. Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance in childhood 
cancer patients. Cancer. 1987 Oct 1;60(7):1651-1656.20


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
133
Status: Approved, Date: 15 September 2020
Attachment 3: Body Surface Area Calculation
BSA should be calculated using a standard nomogram. An example nomogram follows:


JNJ-54179060  (ibrutinib)
Clinical Protocol 54179060LYM3003 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
134
Status: Approved, Date: 15 September 2020
Attachment 4: Instruction for Concomitant Medications to be Used With Precaution
Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration with strong or moderate 
CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. Co-administration 
of ketoconazole, a strong CYP3A inhibitor, in 18 healthy subjects increased dose normalized 
exposure, Cmax and AUC0-last, of ibrutinib by 29- and 24-fold, respectively. A DDI study in 
patients with B-cell malignancies (PCI-32765LYM1003) found that co-administration of 
ibrutinib with the moderate CYP3A inhibitors erythromycin and voriconazole, increased Cmax by 
3.4-fold and 6.7-fold and increased AUC by 3.0-fold and 5.7-fold, respectively. Clinical safety 
data in 66 subjects treated with moderate (n=47) or strong CYP3A inhibitors (n=19) did not 
reveal meaningful increases in toxicities. Strong inhibitors of CYP3A (eg, ketoconazole, 
indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, 
nefazadone, and cobicistat) and moderate inhibitors (eg, voriconazole, erythromycin, 
amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, 
fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone) should be avoided. 
If the benefit outweighs the risk and a strong CYP3A inhibitor must be used, reduce the ibrutinib 
dose by 75% (140 mg/1.7 m2 rounded down to 80 mg/m2 for starting dose of 329 mg/m2 or to 
110 mg/m2 for dose of 440 mg/m2) or stop treatment temporarily (for 7 days or less). If a 
moderate CYP3A inhibitor must be used, reduce ibrutinib by 75% (140 mg/1.7 m2 rounded down 
to 80 mg/m2 for starting dose of 329 mg/m2 or to 110 mg/m2 for dose of 440 mg/m2) for the 
duration of the inhibitor use. No dose adjustment is required in combination with mild inhibitors. 
Monitor the subject closely for toxicity and follow dose modification guidance as needed. Avoid 
grapefruit and Seville oranges during ibrutinib treatment, as these contain moderate inhibitors of 
CYP3A.
Co-administration of ibrutinib with strong inducers of CYP3A decreases ibrutinib plasma 
concentrations by up to 90%. Avoid concomitant use of strong CYP3A inducers
(eg, carbamazepine, rifampin, phenytoin, and St. John’s Wort). Consider alternative agents with 
less CYP3A induction.
Examples of inhibitors, inducers, and substrates can be found in Attachment 5 and at 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers11
and http://medicine.iupui.edu/clinpharm/ddis/main-
table/.10
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 CYP450 
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. 


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In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp) nor other major 
transporters, except OCT2. The dihydrodiol metabolite and other metabolites are P-gp substrates. 
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 and BCRP after a therapeutic dose. There are 
no clinical data available. To minimize the potential for an interaction in the gastrointestinal 
tract, narrow therapeutic range P-gp or BCRP substrates such as digoxin or methotrexate 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.
Concomitant Use of Ibrutinib and Antiplatelet Agents and Anticoagulants
Warfarin or other vitamin K antagonists should not be administered concomitantly with 
ibrutinib. Use of ibrutinib in subjects requiring other anticoagulants or medications that inhibit 
platelet function may increase the risk of bleeding. Subjects with congenital bleeding diathesis 
have not been studied. Ibrutinib should be temporarily stopped at least 3 to 7 days pre- and post-
surgery depending upon the type of surgery and the risk of bleeding.
Subjects requiring the initiation of therapeutic anticoagulation therapy (other than warfarin or a 
vitamin K antagonist) during the course of the study should be discussed with the sponsor’s 
medical monitor.


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Attachment 5: Inhibitors and Inducers of CYP3A
The table below shows the classification of commonly used inhibitors and inducers of CYP3A 
enzymes. Further information can be found at the following websites: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers11
http://medicine.iupui.edu/clinpharm/ddis/main-table/.10  
Inhibitors of CYP3A
Inducers of CYP3A
Strong inhibitors:
carbamazepine
Boceprevir
barbiturates
Clarithromycin
efavirenz
Cobicistat
glucocorticoids
Indinavir
modafinil
Itraconazole
nevirapine
Ketoconazole
oxcarbarzepine
Mibefradil
phenobarbital
Nefazodonene
phenytoin
Nelfinavir
pioglitazone
posaconazole a
rifabutin
Ritonavir
rifampin
Saquinavir
St. John’s Wort
Suboxone
troglitazone
Telaprevir
Telithromycin
Troleandomycin
Moderate inhibitors:
Amiodarone
Amprenavir
Aprepitant
Atazanavir
Ciprofloxacin
Crizotinib
Darunavir
diltiazem 
Dronedarone
Erythromycin
Fluconazole
Fosamprenavir
grapefruit juice
Seville orange juice
Verapamil
voriconazole a
Amiodarone
Weak inhibitors:
Cimetidine
Fluvoxamine
All other inhibitors:
Chloramphenicol
Delaviridine
diethyl-dithiocarbamate
Gestodene
Mifepristone
Norfloxacin
Norfluoxetine
star fruit
a Classification based on internal data.


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Attachment 6: Intrathecal Drug Doses by Age
Intrathecal Drug Doses (mg)
Age (years)
Methotrexate
Hydrocortisone*
Prednisolone*
Cytarabine
<1
8
8
4
15
≥1 to <2
10
10
6
20
≥2 to <3
12
12
8
25
≥3
15
15
10
30
*Other corticosteroids may be administered as per local supply provided that the steroid 
equivalent dose is equal to the prednisolone dose above.


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Attachment 7: Blood Volume Tables
Estimated Maximum Volume of Blood to be Collected From all Subjects in Part 1, by Study Phase and 
Treatment Cycle
Type of Samplea,b
Volume per 
Sample 
No. of 
Samples per 
Subject
Approximate Total 
Volume of Bloodc
Screening
Safety
Hematology
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Serum chemistry
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Serum -hCG pregnancy testsd
2.5 mL
1
2.5 mL
HIV, Hepatitis B, C serologies
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Tetanus, pneumococcal titers
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Cycle 1
Safety
Hematology
2.5 – 5.0 mL
4
10.0 – 20.0 mL
Serum chemistry
2.5 – 5.0 mL
4
10.0 – 20.0 mL
Serum -hCG pregnancy testsd
2.5 mL
1
2.5 mL
Pharmacokinetic samples
0.6 mL
10
6.0 mL
Pharmacodynamic samples
4.0 – 6.0 mL
4
16.0 – 24.0 mL
Biomarker samples
1.2 mL
2
2.4 mL
Protein binding 
1.0 mL
1
1.0 mL
Cycle 2
Safety
Hematology
2.5 – 5.0 mL
2
5.0 – 10.0 mL
Serum chemistry
2.5 – 5.0 mL
2
5.0 – 10.0 mL
Serum -hCG pregnancy testsd
2.5 mL
1
2.5 mL
Pharmacokinetic samples
0.6 mL
5e
3.0 mL
Pharmacodynamic samples
4.0 – 6.0 mL
1e
4.0 – 6.0 mL
Biomarker samples
1.2 mL
1e
1.2 mL
Cycle 3
Safety
Hematology
2.5 – 5.0 mL
2
5.0 – 10.0 mL
Serum chemistry
2.5 – 5.0 mL
2
5.0 –10.0 mL
Serum -hCG pregnancy testsd
2.5 mL
1
2.5 mL
End-of-Treatment Visit
Safety
Hematology
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Serum chemistry
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Pharmacodynamic samples
4.0 – 6.0 mL
1
4.0 – 6.0 mL
Biomarker samples
1.2 mL
1
1.2 mL
First Follow-up Assessment
Safety
Tetanus, pneumococcal titersf
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Monotherapy Cycle 1-3 (if applicable)
Safety
Hematology
2.5 – 5.0 mL
3
7.5 – 15.0 mL
Serum chemistry
2.5 – 5.0 mL
3
7.5 – 15.0 mL
Serum -hCG pregnancy testsd
2.5 mL
3
7.5 mL
End-of-Monotherapy Visit (if applicable)
Safety
Hematology
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Serum chemistry
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Pharmacodynamic samples
4.0 – 6.0 mL
1
4.0 – 6.0 mL
Biomarker samples
1.2 mL
1
1.2 mL
Approximate Totalg
139.0 - 230.5 mL
-hCG=beta-human chorionic gonadotropin; HIV=human immunodeficiency virus.
a. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples. 
b. Sample volumes will be adjusted according to standards for pediatric subjects.
c. Calculated as number of samples multiplied by amount of blood per sample.
d. Serum pregnancy test to be performed only if urine is unavailable.
e. These samples may be collected in Cycle 2 or Cycle 3, but not both.
f. Subjects who enter monotherapy will have sample taken at End-of-Monotherapy Visit
g. An additional biomarker sample may be taken if PD occurs during a follow-up visit
Note: An indwelling intravenous cannula may be used for blood sample collection. 


