Clinical trial NCT05564052
Conditions: Lymphoma, Mantle-Cell
Sponsor: Janssen Research & Development, LLC
Start date: 2022-12-06; Completion date: 2024-09-26
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to provide continued access to treatment for participants who continue to benefit from treatment.

Detailed description:
Mantle cell lymphoma (MCL) is an uncommon and incurable clinicopathologic subtype of B-cell non-Hodgkin Lymphoma (NHL). Ibrutinib is a first-in-class potent, orally administered, covalently-binding small molecule inhibitor of Bruton's tyrosine kinase (BTKi) for the treatment of B-cell malignancies and chronic graft-versus-host disease. The primary hypothesis of the study is to provide continued access to treatment for participants who continue to benefit from treatment. The study will include a screening phase (up to 30 days prior to randomization), a treatment phase (from randomization until study treatment discontinuation). safety assessments include adverse events (AEs), serious adverse events (SAEs), clinical laboratory tests, vital signs, electrocardiogram (ECG), physical examination. The Phase 2 exploratory objectives and endpoints of characterization of pharmacokinetic and pharmacodynamic of ibrutinib may continue to be evaluated using blood samples already collected. The total duration of the study will be up to 2 years 1 month.

Arms: arm 1: Participants will receive rituximab 375 milligrams per meter square (mg/m\^2) intravenously (IV) on Day 1 of Cycles 1 to 6 with ibrutinib 560 milligrams (mg) orally, once daily starting on Day 1 of Cycle 1 until disease progression or unacceptable toxicity (each cycle length is 28 days). arm 2: Participants will receive rituximab 375 mg/m\^2 IV on Day 1 of Cycles 1 to 6 with ibrutinib 420 mg orally, once daily starting on Day 1 of Cycle 1 until disease progression or unacceptable toxicity (each cycle length is 28 days). arm 3: Participants will receive rituximab 375 mg/m\^2 IV on Day 1 of Cycles 1 to 6 with ibrutinib 140 mg orally, twice daily starting on Day 1 of Cycle 1 until disease progression or unacceptable toxicity (each cycle length is 28 days). arm 4: Participants will receive rituximab 375 mg/m\^2 IV on Day 1 of Cycles 1 to 6 (each cycle length is 21 or 28 days) with physician's choice of either lenalidomide 20 mg orally, once daily from Day 1 through Day 21 of 28-day cycle or bortezomib 1.3 mg/m\^2 IV or subcutaneously (SC) on Days 1, 4, 8 and 11 of a 21-day cycle until disease progression or unacceptable toxicity.
Interventions: intervention 1: Ibrutinib intervention 2: Lenalidomide intervention 3: Rituximab intervention 4: Bortezomib
Intervention descriptions: intervention 1: Ibrutinib capsules will be administered orally. intervention 2: Lenalidomide capsules will be administered orally. intervention 3: Rituximab will be administered IV. intervention 4: Bortezomib will be administered either intravenously or subcutaneously.

Protocol documents:
SAP_002.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 15 December 2023
Janssen Research & Development
Statistical Analysis Plan
Amendment 2
A Randomized, Controlled, Open-label, Multicenter, Inferentially Seamless Phase 2/3 
Study of Ibrutinib in Combination with Rituximab Versus Physician’s Choice of 
Lenalidomide Plus Rituximab or Bortezomib Plus Rituximab in Participants with 
Relapsed or Refractory Mantle Cell Lymphoma
Protocol 54179060MCL3004; Phase 2/3 Seamless Design
JNJ-54179060 (ibrutinib)
Status:
Approved
Date:
15 December 2023
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-RIM-651402, 3.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
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.
NCT05564052


JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 15 December 2023
STATISTICAL ANALYSIS PLAN AMENDMENT SUMMARY OF CHANGES TABLE
Document
Date
Amendment 2
15 December 2023
Amendment 1
28 September 2023
Original SAP
21 July 2022
Amendment 2 (15 December 2023)
Overall Rationale for the Amendment: Added ibrutinib 560 mg QD monotherapy analysis 
population, corresponding treatment phase and its safety analysis. See details listed below.
Section Number
and Name
Description of Change
Brief Rationale
4. Populations (Analysis 
Sets) for Analysis
Added Ibrutinib 560 mg QD Monotherapy 
Population
Analysis for participants 
switched to monotherapy
5.1 General Considerations
Added Ibrutinib 560 mg QD Monotherapy Phase
Monotherapy treatment 
phase
5.2 Participant 
Dispositions
Added participants who completed the study and 
removed the word “prematurely” from study 
termination
Participants who died or 
sponsor terminated study 
are considered completion 
of study. Others are 
considered study 
termination.
5.3 Safety Analyses
Added ibrutinib 560 mg QD monotherapy population
Safety analysis to be done 
separately after switching 
to monotherapy
5.3.1 Extent of Exposure
Added extent of exposure for ibrutinib 560 mg QD 
monotherapy group 
To separate treatment 
phase
5.3.2 Adverse Events
Added the same rules for defining treatment 
emergent adverse events for ibrutinib 560 mg QD 
monotherapy phase and distinguished the boundary 
timeframe between the last of the randomized 
treatment and ibrutinib 560 mg QD monotherapy 
phase.
Deleted the sentence of only including serious 
treatment emergent adverse events (TEAE, TEAEs 
leading to treatment discontinuation, and Grade ≥3 
TEAEs.
Removed the wording “death” from listing for 
serious TEAEs
Safety analysis to be done 
separately after switching 
to monotherapy
Follow original protocol to 
report all AEs.
Redundant: “TEAE with 
outcome of death” already 
listed
5.3.2.1 Adverse Events of 
Interest and Other Safety 
Observations
Added appropriate wording for additional other 
safety observations
Considering clinical 
relevancy
5.3.2.2 Death
Added the same rules for defining death count for 
ibrutinib 560 mg QD monotherapy phase and 
distinguished the boundary timeframe between the 
last of the randomized treatment and ibrutinib 560 
mg QD monotherapy phase.
Death is count separately 
after switching to ibrutinib 
560 mg QD monotherapy
5.3.3.1 Clinical Laboratory 
Tests
Removed creation of shift table.
Lab data is few for shift 
table.
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NCT05564052


JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 15 December 2023
Section Number
and Name
Description of Change
Brief Rationale
Evaluable Population” definition
Phase 2 populations: removed dose selection analysis 
setting
Phase 3 population deleted
collected for control arm 
post-treatment
As a result of the early 
study discontinuation
5.1 General Considerations
Post-treatment Follow-up Phase deleted
As a result of the early 
study discontinuation
5.3-5.6 Primary, 
Secondary, and Tertiary 
Endpoint(s) Analysis, 
Multiplicity Adjustment
Due to the early discontinuation of the study, an 
IDMC to monitor safety data, and to review efficacy 
data at interim analysis, is no longer required. 
Sections deleted
Updated as a result of the 
early study discontinuation 
and Objective of Protocol 
Amendment 1
5.3.2 Adverse Events 
Text updated: Only SAEs, Grade ≥3 AEs, and AEs 
leading to treatment discontinuation, regardless of 
seriousness, severity, or presumed relationship to 
study treatment, will be recorded using medical 
terminology in the source document and the eCRF
To clarify safety 
evaluations and safety data 
collection effective at the 
moment of implementation 
of Protocol Amendment 1 
5.3.3.4.2 Concomitant 
Medications
6.5 Appendix 5 Prior and 
Concomitant Medications
Text added: As of implementation of Protocol 
Amendment 1, only concomitant therapy related 
to SAEs and Grade ≥3 AEs up to 30 days after the 
last dose of study treatment, or until the start of 
subsequent anti-lymphoma, whichever is first, 
will be provided
Concomitant medications of special interest and 
Subgroup analysis by CYP3A deleted.
5.4.1 Pharmacokinetics
Text added: At the moment of implementation of 
Protocol Amendment 1, venous blood samples for 
ibrutinib analysis already collected (ibrutinib 
treatment arm only) may be analyzed for ibrutinib 
plasma concentration and may be used for further 
development of the existing population-based PK 
model. No further blood samples will be collected 
from participants for PK evaluation at the 
moment of implementation of protocol 
Amendment 1
Only blood samples 
already received before 
implementation of Protocol 
Amendment 1 can be used 
for PK analysis
6.3 Appendix 3 
Demographics and 
Baseline Characteristics
Baseline TP53 and Ki67 deleted.
Potential inconsistent data 
only collected by 
investigator
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT SUMMARY OF CHANGES TABLE .............................. 2
TABLE OF CONTENTS ............................................................................................................................... 5
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Objectives ........................................................................................................................................ 6
1.2.
Study Design.................................................................................................................................... 6
2.
STATISTICAL HYPOTHESES............................................................................................................ 6
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 6
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 6
5.
STATISTICAL ANALYSES................................................................................................................. 7
5.1.
General Considerations ................................................................................................................... 7
5.1.1.
Pooling Algorithm for Centers....................................................................................................... 7
5.1.2.
Imputation of Missing Date ........................................................................................................... 8
5.2.
Participant Dispositions.................................................................................................................... 9
5.3.
Safety Analyses ............................................................................................................................... 9
5.3.1.
Extent of Exposure ....................................................................................................................... 9
5.3.2.
Adverse Events........................................................................................................................... 10
5.3.2.1.
Adverse Events of Interest and Other Safety Observations.................................................... 11
5.3.2.2.
Death ....................................................................................................................................... 11
5.3.3.
Additional Safety Assessments .................................................................................................. 11
5.3.3.1.
Clinical Laboratory Tests......................................................................................................... 11
5.3.3.1.1.
Creatinine Clearance ........................................................................................................... 12
5.3.3.2.
Vital Signs................................................................................................................................ 12
5.3.3.3.
Electrocardiogram ................................................................................................................... 12
5.3.3.4.
Other Safety Parameters......................................................................................................... 12
5.3.3.4.1.
ECOG................................................................................................................................... 12
5.3.3.4.2.
Concomitant Medications..................................................................................................... 12
5.4.
Other Analyses............................................................................................................................... 13
5.4.1.
Pharmacokinetics ....................................................................................................................... 13
5.4.2.
Immunogenicity........................................................................................................................... 13
5.4.2.1.
Immunogenicity Analysis ......................................................................................................... 13
5.4.2.2.
Other Immunogenicity Analyses.............................................................................................. 13
5.4.3.
Pharmacodynamics .................................................................................................................... 13
5.4.4.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 13
5.4.5.
Biomarkers.................................................................................................................................. 13
6.
SUPPORTING DOCUMENTATION .................................................................................................. 14
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 14
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 15
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 16
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 17
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 18
6.6.
Appendix 6 Medical History ........................................................................................................... 19
6.7.
Appendix 7 Treatment Compliance................................................................................................ 20
6.8.
Appendix 8 Adverse Events of Interest.......................................................................................... 21
6.9.
Appendix 9 Medications of Special Interest................................................................................... 22
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 23
6.11.
Appendix 11 Estimands Examples ................................................................................................ 30
7.
REFERENCES................................................................................................................................... 31
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved,  Date: 15 December 2023
1.
INTRODUCTION
1.1.
Objectives 
As a result of the early study discontinuation, the primary objective of Statistical Analysis Plan 
Amendment 1 is to provide continued access to treatment. The Phase 2 exploratory objectives and 
endpoints of characterization of PK and PD of ibrutinib may continue to be evaluated using blood 
samples already collected prior to implementation of Protocol Amendment 1.
1.2.
Study Design
As a result of the early study discontinuation, the Phase 2 part of this study will not fully enroll, 
and the Phase 3 part will not start. All participants will be given the choice to either remain on the 
randomized treatment arm or switch to ibrutinib monotherapy at 560 mg once daily (unless 
ibrutinib dose was reduced for toxicity reasons). All participants will also be given the option to 
drop rituximab treatment and continue with monotherapy.
2.
STATISTICAL HYPOTHESES
No formal statistical hypothesis testing will be conducted due to early study discontinuation and 
the primary purpose of Protocol Amendment 1 is continued access of study treatment.
3.
SAMPLE SIZE DETERMINATION
Due to the early discontinuation of the study, this is not applicable.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
The analysis sets for Phase 2 part are defined below. 

Intent-to-Treat (ITT) population: defined as all participants randomized into the Phase 2 
part and who will be classified according to the assigned study treatment dosage and control 
group, regardless of the actual treatment received. 

Participants in study treatment arm (Arm A1, A2, A3) and the control arm will be used 
for descriptive analyses, analyses of disposition, demographic, and baseline disease 
characteristics. 

Safety Population: all randomized participants who receive at least one dose of any ibrutinib 
dosage level or control drug. This population will be used for all safety analyses and analyses 
of exposure. All participants will be analyzed according to the treatment which they actually 
received before switching to ibrutinib 560 mg QD monotherapy if occurs. Safety data after 
switching to ibrutinib 560 mg QD monotherapy will be summarized separately.

Ibrutinib 560 mg QD Monotherapy Population: Participants randomized to the 420 mg QD 
or 140 mg BID study treatment arms or control arm and later on switched to ibrutinib 560 mg 
QD monotherapy. Safety data after switching to ibrutinib 560 mg QD monotherapy will be 
summarized under ibrutinib 560 mg QD monotherapy population.

Pharmacokinetic-Evaluable Population: all randomized participants who have received at 
least one dose of any ibrutinib dosage level and have at least one pharmacokinetic sample 
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Status: Approved,  Date: 15 December 2023
obtained post-treatment. The pharmacokinetic-evaluable population will be used to 
summarize pharmacokinetic parameters and metrics of exposure.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
Phase 2: Visit window will be based on phases and cycles:

Screening Phase: prior to the first dose of study treatment.

Treatment Phase: Between the date of the first dose of study treatment and the date of the 
last dose of study treatment before switching to ibrutinib 560 mg QD monotherapy, if occurs. 
As noted above, the term “study treatment” refers to all of the drugs used in the combination 
treatment.

End-of-treatment Phase: Between the date of the last dose of all study treatment +1 and the 
date of the last dose of all study treatment (prior to switching to ibrutinib 560 mg QD 
monotherapy, if occurs) + 30 days. The assessments performed during the ‘End of Treatment 
Visit’ will be included in this phase.

Ibrutinib 560 mg QD Monotherapy Phase: Between the date of switching to ibrutinib 560 
mg QD monotherapy and the date of the last dose of ibrutinib 560 mg QD monotherapy 
treatment.
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 participants who have 
been randomized but not treated, randomization date will be used as the reference date for baseline 
value calculation.
Cycle-based descriptive analysis may be performed for safety parameters during the treatment up 
to date of last dose + 30 days or end of treatment visit, whichever comes later. For the analysis of 
lab measurement by cycle, mean values within each cycle will be used. For the analysis of lab 
grade by cycle, worst grade within each cycle will be used.
Assessments will be presented chronologically by cycle day or study day as described below. 
Unless specified otherwise, date of first dose of study drug (randomization date for participants 
who have been randomized but not treated) will be used as the reference date for study day 
calculation.
Day 1 = reference date.
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.
5.1.1.
Pooling Algorithm for Centers
The data from all investigative sites will be pooled for all analyses. 
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023
5.1.2.
Imputation of Missing Date
Missing date of initial diagnosis, date of death and start and end dates of AE, prior, concomitant, 
and subsequent therapies will be imputed according to the following rules: 

General rules

If date is completely missing or 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 

Start and end dates rules 

Start date should be imputed to be before end date;

If end date is not missing (i.e., not imputed) and is before the imputed start date, then end 
date will be used and imputed start date won’t be used;

If end month and year are not missing and are before the imputed start month and year, 
then end month and year will be used and imputed start month and year won’t be used;

If imputed end date is before start date, then start date will be used and imputed end date 
won’t be used.
However, the above imputation will be modified by the following rules sequentially:

For death: if the imputed date is before the last date that the participant is known to be alive, 
the latter date + 1 day will be used.

If any imputed date is after date of death, then date of death will be used.

For initial diagnosis and prior therapies: if imputed date is on or after the randomization date, 
then randomization date - 1 will be used.

For subsequent therapies: if imputed date is before date of treatment discontinuation, then the 
latter will be used.

For AE and concomitant medications: The imputed start date will be adjusted sequentially 
using the following steps:

If it is in the same month and year but before the first dose date, then the first dose date 
will be used, or if it is in the same month and year but after the last dose date + 30 days, 
then the last dose date + 30 days will be used.