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Estimated Maximum Volume of Blood to be Collected From Each Subject in Part 2, by Study Phase and 
Treatment Cycle
Type of Samplea,b
Volume per 
Sample 
No. of Samples 
per Subject
Approximate Total 
Volume of Bloodc
Screening
Safety
Hematology
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Serum chemistry
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Serum -hCG pregnancy testsd
2.5 mL
1
2.5 mL
HIV, Hepatitis B, C serologies
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Tetanus, pneumococcal titers
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Cycle 1
Safety
Hematology
2.5 – 5.0 mL
4
10.0 – 20.0 mL
Serum chemistry
2.5 – 5.0 mL
4
10.0 – 20.0 mL
Serum -hCG pregnancy testsd
2.5 mL
1
2.5 mL
Pharmacokinetic samples
0.6 mL
4e
2.4 mL
Pharmacodynamic samples
4.0 – 6.0 mL
4
16.0 – 24.0 mL
Biomarker samples
1.2 mL
2
2.4 mL
Cycle 2
Safety
Hematology
2.5 – 5.0 mL
2
5.0 –10.0 mL
Serum chemistry
2.5 – 5.0 mL
2
5.0 –10.0 mL
Serum -hCG pregnancy testsd
2.5 mL
1
2.5 mL
Cycle 3
Safety
Hematology
2.5 – 5.0 mL
2
5.0 –10.0 mL
Serum chemistry
2.5 – 5.0 mL
2
5.0 –10.0 mL
Serum -hCG pregnancy testsd
2.5 mL
1
2.5 mL
Pharmacodynamic samples
4.0 – 6.0 mL
1f
4.0 – 6.0 mL
Biomarker samples
1.2 mL
1f
1.2 mL
End-of-Treatment Visit
Safety
Hematology
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Serum chemistry
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Pharmacodynamic samples
4.0 – 6.0 mL
1
4.0 – 6.0 mL
Biomarker samples
1.2 mL
1
1.2 mL
First Follow-up Assessment
Safety
Tetanus, pneumococcal titersg
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Monotherapy Cycle 1-3 (if applicable)
Safety
Hematology
2.5 – 5.0 mL
3
7.5 – 15.0 mL
Serum chemistry
2.5 – 5.0 mL
3
7.5 – 15.0 mL
Serum -hCG pregnancy testsd
2.5 mL
3
7.5 mL
End-of-Monotherapy Visit (if applicable)
Safety
Hematology
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Serum chemistry
2.5 – 5.0 mL
1
2.5 – 5.0 mL
Pharmacodynamic samples
4.0 – 6.0 mL
1
4.0 – 6.0 mL
Biomarker samples
1.2 mL
1
1.2 mL
Approximate Totalh
131.4 – 222.9 mL
-hCG=beta-human chorionic gonadotropin; HIV=human immunodeficiency virus.
a.
Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples. 
b.
Sample volumes will be adjusted according to standards for pediatric subjects.
c. Calculated as number of samples multiplied by amount of blood per sample.
d. Serum pregnancy test to be performed only if urine is unavailable.
e.
The 4 pharmacokinetic samples are collected on a single day in Cycle 1 (on Day 14) OR Cycle 2 Day 1. 
f. These pharmacodynamic and biomarker samples may be collected in Cycle 1 (on Day 14) OR Cycle 2 or Cycle 3 (predose 
only).
g. Subjects who enter monotherapy will have sample taken at End-of-Monotherapy Visit
h. An additional biomarker sample may be taken if PD occurs during a follow-up visit
Note: An indwelling intravenous cannula may be used for blood sample collection. 


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INVESTIGATOR AGREEMENT
PPD

SAP_001.pdf: 
1
Janssen Research & Development 
Statistical Analysis Plan
A Randomized, Open-label, Safety and Efficacy Study of Ibrutinib in Pediatric and Young 
Adult Patients With Relapsed or Refractory Mature B-cell non-Hodgkin Lymphoma
Protocol 54179060LYM3003; Phase 3
JNJ 54179060  (Ibrutinib)
Status:  
Approved
Date:
4 October 2017
Prepared by:
Janssen Research & Development, LLC
Document No.:
EDMS-ERI-144479215, 1.0
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.
NCT02703272


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 3
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
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 ................................................................................................ 9
2.1.
Visit Windows................................................................................................................................... 9
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 9
2.3.
Analysis Sets.................................................................................................................................... 9
2.3.1.
Efficacy Analysis Set .................................................................................................................... 9
2.3.2.
Safety Analysis Set....................................................................................................................... 9
2.4.
Definition of Subgroups.................................................................................................................... 9
2.5.
Study Day and Cycle Day .............................................................................................................. 10
2.6.
Baseline and Endpoint ................................................................................................................... 11
2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 11
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE ............................................................... 12
3.1.
Study Evaluation Team (SET) ....................................................................................................... 12
3.2.
Data Monitoring Committee (DMC)................................................................................................ 12
3.3.
Interim Analysis.............................................................................................................................. 13
4.
SUBJECT INFORMATION................................................................................................................ 13
4.1.
Demographics and Baseline Characteristics ................................................................................. 13
4.2.
Subject Disposition......................................................................................................................... 14
4.3.
Exposure Related Definitions......................................................................................................... 14
4.4.
Extent of Exposure......................................................................................................................... 15
4.5.
Protocol Deviations ........................................................................................................................ 15
4.6.
Prior and Concomitant Medications ............................................................................................... 15
5.
EFFICACY ......................................................................................................................................... 15
5.1.
Analysis Specifications................................................................................................................... 17
5.2.
Level of Significance ...................................................................................................................... 17
5.3.
Data Handling Rules ...................................................................................................................... 17
5.3.1.
General Analysis Considerations ............................................................................................... 18
5.4.
Primary Efficacy Endpoint.............................................................................................................. 18
5.4.1.
Event-free Survival (EFS) Based on IRC ................................................................................... 18
5.4.2.
Primary Analysis Methods for EFS............................................................................................. 18
5.4.3.
Sensitivity Analysis of EFS ......................................................................................................... 19
5.4.4.
Long-term Survival for EFS ........................................................................................................ 19
5.4.5.
Subgroup Analysis of EFS.......................................................................................................... 19
5.5.
Secondary Endpoints..................................................................................................................... 19
5.5.1.
Overall Survival........................................................................................................................... 19
5.5.2.
Sensitivity Analysis of Overall Survival....................................................................................... 20
5.5.3.
Overall Response Rate............................................................................................................... 20
5.5.4.
Tumor Volume Reduction Rate .................................................................................................. 20
5.5.5.
Time to Response....................................................................................................................... 20
5.5.6.
Subjects Who Proceed to Stem Cell Transplantation ................................................................ 21


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5.5.7.
Other Efficacy Endpoints ............................................................................................................ 21
6.
SAFETY............................................................................................................................................. 21
6.1.
Adverse Events .............................................................................................................................. 21
6.1.1.
All Adverse Events...................................................................................................................... 22
6.2.
Adverse Events of Clinical Interest and Other Safety Observations ............................................. 23
6.3.
Deaths............................................................................................................................................ 23
6.4.
Clinical Laboratory Tests................................................................................................................ 23
6.4.1.
Creatinine Clearance.................................................................................................................. 24
6.5.
Electrocardiogram.......................................................................................................................... 24
7.
PHARMACOKINETICS AND PHARMACODYNAMICS ANALYSIS ............................................... 24
8.
BIOMARKER ANALYSIS.................................................................................................................. 25
9.
CHANGES TO PROTOCOL SPECIFIED ANALYSES..................................................................... 25
10.
REFERENCES................................................................................................................................... 25
ATTACHMENT 1:
ADVERSE EVENTS OF SPECIAL INTEREST ........................................................ 26
LIST OF IN-TEXT TABLES
Table 1:
Subgroup Definitions................................................................................................................. 10
Table 2:
Stopping Boundaries (N=72 subjects, 2 Analyses) .................................................................. 13
Table 3:
Summary of Efficacy Analyses to be Performed ...................................................................... 16
Table 4:
Summary of Adverse Event Analyses to be Performed ........................................................... 22


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ABBREVIATIONS
ANC
absolute neutrophil count
AUC
area under the plasma concentration-time curve
B-AL
Burkitt leukemia
B-ALL
B-cell acute lymphoblastic leukemia
BCR
B-cell receptor
β-hCG
beta-human chorionic gonadotropin
BL
Burkitt lymphoma
BLL
Burkitt-like lymphoma
BSA
body surface area
BTK
Bruton’s tyrosine kinase
CIT
chemoimmunotherapy
CL/F
apparent (oral) plasma clearance
CLL
chronic lymphocytic leukemia
Cmax
maximum observed plasma concentration
CNS
central nervous system
CR
complete response
CRb
complete response biopsy-negative 
CRF
case report form 
CRu
unconfirmed complete response
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
DMC
Data Monitoring committee
ECG
electrocardiogram
eDC
electronic data capture
EFS
event-free survival
EICNHL
European Intergroup Collaboration for Childhood non-Hodgkin Lymphoma
EMA
European Medicines Agency
GCB
germinal center B-cell like
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
ILD
interstitial lung disease
IRB
Institutional Review Board
IRC
Independent Review Committee
ITT
intent-to-treat
IWRS
interactive web response system
LVEF
left ventricular ejection fraction
MCL
mantle cell lymphoma
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition scan
NCI
National Cancer Institute 
NHL
non-Hodgkin lymphoma
ORR
overall response rate
PBPK
physiologically-based pharmacokinetic
PD
progressive disease
PET
positron emission tomography
P-gp
P-glycoprotein
PQC
Product Quality Complaint
PR
partial response
RICE
rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone
RVICI
rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone
SET
Study Evaluation Team


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SF
shortening fraction
SJS
Stevens-Johnson Syndrome
SLL
small lymphocytic lymphoma
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
Vd/F
apparent (oral) volume of distribution


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1.
INTRODUCTION
This clinical study is a part of a comprehensive ibrutinib clinical development plan to evaluate 
the safety and efficacy of ibrutinib for subjects with B-cell malignancies. This is a 2-part, 
multicenter study. A safety and pharmacokinetic run-in part (Part 1) will be conducted before 
starting the randomized part (Part 2) of the study. Part 2 is a randomized, open-label, Phase 3 
study to compare the safety and efficacy of ibrutinib in combination with chemoimmunotherapy 
(CIT [RICE or RVICI]) versus CIT alone in children and young adult subjects with relapsed or 
refractory mature B-cell non-Hodgkin’s lymphoma (NHL).
The purpose of the statistical analysis plan (SAP) is to lay out key elements including definition 
and statistical methods for the planned analyses for the primary, secondary and safety endpoints.
1.1.
Trial Objectives
Primary Objective

Run-in Part (Part 1): Confirm that the pharmacokinetics in pediatric subjects is consistent 
with that in adults.

Randomized Part (Part 2): Assess efficacy (event-free survival [EFS]) of ibrutinib in
combination with RICE or RVICI background therapy compared to RICE or RVICI 
background therapy alone.
Secondary Objectives
The secondary objectives for Run-in Part (Part 1) are:

Evaluate the safety and tolerability of ibrutinib in combination with RICE or RVICI 
background therapy in pediatric subjects with B-cell malignancies

Assess anti-tumor activity of ibrutinib as add-on to RICE or RVICI regimens

Assess disease-specific biomarkers

Assess the pharmacodynamic response

Acceptability and palatability assessment of all ibrutinib formulations
The secondary objectives for Randomized Part (Part 2) are:

Evaluate the safety and tolerability of ibrutinib in combination with RICE or RVICI 
background therapy in pediatric subjects and young adults with B-cell malignancies

Determine the overall response rate (ORR)

Evaluate tumor volume reduction at Day 14

Determine the number and proportion of subjects who proceed to stem cell transplantation

Evaluate the time to response


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
Measure the duration of response

Evaluate long-term survival (EFS at 2 and 3 years)

Evaluate overall survival

Assess disease-specific biomarkers

Assess the pharmacodynamic response, if deemed appropriate based on Part 1 results

Assess the population pharmacokinetics of ibrutinib in pediatric subjects and young adults 

Acceptability and palatability assessment of all ibrutinib formulations
1.2.
Trial Design
This is a 2-part, multicenter study. A safety and pharmacokinetic run-in part (Part 1) will be 
conducted before starting the randomized part (Part 2) of the study. Part 2 is a randomized, 
open-label, Phase 3 study to compare the safety and efficacy of ibrutinib in combination with 
CIT (RICE or RVICI) versus CIT alone in children and young adult subjects with relapsed or 
refractory mature B-cell NHL. All subjects in Part 1 will receive ibrutinib in combination with 
CIT (investigator choice of RICE or RVICI); 6 to approximately 24 pediatric subjects (1 to 
<18 years) will be enrolled to allow confirmation of the dose regimen. Enrollment will begin 
with children in the 2 older age groups (6-11, 12-17 years) to assess pharmacokinetic and safety 
data before allowing enrollment of children in the youngest age group (1-5 years). The SET will 
meet to decide on any changes to the starting dose for each age group, and when enrollment may 
begin for the youngest age group. At a minimum, the first 2 subjects in each age group will 
enroll into Part 1 before recruitment of children in that age group will begin in Part 2. In Part 2, 
approximately 72 additional subjects will be randomized in a 2:1 ratio to receive ibrutinib in 
combination with CIT (investigator choice of RICE or RVICI) or CIT alone; at least 40 subjects 
are targeted to be of age 1 to <18 years and at least 10 of the 40 subjects are targeted to be age 
<11 years. Subjects will be stratified by histology (Burkitt lymphoma [BL]/Burkitt leukemia 
[B-AL] versus other) and by background therapy (RICE versus RVICI). Pharmacokinetic 
samples will be obtained during Part 2 of the study to characterize the pharmacokinetics in 
pediatric subjects. 
Part 1 and Part 2 of the study will be conducted in 3 phases: a Pretreatment (Screening) Phase, a 
Treatment Phase, and a Posttreatment Phase. The Treatment Phase will extend from 
enrollment/randomization until 1 of the following: 1) completion of 3 cycles of therapy, 
2) transplantation, if clinically indicated, or 3) disease progression, whichever comes first. 
Subjects will begin the Posttreatment Phase after completion of combination therapy. During the 
Posttreatment Phase, subjects on ibrutinib with a response of PR or better will continue on 
ibrutinib monotherapy for three 28-day cycles as described below (see Dosage and 
Administration). All subjects will be followed to assess disease progression as described below 
(see Efficacy Evaluations/Endpoints). The Posttreatment Phase will continue until death, loss to 
follow up, consent withdrawal, or study end, whichever occurs first. The end of study is defined 
as when approximately 60 EFS events have occurred in Part 2 (death, disease progression, or 