If it is in the same month and year but after the 1st subsequent systemic therapy start date, 
then the latter will be used.
NCT05564052


JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023
5.2.
Participant Dispositions
The number of participants in the following disposition categories will be summarized throughout 
the study by treatment group and overall:

Participants randomized

Participants who received study treatment

Participants who completed the study

Participants who discontinued study treatment

Reasons for discontinuation of study treatment

Participants who terminated the study 

Reasons for termination of study
Listings of participants will be provided for the following categories:

Participants who discontinued study treatment

Participants who completed or terminated the study 
5.3.
Safety Analyses
Unless otherwise specified, all safety analyses will be conducted on the safety analysis set based 
on actual treatment received. However, safety data after switching to ibrutinib 560 mg QD 
monotherapy will be summarized based on ibrutinib 560 mg QD monotherapy population 
separately.
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.
For all continuous safety variables, descriptive statistics by treatment group will include the N, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by treatment group using frequency counts and percentages. 
Frequencies of ECOG scores at baseline will be reported. 
5.3.1.
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 both study drugs.
The number and percentage of participants with dose reduction and dose interruption will be 
summarized. Dose reduction and dose interruption due to adverse events will be summarized for 
both treatment groups and ibrutinib 560 mg QD monotherapy group. In addition, dose reduction 
and dose interruption due to concomitant use of CYP3A4/5 inhibitor will be summarized for 
ibrutinib treatment.
NCT05564052


JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023
5.3.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent Adverse 
Events (TEAEs) will be summarized and are defined as any new or worsening AE occurring at or 
after the initial administration of study treatment through the day of last dose plus 30 days or prior 
to the start of subsequent anticancer therapy, whichever is earlier, or the follow-up AE (linked to 
an existing TEAE) with onset date and time beyond 30 days after the last dose of study treatment 
but prior to the start of subsequent therapy.
If the event occurs on the day of the initial administration of study treatment, and either event time 
or time of administration are missing, then the event will be assumed to be treatment emergent. 
If the event date is recorded as partial or completely missing, or time of administration is 
missing, then the event will be considered to be treatment emergent unless it is known to be prior 
to the first administration of study treatment based on partial onset date or resolution date, or later 
than 30 days after last study drug administration. If any event is considered drug-related regardless 
of the start date of the event; or the event that is present at baseline but worsens in toxicity grade
or is subsequently considered drug-related by the investigator, then this event will be assumed to 
be treatment-emergent. The same rules apply to adverse events that occurred during ibrutinib 
560mg QD monotherapy phase. For participants who switch to ibrutinib 560 mg QD monotherapy, 
treatment-emergent adverse events that occur on or after the first day of ibrutinib monotherapy 
will be included in summaries for the monotherapy phase except for events considered related to 
rituximab or lenalidomide, which will be included in summaries for the randomized treatment 
phase.
TEAEs will be summarized by SOC and PTs. Unless otherwise specified, at each level (e.g., 
system organ class and/or preferred term) of participant summarization in reporting the incidence 
of the AE, a participant is counted once if one or more events were recorded. For summarizing 
new onset events, all event records of the same preferred term from the same participant are to be 
linked by the onset date and the end date. If an event is followed by another event of the same 
preferred term with an onset date the same as or 1 day after the end date of the previous record and 
any features of the adverse event (i.e., toxicity grades/seriousness/action taken) are different 
between these two records, these 2 records should be linked together and considered as one event. 
A Grade 5 event will be linked to previous event of the same preferred term if the onset date of the 
Grade 5 record is the same or one day after the end date of previous record. Tables will be sorted 
by descending frequency in incidence (from the highest to lowest incidence). For each TEAE the 
number and percentage of participants who experience at least 1 occurrence of the given event will 
be summarized.
In addition to the summary tables, listings will be provided for participants who:

Had Serious TEAEs 

Had TEAE with outcome of death

Had TEAE of Grade≥3

Had TEAEs leading to treatment discontinuation
NCT05564052


JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved,  Date: 15 December 2023
5.3.2.1.
Adverse Events of Interest and Other Safety Observations 
There is no AEs of Interest (AEIs) for this study. 
Other Safety Observations 
Other malignancies are defined as new malignant tumors including solid tumors, skin malignancies 
and hematologic malignancies and are to be reported by investigators for the duration of study 
treatment and during any protocol-specified follow-up periods including post-progression 
follow-up for OS. Summary tables for other malignancies occurring during the entire study and 
during the treatment-emergent reporting period by PT will be provided, categorized by 3 groups: 
non-melanoma skin cancer, melanoma skin cancer, and non-skin cancer. 
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.
Additional other safety observations will be summarized by treatment group if considered 
clinically relevant based on review of the data after the final database lock.
5.3.2.2.
Death 
Deaths will be displayed by actual treatment received. For the ibrutinib 560 mg QD monotherapy 
phase, if death occurred on or after first day of monotherapy, it will be included in monotherapy 
only unless death due to AE that is related to rituximab or lenalidomide, which will be included in 
summaries for the randomized treatment phase. Frequencies for the following parameters will be 
included in the summary table:

Number of participants who died

Cause of death
A listing of participants who died will be provided.
5.3.3.
Additional Safety Assessments 
5.3.3.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the safety analysis set.
Laboratory data of hematology and serum chemistry up to 30 days after the last dose or the start 
of subsequent anticancer therapy, whichever is earlier, will be reported in SI units. Applicable 
laboratory results will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v5.0. Note, toxicity grading for creatinine increase will 
be based on the NCI CTCAE v5.0 criteria but limited only to the part based on the upper limit of 
normal (ULN); the other part that is based on the change from baseline will not be used for toxicity 
grading. Toxicity grading for all other laboratory parameters will be based on the NCI CTCAE 
v5.0 criteria as is. Generic normal ranges will be applied whenever reference ranges are not 
available. The following laboratory tests will be analyzed: 
NCT05564052


JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023

Hematology: hemoglobin, WBC, ANC, absolute lymphocyte counts (ALC), and platelets

Chemistry: sodium, creatinine, CrCL, AST, alanine aminotransferase (ALT), alkaline 
phosphatase (AST), LDH, total bilirubin, albumin, potassium, calcium, phosphate, uric acid
Descriptive statistics (mean, standard deviation, median and range) will be calculated for the raw 
data and for their changes from baseline at each time point of assessment as well as for the changes 
from baseline to the last value.  Worst toxicity for hematology and clinical chemistry during 
treatment will also be summarized. 
5.3.3.1.1.
Creatinine Clearance
CrCL is calculated using the Cockcroft-Gault formula:
for males, the factor is 1 instead of 0.85.
A shift summary from baseline to worst on-treatment toxicity grade for CrCL will be provided.
5.3.3.2.
Vital Signs 
Continuous vital sign parameters including blood pressure, heart rate, temperature, height, weight, 
and body surface area will be summarized and/or listed. 
5.3.3.3.
Electrocardiogram
Not applicable.
5.3.3.4.
Other Safety Parameters
5.3.3.4.1.
ECOG
Frequencies of ECOG scores at baseline will be reported.
5.3.3.4.2.
Concomitant Medications
Use of concomitant therapies other than antineoplastic agents or other systemic therapies for MCL 
between treatment start and the end of the study will be provided by ATC class and drug generic 
term. Multiple medication usage by a participant will be counted only once for that therapeutic 
class. Concomitant medications are defined as medications that were taken at any time on 
treatment (i.e., from the date of the first dose of study treatment through 30 days after the last dose 
of study treatment). 
As of implementation of Protocol Amendment 1, only concomitant therapy related to SAEs and 
Grade ≥3 AEs up to 30 days after the last dose of study treatment, or until the start of subsequent 
anti-lymphoma, whichever is first, will be provided.
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved,  Date: 15 December 2023
5.4.
Other Analyses
5.4.1.
Pharmacokinetics 
At the moment of implementation of Protocol Amendment 1, venous blood samples for ibrutinib 
analysis already collected (ibrutinib treatment arm only) may be analyzed for ibrutinib plasma 
concentration and may be used for further development of the existing population-based 
PK model. No further blood samples will be collected from participants for PK evaluation at the 
moment of implementation of protocol Amendment 1.
Descriptive statistics (N, mean, SD, median, range, CV (%) and IQ range) may be used to 
summarize ibrutinib plasma concentrations at each sampling time point. PK data may be displayed 
graphically, such as mean +/- SD PK concentrations over time.
Ibrutinib plasma concentrations below the LLOQ will be imputed as zero in the summary statistics.
All participants and samples excluded from the analysis will be clearly documented.
If sufficient data are available, then population PK analysis using plasma concentration time data 
of ibrutinib may be performed using nonlinear mixed-effects modeling. Details will be given in a 
population PK analysis plan, and the results of the analysis will be presented in a separate report.
5.4.2.
Immunogenicity
5.4.2.1.
Immunogenicity Analysis
Not applicable.
5.4.2.2.
Other Immunogenicity Analyses
Not applicable.
5.4.3.
Pharmacodynamics 
At the moment of implementation of Protocol Amendment 1, venous blood samples for ibrutinib 
analysis already collected may be used for BTK and/or ITK occupancy (free and total) evaluation. 
No further blood samples will be collected from participants for PD evaluation at the moment of 
implementation of protocol Amendment 1.
5.4.4.
Pharmacokinetic/Pharmacodynamic Relationships
Not applicable.
5.4.5.
Biomarkers
Refer to Section 5.4.3 for BTK and/or ITK occupancy. 
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
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Status: Approved,  Date: 15 December 2023
6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
CRF
case report form
eCRF
IDMC
electronic case report form
independent Data Monitoring Committee
IQ
interquartile
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PK
PopPK ER
pharmacokinetic(s)
Population pharmacokinetic and exposure-response
r/r
relapsed or refractory
SAE
serious adverse event
SAP
Statistical Analysis Plan
SMQs
SOC
standardised MedDRA queries
system organ class
TEAE
treatment-emergent adverse event
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Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023
6.2.
Appendix 2 Changes to Protocol-Planned Analyses
Not applicable.
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
16
Status: Approved,  Date: 15 December 2023
6.3.
Appendix 3 Demographics and Baseline Characteristics
All demographic and baseline characteristics will be summarized for the ITT population using 
descriptive statistics. Participant enrollment will be summarized by region, site, and country. 
The following demographics and baseline disease characteristics information will be summarized 
for ITT participants:

Demographics: Age (continuous and grouped as ≥50 vs. <50 or ≥65 vs. <65), sex (male or 
female), race, region, ethnicity

Baseline disease characteristics: Time from the initial diagnosis to randomization, Serum 
β2 microglobulin, stage of MCL at study entry (II or III or IV), type of histology, simplified 
sMIPI score (low risk / intermediate risk vs. high risk), Eastern Cooperative Oncology Group 
(ECOG) performance status score (0 vs. 1), endoscopy, hepatic impairment, renal 
function impairment, and histology group (grouped as Blastoid/Pleomorphic vs. 
Non-Blastoid/Non-Pleomorphic vs Unknown)

Extent of disease: Number of lesions, extranodal disease, tumor bulk (grouped as <5 cm, 
≥5 cm), tumor burden, baseline lymphoma symptoms, bone marrow involvement, and 
baseline lactic acid dehydrogenase (LDH)

Hematology: hemoglobin (Hgb), white blood cell count (WBC), absolute neutrophil count 
(ANC), and platelets

Chemistry: sodium, potassium, creatinine clearance (CrCL), creatinine, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactic acid 
dehydrogenase (LDH), total bilirubin, albumin, calcium, magnesium, phosphate, and uric acid

Vital signs: height (cm), weight (kg), temperature (C°), systolic blood pressure, diastolic blood 
pressure, heart rate, body surface area (BSA)

Coagulation: Prothrombin international normalized ratio (INR), and activated partial 
thromboplastin time (aPTT)
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Status: Approved,  Date: 15 December 2023
6.4.
Appendix 4 Protocol Deviations 
Participants with major protocol deviations will be listed by treatment group. Protocol deviations 
will be based on clinical review primarily on the following aspects (but not limited to): 
(1) eligibility criteria, (2) treatment compliance, (3) participant safety (4) efficacy assessment 
deviation. 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. The major protocol 
deviations will be reviewed and/or classified based on clinical review of the protocol deviations.
Major protocol deviations due to COVID-19 will be summarized and listed by treatment group.
Listing of minor protocol deviations due to COVID-19 will also be provided. Summary table and
listing of study assessment compliance will be presented.
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
18
Status: Approved,  Date: 15 December 2023
6.5.
Appendix 5 Prior and Concomitant Medications
Use of concomitant therapies other than antineoplastic agents or other systemic therapies for MCL 
between treatment start and the end of the study will be provided by ATC class and drug generic 
term. Multiple medication usage by a participant will be counted only once for that therapeutic 
class. Concomitant medications are defined as medications that were taken at any time on 
treatment (i.e., from the date of the first dose of study treatment through 30 days after the last dose 
of study treatment). 
NCT05564052


JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
19
Status: Approved,  Date: 15 December 2023
6.6.
Appendix 6 Medical History
Medical history will be summarized by body system class and preferred term.
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023
6.7.
Appendix 7 Treatment Compliance
Compliance will be summarized descriptively for each study arm. Compliance to randomized 
treatment versus actual treatment will be presented in the participant disposition summary table 
specified in Section 5.2.
Treatment compliance will be assessed using Section 5.3.1. 
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Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023
6.8.
Appendix 8 Adverse Events of Interest
Refer to Section 5.3.2.1.
NCT05564052


JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 December 2023
6.9.
Appendix 9 Medications of Special Interest
Refer to Section 5.3.3.4.2 for details.
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JNJ-54179060 (ibrutinib)
Statistical Analysis Plan 54179060MCL3004, Amendment 2
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
23
Status: Approved,  Date: 15 December 2023
6.10.
Appendix 10 Laboratory Toxicity Grading
The grading scale use for lab assessments is based on ‘Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0’.
If a laboratory value falls within the grading as specified below but also within the local laboratory 
normal limits, the value is considered to be normal and will be reset to grade 0.
Pre-baseline measurements will use the same grading ranges as applied to baseline measurements. 
In case a test has two sets of ranges – one for baseline normal and one for baseline abnormal, the 
one for baseline normal will be applied for all measurements taken pre-baseline and on baseline.
Text in gray italic in the table is present in the grading scale but is not applied by Janssen when 
grading lab data.
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Statistical Analysis Plan 54179060MCL3004 Amendment 2
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Status: Approved,  Date: 15 December 2023
6.11.
Appendix 11 Estimands Examples
Not applicable.
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Status: Approved,  Date: 15 December 2023
7.
REFERENCES
Not applicable.
NCT05564052

Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 08 June 2023
Janssen Research & Development *
Clinical Protocol
A Randomized, Controlled, Open-label, Multicenter, Inferentially Seamless Phase 2/3
Study of Ibrutinib in Combination with Rituximab Versus Physician’s Choice of
Lenalidomide Plus Rituximab or Bortezomib Plus Rituximab in Participants with
Relapsed or Refractory Mantle Cell Lymphoma
Study Name: VEGA
Short Title
Seamless Phase 2/3 Study of Ibrutinib With Rituximab in Relapsed/Refractory Mantle Cell
Lymphoma
Protocol 54179060MCL3004; Phase 2/3 Seamless Design
Amendment 1
JNJ-54179060 (ibrutinib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. 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, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; 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.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency identifier Number(s):
IND: 102688
EudraCT NUMBER: 2022-000364-21
EU CTR NUMBER: 2023-503618-64
Status: 
Approved
Date: 
08 June 2023
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-RIM-641149, 2.0
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.
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 08 June 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Country/Territory Affected  
Date
Amendment 1 
All 
08 June 2023
Original Protocol 
All 
21 July 2022
Amendment 1 (08June 2023)
Overall Rationale for the Amendment: As a result of the decision for early study
discontinuation, the overall reason for the amendment is to stop enrollment and to ensure that
participants on the study benefiting from study treatment will continue to receive study treatment,
either in this study, or rollover to a long-term extension study, or through commercial access. The
electronic case report form (eCRF) collection period will end, and the clinical database will be
closed as soon as possible but no later than when the last study participant has completed the first
6 cycles of study treatment or switched to ibrutinib monotherapy at 560 mg once daily, whichever
occurs first. All eCRF data collected up to this timepoint will be included in the final Clinical
Study Report.
All participants will be given the choice to either remain on the randomized treatment arm or
switch to ibrutinib monotherapy at 560 mg once daily (unless ibrutinib dose was reduced for
toxicity reasons). All participants will also be given the option to drop rituximab treatment and
continue with monotherapy.
Additionally, this amendment provides additional clarification that participants benefiting from
study treatment, and for whom commercial access is not readily available due to local
reimbursement regulation and access agreement, will be able to continue to receive treatment.
In the following table, new text added to the protocol is shown in bold. Deleted text is shown in strike
through.
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JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date: 08 June 2023
Section Number 
and Name
Description of Change 
Brief Rationale
1.2 Schema 
Figure 1: Schematic Overview: Phase 2 Part of the 
Study for Dose Selection –revised. Text added: 
Upon implementation of Protocol Amendment 1, 
investigators will discuss treatment options with 
the participants and will be given the choice to 
either remain on the randomized treatment arm 
or switch to ibrutinib monotherapy at 560 mg
once daily (unless ibrutinib dose was reduced for
toxicity reasons). All participants will also be
given the option to drop rituximab treatment and
continue with monotherapy
Details of post-treatment Follow-up removed
Figure 2: Schematic Overview: Phase 3 Part of the
Study for Safety and Efficacy - deleted
To provide updated
schematic overview of the
Phase 2 part of the study
effective upon
implementation of Protocol
Amendment 1
1.3 Schedule of Activities 
Revised to reflect procedures only for participants 
who have received <6 cycles of study treatment 
Note added: Refer to Section 10.13(Appendix 13) 
for a description of the study procedures for
participants who continue to receive study
treatment after eCRF data collection has ended
and the clinical database has been closed
To provide details of study
procedures effective upon
implementation of Protocol
Amendment 1
1.3 Schedule of Activities, 
Clinical Laboratory Tests, 
Serum immunoglobulins 
10.1 Appendix 1: Clinical 
Laboratory Tests 
Lines deleted 
Text deleted: Beta2 microglobulin and serum Ig
levels (IgG, IgM, IgA).
No longer applicable
following implementation
of Protocol Amendment 1
1.3 Schedule of Activities, 
Clinical Laboratory Tests: 
PK blood samples; PD 
blood samples 
Schedule for blood sample collections for PK and 
PD evaluations deleted 
Associated footnotes deleted 
Only blood samples
already received before
implementation of Protocol
Amendment 1 can be used
for PK and PD analysis
2.1 Study Design  
Section updated and text included: As a result of the 
early study discontinuation, the Phase 2 part of 
this study will not fully enroll, and the Phase 3 
part will not start. The objective of the study is to
provide continued access to study treatment for
participants who continue to benefit from
treatment
To update Study Design as
a result of early study
discontinuation
3. Objectives and 
Endpoints 
Primary objective revised and text added: As a 
result of the early study discontinuation, the 
primary objective of Protocol Amendment 1 is to 
provide continued access to treatment. The 
Phase 2 exploratory objectives and endpoints of 
characterization of PK and PD of ibrutinib may
continue to be evaluated using blood samples
already collected prior to implementation of
Protocol Amendment 1
Updated Objectives and
Endpoints as a result of the
early study discontinuation
and implantation of
Protocol Amendment 1
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JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date: 08 June 2023
Section Number 
and Name
Description of Change 
Brief Rationale
Phase 2 primary objectives and endpoints deleted;
Phase 3 Primary, Secondary and Exploratory
objectives and endpoints deleted
Phase 2 PD endpoint updated: BTK and/or ITK 
occupancy at various doses of ibrutinib and at 
different timepoints to identify dose occupancy 
relationships. PK parameters removed and only 
system exposure will be evaluated
To update PD and PK
evaluations. Included the
option to also evaluate ITK
occupancy
Hypothesis 
Phase 2 hypothesis updated: No formal testing will 
be conducted due to early study discontinuation 
and the primary purpose of Protocol 
Amendment 1 is continued access of study
treatment.
Phase 3 hypothesis deleted
Hypothesis updated as a
result of the early study
discontinuation
4.1 Overall Design  
4.4 End of Study 
Definition  
Section updated with information regarding the 
option for all participants to switch to ibrutinib 
monotherapy at 560 mg QD (unless ibrutinib dose 
was reduced for toxicity reasons). 
Text updated: During the study, safety evaluations 
will include AE monitoring, physical examinations 
per standard of care, vital signs, 12-lead ECG (as
clinically indicated), concomitant medication usage,
and clinical laboratory parameters (hematology,
chemistry, coagulation, as clinically indicated).
Text added: an End of Treatment visit for a safety
assessment should take place within 30 days
(+14-day window) after the last dose of study
treatment, or before the start of subsequent anti-
cancer therapy, if earlier
Section updated and text added: The clinical
database will close and no further data will be
collected in the eCRFs as soon as possible but no
later than when the last study participant has
completed the first 6 cycles of study treatment.
Only data collected in the eCRF during the data
collection period will be included in the final
Clinical Study Report.
The sponsor will ensure that participants
benefiting from study treatment can continue to
receive study treatment after this time until study
treatment is available commercially, available
from another source, or until study completion,
whichever occurs earlier
The study is considered completed once all
participants still receiving study treatment have
transitioned to commercial or alternative access,
have stopped receiving study treatment, or upon a
decision by the sponsor to terminate the study,
whichever occurs earlier
To provide details of
updated study design and
End of Study definition
effective upon
implementation of Protocol
Amendment 1
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JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date: 08 June 2023
Section Number 
and Name
Description of Change 
Brief Rationale
1.3 Schedule of Activities; 
8.1.4 Post-treatment 
Follow-up Phase; 
6.6 Continued Access to 
Study Treatment After the
End of the Study
4.2 Scientific Rationale for 
Study Design 
Post-treatment Follow-Up Phase columns deleted 
Section deleted 
Section deleted
Section deleted and text added:  As a result of the
early study discontinuation, the objective of the
study is to provide continued access to study
treatment for participants who continued to
benefit from treatment
No longer applicable
following implementation
of Protocol Amendment 1
6.1 Study Treatment(s) 
Administered; 
6.3 Measures to Minimize 
Bias: Randomization and
Blinding
Sections revised and text deleted 
Updated as the Phase 3
part of the study will not
start
8.1 Study Procedures 
(8.1.1 Overview) 
8.1.3 Open-label 
Treatment Phase 
Text removed for approximate amount of blood 
drawn in the Phase 2 and Phase 3 parts of the study: 
Section amended to remove details of administration 
of the FACT-Lym and PRO questionnaire; 
evaluation of possible toxicities, dose modifications; 
and disease progression. Text added: The sponsor 
recommends disease evaluations be performed
per standard of care
Blood sample volumes
removed due to revised
study assessments
To update Treatment Phase
procedures effective upon
implementation of Protocol
Amendment 1
8.2.1 Efficacy Assessments 
8.2.1.1 PET Scan; 8.2.1.2 
Radiographic Image 
assessments (CT/MRI);
8.2.1.3 Bone Marrow 
Assessment;
8.2.1.4 Endoscopy
8.2.1.5 Biopsies of Other
Sites; 8.2.1.6 Physical
Examination
Response assessments updated as follows: To
determine whether continued study treatment is
warranted, investigators should monitor and
assess participants for response to treatment or
disease progression per standard of care
preferably using the Lugano Criteria (Cheson
2014). Disease status and date of disease
progression should be documented 
Sections deleted
Following implementation
of Protocol Amendment 1,
these assessments will be
performed per standard of
care
8.2.1.7 Patient-Reported 
Outcomes 
Section deleted 
No longer required
following implementation
of Protocol Amendment 1
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JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved, Date: 08 June 2023
Section Number 
and Name
Description of Change 
Brief Rationale
8.2.2.1 Assessment of 
Disease response and 
Progressive Disease 
Details of IRC review of progressive disease deleted 
Text updated: For all participants with disease 
progression by the investigator, the investigator 
should notify the sponsor medical monitor within 24 
hours promptly when of becoming aware of the
progression including after database closure.
No longer required due to
the early termination of the
study
To clarify the disease
progression notification
instructions
8.5 Pharmacokinetics 
Section updated to remove details of the schedule for 
blood sample collection for PK analysis. 
Text added: Upon implementation of Protocol 
Amendment 1, venous blood samples for ibrutinib 
analysis already collected (ibrutinib treatment 
arm only) may be used for further development of
the existing population-based PK model. No
further blood samples will be collected from
participants for PK evaluation upon
implementation of protocol Amendment 1
Only blood samples
already received before
implementation of Protocol
Amendment 1 can be used
for PK analysis
8.6 Pharmacodynamic 
Evaluations 
Section updated to remove details of the schedule for 
blood sample collection for PD analysis. 
Text added: Upon implementation of Protocol 
Amendment 1, venous blood samples for ibrutinib 
analysis already collected may be used for BTK 
and/or ITK occupancy (free and total) evaluation.
No further blood samples will be collected from 
participants for PD evaluation upon 
implementation of protocol Amendment 1
Only blood samples
already received before
implementation of Protocol
Amendment 1 can be used
for PD analysis
Included the option to also
evaluate ITK occupancy
8.8 Sample Collection and 
handling (Study Specific 
Materials) 
Text deleted: Progressive disease notification form 
(see Section 8.2.2.1) and PRO questionnaires and 
user manuals: PRO questionnaires will include the 
FACT Lym. Sample questionnaires are provided in
Section 10.9 (Appendix 9).
No longer required
following implementation
of Protocol Amendment 1
8.3 Safety Assessments 
1.3 Schedule of Activities; 
8.1.3 Open-label 
Treatment Phase; 
8.3 Safety Assessments; 
8.4 Adverse Events,
Serious Adverse Events,
and Other Safety Reporting
10.3.1 Adverse Event 
Definitions and 
Classifications 
Text included that safety evaluations should be 
performed as clinical indicated. 
Text included that safety data collection will be 
limited to SAEs, Grade ≥3 AEs and AEs leading to 
treatment discontinuation, and concomitant
medications related to SAEs and Grade ≥3 AEs”
Text updated: All SAEs, AEs, Grade ≥3 AEs and
AEs leading to treatment discontinuation,
regardless of seriousness, severity, or presumed
relationship to study treatment, must be recorded
using medical terminology in the source document
and the eCRF
To clarify safety
evaluations and safety data
collection effective upon
implementation of Protocol
Amendment 1
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JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved, Date: 08 June 2023
Section Number 
and Name
Description of Change 
Brief Rationale
6.7 Concomitant Therapy  
Text added: As of implementation of Protocol 
Amendment 1, only concomitant therapy related 
to SAEs and Grade ≥3 AEs up to 30 days after the 
last dose of study treatment, or until the start of 
subsequent anti-lymphoma, whichever is first, 
needs to be recorded
To clarify safety
evaluations and safety data
collection effective upon
implementation of Protocol
Amendment 1
6.7 Concomitant Therapy; 
8.3 Safety Assessments; 
10.3 1 Adverse Events 
Definitions and 
Classifications 
Text added: For participants who continue to 
receive study treatment after the end of the eCRF 
collection and clinical database closure, only 
SAEs and pregnancy information will be 
documented in the participant file/source notes 
and reported to the sponsor’s Global Medical
Safety database only until the end of the study
(see Section 4.4) and as described in Section 10.13
(Appendix 13)
To describe the SAE and
pregnancy reporting
procedures after the end of
eCRF data collection and
clinical database closure
8.4.5 Pregnancy  
Text added: After the end of eCRF data collection 
and clinical database closure, pregnancy 
reporting will continue as described above and in 
Section 10.13(Appendix 13) 
To describe the pregnancy
reporting procedures after
the end of eCRF data
collection and database
closure
(Lenalidomide) 
Text updated: If pregnancy occurs, study treatment 
should be discontinued immediately and the 
participant should be referred to an obstetrician 
experienced in reproductive toxicity for further 
evaluation and counseling. The sponsor will collect 
information on the outcome of the pregnancy and
health of the baby for 1 year after birth or until
the outcome of an adverse pregnancy event is
known or resolved
To clarify sponsor’s
responsibility should
pregnancy occur for
participants receiving
lenalidomide
9 Statistical 
Considerations; 
9.1 Statistical Hypotheses; 
9.2 Sample Size 
Determination; 
9.3 Participant Analysis
Sets; 9.4 Statistical
Analyses; 9.4.1 General
Considerations;
9.4.2 Primary Endpoint;
9.4.3 Secondary
Endpoints;
9.4.3.1 Definitions;
9.4.3.2 Analysis;
9.4.4 Exploratory
Endpoints; 9.5 Interim
Analysis; 9.6 Independent
Data Monitoring
Committee;
10.2.6 Committees
Structure
Sections deleted and text added to Section 9: Due to 
the early termination of the study, an IDMC to 
monitor safety data, and to review efficacy data, 
is no longer required. Data will be summarized, 
and descriptive statistics will be presented. 
Statistical considerations
and IDMC no longer
required following
implementation of Protocol
Amendment 1
10.2.2 Financial Disclosure Section deleted 
No longer required
following implementation
of Protocol Amendment 1
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JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date: 08 June 2023
Section Number 
and Name
Description of Change 
Brief Rationale
5.3 Restrictions During 
Study Participation  
Text revised: For participants randomized to 
lenalidomide, Ttwo negative pregnancy tests must 
be obtained prior to initiating study treatment. The 
first test should be performed at screening and the 
second test within 24 hours prior to the first dose of 
study treatment.  For participants randomized to
lenalidomide, wWeekly pregnancy tests are required
during the first month, then monthly thereafter in
females with regular menstrual cycles or every
2 weeks in females with irregular menstrual cycles.
To provide further clarity
for pregnancy test
requirements for
participants receiving
lenalidomide
6.1 Study Treatment(s) 
Administered 
Table 4 Description of Ibrutinib, Rituximab, 
Lenalidomide, and Bortezomib, and Study Treatment 
Administration Instructions –text corrected: IV 
infusion - rituximab 
To clarify that rituximab is
administered as an IV
infusion and not as an IV
injection
Authorization status of ibrutinib, Rituximab, 
Lenalidomide, and Bortezomib in the EU added 
Required as this study will
be performed under the EU
CTR
6.5.3 Dose Modifications 
(Lenalidomide) 
Table 9 Lenalidomide Dose Modifications for 
Hematologic Toxicities 
Text added for recommended course for platelets 
≥50,000/µL and neutrophils ≥1,000/µL: If previous 
dose was 5 mg, reduce dose to 2.5 mg daily or
5 mg every other daya;
Do not dose below 2.5 mg daily or 5 mg every
other daya:
Footnote added: aIf using locally sourced
lenalidomide, refer to local label for lowest dose
level allowed
To clarify dose reduction
instructions if previous
lenalidomide dose was
5 mg
8.8 Sample Collection and 
Handling (Study-specific 
Materials) 
Text modified: IWRS manual instructions and 
guidance and supplies 
Text amended as there is
no official IWRS manual
available
9.4.5 Safety Analyses 
(Statistical Considerations) 
Text updated: Any new or worsening AE occurring 
at or after the initial administration of study 
treatment through the day of last dose plus 30 days, 
or until prior to the start of a subsequent anticancer 
therapy, if whichever is earlier, or any follow-up
AE (linked to an existing TEAE) with onset date
and time beyond 30 days after the last dose of
study treatment but prior to the start of
subsequent therapy, or any AE that is considered
treatment-related regardless of the start date of
the event, is considered to be treatment-emergent
To update the definition of
a treatment emergent AE
and to align the Statistical
Analysis Plan and protocol
10.1 (Appendix 1): 
Clinical Laboratory Tests 
Text updated: Screening for Hepatitis B and C will 
include the following evaluations: Hepatitis B 
surface antigen, Hepatitis B surface antibody,
Hepatitis B core antibody, and Hepatitis C antibody
To include Hepatitis B
surface antigen evaluation
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved, Date: 08 June 2023
Section Number 
and Name
Description of Change 
Brief Rationale
10.3.3 (Appendix 3): 
Severity Criteria (Adverse 
Events) 
Text updated: Any AE will be graded as per the 
above. Should an AE become fatal or have a fatal 
outcome, the original grade is not changed but
“fatal” shall be reported as an outcome.
Only in the following cases a Grade 5 event is to be
reported:
• Death NOS: Only for deaths due to unknown
reason (pending follow up information; if further
information becomes available this should be
adapted as adequate)
• Sudden death: A sudden (defined as
instantaneous or within 1 hour of the onset of
symptoms) cessation of life that cannot be attributed
to a CTCAE term
The investigator should must use clinical judgment
in assessing the severity of events not directly
experienced by the participant (eg, laboratory
abnormalities),
To align with the current
sponsor protocol template
Throughout the protocol 
Protocol template-driven updates were made where 
applicable. 
To align with updates to
the sponsor’s oncology
protocol template.
Title page; 1.1 Synopsis 
Added the EU CTR number 
To add the EU CTR
registry number for this
study
Throughout the protocol 
Revisions and modifications were made throughout 