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lack of CR or PR after 3 cycles of treatment based on blinded independent event review), or the 
sponsor terminates the study, whichever comes first.
1.3.
Statistical Hypotheses for Trial Objectives
The primary statistical hypothesis of this study is that the addition of ibrutinib to a salvage CIT 
regimen will extend EFS compared to CIT alone in pediatric and young adult subjects with 
relapsed or refractory mature B-cell NHL.
For the primary efficacy analysis, EFS will be compared between treatment groups using a 
non-stratified log-rank test. The estimate of the hazard ratio between the 2 treatment groups and 
its associated 90% confidence interval will be computed based on the non-stratified Cox 
proportional hazards model.
1.4.
Sample Size Justification
Since Part 1 is to confirm that the pharmacokinetics in pediatric subjects is consistent with 
adults, no formal power calculations to pre-determine sample size were performed. The required 
number of subjects in Part 1 is based on pharmacokinetics results and clinical judgment. 
In Part 2, approximately 72 subjects will be randomized. The sample size calculation for the 
randomized part (Part 2) is based on the assumption of 100% improvement (hazard ratio = 0.5) 
in median EFS in subjects receiving ibrutinib plus CIT (RICE or RVICI) compared with CIT 
(RICE or RVICI) (10 months versus 5 months). Utilizing a 2:1 randomization, this study will 
enroll approximately 72 subjects (approximately 48 subjects treated with ibrutinib [and RICE or 
RVICI background therapy]) during Part 2. Based on a total of 60 events for the 2 treatment 
groups, this study will have at least 80% power, given a 1-sided alpha of 0.05. An accrual rate of 
1.44 subjects per month will result in a study duration of approximately 4.2 years.
1.5.
Randomization and Blinding
Central randomization will be implemented in Part 2 of this study. Subjects will be randomly 
assigned to 1 of 2 treatment groups based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. The randomization will be 
balanced by using randomly permuted blocks and will be stratified by histology and background 
therapy, then randomized in a 2:1 ratio to either Treatment Arm A (ibrutinib and RICE or RVICI 
background therapy) or Treatment Arm B (RICE or RVICI background therapy only). The 
interactive web response system (IWRS) will assign a unique treatment code, which will dictate 
the treatment assignment and matching study drug kit for the subject. The requestor must use his 
or her own user identification and personal identification number when contacting the IWRS, 
and will then provide the relevant subject details to uniquely identify the subject.
As this is an open-label study, blinding procedures are not applicable.


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2.
GENERAL ANALYSIS DEFINITIONS
Part 1 and Part 2 will be analyzed separately. The below specifications apply mainly to Part 2 
unless otherwise noted.    
2.1.
Visit Windows
Visit windowing will be based on phases and cycles:
Pretreatment (Screening) Phase: The Screening Phase will occur within 14 days before 
administration of study drug.
Treatment Phase: The Treatment Phase will extend from enrollment/randomization until 1 of 
the following: 1) completion of 3 cycles of therapy, 2) transplantation, if clinically indicated, or 
3) disease progression, whichever comes first.
Posttreatment Phase: Subjects will begin the Posttreatment Phase after completion of 
combination therapy. This is defined as starting from the last dose of study medication + 1 day 
until death, loss to follow up, consent withdrawal, or study end, whichever occurs first.
2.2.
Pooling Algorithm for Analysis Centers 
The data from all investigative centers (study sites) will be pooled for all analyses. 
2.3.
Analysis Sets
2.3.1.
Efficacy Analysis Set
The intent-to-treat (ITT) Population will consist of all randomized subjects; subjects will be 
analyzed based on randomization, regardless of study drug received. The ITT population will be 
used for all efficacy analyses, subject disposition and biomarker analyses. The primary efficacy 
analysis is based on the ITT population for data collected in the Part 2. For Part 1, efficacy will 
be provided as a secondary endpoint.
2.3.2.
Safety Analysis Set
The Safety population will consist of all subjects who received at least 1 dose of treatment. The 
safety population will be used for all safety analyses and subjects will be analyzed based on 
actual study drug received. 
2.4.
Definition of Subgroups
Subgroup analysis will be performed for the selected variables to assess the internal consistency 
of the treatment benefit and/or safety (Table 1). The subgroup variables and the cutoff values are 
subject to change if warranted to better represent the data.


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Table 1:
Subgroup Definitions
Subgroup
Definition of Subgroup
Analysis Type
Age
1-5 years, 6-11 years, 12-17 years
D, E, S
Sex
Male, Female
D, E, S
Race
White, Non-White
D, E, S
Histology/Diagnosis  
Burkitt lymphoma [BL]/Burkitt leukemia 
[B-AL] versus DLBCL vs. other
E
Background therapy 
RICE versus RVICI
E
Geographic region
United States, Europe including Eastern 
Europe, and Other
D, E, S
Elevated LDH at Baseline
No (<350 U/L), Yes (350 U/L)
E
Phosphor-BTK, as well as SYK, STAT3, 
caspase-3, BCL-xL, and cIAP1 expression 
B-cell Proteomics
E
B-cell receptor (BCR)/CD79B, CARD11, and 
MYD mutations
BCR pathway mutations
E
c-MYC, immunoglobulin, and T-cell receptor 
gene rearrangements at baseline
Baseline genetics
E
Concomitant use of any CYP3A inhibitor 
Yes, No
S
Insert table abbreviations
Cytopenia is defined as yes if platelet count ≤ 100,000/uL, Hgb ≤ 11g/dL, or ANC ≤ 1500/uL is observed.
analysis type D= demographic and baseline disease characteristics
analysis type E= efficacy (EFS, OS, ORR)
analysis type S= safety (adverse events) 
2.5.
Study Day and Cycle Day
Assessments will be presented chronologically by study day or cycle day as described below. 
For efficacy data, the randomization date is considered as the reference date (Day 1). For safety 
data, date of first dose of study medication (randomization date for subjects who have been 
randomized but not treated) will be used as the reference date (Day 1).
Reference date (Day 1) = randomization date (for efficacy data), or first dose date of study 
medication (for safety data).
Study Day = assessment date – reference date + 1 for assessment performed on or after the 
reference date; assessment date – reference date for assessment performed before the reference 
date. 
Cycle Day = assessment date - date of the first dose for the cycle + 1. 
Cycles
In defining treatment cycles in a combination therapy setting, the entire combination must be 
taken into account. Therefore, the nominal cycles as defined in protocol and recorded on the 
Case Report Form (CRF) will be used in the statistical analyses.


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Cycles will be 28 days long; however, if count recovery occurs quickly and the investigator 
deems a subject ready to proceed with the next cycle of therapy, cycles can be shortened to as 
few as 21 days. As long as there is no disease progression after Cycle 1 or 2, a second and third 
cycle of therapy will be given, respectively.
2.6.
Baseline and Endpoint 
Unless specified otherwise, the baseline value is defined as the last non-missing value collected 
on or before the administration of the first dose of study medication. For subjects who have been 
randomized but not treated with any dose, randomization date will be used as the reference date 
for baseline value calculation.
2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
In general, imputation of missing dates will be made for AE onset date, AE resolution date, date 
of death, start and end dates of prior, concomitant and subsequent therapies, and date of initial 
diagnosis according to the following rules. Start date will be imputed before end date.  

If date is completely missing, no imputation will be made. 

If year is missing, no imputation will be made.

If only year is present but month and day are missing, then June 30th will be used.

If only day is missing but year and month are available, then the 15th of the month will be 
used. 
However, the above imputations will be modified by the following rules:

For initial diagnosis if such imputed date is on or after the randomization date, then 
randomization date - 1 will be used. 

If such imputed date for prior therapies or initial diagnosis is on or after the randomization 
date, then randomization date - 1 will be used. If such imputed date for subsequent therapies 
is before date of last dose, then date of last dose +1 will be used.

The imputed start date for subsequent therapies will be adjusted sequentially using the 
following steps:

If the imputed start date is before the treatment discontinuation date or last dose date if 
no treatment discontinuation date but in the same year and month, then the treatment 
discontinuation date or last dose date if no treatment discontinuation date will be used. 

If subsequent therapy end date is not missing and is before the imputed subsequent 
therapy start date, then the subsequent therapy end date will be used as the start date.

If the imputed date is for a date of death and is before the last date that the subject is known 
to be alive, the latter date will be used.

The imputed AE start date will be adjusted sequentially using the following steps:

If the imputed date is in the same year and month as but day before the first dose date, 
then the first dose date will be used, or if it is in the same year and month as but day 
after the last dose date + 30 days, then the last dose date + 30 days will be used. 


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
If AE end date is not missing and the imputed AE start date is after the AE end date, 
then the AE end date will be used.

If the imputed AE start date and is after date of death, then date of death will be used

If the imputed AE start date is in the same month and year but after the 1st subsequent 
therapy start date, then 1st subsequent therapy start date will be used.

If the imputed date is for an AE end date and is after the death date, then the death date will 
be used, or if the imputed AE end date is before the AE start date, then the AE start date will 
be used.

The AE imputation rule will be used for concomitant medication.
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE 
3.1.
Study Evaluation Team (SET)
A SET composed of study investigators and internal sponsor team members will convene (for all 
subjects in Part 1 and the first 2 subjects in each age group if not enrolled until Part 2) to evaluate 
the safety of ibrutinib in combination with CIT to determine if the dose is appropriate and when 
enrollment may start in the youngest age group. Safety review by the SET will include 
non-hematologic toxicities that required withholding study treatment for more than 10 days or 
cardiac rhythm abnormalities in those subjects receiving RVICI.
3.2.
Data Monitoring Committee (DMC)
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in this study and review the interim analysis results. 
The DMC will consist of at least 1 medical expert in the relevant therapeutic area and at least 
1 statistician. The DMC responsibilities, authorities, and procedures will be documented in its 
charter.
The committee will meet periodically to review interim data. After the review, the DMC will 
make recommendations regarding the continuation of the study. The details will be provided in a 
separate DMC charter. At the interim analysis, the DMC may recommend stopping the study for 
either futility or efficacy, if the pre-specified stopping boundary is crossed.


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3.3.
Interim Analysis 
During Part 2, an external DMC will be used for the review of safety and will conduct an interim 
analysis. The pre-planned interim analysis will be conducted when approximately 30 EFS events 
are reached. An external DMC will determine the appropriateness for early stopping using the 
nonbinding stopping rules (Table 2) as well as other efficacy and safety endpoints. The 1-sided 
p-value required for early stopping for futility is ≥0.367 and efficacy is ≤0.006 if there are 
30 EFS events at the interim analysis. This design employs the sequential testing approach as 
described by O’Brien and Fleming (1979)1 to preserve the Type–I error rate. 
Table 2:
Stopping Boundaries (N=72 subjects, 2 Analyses)
Analysis 
Number
EFS events 
Approximate 
Time
Number of 
Subjects
Cumulative Error
Stopping Boundary
p-value (1-sided)
Observed Hazard 
Ratio
Alpha
Beta
Efficacy
Futility
Efficacy
Futility
Efficacy
Futility
Interim  
30 (50%)
32 months 
46
0.006
0.07
≤0.006
≥0.367
<0.378
≥0.878
Final 
60 (100%)
50 months 
72 
0.050
0.2
≤0.048
--------
<0.632
--------
EFS=event-free survival.
4.
SUBJECT INFORMATION
All statistical analyses will be performed using statistical analysis system (SAS®). Analyses of 
disposition, demographic, baseline disease characteristics, and prior and concomitant therapy
will be conducted on the ITT population. Analyses of treatment compliance and extent of 
exposure will be conducted on the safety population. No statistical testing is planned.
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 (SD), median, minimum, and maximum. All categorical endpoints will be 
summarized using frequencies and percentages. Percentages will be calculated by dividing the 
number of subjects with the characteristic of interest by the number of subjects in the analysis 
population.
4.1.
Demographics and Baseline Characteristics
Subject demographics and baseline disease characteristics will be summarized using descriptive 
statistics.

Demographics and baseline characteristics: age, sex, race, ethnicity, geographic region, 
height (cm), weight (kg), systolic blood pressure/diastolic pressure (SBP/DBP (mmHg), 
body surface area (m2)


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
Baseline disease characteristics: time from initial diagnosis to randomization; time from 
progression/relapse 
since 
last 
line 
of 
treatment 
to 
randomization;
diagnosis 
(relapsed/refractory BL, Burkitt-like lymphoma, B-AL, diffuse large B-cell lymphoma 
(DLBCL), DLBCL not otherwise specified, or other pediatric mature B-cell NHL.);
Lansky-Karnofsky performance status; cytopenia; Phosphor-BTK, as well as SYK, STAT3, 
caspase-3, BCL-xL, and cIAP1 expression; B-cell receptor (BCR)/CD79B, CARD11, and 
MYD mutations; c-MYC; immunoglobulin; T-cell receptor gene rearrangements; and drug 
acceptability and palatability assessment (Visual analog scale)

Hematology: hemoglobin, platelet count, white blood cell count, absolute neutrophil count,
absolute lymphocyte count

Chemistry: sodium, potassium, blood urea nitrogen, creatinine, aspartate aminotransferase, 
albumin, alkaline phosphatase, total bilirubin, lactic acid dehydrogenase, uric acid, alanine 
aminotransferase
4.2.
Subject Disposition
Disposition information will be summarized for the ITT population and safety population. 
Subject enrollment will be summarized by region, country, and investigator. The number of 
subjects undergoing, discontinuing, and completing the study treatment as well as their reasons 
for treatment discontinuation will be summarized. 
Descriptive statistics will be provided for time on study. Time on study is defined the same way 
as OS with reversed censoring, ie, subjects who died will be censored. Based on this definition, 
time on study is the same as length of follow up. The Kaplan-Meier method will be used to 
estimate the median time on study.
4.3.
Exposure Related Definitions  
Treatment duration is the interval between date of first dose and end-of-treatment date. If date of 
end of treatment is not available, use last available treatment date.
Number of treatment cycles = the last cycle number - the first cycle number + 1.
The individual anticancer drugs that make up study treatment should be summarized separately. 
For the treatment phase, dosing information includes total dose received (the sum of actual dose 
administered), average dose level per administration (the ratio of total dose and treatment 
duration in cycles), and relative dose intensity:
  	
	  	
	 	 
	   ℎ  
Use the highest level of dose reduction to summarize categories - ‘One dose reduction’ and ‘Two 
dose reductions’. 