the protocol to increase clarity, for consistency
within this protocol, or to correct omissions and
errors. Links and cross-references were
corrected/updated.
Minor errors were noted.
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved, Date: 08 June 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................. 12
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 15
ABBREVIATIONS ...................................................................................................................................... 16
1. 
PROTOCOL SUMMARY................................................................................................................... 18
1.1. 
Synopsis......................................................................................................................................... 18
1.2. 
Schema.......................................................................................................................................... 21
1.3. 
Schedule of Activities (SoA)........................................................................................................... 22
2. 
INTRODUCTION................................................................................................................................ 25
2.1. 
Study Rationale.............................................................................................................................. 25
2.2. 
Background.................................................................................................................................... 26
2.2.1. 
Mantle Cell Lymphoma............................................................................................................... 26
2.2.2. 
Treatment for Relapsed or Refractory Mantle Cell Lymphoma.................................................. 26
2.2.3. 
Investigational Product Name and Description .......................................................................... 27
2.2.4. 
Nonclinical Studies With Ibrutinib ............................................................................................... 27
2.2.5. 
Clinical Pharmacokinetic Data With Ibrutinib.............................................................................. 27
2.2.6. 
Clinical Efficacy of Ibrutinib in Mantle Cell Lymphoma............................................................... 27
2.2.7. 
Studies of Ibrutinib in Combination With Rituximab in Subjects with MCL................................. 28
2.2.8. 
Study Drugs Used in Combination With Ibrutinib and Comparator Therapies........................... 29
2.2.8.1. 
Rituximab................................................................................................................................. 29
2.2.8.2. 
Lenalidomide ........................................................................................................................... 30
2.2.8.3. 
Bortezomib............................................................................................................................... 30
2.3. 
Benefit-Risk Assessment............................................................................................................... 31
2.3.1. 
Risks for Study Participation....................................................................................................... 31
2.3.1.1. 
Risks Relevant With Ibrutinib................................................................................................... 31
2.3.1.2. 
Risks Relevant With Rituximab ............................................................................................... 32
2.3.1.3. 
Risks Relevant With Lenalidomide.......................................................................................... 32
2.3.1.4. 
Risks Relevant With Bortezomib............................................................................................. 32
2.3.2. 
Benefits for Study Participation .................................................................................................. 32
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 33
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 33
4. 
STUDY DESIGN ................................................................................................................................ 33
4.1. 
Overall Design................................................................................................................................ 33
4.2. 
Scientific Rationale for Study Design............................................................................................. 35
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 35
4.3. 
Justification for Dose...................................................................................................................... 35
4.4. 
End of Study Definition................................................................................................................... 37
5. 
STUDY POPULATION ...................................................................................................................... 37
5.1. 
Inclusion Criteria............................................................................................................................ 38
5.2. 
Exclusion Criteria........................................................................................................................... 40
5.3. 
Restrictions During Study Participation.......................................................................................... 43
5.4. 
Lifestyle Considerations................................................................................................................. 44
5.4.1. 
Meals and Dietary Restrictions for Participants Receiving Ibrutinib........................................... 44
5.5. 
Screen Failures.............................................................................................................................. 44
6. 
STUDY TREATMENT AND CONCOMITANT THERAPY ................................................................ 45
6.1. 
Study Treatment(s) Administered .................................................................................................. 45
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 47
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved, Date: 08 June 2023
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 47
6.4. 
Study Treatment Compliance ........................................................................................................ 48
6.5. 
Dose Modification........................................................................................................................... 49
6.5.1. 
Ibrutinib....................................................................................................................................... 49
6.5.2. 
Rituximab.................................................................................................................................... 51
6.5.3. 
Lenalidomide .............................................................................................................................. 51
6.5.4. 
Bortezomib.................................................................................................................................. 53
6.6. 
Treatment of Overdose .................................................................................................................. 56
6.7. 
Concomitant Therapy..................................................................................................................... 57
6.7.1. 
Permitted Concomitant Medications........................................................................................... 58
6.7.2. 
Medications to be Used with Caution ......................................................................................... 58
6.7.2.1. 
CYP3A Inhibitors/Inducers ...................................................................................................... 58
6.7.2.2. 
Antiplatelet Agents and Anticoagulants................................................................................... 60
6.7.2.3. 
Drugs That may Have their Plasma Concentration Altered by Ibrutinib.................................. 60
6.7.2.4. 
Drugs That may Increase the Risk for Thrombosis................................................................. 60
6.7.3. 
Prohibited Concomitant Medications.......................................................................................... 60
6.7.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures.......................................... 61
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 61
7.1. 
Discontinuation of Study Treatment............................................................................................... 61
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 62
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 62
7.3. 
Lost to Follow-up............................................................................................................................ 62
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 63
8.1. 
Study Procedures........................................................................................................................... 63
8.1.1. 
Overview..................................................................................................................................... 63
8.1.2. 
Screening Phase ........................................................................................................................ 63
8.1.3. 
Open-label Treatment Phase ..................................................................................................... 64
8.2. 
Efficacy........................................................................................................................................... 64
8.2.1. 
Efficacy Assessments................................................................................................................. 64
8.2.2. 
Efficacy Criteria........................................................................................................................... 64
8.2.2.1. 
Assessment of Disease Response and Progressive Disease ................................................ 64
8.2.2.2. 
Definition of Measurable and Assessable Disease ................................................................. 64
8.2.2.3. 
Response Categories.............................................................................................................. 65
8.3. 
Safety Assessments....................................................................................................................... 66
8.3.1. 
Adverse Events........................................................................................................................... 67
8.3.2. 
Clinical Laboratory Tests ............................................................................................................ 67
8.3.3. 
Vital Signs................................................................................................................................... 68
8.3.4. 
Physical Examination.................................................................................................................. 68
8.3.5. 
Electrocardiograms..................................................................................................................... 68
8.3.6. 
ECOG Performance Status ........................................................................................................ 68
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 68
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 69
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 69
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 70
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 70
8.4.5. 
Pregnancy................................................................................................................................... 70
8.4.6. 
Disease-related Events and Disease-related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events............................................................................................. 71
8.5. 
Pharmacokinetics........................................................................................................................... 72
8.5.1. 
Evaluations ................................................................................................................................. 72
8.5.2. 
Pharmacokinetic Parameters ..................................................................................................... 72
8.6. 
Pharmacodynamic Evaluations...................................................................................................... 72
8.7. 
Biomarkers..................................................................................................................................... 72
8.7.1. 
Biomarker Assessments............................................................................................................. 72
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved, Date: 08 June 2023
8.7.2. 
Formalin-Fixed Paraffin-Embedded Tumor Tissue and Lymph Node Biopsies ......................... 73
8.8. 
Sample Collection and Handling.................................................................................................... 73
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 74
9.1. 
Safety Analyses ............................................................................................................................. 74
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 76
10.1. 
Appendix 1: Clinical Laboratory Tests ........................................................................................... 76
10.2. 
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations......................................... 77
10.2.1. 
Regulatory and Ethical Considerations ...................................................................................... 77
10.2.2. 
Informed Consent Process ......................................................................................................... 80
10.2.3. 
Data Protection ........................................................................................................................... 81
10.2.4. 
Long-Term Retention of Samples for Additional Future Research ............................................ 82
10.2.5. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 82
10.2.6. 
Data Quality Assurance.............................................................................................................. 84
10.2.7. 
Case Report Form Completion................................................................................................... 84
10.2.8. 
Source Documents ..................................................................................................................... 85
10.2.9. 
Monitoring ................................................................................................................................... 85
10.2.10. On-Site Audits............................................................................................................................. 86
10.2.11. Record Retention........................................................................................................................ 86
10.2.12. Study and Site Start and Closure ............................................................................................... 87
10.3. 
Appendix 3: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting................................................................................................................................. 88
10.3.1. 
Adverse Event Definitions and Classifications ........................................................................... 88
10.3.2. 
Attribution Definitions.................................................................................................................. 90
10.3.3. 
Severity Criteria.......................................................................................................................... 90
10.3.4. 
Special Reporting Situations ...................................................................................................... 90
10.3.5. 
Procedures ................................................................................................................................. 91
10.3.6. 
Other Malignancies..................................................................................................................... 93
10.3.7. 
Product Quality Complaint Handling........................................................................................... 93
10.3.8. 
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 93
10.4. 
Appendix 4: Contraceptive Guidance and Lenalidomide Global / Local PPP/REMS
Programs........................................................................................................................................ 94
10.5. 
Appendix 5: ECOG Performance Status Score ............................................................................. 97
10.6. 
Appendix 6: Calculating the Simplified MIPI for MCL .................................................................... 98
10.7. 
Appendix 7: New York Heart Association Classification of Functional Capacity........................... 99
10.8. 
Appendix 8: Child-Pugh Score for Participants With Liver Impairment ....................................... 100
10.9. 
Appendix 9: Sample FACT-Lym (Version 4)................................................................................ 101
10.10. Appendix 10: Guidance on Study Conduct During the COVID-19 Pandemic ............................. 104
10.11. Appendix 11: Hepatitis B Virus Screening ................................................................................... 110
10.12. Appendix 12: Calculated and Measured Creatinine Clearance................................................... 111
10.13. Appendix 13: Continuation of Study Treatment After the End of eCRF Data Collection
and Clinical Database Closure to the End of the Study............................................................... 112
10.14. Appendix 14: Protocol Amendment History................................................................................. 114
11. REFERENCES................................................................................................................................. 115
INVESTIGATOR AGREEMENT............................................................................................................... 117
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved, Date: 08 June 2023
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Schedule of Activities................................................................................................................ 22
Table 2: 
Clinical Efficacy of Ibrutinib Monotherapy in Relapsed or Refractory Mantle Cell
Lymphoma................................................................................................................................ 27
Table 3: 
Mitigation Strategies for Risks Associated with Ibrutinib .......................................................... 31
Table 4: 
Description of Ibrutinib, Rituximab, Lenalidomide, and Bortezomib, and Study
Treatment Administration Instructions ...................................................................................... 46
Table 5: 
Recommended Dose Modifications for Non-cardiac Events for Participants who
Started Ibrutinib at 560 mg QD or 420mg QD ......................................................................... 49
Table 6: 
Recommended Dose Modifications for Non-cardiac Events for Participants who
Started Ibrutinib at 140 mg BID ................................................................................................ 50
Table 7: 
Recommended Dose Modifications for Events of Cardiac Failure or Cardiac
Arrhythmias for Participants who Started Ibrutinib at 560 mg QD or 420 mg QD .................... 50
Table 8: 
Recommended Dose Modifications for Events of Cardiac Failure or Cardiac
Arrhythmias for Participants who Started Ibrutinib at 140 mg BID ........................................... 50
Table 9: 
Lenalidomide Dose Modifications for Hematologic Toxicities .................................................. 52
Table 10: Recommended Lenalidomide Dosage for Participants with Renal Impairment ....................... 52
Table 11: Bortezomib Dose Modifications ................................................................................................ 54
Table 12: Recommended Dose Modification for Bortezomib-related Neuropathic Pain and/or
Peripheral Sensory of Motor Neuropathy ................................................................................. 54
Table 13: Bortezomib Dose Modifications for Hematologic Toxicities...................................................... 55