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4.4.
Extent of Exposure
Descriptive statistics (n, mean, standard deviation, median, and range) will be provided for total 
number of cycles, treatment duration, and dosing information for all study medications 
(ibrutinib, rituximab, ifosfamide, carboplatin, etoposide, vincristine, idarubicin, and 
dexamethasone).  
The number and percentage of subjects with dose reduction and dose interruption will be 
summarized. In addition, subjects with dose modifications and reasons for dose modifications 
will be summarized. 
Details of exposure related definition is specified in Section 4.3.
4.5.
Protocol Deviations
Subjects with eligibility and major protocol deviations will be listed by treatment group.
Protocol deviations will be based on clinical review, but not limited to, the following aspects: 
(1) eligibility criteria, (2) patient safety, (3) efficacy assessment deviation, and (4) treatment 
compliance. Protocol deviations will be closely monitored during the execution of the study and 
the final set of protocol deviation criteria will be finalized before database lock.
4.6.
Prior and Concomitant Medications
For summarization purposes, medications will be coded to a generic term based on the World 
Health Organization (WHO) dictionary. Medications administered prior to the first dose of study 
medication will be considered prior medications. Concomitant therapies include those taken on 
or after first dose date through the date of last dose of study drug. Using this definition, a 
medication can be classified as both prior and concomitant.
Incidence of prior and concomitant medications will be summarized by Anatomical Therapeutic 
Chemical (ATC) class and drug generic term. Prior anticancer therapy will be summarized by 
type (eg, radiotherapy, surgery, chemotherapy). Best response to last line of prior therapy will 
also be summarized.
The following concomitant medications of special interest will also be summarized:

Anti-coagulation and anti-platelets.

CYP3A inhibitors/inducers

Growth factors/ cytokines by background therapy 

Transfusions
5.
EFFICACY
Analysis of efficacy endpoints will be conducted on the ITT population. Table 3 summarizes the 
efficacy endpoints and analysis methods to be performed.


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Table 3:
Summary of Efficacy Analyses to be Performed
Endpoint
Analysis
Analysis Method
Population
Primary
Event-free Survival 
(EFS) as assessed by 
IRC
Primary
Non-stratified log-rank test, non-stratified Cox regression 
model, all PD and death considered as events regardless of 
subsequent antilymphoma therapy or a conditioning regimen 
for stem cell transplantation. EFS is defined as the time 
interval from randomization to death, disease progression, or 
lack of CR or PR after 3 cycles of treatment.
ITT
Sensitivity 1)
Alternative censoring rule 1: subjects who received 
subsequent antilymphoma therapy or a conditioning 
regimen for cell transplantation are considered to have 
had an EFS event at the initiation of subsequent therapy
2)
Alternative censoring rule 2: subjects who received 
subsequent antilymphoma therapy or a conditioning 
regimen for cell transplantation are censored at the last 
disease assessment showing no evidence of PD before 
the use of subsequent therapy
3)
Alternative censoring rule 3: subjects will be censored at 
the last disease assessment if they progress, die or have
not responded after missing ≥2 planned disease 
assessment visits.
4)
Investigator assessed EFS by non-stratified log-rank test 
and non-stratified Cox regression model; concordance 
rate between the IRC-determined EFS and investigator-
determined EFS 
ITT
Subgroup 
Non-stratified Cox regression model within each subgroup
ITT
Secondary
Long-term survival 
(EFS) at 2 and 3 
years
IRC assessed chi-square test for 2 and 3 year EFS rate. 
ITT
Overall Survival
Primary
Non-stratified log-rank test, non-stratified Cox regression 
model, as the time interval from enrollment (Part 1) or 
randomization (Part 2) to all deaths considered as events 
regardless of subsequent antilymphoma therapy or a 
conditioning regimen for stem cell transplantation.
ITT
Sensitivity Censored at subsequent antilymphoma therapy or a 
conditioning regimen for stem cell transplantation.
Subgroup
Non-stratified Cox regression model within each subgroup
ITT
Overall Response in 
Part 1
Listing of IRC and investigator assessments for those subjects 
who respond. 
Enrolled 
subjects
Overall Response 
Rate in Part 2
Primary
IRC assessed ORR chi-square test, Logistic regression model
ITT subjects 
with measurable 
disease at 
baseline
Sensitivity Investigator assessed ORR chi-square test, Logistic 
regression model
Subgroup
Logistic regression model
Tumor Volume 
Reduction Rate
Analysis of variance (t-test) for percent decrease in the sum 
of the products of the lesion diameters at Day 14
ITT subjects 
with measurable 
disease at 
baseline
Time to Response
Non-stratified log-rank test, as the time interval from 
randomization to response for those subjects who respond as 
ITT subjects
who responded


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Table 3:
Summary of Efficacy Analyses to be Performed
Endpoint
Analysis
Analysis Method
Population
assessed by IRC.
Duration of Response
Non-stratified log-rank test, as the time interval from date of 
initial documentation of a response to the date of first 
documented evidence of progressive disease (PD) or death as 
assessed by IRC.
ITT subjects
who responded
Rate of Subjects Who 
Proceed to Stem Cell 
Transplantation
Chi-square test for percent of subjects who proceed to stem 
cell transportation, Logistic regression model.
ITT
Other 
Subsequent Therapy
Descriptive summary
Non-stratified log-rank test for the effect of subsequent 
antilymphoma therapy or a conditioning regimen for stem 
cell transplantation on overall survival, will be performed, as 
appropriate.
ITT subjects 
Risk factors
Non-stratified Cox proportional hazards model using 
covariates to analyze the effect on EFS and survival will be 
performed, as appropriate. 
ITT
5.1.
Analysis Specifications
5.2.
Level of Significance
All statistical testing will be performed using a 2-sided test at the 10% level of significance,
unless otherwise noted. Confidence intervals will be presented as 2-sided 90% confidence 
intervals.
Testing of Secondary Endpoints
The secondary endpoints are to be tested sequentially at the nominal 0.10 significance level
(2-sided). The order of these endpoints is as follows: 
1.
ORR
2. Rate of subjects who proceed to stem cell transplantation
3. Duration of Response
4.
OS
5. Tumor volume reduction rate
6. Time to Response
A secondary hypothesis will be tested if and only if the primary hypothesis is rejected along with 
all the secondary hypotheses that precede it.
5.3.
Data Handling Rules
Unless specified otherwise, imputation rules for missing and partial dates are described in 
Section 2.7. 


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5.3.1.
General Analysis Considerations
Descriptive statistics and subject listings will be used to summarize the data. For continuous 
variables, the number of observations, means, standard deviations, medians, and ranges will be 
used. For discrete variables, frequency will be provided. For time-to-event variables, 
Kaplan-Meier estimates will be provided.
Comparisons between the 2 treatment arms in Part 2 will be performed as follows: for the 
continuous variables representing change from baseline to a particular postbaseline timepoint, 
analysis of variance will be used. For discrete variables, Chi-square test will be used. For 
time-to-event variables, non-stratified log-rank test and non-stratified Cox proportion hazard 
model will be used unless specified otherwise. All tests will be conducted at 2-sided test at the 
10% level of significance and 90% confidence intervals will be provided, unless otherwise 
stated.
Unless otherwise specified, disease progression and disease response will be based on 
assessments from an IRC, according to principles adapted from the International Pediatric NHL 
Response Criteria (Sandlund 2015).2 Disease response will be evaluated by radiological imaging, 
physical examination, or other procedures as necessary, including but not limited to review of 
hematology, clinical chemistry, and lumbar puncture results. Criteria for response categories, as 
well as the process and convention of the IRC are detailed in a separate IRC charter.
5.4.
Primary Efficacy Endpoint
5.4.1.
Event-free Survival (EFS) Based on IRC
The primary efficacy endpoint is EFS in Part 2, which is defined as the time interval from 
randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment, 
based on blinded independent event review by the IRC, whichever occurs first. The process and 
conventions of the IRC will be detailed in a separate IRC charter. The analysis of the primary 
endpoint (EFS) will be based on the ITT population. 
5.4.2.
Primary Analysis Methods for EFS
Subjects who continue to respond after 3 cycles of treatment, are progression free and alive will 
be censored at the date of last disease assessment. Subjects with no baseline or any post-baseline 
disease assessment will be censored at the date of randomization.
The analysis of the primary endpoint (EFS) will be based on the ITT population. For the primary 
efficacy analysis, EFS will be compared between treatment groups using a non-stratified 
log-rank test. The Kaplan-Meier method will be used to estimate the distribution functions of 
EFS for each treatment group. The number of events, subjects censored, the estimate of medians, 
and 90% confidence interval for the medians will be presented. The plot of EFS using the 
Kaplan-Meier method will be presented. The estimate of the hazard ratio between the 2 treatment 
groups and its associated 90% confidence interval will be computed based on the non-stratified 
Cox proportional hazards model.


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5.4.3.
Sensitivity Analysis of EFS
Sensitivity analysis will be performed for EFS as follows:
1.
Use of subsequent antilymphoma therapy or a conditioning regimen for cell transplantation 
prior to documented PD or death.
Two alternative censoring rules will be performed for subjects who start subsequent therapy 
prior to first documentation of disease progression or death due to any cause: 
a.
Subjects will be considered to have had an EFS event at the initiation of subsequent 
therapy.
b.
Subjects will be censored at the last disease assessment showing no evidence of PD 
before the use of subsequent antineoplastic therapy.
2.
Disease assessment follow up: Subjects will be censored at the last disease assessment if 
they progress, die or have not responded after missing ≥2 planned disease assessment visits. 
3.
EFS based on investigator assessments: For this sensitivity analysis, the same censoring 
rules and analysis methods used for primary analysis of IRC reported EFS will be used.  The 
concordance rate between the IRC-determined EFS and investigator-determined EFS will be 
evaluated. The number and percentage of the following cases determined by investigator and 
by IRC will be cross-tabulated:
a.
PD events and censored cases
b.
CR or PR after 3 cycles of treatment
5.4.4.
Long-term Survival for EFS
To evaluate long-term survival for EFS the proportion of subjects with EFS at 2 and 3 years will 
be analyzed using a 2-sided chi-square test at the 10% level of significance. This will be done for 
IRC and investigator assessed EFS.  
5.4.5.
Subgroup Analysis of EFS
Subgroup analysis will be performed for the selected potential prognostic variables (as listed in 
Section 2.4) to assess the consistency and robustness of the treatment benefit for EFS. A 
non-stratified log-rank test analysis method for EFS will be used for each of the subgroup 
analyses. Median EFS with 90% CI, and hazard ratio between the 2 treatment groups within each 
subgroup and their 90% CI will be calculated using non-stratified Cox regression model. 
Subgroup analysis will be presented graphically in a forest plot.  
5.5.
Secondary Endpoints
5.5.1.
Overall Survival
Overall survival is defined as the duration from the date of enrollment (in Part 1) or 
randomization (in Part 2) to the date of the subject’s death. Overall survival will be analyzed 
using the non-stratified log-rank test for treatment comparison in Part 2. Survival time of living 
subjects will be censored on the last date a subject is known to be alive or lost to follow-up.


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The overall survival distribution and median overall survival with its 90% confidence interval 
will be estimated using the Kaplan-Meier product-limit method. The hazard ratio for 
ibrutinib+CIT relative to CIT alone and its associated 90% confidence interval will be calculated 
based on the non-stratified Cox proportional hazards model.
The same subgroup analysis used for EFS will be performed for OS if the number of events 
within each subgroup is sufficient.
5.5.2.
Sensitivity Analysis of Overall Survival
Sensitivity analysis will be performed for OS where censoring occurs at subsequent 
antilymphoma therapy or conditioning regimen for stem cell transplantation.
5.5.3.
Overall Response Rate
Overall response rate is defined as the proportion of subjects achieving a best overall response of 
either CR (including CRb and CRu) or PR as evaluated by IRC.
All randomized subjects with a measurable disease at baseline will be included in this analysis. 
Subjects with missing post-randomization data are considered non-responders. 
Overall response rate will be estimated according to the crude proportion of confirmed 
responders (PR or better) based on the best overall response and summarized by treatment arm. 
Overall response rate will be compared between treatment arms using a 2-sided chi-square test at 
the 10% level of significance and 90% confidence intervals.
The relative risk (ibrutinib + CIT vs. CIT) will be reported along with the associated 95% 
confidence interval. Statistical inference will be evaluated using Chi-square statistic. 
For overall response rate based on investigators’ assessment, same analysis methods used for 
IRC reported overall response will be used. 
Subgroup analysis for ORR may be performed if the number of responders within each subgroup 
is sufficient.
For enrolled subjects in Part 1, IRC and investigator response will be listed.
5.5.4.
Tumor Volume Reduction Rate
The tumor volume reduction rate will be measured as the mean change in the sum of the 
products of the lesion diameters (SPD) from baseline to Day 14. The means will be compared 
between treatment arms using a 2-sided t-test at the 10% level of significance. The mean 
difference and its associated 90% confidence interval will be provided.
5.5.5.
Time to Response
Time to response for subjects with either CR (including CRb and CRu) or PR as assessed by IRC 
is defined as the interval between the date of randomization and the date of initial documentation 


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of a response. Descriptive summary for time to response will be provided for each treatment 
group
Duration of Response
Duration of response for subjects achieving either CR (including CRb and CRu) or PR is defined
as the interval between date of initial documentation of a response to the date of first documented 
evidence of progressive disease (PD) or death as assessed by IRC. The distribution for duration 
of response and median survival time with its 90% confidence interval will be estimated using 
the Kaplan-Meier product-limit method.
5.5.6.
Subjects Who Proceed to Stem Cell Transplantation
The rate of subjects who proceed to stem cell transplantation will be estimated according to a 
proportion summarized by treatment arm. The rate will be compared between treatment arms 
using a 2-sided chi-square test at the 10% level of significance and 90% confidence intervals.
Logistic regression analysis will also be performed to estimate an odds ratio and the associated 
90% CI between the 2 treatment groups. 
5.5.7.
Other Efficacy Endpoints
Exploratory efficacy endpoints are as follows:

Non-stratified Cox proportional hazards model using covariates to analyze the effect on EFS 
and survival will be performed, as appropriate.

Non-stratified log-rank test for the effect of subsequent antilymphoma therapy or a 
conditioning regimen for stem cell transplantation on overall survival, will be performed as 
appropriate.

The number (%) of subjects with subsequent antilymphoma therapy or a conditioning 
regimen for stem cell transplantation will be summarized by therapy type. A listing of 
subjects with subsequent therapy will also be provided.
6.
SAFETY
Safety will be analyzed using the incidence and severity of AEs, laboratory tests, and 
electrocardiogram (ECG) measurements. Unless specified otherwise, all safety analyses will be 
based on the safety analysis set. Descriptive statistics will be reported for all safety data. 
Inferential statistics are not planned to be performed on safety data.
The baseline value for safety analysis is defined as the value collected at the time closest to and 
prior to the start of study medication.
Unless otherwise stated, safety data will be summarized by treatment arm as treated.
6.1.
Adverse Events
Table 4 provides a summary of adverse events analyses to be performed.