Table 14: Recommended Starting Dose Modification for Bortezomib in Participants with Hepatic
Impairment................................................................................................................................ 56
Table 15: Recommended Ibrutinib Dose Modifications for Co-administration with CYP3A
Inhibitors ................................................................................................................................... 59
Table 16: Response Assessments Based on the Lugano Criteria........................................................... 65
FIGURES
Figure 1: Schematic Overview: Phase 2 Part of the Study...................................................................... 21
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved, Date: 08 June 2023
ABBREVIATIONS
AE 
adverse event
ALT  
alanine aminotransferase
ANC  
absolute neutrophil count
aPTT  
activated partial thromboplastin time
AST  
aspartate aminotransferase
AUC  
area under the plasma concentration-time curve
B-cell 
B-lymphocyte
BID  
twice daily
BR 
bendamustine and rituximab
BTK  
Bruton’s tyrosine kinase
BTKi 
inhibitor of Bruton’s tyrosine kinas
CI 
confidence interval
CLL 
chronic lymphocytic leukemia
CR  
complete response
CrCl 
creatinine clearance
CRF  
case report form
CT  
computed tomography (scan)
CYP  
cytochrome P450
DMC  
Data Monitoring Committee
ECG  
electrocardiogram
ECOG  
Eastern Cooperative Oncology Group
eDC  
electronic data capture
EU  
European Union
FACT-Lym  
Functional Assessment of Cancer Therapy-Lymphoma
FDA  
US Food and Drug Administration
FDG  
[18F]-fluorodeoxyglucose
FFPE 
formalin-fixed paraffin-embedded tumor (tissue)
FL 
follicular lymphoma
FOIA  
Freedom of Information Act
GCP  
Good Clinical Practice
GI 
gastrointestinal
HBcAB  
hepatitis B core antibody
HBsAG  
hepatitis B surface antigen
HBV  
hepatitis B virus
HEV  
hepatitis E virus
HR  
hazard ratio
HRQoL 
health-related quality of life
ICF  
informed consent form
ICH  
International Conference on Harmonisation
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
ITK  
Interleukin-2-inducible T-cell kinase
INR  
international normalized ratio
IRB  
Institutional Review Board
IRC  
Independent Review Committee
ITT  
intent-to-treat (population)
IV  
intravenous
IWRS  
interactive web response system
MCL 
mantle cell lymphoma
MRI 
magnetic resonance imaging
MTD  
maximum tolerated dose
MZL 
marginal zone lymphoma
NCCN  
National Comprehensive Cancer Network
NCI CTCAE  
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL 
non-Hodgkin Lymphoma
NONMEM  
nonlinear mixed-effects modeling
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved, Date: 08 June 2023
ORR  
overall response rate
OS  
overall survival
P-gp 
P-glycoprotein
PCR  
polymerase chain reaction
PD 
pharmacodynamic(s)
PET  
positron emission tomography
PFS  
progression-free survival
PK 
pharmacokinetic(s)
POD  
progression of disease
POCBP  
Participants of Childbearing Potential
PPP  
Pregnancy Prevention Plan
PQC  
product quality complaint
PR 
partial response
PRO  
patient-reported outcome(s) (paper or electronic as appropriate for this study)
QD 
once daily
REMS  
Risk Evaluation and Mitigation Strategy
RNA  
ribonucleic acid
ROW  
Rest of the World
r/r 
relapsed or refractory
RT-PCR  
real-time polymerase chain reaction
SAE 
serious adverse event
sMIPI 
simplified Mantle Cell Lymphoma International Prognostic Index
SC 
subcutaneous
SIPPM  
Site Investigational Product and Procedures Manual
SmPC  
Summary of Product Characteristics
TFR  
tumor flare reaction
TLS  
tumor lysis syndrome
TP53 
tumor protein 53
TTNT  
time-to-next treatment
ULN  
upper limit of normal
US  
United States
USPI 
United States Package Insert
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved, Date: 08 June 2023
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Randomized, Controlled, Open-label, Multicenter, Inferentially Seamless Phase 2/3 Study of Ibrutinib in
Combination With Rituximab Versus Physician’s Choice of Lenalidomide Plus Rituximab or Bortezomib
Plus Rituximab in Participants with Relapsed or Refractory Mantle Cell Lymphoma
Short title: Seamless Phase 2/3 Study of Ibrutinib with Rituximab in Relapsed/Refractory Mantle Cell
Lymphoma
IND: 102688
EudraCT NUMBER: 2022-000364-21
EU CTR NUMBER: 2023-503618-64
Ibrutinib (IMBRUVICA®; PCI-32765; JNJ-54179060) is a first-in-class, potent, orally administered,
covalently-binding small molecule Bruton’s Tyrosine Kinase inhibitor (BTKi) currently being
co-developed by Janssen Research & Development, LLC and Pharmacyclics LLC (an AbbVie company)
for the treatment of B-lymphocyte (B-cell) malignancies and chronic graft-versus-host disease. Ibrutinib is
approved in many countries globally for the treatment of adult patients with relapsed or refractory (r/r)
mantle cell lymphoma (MCL) as a monotherapy. Due to the sponsor’s decision for early  study
discontinuation, major changes are incorporated throughout this Protocol Amendment 1 to reflect this.
RISK/BENEFIT
Management of r/r MCL can be challenging due to advanced patient age and increased aggressiveness of
disease over time. Phase 2 studies of ibrutinib in combination with rituximab resulted in higher response
rates and longer progression-free survival (PFS) and overall survival (OS) in subjects with r/r MCL
compared with historical data from ibrutinib monotherapy studies. Risks associated with ibrutinib treatment
include hemorrhage, atrial fibrillation and hypertension, and measures will be taken in this study to
minimize risks to participants, including close monitoring and dose modifications. The potential risks are
justified by the anticipated benefits that may be afforded to participants with r/r MCL. Bortezomib and
lenalidomide are approved agents for the treatment of MCL and are to be given with or without rituximab.
The overall benefit-risk assessment in this study is expected to be positive for the study participants.
OBJECTIVES
The primary objective is to provide continued access to study treatment for participants who continued to
benefit from treatment.
HYPOTHESIS
Phase 2: No formal statistical hypothesis testing will be conducted.
OVERALL DESIGN
This study was designed as a randomized, open-label, international, multicenter, inferentially seamless
Phase 2/3 adaptive study. As a result of the early study discontinuation, the Phase 2 part of this study will
not fully enroll, and the Phase 3 part will not start.
Participants will be randomized 1:1:1:1 to Treatment Arm A1 (ibrutinib 560 mg once daily
[QD] +rituximab) or Treatment Arm A2 (ibrutinib 420 mg QD +rituximab) or Treatment Arm A3
(ibrutinib 140 mg twice daily [BID] +rituximab) or Treatment Arm B (physician’s choice of
lenalidomide +rituximab or bortezomib +rituximab). Upon implementation of Protocol Amendment 1, all
participants will be given the option to switch to ibrutinib 560 mg QD monotherapy (unless ibrutinib dose
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved, Date: 08 June 2023
was reduced for toxicity reasons). All participants will also be given the option to drop rituximab treatment
and continue with monotherapy.
Randomization will be stratified by sMIPI score, prior lines of therapy, and geographical region. Selection
of physician's choice of comparator must be made for every participant prior to randomization. The study
will include a Screening Phase (up to 30 days prior to randomization), and a Treatment Phase (from
randomization until study treatment discontinuation). An End-of-Treatment visit for a safety assessment
should take place within 30 days (+14-day window) after the last dose of study treatment or before the start
of subsequent anti-cancer therapy, if earlier. The electronic case report form (eCRF) data collection
period will end, and the clinical database will be closed. All eCRF data collected up to this
timepoint will be included in the final Clinical Study Report.
Participants benefiting from study treatment may continue to receive study treatment after the end of eCRF
data collection and clinical database closure until study treatment is commercially available, available from
another source, or until study completion, whichever occurs earlier.
The study is considered completed when all participants still receiving study treatment have transitioned to
commercial or alternative access to study treatment, have stopped receiving study treatment, or upon a
decision by the sponsor to terminate the study, whichever occurs earlier.
TREATMENT GROUP AND DURATION
Participants in Treatment Arms A1, A2 and A3 will receive ibrutinib orally (560 mg QD, 420 mg, QD, or
140 mg BID, respectively, 28-day cycle) until disease progression or unacceptable toxicity. Participants in
Treatment Arm B will receive either lenalidomide (20 mg [or 10 mg if creatinine clearance (CrCl) is 30 to
<60 mL/min] orally QD on Days 1 through 21 of a 28-day cycle) or bortezomib (1.3 mg/m2 intravenously
[IV] or subcutaneously [SC] on Days 1, 4, 8, and 11 of a 21-day cycle) until disease progression or
unacceptable toxicity. Participants in all treatment arms will have the choice to also receive rituximab
(375 mg/m2 IV) on Day 1 of Cycles 1 to 6.
Upon implementation of Protocol Amendment 1, all participants will be given the choice to either remain
on the randomized treatment arm or switch to ibrutinib monotherapy at 560 mg QD (unless ibrutinib dose
was reduced for toxicity reasons). Participants will continue with the chosen dosing regimen (the regimen
they were assigned to during randomization, or the ibrutinib 560 mg monotherapy dose regimen) until the
investigator determines that the participant is no longer benefiting from treatment (ie, disease progression
or unacceptable toxicity has occurred), the participant withdraws consent, alternative access to study
treatment is available and feasible (eg, rollover to a long-term extension study, patient assistance program,
or commercial source of study treatment) or until the end of the study, whichever occurs earlier. The sponsor
will ensure that participants enrolled in the study who are benefiting from study treatment can continue to
receive treatment after study end through alternative access.
EFFICACY EVALUATIONS
Assessment of tumor response and progression will be conducted in accordance with the Lugano Criteria
(Cheson 2014). The investigator will evaluate sites of disease by radiological imaging, physical
examination, bone marrow biopsy, or other procedures as per standard of care.
To determine whether continued study treatment is warranted, investigators should monitor and assess
participants for response to treatment or disease progression per standard of care preferably using the
Lugano Criteria (Cheson 2014). Only disease status and date of disease progression should be documented
in the eCRF. After the eCRF data collection period has ended, notification of progressive disease should be
sent to the medical monitor via email. Refer to the Appendix (Continuation of Study Treatment After the
End of eCRF Data Collection and Clinical Database Closure to the End of the Study) for further guidance
on study procedures after the end of eCRF data collection.
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PHARMACOKINETIC EVALUATIONS
Upon implementation of Protocol Amendment 1, venous blood samples for ibrutinib analysis already
collected (ibrutinib treatment arm only) may be used for further development of the existing population-
based PK model.
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
Upon implementation of Protocol Amendment 1, venous blood samples for ibrutinib analysis already
collected may be used for Bruton’s Tyrosine Kinase (BTK) and/or Interleukin-2-inducible T-cell kinase
(ITK) occupancy (free and total) evaluation. A portion of the formalin-fixed paraffin-embedded tumor
(FFPE) block or slides collected for confirmation of diagnosis may be evaluated for biomarker assessments
(eg, Ki-67, and tumor protein 53 [TP53], and other genes).
SAFETY EVALUATIONS
Safety evaluations should be performed as clinically indicated and can include physical examinations and
relevant clinical laboratory tests. Participants should be periodically monitored clinically for atrial
fibrillation, and electrocardiograms (ECGs) should also be performed at the investigator’s discretion,
particularly in participants with arrhythmic symptoms (eg, palpitations, lightheadedness, or new onset
dyspnea).
All serious adverse events (SAEs) occurring during the study must be reported to the sponsor by study-site
personnel within 24 hours of their knowledge of the event. The sponsor will collect SAE data by the SAE
reporting process. Safety data collection will be limited to SAEs, Grade ≥3 AEs, and AEs leading to
treatment discontinuation; and concomitant medications related to SAEs and Grade ≥3 AEs.
For participants who continue to receive study treatment after the end of the eCRF collection and clinical
database closure, only SAEs and pregnancy information will be documented in the participant file/source
notes and reported to the sponsor’s Global Medical Safety database only until the end of the study. The
sponsor will no longer perform on-site monitoring visits (unless specifically required) but will perform
remote monitoring visits.
STATISTICAL METHODS
Due to the early termination of the study, an Independent Data Monitoring Committee (IDMC) to monitor
safety data, and to review efficacy data, is no longer required. Data will be summarized, and descriptive
statistics will be presented.
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1.2. 
Schema
Figure 1: 
Schematic Overview: Phase 2 Part of the Study
BID twice daily; IV intravenous; MCL mantle cell lymphoma; QD once daily; SC subcutaneous
a. 
A cycle is defined as 28 days.
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paraffin-embedded; POCBP Participants of Childbearing Potential; GI=gastrointestinal; h=hour(s); ICF=informed consent form; len=lenalidomide; min=minutes;
MCL=mantle cell lymphoma; MRI=magnetic resonance imaging; PCR=polymerase chain reaction; PET= positron emission tomography; POD=progression of disease;
PD=pharmacodynamics; PK=pharmacokinetics; Pts=participants; SoA=schedule of activities; SOC=standard of care; wk=week
Note: Guidelines for study intervention administration affected by the Coronavirus Disease 2019 (COVID-19) pandemic are found in Section 10.10 (Appendix 10).
a. 
If a participant's weight changes by more than 10% from baseline, the weight used for calculating the dose of bortezomib and rituximab should be re calculated
b. 
Rituximab: 28-day cycle in combination with ibrutinib or lenalidomide, and 21-day cycle in combination with bortezomib. It is recommended that ibrutinib is
administered prior to rituximab.
c. 
Randomization to Arm A (A1: ibrutinib 560 mg QD, or A2: ibrutinib 420 mg QD, or A3: ibrutinib 140 mg BID); randomization to Arm B (selection must be made
prior to randomization).
d. 
Must be obtained within 48 hours of Day 1 of each cycle and reviewed prior to dosing.
e. 
For lenalidomide participants, a pregnancy test is required at EOT. A medically supervised pregnancy test should be repeated every 4 weeks, including at least
4 weeks after last dose of treatment, except in case of tubal sterilization. If pregnancy occurs, the sponsor will collect information on the outcome of the pregnancy
and health of the baby for 1 year after birth or until the outcome of an adverse pregnancy event is known or resolved.
f. 
Buccal swab should be submitted with tumor samples (archival or fresh biopsy) at Screening. Only 1 set of buccal swab is needed.
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2. 
INTRODUCTION
Ibrutinib (IMBRUVICA®, PCI-32765; JNJ-54179060) is a first-in-class potent, orally
administered, covalently-binding small molecule BTKi currently being co-developed by Janssen
Research & Development, LLC and Pharmacyclics LLC (an AbbVie company) for the treatment
of B-cell malignancies and chronic graft-versus-host disease. Ibrutinib is approved in many
countries globally for the treatment of adult patients with r/r MCL as a monotherapy, with
accelerated approval in the United States (US) for the treatment of adult patients with MCL who
have received at least one prior therapy. Ibrutinib was first recommended for r/r MCL per national
Comprehensive Cancer Network (NCCN) guidelines in 2014.
Relevant clinical information is discussed within this section. For the most comprehensive clinical
and nonclinical information regarding the efficacy and safety of ibrutinib, refer to the latest version
of the Investigator's Brochure and Addenda/Supplements for ibrutinib and product label
(IMBRUVICA® USPI 2022; IMBRUVICA® SmPC 2022). The term “study treatment”
throughout the protocol, refers to ibrutinib and rituximab, lenalidomide and rituximab, and
bortezomib and rituximab, as defined in Section 6.1, Study Treatments Administered. 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. The term “participant” refers to a subject
in the study.
2.1. 
Study Rationale
Since the initial approval in the US on 13 November 2013, subsequent addition to the NCCN
guidelines (version 1, 2014) and approval in the European Union (EU) (2014) and other countries
worldwide, ibrutinib has become an established standard of care for r/r MCL which has brought
significant benefit as a chemotherapy-free, targeted, oral therapy to patients suffering from this
aggressive lymphoma. A program of Phase 2 and 3 studies have established ibrutinib monotherapy
treatment as an effective standard therapy in r/r MCL. However, results from a single arm Phase 2
investigator-initiated study demonstrated higher response rates and longer PFS with
ibrutinib +rituximab compared with historical data for ibrutinib monotherapy (Section 2.2.7).
This study was designed as a randomized, multicenter, open-label, inferentially seamless Phase
2/3 study to determine the recommended daily dosage of ibrutinib when administered in
combination with rituximab (Phase 2) and to evaluate whether the combination of
ibrutinib +rituximab will result in superior efficacy, compared with the combination of
physician’s choice of either lenalidomide + rituximab or bortezomib + rituximab, in participants
with r/r MCL who are BTKi naïve (Phase 3).
As a result of the early study discontinuation, the Phase 2 part of this study will not fully enroll,
and the Phase 3 part will not start. The objective of the study is to provide continued access to
study treatment for participants who continue to benefit from treatment.
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2.2. 
Background
2.2.1. 
Mantle Cell Lymphoma
Mantle cell lymphoma is an uncommon and incurable clinicopathologic subtype of B-cell
non-Hodgkin Lymphoma (NHL), and accounts for about 6-9% of all NHL cases in the Western
world (Lai 2000). The annual incidence of MCL has increased during recent decades to
4-8/1000,000 and occurs more frequently in older adults (Zhou 2008).
Most patients with MCL are male (median age: 65 years) who present with advanced stage disease
(ie, Stage III or IV) with most cases following an aggressive clinical course (Dreyling 2014). In
the US, the MCL incidence rate is highest in non-Hispanic whites (0.73, 95% CI 0.71-0.76)
significantly higher than those of the other races (Wang 2014). For the 40 64 and 65+ age groups,
non-Hispanic whites have the highest MCL incidence rates, which does not translate in a
significant difference in 5-year relative survival rates. When stratified by age, for the 40 64 years
group, non-Hispanic whites have a higher survival rate (63.1%) than Hispanic whites (51.4%). For
the 65+ years group, non-Hispanic whites have the best survival rate (44.4%), while blacks have
the worst (34.9%). However, these racial differences were found to be not significant in a
multivariate analysis.
Though the clinical course of MCL may be somewhat indolent at diagnosis, the course invariably
becomes aggressive over time and is considered incurable with standard therapies. Some patients
with MCL may achieve long-term, disease-free survival after allogenic stem cell transplantation,
but in general, the disease is characterized by a series of relapses with a median OS of 8 to 10 years
(Wu 2020).
2.2.2. 
Treatment for Relapsed or Refractory Mantle Cell Lymphoma
Management of MCL at relapse can be very challenging due to advanced patient age and increased
aggressiveness of disease over time. The number of treatment options have increased over the last
decade, and treatment choice is dependent on patient factors, prior therapy, and remission duration.
Approved therapy options at relapse which are preferred per NCCN version 3 2022 guidelines
(NCCN 2022) include the BTKi ibrutinib, acalabrutinib and zanubrutinib (all accelerated
approvals by the Food and Drug Administration [FDA]). Other approved targeted agents include
bortezomib (full approval) and an immunomodulating drug, lenalidomide (full approval), and are
recommended to be administered with or without rituximab (bortezomib) and with rituximab