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Table 4:
Summary of Adverse Event Analyses to be Performed
Category
Analysis
Sorted By
Cut off
Drug-
Related 
TEAE
General
Overall summary

TEAEs
SOC+ PT+ toxicity grade;
PT+ toxicity grade
10%, 5%

Serious TEAEs
SOC+ PT + toxicity grade;
PT+ toxicity grade
2%

Grade 3 or worse TEAE
PT+ toxicity grade
2%

TEAEs leading to treatment 
discontinuation 
(ibrutinib+CIT/CIT)
PT + toxicity grade

TEAEs leading to death
PT + toxicity grade
TEAEs leading to dose
modification or modification 
(ibrutinib+CIT/CIT)
PT + toxicity grade
AEs of clinical interest
(Hemorrhagic events)
PT + toxicity grade
Other safety observations (eg,
other malignancies, eye disorder)
PT + toxicity grade
Deaths within 30 days of last dose Reason for death
Atrial Fibrillation and Atrial 
Flutter: overall summary 
Subgroup
Overall summary
TEAEs
SOC+ PT+ toxicity grade
Exposure adjusted 
incidence rate 
Overall summary
TEAEs
SOC+ PT+ toxicity grade;
PT+ toxicity grade
1 per 
100 patient 
month
Serious TEAEs
SOC+ PT + toxicity grade;
PT+ toxicity grade
0.1 per 
100 patient
month
6.1.1.
All Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA), version 19.0 or higher. These coded 
AE terms are referred to as preferred terms (PT); classification into System Organ Class (SOC) 
is a result of the coding process.
Treatment-emergent AEs (TEAEs) are defined as 1) those that occur in TEAE period as defined 
below 2) present before first dose, but worsened in toxicity grade during treatment; 3) had 
missing start date and its end date is during the treatment; 4) was a drug-related event.
Drug-related AEs are those assessed by investigator as being possible, probable, or very likely 


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related to study drug. To determine TEAE, partially missing AE start dates will be imputed 
according to the rules stated in Section 2.7.
For each TEAE, the percentage of subjects who experience at least 1 occurrence of the given 
event will be summarized. Tables will be sorted by frequency in incidence (the highest to lowest 
incidence). 
For subjects using CYP3A inhibitor during treatment-emergent period, all TEAEs will be 
summarized by SOC, PT, maximum severity, any CYP3A inhibitor (Yes vs. No), and strong 
CYP3A inhibitor (Yes vs. No). 
Treatment-Emergent Period
In general, the treatment-emergent period is defined as the time from first dose date through 
30 days after last dose date, or day before subsequent antilymphoma therapy or a conditioning 
regimen for stem cell transplantation, whichever occurs first.
6.2.
Adverse Events of Clinical Interest and Other Safety Observations
Hemorrhagic events will be identified by hemorrhage Standardized MedDRA Query [SMQ] 
excluding laboratory terms and be tabulated. Major hemorrhage is a subset of hemorrhagic 
events which are Grade ≥3 or serious or belong to central nervous system (CNS)
hemorrhage/hematoma (preferred terms are listed in Attachment 1).  
Other malignancies: are defined as new malignant tumors including solid tumors, skin 
malignancies and hematologic malignancies and 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.
Adverse events of interest and other safety observations will be summarized by treatment arms.
6.3.
Deaths
A summary of the number of deaths during the treatment phase and up to 30 days after last dose 
will be provided, along with the primary cause of death. In particular, frequencies of deaths due 
to study treatment-related adverse events will also be reported. A death is study medication-
related death if the primary cause is a drug related AE.
6.4.
Clinical Laboratory Tests
Laboratory data of hematology and serum chemistry up to 30 days after last dose or the end of 
treatment visit date, whichever is later, will be reported in SI units.
Laboratory results will be graded according to NCI-CTCAE version 4.03 or later. Note that 
toxicity grading for creatinine increase will be based on the NCI CTC v4.03 or later criteria, but 
limited only to the part based on the upper limit of normal (ULN), the other part, that is based on 
change from baseline, will not be used for toxicity grading. Generic normal ranges will be 
applied whenever reference ranges are not available. 


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The following laboratory tests will be analyzed:

Hematology: hemoglobin, platelet count, white blood cell count, absolute neutrophil count,
absolute lymphocyte count

Chemistry: sodium, potassium, blood urea nitrogen, creatinine, aspartate aminotransferase, 
albumin, alkaline phosphatase, total bilirubin, lactic acid dehydrogenase, uric acid, alanine 
aminotransferase

Serum or urine pregnancy testing for young women of childbearing potential only
Descriptive statistics (mean, standard deviation, median, and range) will be calculated for the 
raw data and for their changes from baseline at each timepoint of assessment as well as for the 
changes from baseline to the last value. Parameters will be summarized by toxicity grade. 
Change from baseline to the worst grade during the treatment will be provided as shift tables for 
selected parameters. In addition, treatment-emergent worsening in toxicity grade will be 
summarized for selected hematology and chemistry parameters. 
The frequencies of abnormal treatment emergent uric acid will be summarized by treatment arm.
6.4.1.
Creatinine Clearance
Creatinine clearance (CrCl) is calculated using Schwartz’s formula:
CrCl =
(k * Ht)
Crserum
Note: K =0.55 for girls and boys ≤10yrs
K=0.70 for boys > 10yrs     
6.5.
Electrocardiogram
QT prolongation and other clinically significant ECG abnormalities will be summarized and 
listed. Descriptive statistics will be calculated for the ECG parameters at baseline. 
The ECG parameters that will be summarized are heart rate, RR interval, QT interval, and QTc. 
The QTc will be computed using Bazett’s correction, ie, QTcB = /√, and Fridericia’s 
correction, ie, QTcF = /√

.
All treatment-emergent abnormal findings will be tabulated, displaying the number of subjects 
with abnormal findings after dosing up to the end (Day 28) of the last cycle. An abnormal 
finding is considered to be treatment-emergent if it occurred during treatment and up to 30 days 
after the last dose.
7.
PHARMACOKINETICS AND PHARMACODYNAMICS ANALYSIS
Details of analysis plan in PK/PD and results will be presented in a separate report.


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8.
BIOMARKER ANALYSIS
Details of analysis plan in biomarker and results will be presented in a separate report.
9.
CHANGES TO PROTOCOL SPECIFIED ANALYSES
10.
REFERENCES
1.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549-556.
2.
Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response 
Criteria. J Clin Oncol. 2015;33:2106-2111.


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ATTACHMENT 1:
ADVERSE EVENTS OF SPECIAL INTEREST
Preferred terms for CNS hemorrhage are as follows:

Acute haemorrhagic leukoencephalitis

Basal ganglia haemorrhage

Brain stem haemorrhage

Brain stem haematoma

Central nervous system haemorrhage

Cerebellar haematoma

Cerebellar haemorrhage

Cerebral arteriovenous malformation haemorrhagic

Cerebral haematoma

Cerebral haemorrhage

Cerebral microhaemorrhage

Encephalitis haemorrhagic

Epidural haemorrhage

Extradural haematoma

Haemorrhage intracranial

Haemorrhagic cerebral infarction

Haemorrhagic stroke

Haemorrhagic transformation stroke

Intracerebral haematoma evacuation

Intracranial haematoma

Intracranial tumour haemorrhage

Intraventricular haemorrhage

Pituitary haemorrhage

Putamen haemorrhage

Ruptured cerebral aneurysm

Spinal cord haemorrhage

Spinal epidural haematoma

Spinal epidural haemorrhage

Spinal subarachnoid haemorrhage

Spinal haematoma

Spinal subdural haematoma

Spinal subdural haemorrhage

Subarachnoid haemorrhage

Subdural haematoma

Subdural haemorrhage

Subgaleal haematoma

Thalamus haemorrhage