(lenalidomide).
Additional suggested regimens considered useful in certain circumstances include
bendamustine +rituximab or bendamustine +rituximab and cytarabine (RBAC500) if not
previously given, ibrutinib with rituximab and lenalidomide, ibrutinib with venetoclax, venetoclax
with or without rituximab, and rituximab with dexamethasone, cisplatin, cytarabine (DHAP), or
with dexamethasone, cytarabine, oxaliplatin (DHAX) or gemcitabine, oxaliplatin (GemOx). Most
recently, brexucabtagene autoleucel, a CAR-T-cell therapy, received accelerated approval for r/r
MCL. However, current therapies for r/r MCL are infrequently curative and unable to overcome
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high-risk disease features. The proposed study is hypothesized to improve the depth and duration
of response.
2.2.3. 
Investigational Product Name and Description
Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] pyrimidin-1-yl]-1-
piperidinyl]-2-propen-1-one and has a molecular weight of 440.50 g/mole (anhydrous basis).
Ibrutinib is a white to off-white solid. It has a single chiral center and is the R-enantiomer. The
investigational drug product, ibrutinib, is an oral capsule formulation containing micronized
ibrutinib.
2.2.4. 
Nonclinical Studies With Ibrutinib
For the most comprehensive nonclinical information regarding ibrutinib, refer to the latest version
of the Investigator’s Brochure and product label (IMBRUVICA® USPI 2022; IMBRUVICA®
SmPC 2022).
2.2.5. 
Clinical Pharmacokinetic Data With Ibrutinib
For the most comprehensive clinical PK information regarding ibrutinib, refer to the latest version
of the Investigator’s Brochure and product label (IMBRUVICA® USPI 2022; IMBRUVICA®
SmPC 2022).
2.2.6. 
Clinical Efficacy of Ibrutinib in Mantle Cell Lymphoma
Efficacy data from studies of ibrutinib as monotherapy in subjects with r/r MCL are presented in
Table 2. Efficacy results from Studies PCYC-04753, PCYC-1104-CA, PCI-32765MCL2001, and
PCI-32765MCL3001 demonstrate that ibrutinib has activity as a single agent in treatment of
subjects with r/r MCL.
Table 2: 
Clinical Efficacy of Ibrutinib Monotherapy in Relapsed or Refractory Mantle Cell Lymphoma
Study  
Description
No. of
Subjects 
Efficacy Results (Final Analysis)
PCYC-04753
Phase 1, open-label,
dose-escalation,
monotherapy,
multicenter study in
subjects with r/r B-cell
malignancies
9 with a 
diagnosis of 
MCL 
Median time on study: 8.0 mo
Median PFS: 11.6 mo
Objective response: 7 of 9 subjects (78%)
CR: 3 of 9 subjects
PR: 4 of 9 subjects
PCYC-1104-CA
(Wang 2015)
Phase 2, open-label,
monotherapy,
multicenter study in
subjects with r/r MCL
111
Median time on study: 26.7 mo
Median PFS: 13.0 mo
CR rate: 23%
ORR: 66.7%
Median DOR: 17.5 mo
Median OS: 22.5 mo
PCI-32765
MCL2001
Phase 2, single-arm,
monotherapy,
multicenter study in
subjects with relapsed
MCL
120
Median time on study: 25.3 mo
Median PFS: 10.1 mo
CR rate: 24.5%
ORR:66.4%
Median DOR: 21.3 mo
Median OS: 25.4 mo
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Study  
Description 
No. of
Subjects 
Efficacy Results (Final Analysis)
PCI-32765 
MCL3001 
Phase 3, randomized, 
open-label, comparator 
(ibrutinib vs 
temsirolimus), 
monotherapy, 
multicenter study in 
subjects with r/r MCL 
ibrutinib
(n=139)
temsirolimus
(n=141)
Median time on study: 38.7 mo ibrutinib vs 38.7 mo
tem
PFS: HR 0.45 (95% CI: 0.35, 0.60), p<0.0001
Median PFS: 15.6 mo ibrutinib vs 6.2 mo tem
CR rate: 23.0% ibrutinib vs 2.8% tem
ORR: 77.0% ibrutinib vs 46.8% tem, p<0.0001
OS: HR 0.74 (95% CI: 0.54, 1.02), p=0.0621
CI=confidence interval; CR=complete response; DOR=duration of response; HR=hazard ratio; MCL=mantle cell
lymphoma; mo=months; No.=number; ORR=overall response rate; OS=overall survival; PFS=progression-free
survival; PR=partial response; r/r=relapsed or refractory; tem=temsirolimus; vs=versus
For further details on the efficacy and safety data from these studies, refer to the ibrutinib
Investigator’s Brochure.
2.2.7. 
Studies of Ibrutinib in Combination With Rituximab in Subjects with
MCL
Following on from Study PCYC-1104-CA (Section 2.2.6), it was hypothesized that by adding
rituximab to ibrutinib, MCL cells associated with the ibrutinib redistribution lymphocytosis could
be targeted, leading to more potent antitumor activity (Jain 2018; Wang 2016). Fifty participants
with r/r MCL were enrolled in an open-label, Phase 2 investigator-initiated study. Participants
received ibrutinib (560 mg daily administered orally) until progressive disease or unacceptable
toxic effects, in combination with rituximab. Participants received rituximab at 375 mg/m² IV once
weekly for 4 weeks during Cycle 1 (one cycle was 28 days), then on Day 1 of Cycles 3 8, and
thereafter once every other cycle for up to 2 years. Median age was 67 years (range: 45-86 years),
and the median number of previous treatment regimens was 3 (range: 1 9). At a median follow-
up of 16.5 months, 44 (88%) participants achieved an objective response, with 22 (44%)
participants achieving a CR, and 22 (44%) a partial response (PR). The only Grade 3 AE in ≥10%
of participants was atrial fibrillation in 6 (12%) participants. Grade 4 diarrhea and neutropenia
occurred in 1 participant each. Adverse events that led to discontinuation of therapy were atrial
fibrillation in 3 (6%) participants, liver infection and bleeding in 1 (2%) participant each. Two
participants died while on-study from cardiac arrest and septic shock.
Long-term follow-up from this study showed continued efficacy with the combination of
ibrutinib +rituximab in participants with r/r MCL (Jain 2018). At a median follow-up time of
47 months (range: 1 52 months), median duration on treatment was 16 months
(range: 1-53 months) with a median number of 17 treatment cycles (range: 1 56). Twenty-nine
participants (58%) achieved complete remission and of these, 12 participants continued study
treatment. The median PFS was 43 months, and median OS was not reached. The most frequent
Grade 1 and Grade 2 toxicities were fatigue, diarrhea, nausea, arthralgias and myalgias. No
participant had long term toxicities.
The combination of ibrutinib +rituximab was assessed in a Phase 2 investigator-initiated study in
previously untreated elderly (≥65 years) participants with MCL (Jain 2020). Participants received
ibrutinib (560 mg orally daily administered orally) until disease progression or unacceptable
toxicity, and rituximab 375 mg/m2 IV on Days 1, 8, 15 and 22 in Cycle 1, followed by rituximab
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on Day 1 of Cycles 3-8, then on Day 1 every 2 months for up to 2 years. The median follow-up
was 36.2 months (range: 6-48 months). The ORR was 96% (66% CR, 30% PR, and 4% stable
disease). Median number of ibrutinib +rituximab cycles to reach CR was 8 (range: 3-51 cycles).
The Median PFS and OS were not reached. The most frequent Grade 3-4 toxicities were atrial
fibrillation (22%), fatigue (18%), diarrhea, myalgias, and shortness of breath (each 14% of
participants), neutropenia and pain (each 8% of participants). There were no Grade 5 toxicities.
The sponsor-initiated Study PCI-32765MCL3002 was a Phase 3, placebo-controlled study that
evaluated the efficacy and safety profile of therapy with ibrutinib in combination with
bendamustine and rituximab (BR) in elderly participants (≥65 years) with newly diagnosed MCL.
Participants received ibrutinib (N 261) 560 mg orally once daily on a 28-day cycle, or placebo
(N 262). until disease progression, unacceptable toxicity, or study end, in combination with BR
background therapy (bendamustine: 90 mg/m2 IV on Days 1 and 2 of Cycles 1-6, for a maximum
of six 28-day cycles, and rituximab: 375 mg/m2 IV on Day 1 of Cycles 1-6 unless disease
progression or unacceptable toxicity). After Cycle 6, participants with CR or PR continued to
receive rituximab on Day 1 of every second cycle for a maximum of 12 additional doses unless
progression of disease or unacceptable toxicity.
At the primary analysis, with a median follow up of 84.7 months, the study met its primary
endpoint of investigator-assessed PFS, with ibrutinib +BR significantly reducing the risk of
disease progression or death by 25% compared with placebo +BR (HR 0.75; 95% CI: 0.59, 0.96;
p 0.011]). The median PFS was 80.6 months for ibrutinib +BR and 52.9 months for
placebo +BR. The CR rate was higher for ibrutinib +BR than placebo +BR (65.5% vs 57.6%)
but did not reach statistical significance (p 0.0567). With a median follow-up of 84.7 months, OS
similar between ibrutinib +BR and placebo +BR (104 and 107 deaths, respectively), with a HR
of 1.07 (95% CI: 0.81, 1.40; p 0.648). Median OS was not reached for either treatment group; the
estimated 60-month OS rates were 65% for ibrutinib +BR and 67% for placebo +BR. This study
is ongoing for collection of additional survival data.
The overall safety profile of ibrutinib +BR was consistent with the known safety profiles of
ibrutinib and BR. There was a higher incidence of AEs in the ibrutinib +BR arm than the
placebo +BR arm as follows: Grade 3 or higher AEs (92.7% vs 84.6%), serious adverse events
(SAEs) (76.1% vs 60.0%), AEs leading to study drug discontinuation (45.2% vs 26.5%), AEs
leading to study drug dose reduction (23.2% vs 10.0%), and AEs leading to death (11.2% vs 7.3%).
Major hemorrhage events were generally comparable between the ibrutinib +BR and
placebo +BR arms (5.8% vs 4.2%), and atrial fibrillation occurred more frequently in the
ibrutinib +BR arm (36 [13.9%] participants) than the placebo +BR arm (17 [6.5%] participants).
2.2.8. 
Study Drugs Used in Combination With Ibrutinib and Comparator
Therapies
2.2.8.1. 
Rituximab
Rituximab is a CD20-directed cytolytic antibody indicated for the treatment of adult patients with
NHL, including r/r CD20-positive follicular B-cell NHL as a single agent, and previously
untreated CD20-positive diffuse large B-cell NHL in combination with cyclophosphamide,
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doxorubicin, vincristine, and prednisone (CHOP) (RUXIENCE® USPI 2021; RUXIENCE®
SmPC 2022).
2.2.8.2. 
Lenalidomide
Lenalidomide is an immunomodulatory agent that has demonstrated clinical benefit for patients
with r/r MCL. Lenalidomide as monotherapy, is indicated for the treatment of adult patients with
r/r MCL, and in combination with rituximab for adult patients with previously treated follicular
lymphoma (FL) (Lenalidomide Accord SmPC 2022 [or local label if locally sourced]).
An open-label, Phase 1/2 trial in participants with r/r MCL was conducted to identify the maximum
tolerated dose (MTD) of lenalidomide when combined with rituximab (Phase 1, N 14), and the
efficacy and safety of the lenalidomide +rituximab combination (Phase 2, N 44). In Phase 1,
participants received 10, 15, 20, and 25 mg of daily oral lenalidomide on Days 1 21 of each 28-day
cycle. Rituximab 375 mg/m² IV was also administered in 4 weekly doses during Cycle 1 only. In
Phase 2, participants received rituximab plus the MTD of lenalidomide, following the same cycles
as for Phase 1. Treatment in both phases continued until disease progression, stem-cell
transplantation, or severe toxicity. The MTD was 20 mg lenalidomide when combined with
rituximab. Among 44 participants in Phase 2, 25 (57%) had an overall response: 16 (36%) had a
CR and 9 (20%) had a PR. The median response duration was 18.9 months, median PFS was
11.1 months, and the median OS was 24.3 months (Wang 2012).
For details of studies with single agent lenalidomide in r/r MCL, refer to the product label
(Lenalidomide Accord SmPC 2022 [or local label if locally sourced]).
2.2.8.3. 
Bortezomib
Bortezomib is a first in class proteasome inhibitor. Bortezomib in combination with rituximab,
cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with
previously untreated MCL who are unsuitable for hematopoietic stem cell transplantation
(VECLADE® USPI 2021; VELCADE® SmPC 2021).
In a Phase 3, randomized, open-label study in r/r B-cell NHL, participants received
bortezomib +rituximab (N 336) or rituximab alone (N 340). Participants were randomly
assigned (1:1) to receive five 35-day cycles consisting of rituximab 375 mg/m2 IV on Days 1, 8,
15, and 22 of Cycle 1, and on Day 1 of Cycles 2-5, either alone or with bortezomib 1.6 mg/m2 IV
on Days 1, 8, 15, and 22 of all cycles. With a median follow-up of 33.9 months, median PFS per
IRC assessment was significantly longer with bortezomib +rituximab than with rituximab alone,
12.8 months versus 11.0 months, respectively; p 0.039. The HR was 0.82, corresponding to a 22%
improvement in PFS with bortezomib +rituximab compared with rituximab alone (Coiffier 2011).
The efficacy and safety of bortezomib in combination with rituximab was demonstrated in a
Phase 2 open-label, single-arm study in 155 participants with r/r MCL. With a median follow-up
of more than 13 months, the ORR (CR+CRu+PR) was 31.0% (N 48), the CR rate (CR+CRu) was
8.0% (N 120 and the median duration of response (CR+CRu+PR) was 9.3 months (N 48)
(VELCADE® USPI 2021).
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2.3. 
Benefit-Risk Assessment
2.3.1. 
Risks for Study Participation
2.3.1.1. 
Risks Relevant With Ibrutinib
Mitigation strategies for risks associated with ibrutinib are presented in Table 3.
Table 3: 
Mitigation Strategies for Risks Associated with Ibrutinib
Risksa 
Mitigation Strategies
Bleeding-related 
events 
Use of either anticoagulant or antiplatelet agents concomitantly with ibrutinib increases the risk
of major bleeding. A higher risk for major bleeding was observed with anticoagulant than with
antiplatelet agents. Consider the risks and benefits of anticoagulant or antiplatelet therapy when
co-administered with ibrutinib. Monitor for signs and symptoms of bleeding
Supplements such as fish oil and vitamin E preparation should be avoided
Ibrutinib should be held for at least 3 to 7 days pre- and post-surgery depending upon the type
of surgery and the risk of bleeding
Guidance for participants who require surgical intervention or an invasive procedure while
receiving ibrutinib is provided in Section 6.7.4. Guidance on use of antiplatelet agents and
anticoagulants is provided in Section 6.7.2.2
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/µL), often associated
with reduction of lymphadenopathy, has 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 in the absence of other clinical findings. Lymphocytosis
typically occurs during the first month of ibrutinib therapy and typically resolves withing a
median of 8 weeks in subjects with MCL
Leukostasis 
A high number of circulating lymphocytes (>400,000/µL) may confer increased risk. Consider
temporarily withholding ibrutinib. Participants should be closely monitored. Administer
supportive care including hydration and/or cytoreduction as indicated
Infections 
Consider prophylaxis according to standard of care in participants who are at increased risk for
opportunistic infections (see Section 6.7.1). Although causality has not been established, cases
of progressive multifocal leukoencephalopathy and hepatitis B reactivation have occurred in
participants treated with ibrutinib. Cases of hepatitis E, which may be chronic, have occurred
in participants treated with ibrutinib. Participants should be monitored for signs and symptoms
(such as fever, chills, weakness, confusion, vomiting, jaundice, and abnormal liver function
tests) and appropriate therapy should be instituted as indicated
Cytopenias 
Monitor complete blood counts monthly
Interstitial lung 
disease 
Monitor participants for pulmonary symptoms indicative of interstitial lung disease. If
symptoms develop, follow the protocol dose modification guidelines (see Section 6.5.1). If
symptoms persist, consider the risks and benefits of ibrutinib treatment and follow the dose
modification guidelines (see Section 6.5.1)
Cardiac
arrhythmias and
cardiac failure
Fatal and serious cardiac arrhythmias or cardiac failure have occurred in participants treated
with ibrutinib. Participants with significant cardiac comorbidities may be at greater risk of
events, including sudden fatal cardiac events. Atrial fibrillation, atrial flutter, ventricular
tachyarrhythmia, and cardiac failure, have been reported, particularly in participants with acute
infections, or cardiac risk factors including hypertension, diabetes mellitus, and a previous
history of cardiac arrhythmia
Appropriate clinical evaluation of cardiac history and function should be performed prior to
initiating ibrutinib. Participants should be carefully monitored during treatment for signs of
clinical deterioration of cardiac function and clinically managed. Consider further evaluation
(eg, ECG, echocardiogram) as indicated for participants in whom there are cardiovascular
concerns. Consider the risks and benefits of ibrutinib treatment and follow the dose modification
guidelines (Section 6.5.1)
Tumor lysis 
syndrome (TLS) 
Participants at risk of TLS are those with high tumor burden prior to treatment. Monitor
participants closely and take appropriate precautions
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Table 3: 
Mitigation Strategies for Risks Associated with Ibrutinib
Risksa 
Mitigation Strategies
Non-melanoma 
skin cancer
Monitor participants for the appearance of non-melanoma skin cancer
Hypertension
Regularly monitor blood pressure in participants treated with ibrutinib and initiate or adjust
antihypertensive medication throughout treatment with ibrutinib as appropriate
Cardiovascular 
accidents 
Regular monitoring and appropriate treatment of conditions that can contribute to the
occurrence of these events is recommended
Diarrhea
These events are rarely severe and are generally managed with supportive therapies including
antidiarrheals and antiemetics. Participants should be monitored carefully for gastrointestinal
AEs and cautioned to maintain fluid intake to avoid dehydration. Medical evaluations should
be made to rule out other etiologies such as Clostridium difficile or other infections agents.
Should symptoms be severe or prolonged, ibrutinib treatment should be modified as directed in
Section 6.5.1
Rash
Participants should be closely monitored for signs and symptoms suggestive of severe
cutaneous adverse reactions, including Stevens-Johnson syndrome. Participants receiving
ibrutinib should be observed closely for rashes and treatment symptomatically, including
interruption of the suspected agent as appropriate
a 
Source: Ibrutinib Investigator’s Brochure, Edition 15, 2021.
2.3.1.2. 
Risks Relevant With Rituximab
For full details of warnings, precautions and AEs associated with treatment with rituximab, refer
to the product label (RUXIENCE® USPI 2021; RUXIENCE® SmPC 2022).
2.3.1.3. 
Risks Relevant With Lenalidomide
Lenalidomide is an analog of thalidomide, which is a known human teratogen that causes severe
birth defects or embryo-fetal death. Due to the embryo-fetal risk associated with
immunomodulatory drugs, all participants receiving lenalidomide must adhere to the applicable
Pregnancy Prevention Program (PPP) for lenalidomide (see Section 5.3 and Section 10.4
[Appendix 4] for further details).
For further details of the warnings, precautions and AEs associated with treatment lenalidomide,
refer to the product label (Lenalidomide Accord SmPC 2022 [or local label if locally sourced]).
2.3.1.4. 
Risks Relevant With Bortezomib
For full details of warnings, precautions and AEs associated with treatment with bortezomib, refer
to the product label (VELCADE® USPI 2021; VELCADE® SmPC 2021).
2.3.2. 
Benefits for Study Participation
In the Phase 2 studies described in Section 2.2.7, treatment with ibrutinib in combination with
rituximab resulted in higher response rates and longer PFS and OS in subjects with MCL compared
with historical data from ibrutinib monotherapy studies. Considering the results from these studies,
participants may benefit from this combination treatment in this study. Bortezomib and
lenalidomide are approved agents for the treatment of MCL and to be given with or without
rituximab.
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2.3.3. 
Benefit-Risk Assessment for Study Participation
Taking into account the risks and the measures taken to minimize risks to participants, such as
periodic monitoring and dose modifications, the potential risks identified in association with
ibrutinib +rituximab are justified by the anticipated benefits that may be afforded to participants
with r/r MCL. The overall benefit-risk assessment in this study is expected to be positive for the
participants in this study.
3. 
OBJECTIVES AND ENDPOINTS
As a result of the early study discontinuation, the primary objective of Protocol Amendment 1 is
to provide continued access to treatment for participants who continue to benefit from treatment.
The Phase 2 exploratory objectives and endpoints of characterization of PK and PD of ibrutinib
may continue to be evaluated using blood samples already collected prior to implementation of
Protocol Amendment 1.
Objectives 
Endpoints
Exploratory
 
To characterize the pharmacokinetics of 
ibrutinib when administered in combination 
with rituximab 
 
To assess the pharmacodynamics of ibrutinib
when administered in combination with
rituximab
 
Systemic exposure
 
BTK and/or ITK occupancy at various doses
of ibrutinib and at different timepoints
BTK=Bruton’s Tyrosine Kinase; ITK= Interleukin-2-inducible T-cell kinase
HYPOTHESIS
Phase 2
No formal statistical hypothesis testing will be conducted.
4. 
STUDY DESIGN
4.1. 
Overall Design
This study was designed as a randomized, controlled, open-label, international, multicenter,
inferentially seamless Phase 2/3 adaptive study. As a result of the early study discontinuation, the
Phase 2 part of this study will not fully enroll, and the Phase 3 part will not start.
Participants will be randomized 1:1:1:1 to Treatment Arm A1 (ibrutinib 560 mg QD +rituximab)
or Treatment Arm A2 (ibrutinib 420 mg QD +rituximab) or Treatment Arm A3 (ibrutinib 140 mg
BID +rituximab), or Treatment Arm B (physician’s choice of lenalidomide +rituximab or
bortezomib +rituximab).
Randomization of the study will be stratified by simplified Mantle Cell Lymphoma International
Prognostic Index  (sMIPI) score (low/intermediate vs high) (Hoster 2008; Section 10.6
[Appendix 6]), prior lines of therapy (1 prior line with progression of disease [POD]24 [POD
within 24 months of diagnosis] vs 1 prior line with POD>24 [POD >24 months after diagnosis] vs
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>1 prior line), and by geographical region (US/EU vs Rest of the World [ROW]). Selection of
physician’s choice must be made for every participant prior to randomization.
This study will include a Screening Phase, and a Treatment Phase. The Screening Phase will be up
to 30 days prior to randomization. The Treatment Phase will extend from randomization until study
treatment discontinuation.
To determine whether continued treatment is warranted, investigators should monitor and assess
participants for response to treatment or disease progression per standard of care preferably using
the Lugano Criteria (Cheson 2014). Disease status and date of disease progression before the
completion of 6 cycles of study treatment should be documented in the electronic case report form
(eCRF). After 6 cycles of study treatment, the eCRF data collection period will end so notification
of progressive disease to the medical monitor should be via email.
During the study, safety evaluations will include AE monitoring, physical examinations per
standard of care, vital signs, 12-lead ECG, as clinically indicated, concomitant medication usage,
and clinical laboratory parameters (hematology, chemistry, coagulation, as clinically indicated). At
each site visit, participants will be evaluated for toxicity. All study evaluations will be conducted
per the Schedule of Activities (Table 1).
Upon implementation of Protocol Amendment 1, all participants will be given the choice to either
remain on the randomized treatment arm or switch to ibrutinib monotherapy at 560 mg QD (unless
ibrutinib dose was reduced for toxicity reasons). All participants will also be given the option to
drop rituximab treatment and continue with monotherapy.
Participants will continue with the chosen dosing regimen (the one to which they were assigned to
during randomization or the ibrutinib 560 mg dose regimen) until the investigator determines that
the participant is no longer benefiting from treatment (ie, disease progression or unacceptable
toxicity has occurred), the participant withdraws consent, alternative access to study treatment is
available and feasible (eg, rollover to a long-term extension study, patient assistance program or
commercial source of ibrutinib), or until the end of the study, whichever occurs earlier.
An End-of-Treatment visit for a safety assessment should take place within 30 days (+14-day
window) after the last dose of study treatment or before the start of subsequent anti-cancer therapy,
if earlier. The eCRF data collection period will end, and the clinical database will be closed. All
eCRF data collected up to this timepoint will be included in the final Clinical Study Report.
Participants benefiting from study treatment may continue to receive study treatment after the end
of eCRF data collection and clinical database closure until study treatment is commercially
available, available from another source, or until study completion, whichever occurs earlier (see
Section 4.4).
The study is considered completed when all participants still receiving study treatment have
transitioned to commercial or alternative access to study treatment, have stopped receiving study
treatment, or upon a decision by the sponsor to terminate the study, whichever occurs earlier. A
diagram of the study design for the Phase 2 part of the study is provided in Section 1.2 (Figure 1).
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4.2. 
Scientific Rationale for Study Design
As a result of the early study discontinuation, the original objective of the study no longer applies.
The aim of the sponsor with Protocol Amendment 1 is to provide continued access to study
treatment for participants who continued to benefit from treatment.
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants 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 participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled. Written
consent/assent may be obtained through various sources (eg, paper or electronic such as eConsent,
eSignature, or digital signature) as determined by regulations as well as study and/or patient
preferences. Following the implementation of Protocol Amendment 1, the total blood volume to be
collected will be minimal, and only for the purpose of study procedures including safety.
4.3. 
Justification for Dose
Data from Study PCYC-04753 showed that although ibrutinib is rapidly eliminated from the
plasma after oral administration, QD dosing is adequate to sustain maximal BTK occupancy for
24 hours postdose at dose levels ≥2.5 mg/kg. Although the BTK occupancy was above 90% at
ibrutinib doses ≥2.5 mg/kg in this study, the data are from combined B-cell malignancy cohorts
containing small numbers of subjects with MCL (ie, 9 subjects with r/r MCL). Based on these data,
simulations on BTK occupancy were performed with a maximal efficacy (Emax) model at different
dose levels (140 mg, 280 mg, 420 mg, and 560 mg once daily) in a population of virtual subjects.
The results showed a higher percentage of subjects with occupancy of >90% at 560 mg compared
with 280 mg QD (91.9 % for 560 mg vs 75.7% for 280 mg). Moreover, the dose of 560 mg QD
appeared to have a manageable safety profile and objective responses were observed in  MCL
patients.
Further exposure-response analyses in subjects with MCL receiving single-agent ibrutinib
560 mg/day (Studies 1104, MCL2001, MCL3001, and 04753) did not reveal an exposure-response
relationship for efficacy (ORR) across the observed exposure range. In addition, no clear exposure-
response relationship for PFS was observed in study MCL3002, in which ibrutinib was combined
with chemoimmunotherapy (bendamustine-rituximab). With regards to safety, ibrutinib exposure
was associated with the incidence of atrial fibrillation and any hemorrhage within the exposure
range obtained in the ibrutinib treatment arm in Study MCL3002. The predicted incidence of atrial
fibrillation decreased from 11.9% for an ibrutinib area under the plasma concentration-time curve
(AUC) of 349 h.ng/mL (median AUC associated with 560 mg QD dosing) to 10.9% for an AUC
of 262 h.ng/mL (median AUC predicted for 420 mg QD dosing). Similarly, the incidence of any
hemorrhage decreased with a 25% reduction in 560 mg QD dose from 29.4% to 27.4% for subjects
receiving no CYP3A inhibitor comedication and from 43.8% to 41.3% for subjects receiving
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CYP3A inhibitor comedication. The exposure-response relationship for atrial fibrillation was not
observed in Studies 1104, MCL2001, MCL3001 and 04753.
Recently, a new covalent binding time-dependent PK/PD model was built using published data to
describe the BTK occupancy in CLL patients. Due to limited data from MCL patients and lack of
information on BTK dynamics between MCL and CLL biology, this model was adapted to reflect
the biology of MCL. BTK dynamics in the more aggressive MCL biology assumed faster BTK
turnover (Scenario 1) or higher baseline free BTK concentrations (Scenario 2). The results for the
first scenario showed 96.2%, 91.6%, 78.1%, and 98.7% of subjects with occupancy of >90% for
the 560 mg, 420 mg, 280 mg QD, and 140 mg BID, respectively, at trough plasma concentrations
(Ctrough). The results for the second scenario showed 100% of subjects with occupancy of >90%
for all 4 dose levels. Given the uncertainty in BTK assumptions in the MCL population, and to
ensure maximum BTK occupancy in the majority of the subjects, 420 mg QD and 140 mg BID
were selected for the lower doses to be evaluated in this study. Using these doses, the currently
labelled dose (560 mg/day) is evaluated side-by-side with 420 mg/day which is 25% lower and
predicted to have lower overall exposure (free maximum observed plasma concentration [Cmax],
AUC, and minimum plasma drug concentration [Cmin]). The 140 mg BID  dose is 50% lower
(280 mg total daily dose) compared with 560 mg/day and is predicted to have lower (free) Cmax
and AUC.  However, (free) Cmin  is similar to the 420 mg/day dose level, which may be important
for efficacy (maintaining BTK occupancy). With these dose levels, certain AE rates may be
positively impacted with the resulting lower exposures.
Furthermore, it is hypothesized that by combining ibrutinib with rituximab, MCL cells associated
with the ibrutinib redistribution lymphocytosis could be targeted, leading to more potent antitumor
activity and thus positively impacting efficacy. Combination studies of ibrutinib 560 mg orally
QD with rituximab 375 mg/m2 IV demonstrated a positive impact on efficacy while no new safety
issues were noted with this combination (Section 2.2.7). However, ibrutinib and rituximab as
anti-CD20 therapy have overlapping unfavorable effects. Amongst these, the most common
(10%) ADRs of any grade reported in patients treated with either ibrutinib or rituximab include
upper respiratory tract infection/bronchitis, neutropenia, thrombocytopenia, nausea, rash,
fever/pyrexia, and headache. In addition, common safety warnings and precautions for ibrutinib
and rituximab include infections (including hepatitis B reactivation and progressive multifocal
leukencephalopathy (PML), cardiac disorders (including arrythmia and cardiac failure), and
cytopenias (IMBRUVICA® SmPC 2022; RUXIENCE® SmPC 2022).
The proposed dose for lenalidomide is 20 mg orally once daily on Days 1 through 21 of a 28-day
cycle until disease progression or unacceptable toxicity is based on a Phase 1/2 study in 52 subjects
with r/r MCL (see Section 2.2.8.2). In this study the maximum tolerated dose of lenalidomide was
identified as 20 mg when combined with rituximab 375 mg/m2 IV. This combination was effective,
with an ORR of 57%, a median duration of response of 18.8 months, and was associated with less
severe toxicities than 25 mg lenalidomide plus rituximab and, therefore, allowing longer drug
exposure (Wang 2012).
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The proposed dose for bortezomib is 1.3 mg/m2 IV or SC on Days 1, 4, 8, and 11 of a 21-day cycle
until disease progression or unacceptable toxicity which is the dose used for the treatment of adult
patients with MCL as detailed in the product label (VELCADE USPI® 2021; VELCADE® SmPC
2021). The proposed dose for rituximab is 375 mg/m2 IV which is the recommended dose for the
treatment of NHL and chronic lymphocytic leukemia (CLL) as detailed in the product label
(RUXIENCE® USPI 2021; RUXIENCE® SmPC 2022).
4.4. 
End of Study Definition
The clinical database will close and no further data will be collected in the eCRFs as soon as
possible but no later than when the last study participant has completed the first 6 cycles of study
treatment. Only data collected in the eCRF during the data collection period will be included in
the final Clinical Study Report.
The sponsor will ensure that participants benefiting from study treatment will be able to continue
receiving study treatment after the end of eCRF data collection and clinical database closure until
study treatment is commercially available, or available from another source, or study completion,
whichever occurs earlier. Refer to Section 10.13 (Appendix 13) for further guidance on data
collection and reporting procedures for participants who continue study treatment after the end of
eCRF data collection.
The study is considered completed when all participants still receiving study treatment have
transitioned to commercial or alternative access to study treatment, have stopped receiving study
treatment, or upon a decision by the sponsor to terminate the study, whichever occurs earlier.
5. 
STUDY POPULATION
Screening for eligible participants will be performed up to 30 days before randomization. Refer to
Section 5.5, Screen Failures, for conditions under which the repeat of any screening procedures
are allowed.
The inclusion and exclusion criteria for enrolling participants of this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
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5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Be ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is
taking place) at the time of informed consent.
2. 
Have pathologically confirmed MCL, with documentation of either overexpression of
cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or
evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH),
or polymerase chain reaction (PCR) (see Section 8.1.2).
 A report from the local laboratory is acceptable; however, it must be reviewed and
approved by the central pathology laboratory to verify the above criteria prior to
randomization.
 If the report from the local laboratory is not available prior to randomization, or
the central laboratory is not able to confirm MCL diagnosis based on the local
laboratory report, a newly obtained tissue sample or most recent dated FFPE
archival tissue sample is required to confirm MCL diagnosis prior to enrollment.
The tumor tissue block or slides must be sent to the central pathology laboratory
for confirmation of MCL diagnosis prior to randomization. If central laboratory is
not able to confirm diagnosis from the archived tissue sample, a fresh tissue
sample is required.
 If Cyclin D1 and t(11;14) are negative, but the central laboratory confirms MCL,
participants can still enroll into the study.
3. 
At least 1 prior treatment regimen for MCL excluding BTKi.
4. 
Documented disease progression or relapse following the last anti-MCL treatment.
5. 
At least 1 measurable site of disease on cross-sectional imaging that is ≥2.0 cm in the
longest diameter and measurable in 2 perpendicular dimensions per computed
tomography (CT).
6. 
Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1 (see
Section 10.5 [Appendix 5]).
7. 
Adequate hematologic function independent of transfusion and growth factor support
for at least 7 days prior to first dose, with the exception of pegylated granulocyte-colony
stimulating factor (G-CSF) (pegfilgrastim) and darbopoeitin which requires at least
14 days prior to the first dose), defined as:
a. Absolute neutrophil count (ANC) 1000/mm3
b. Platelets 50,000/mm3
c. Hemoglobin ≥8.0 g/dL
8. 
Adequate hepatic and renal function defined as:
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤3 x upper limit of normal (ULN)
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b. Total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert’s
syndrome or of non-hepatic origin (in which case direct bilirubin
≤1.5 x ULN is required)
c. Estimated creatinine clearance (Cockroft‑Gault [Cockroft 1976])
≥30 mL/min (see Section 10.12 [Appendix 12]).
9. 
Prothrombin time <1.5 x ULN/international normalized ratio (INR) <1.5 and activated
partial thromboplastin time (aPTT) <1.5 x ULN (unless abnormalities are unrelated to
coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K
antagonists, then INR must be ≤3.0.
10. 
Participants must not be diagnosed or treated for malignancy other than MCL. Allowed
recent second or prior malignancies are as follows:
 
Any malignancy that was not progressing nor requiring treatment change in the last
12 months.
 
Malignancies treated within the last 12 months and considered at very low risk for
recurrence:
 
Non-muscle invasive bladder cancer (solitary Ta-PUNLMP or low grade,
<3 cm, no carcinoma in situ [CIS]).
 
Skin cancer (non-melanoma or melanoma).
 
Non-invasive cervical cancer.
 
Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma
in situ, localized breast cancer and receiving antihormonal agents.
 
Localized prostate cancer (M0, N0) with a Gleason Score ≤7a, treated locally
only (Radical Prostatectomy/Radiation Therapy/focal treatment).
11. 
A female ofchildbearing potential must have a negative highly sensitive serum pregnancy
test at screening and must agree to further serum or urine pregnancy tests during the study.
12. 
A female must be:
a. Not of childbearing potential, or
b. Of childbearing potential and
1) Practicing true abstinence; or
2) Practicing ≥1 highly effective method of contraception (see Section 10.4
[Appendix 10.4] for further information). A female using oral contraceptives
must use an additional contraceptive method. See Section 6.7.2.4 for details
regarding concomitant use of estrogen containing products and lenalidomide.
NOTE: Participant must agree to continue the above throughout study treatment and for
4 weeks following ibrutinib or lenalidomide treatment, 3 months following bortezomib
treatment, and 12 months following rituximab treatment.
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NOTE: If a female becomes of childbearing potential after start of the study the female
must comply with point (2) as described above.
13. 
A female must agree not to donate eggs (ova, oocytes) or freeze for future use, for the
purposes of assisted reproduction during the study and for 6 months after receiving the
last dose of study treatment.
14. 
A female must not be pregnant, or planning to become pregnant, while receiving study
treatment or 4 weeks following lenalidomide treatment and must not breastfeed during
study treatment or 12 months following rituximab treatment.
15. 
A male must wear a condom (with or without spermicidal foam/ gel/ film/
cream/suppository) when engaging in any activity that allows for passage of ejaculate to
another person during the study and for a minimum of 3 months after receiving the last
dose of study treatment. If a female partner is of childbearing potential, she must also be
practicing a highly effective method of contraception.
NOTE: If the male participant is vasectomized, he still must wear a condom (with or
without spermicidal foam/gel/film/cream/suppository), but his female partner is not
required to use contraception.
16. 
A male must agree not father a child or donate sperm for the purpose of reproduction
during the study and for a minimum of 3 months after receiving the last dose of study
treatment.
17. 
Must sign an informed consent form (ICF) indicating that the participant understands the
purpose of, and procedures required for, the study and is willing to participate in the study.
18. 
Be willing and able to adhere to the lifestyle restrictions specified in this protocol.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Prior therapy with ibrutinib or other BTK inhibitor.
2. 
Major surgery within 4 weeks of randomization.
3. 
Participants with any contraindications to one of the study treatments including
hypersensitivity to the active substance or to any of the excipients of ibrutinib,
rituximab, lenalidomide, bortezomib or its excipients (refer to the ibrutinib
Investigator’s Brochure or product labels).
4. 
Concurrent enrollment in another therapeutic investigational study.
5. 
Known central nervous system lymphoma.
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6. 
Prior treatment with both lenalidomide and bortezomib. Prior treatment with only 1 of
these therapies is allowed, but the investigator must select the other therapy as the
potential comparator regimen at randomization.
7. 
Anticancer therapy including chemotherapy, radiotherapy, small molecule, monoclonal
antibody and investigational agents 21 days (or at least 5 drug half-lives, whichever is
shorter) prior to first administration of study treatment.
8. 
History of stroke or intracranial hemorrhage within 6 months prior to randomization.
9. 
Ongoing treatment with agents known to be strong CYP3A inhibitors.
10. 
Active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia,
or uncontrolled hypertension or Class II, III or IV congestive heart failure as defined by
the New York Heart Association Functional Classification (see Section 10.7
[Appendix 7]); or a history of myocardial infarction, unstable angina, or acute coronary
syndrome within 1 year prior to randomization (if >1 year, a cardiology consultation
documenting cardiac clearance is required to be eligible) or hypertension, despite
treatment with 3 or more anti-hypertensive medications, with screening systolic blood
pressure >160 mm Hg or diastolic blood pressure >100 mm Hg.
11. 
Currently active, clinically significant Child-Pugh Class B or C hepatic impairment
according to Child-Pugh classification. Refer to (Section 10.8  [Appendix 8]) for
Child-Pugh classification.
12. 
Vaccinated with live, attenuated or replicating viral vector vaccines within 4 weeks of
randomization.
13. 
Any uncontrolled active systemic infection or any life-threatening illness, medical
condition, or organ system dysfunction which, in the investigator’s opinion, could
compromise the participant’s safety, interfere with the absorption or metabolism of
ibrutinib capsules, or put the study outcomes at undue risk (including uncontrolled
diabetes mellitus or HbA1C >7).
14. 
Known history of Human Immunodeficiency Virus (HIV).
15. 
Active hepatitis B or C virus infection according to local laboratory range, on all
available tests for the past 6 months or other clinically active liver disease.
Seropositive for hepatitis B: defined by a positive test for hepatitis B surface antigen
[HBsAg]. Participants with resolved infection (ie, participants who are HBsAg negative
with antibodies to total hepatitis B core antigen [anti-HBc] with or without the presence
of hepatitis B surface antibody [anti-HBs]) must be screened using real-time
polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA
levels. Those who are RT-PCR positive will be excluded. Participants with serologic
findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic
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marker) AND a known history of prior HBV vaccination, do not need to be tested for
HBV DNA by RT-PCR  (see Appendix 11 [Section 10.11, Hepatitis B Virus
Screening]).
Known hepatitis C infection or positive serologic testing for hepatitis C virus (anti-HCV
antibody.
Positive hepatitis C antibody test result at screening or within 3 months prior to starting
study treatment. NOTE: Participants with positive hepatitis C antibody due to prior
resolved disease can be enrolled only if a confirmatory negative hepatitis C RNA test
is obtained.
Positive hepatitis C RNA test result at screening or within 3 months prior to first dose
of study treatment. NOTE: Test is optional and participants with negative hepatitis C
antibody test are not required to also undergo hepatitis C RNA testing.
Active or chronic persistent hepatitis E virus (HEV) infection: participants seropositive
for Hepatitis E (anti-Hep E IgG positive) must be screened (serum or stool) using
real-time polymerase chain reaction (RT-PCR) measurement of HEV RNA levels.
Those who are RT-PCR positive will be excluded.
16.. 
Known bleeding disorders.
17. 
Inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any
disease or medical condition significantly affecting gastrointestinal (GI) function.
18. 
Prior stem cell transplant that requires ongoing immunosuppressive therapy or clinical
graft versus host disease.
19. 
Only applicable if investigator selects bortezomib as the potential comparator prior to
randomization. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined
by the National Cancer Institute Common Terminology Criteria for Adverse Events,
Version (NCI-CTCAE) Version 5.0.
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5.3. 
Restrictions During Study Participation
Potential participants must be willing and able to adhere to the following restrictions during the
study to be eligible for participation:
1. 
A female participant ofchildbearing potential must remain on a highly effective method
of birth control (see inclusion criteria). Contraception must begin 4 weeks before
initiating study treatment, and continue during the Treatment Phase, during dose
interruptions and continuing for at least 4 weeks following ibrutinib or lenalidomide
treatment; 3 months following bortezomib treatment; and 12 months following
rituximab treatment. In addition, females must not donate ova during the study, or for
6 months after the last dose of study treatment.
2. 
For participants randomized to lenalidomide, two negative pregnancy tests must be
obtained prior to initiating study treatment. The first test should be performed at
screening and the second test within 24 hours prior to the first dose of study treatment.
Weekly (±2 days) pregnancy tests are required during the first month, then monthly
(-2 days) thereafter in females with regular menstrual cycles or every 2 weeks (±2 days)
in females with irregular menstrual cycles. Additional pregnancy tests may be required,
as specified in the local lenalidomide Risk Evaluation and Mitigation Strategy (REMS)
(where lenalidomide is supplied locally) or the Lenalidomide Global PPP (where
lenalidomide is supplied centrally and no local lenalidomide REMS program exists).
3. 
A man who has not had a vasectomy and who is sexually active with a pregnant female
or a female of childbearing potential must agree to use a barrier method of birth control
eg, condom with spermicidal foam/gel/film/cream/suppository during the study and for
at least 3 months after the study. All men must not donate sperm during the study, during
dose interruptions, or for at least 3 months after the last dose of study treatment. The
exception to this restriction is that if the participant’s female partner is surgically sterile,
a second method of birth control is not required.
4. 
Because of the embryo-fetal risk of lenalidomide all participants must adhere to the
local lenalidomide REMS program (when lenalidomide is supplied locally), or the
Lenalidomide Global PPP (when lenalidomide is supplied centrally and no local
lenalidomide REMS program exists).
5. 
Participants must not donate blood during treatment, during dose interruptions and for
at least 7 days following discontinuation of lenalidomide.
NOTE: Investigators must ensure that all study enrollment criteria have been met at screening. If
a participant's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before randomization such that the participant no
longer meets all eligibility criteria, then the participant must be excluded from participation in the
study. Refer to Section 5.5, Screen Failures, which describes options for retesting. The required
source documentation to support meeting the enrollment criteria are noted in Section 10.2:
Regulatory, Ethical, and Study Oversight Considerations (Appendix 2).
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5.4. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the study to be eligible for participation:
1. 
Refer to Section 6.7, Concomitant Therapy for details regarding prohibited and therapy
during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3. 
Carry a “wallet study card” with pertinent information about the study for the duration
of study participation.
5.4.1. 
Meals and Dietary Restrictions for Participants Receiving Ibrutinib
Participants should avoid consuming food and beverages containing grapefruit, Seville oranges
(including marmalade containing Seville oranges), blood oranges, pomelos, tangelos, and star fruit
as these contain certain ingredients that inhibit CYP3A4/5 enzymes. Supplements such as fish oil
and vitamin E preparations should be avoided.
Participants should refrain from taking the study drug on the morning of study visits designated
for PK sampling until seen at the site. See Section 6.1 (Table 4) for dosing instructions before and
during PK sampling visits.
5.5. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not enrolled into
the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened once. Retesting of abnormal screening values that led to exclusion are allowed during
the screening phase (to reassess eligibility). The last result obtained prior to the first dose of study
drug will be used to determine eligibility. The measurements collected at the time closest to, but
prior to, the start of study drug administration will be defined as the baseline values for safety
assessment and treatment decisions.
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6. 
STUDY TREATMENT AND CONCOMITANT THERAPY
6.1. 
Study Treatment(s) Administered
Study participants in Treatment Arm A1, A2 or A3 will receive ibrutinib orally (560 mg QD, or
420 QD, or 140 mg BID, respectively, 28-day cycle) until disease progression or unacceptable
toxicity. Participants in Treatment Arm B will receive either lenalidomide (20 mg [or 10 mg if
CrCl is 30 to <60 mL/min] orally once daily on Days 1 through 21 of a 28-day cycle) or bortezomib
(1.3 mg/m2 IV or SC on Days 1, 4, 8, and 11 of a 21-day cycle) until disease progression or
unacceptable toxicity. Participants in all treatment arms will have the choice to also receive
rituximab (375 mg/m2 IV) on Day 1 of Cycles 1 to 6 (28-day cycle in combination with ibrutinib
or lenalidomide, and 21-day cycle in combination with bortezomib). For participants on ibrutinib
+ rituximab, it is recommended that ibrutinib is administered prior to rituximab on Day 1 of
Cycles 1 to 6.
Dosing instructions for ibrutinib, rituximab, lenalidomide, and bortezomib are detailed in Table 4.
Refer to the Site Investigational Product and Procedures Manual (SIPPM) for details regarding the
drug products and information describing study drug administration, and storage. It is strongly
recommended that premedication guidelines are followed per study drug package insert(s). Study
drug administration must be captured in the source documents and the case report form (CRF).
Refer to the respective Investigator’s Brochure or product labels for a list of excipients. Study-site
personnel will instruct participants on how to store study drugs for at home use as indicated for
this protocol. Sufficient study drugs required until the next visit will be dispensed. The study
treatments in this study are designated as follows:
Designation 
Product
Investigational Medicinal Products 
Ibrutinib, Rituximab, Lenalidomide, Bortezomib
Authorization status in the EU:
Authorized 
Ibrutinib
Rituximab
Lenalidomide
Bortezomib
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Table 4: 
Description of Ibrutinib, Rituximab, Lenalidomide, and Bortezomib, and Study Treatment
Administration Instructions
Arm Name 
Arm A1, A2 and A3 
Arm B
Treatment Name 
Ibrutinib + Rituximab 
Lenalidomide + Rituximab OR
Bortezomib + Rituximab
Dose Formulation 
Ibrutinib –capsules 
Rituximab –IV  
Lenalidomide –capsules
Bortezomib –IV or SC
Rituximab –IV
Unit Dose Strength(s) 
Ibrutinib –560 mg QD (4×140 mg) 
Ibrutinib –420 mg QD (3×140 mg) 
Ibrutinib –140 mg BID  
Rituximab –375 mg/m2
Lenalidomide –20 mg
Bortezomib –1.3 mg/m2
Rituximab –375 mg/m2
Dosage Level(s) and 
Frequency  
Ibrutinib –until disease progression or 
unacceptable toxicity  
Rituximab –375 mg/m2 IV on Day 1 of 
Cycles 1 to 6 
Lenalidomide –20 mg (orally
once daily on Days 1 through 21
of a 28-day cycle) until disease
progression or unacceptable
toxicity
Bortezomib –1.3 mg/m2 IV or SC
on Days 1, 4, 8, & 11 of a 21-day
cycle) until disease progression or
unacceptable toxicity
Rituximab –375 mg/m2 IV on
Day 1 of Cycles 1 to 6
Route of Administration 
Oral - ibrutinib 
IV infusion - rituximab 
Oral - lenalidomide
IV injection –bortezomib
IV infusion - rituximab
SC –bortezomib
Dosing instructions 
The ibrutinib capsules are to be taken 
around the same time each day with 
approximately 240 mL of water (ie, 
8 ounces). 
The 
capsules 
should 
be 
swallowed whole and should not be opened, 
broken, or chewed. Ibrutinib can be taken 
with or without food. 
The participant should refrain from taking 
the study drug on the morning of study 
visits designated for PK sampling. It is 
recommended that ibrutinib is administered
prior to rituximab on Day 1 of Cycles 1 to 6.
If a dose of study drug is not taken at the
scheduled time, it can be taken as soon as
possible on the same day with a return to the
normal schedule the following day. The
participant should not take extra capsules to
make up the missed dose
The lenalidomide capsules are to
be taken at about the same time
each day, either with or without
food.  The capsules should be
swallowed whole and should not
be opened, broken, or chewed
When bortezomib is given IV,
administer at a concentration of
1 mg/mL, or given SC, administer
at a concentration of 2.5 mg/mL
When bortezomib is given IV,
administer as a 3 to 5 second
bolus IV injection
BID twice daily; CYP cytochrome P450; IV intravenous; PK pharmacokinetic; QD once daily; SC subcutaneous
For a definition of study treatment overdose, refer to Section 6.6, Treatment of Overdose.
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6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study drugs must be stored at controlled temperatures according to the label. Refer to the
SIPPM for additional guidance on study drug preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried
and accounted for throughout the study. The dispensing of study drug to the participant, and the
return of study drug from the participant (if applicable), must be documented on the drug
accountability form. Participants or their legally acceptable representative, where applicable, must
be instructed to return all original containers, whether empty or containing study drug. The study
treatment administered to the participant must be documented on the treatment accountability
form. All study drugs 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 drugs 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 participant, 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 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.
Study drugs 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(s) will be supplied only
to participants enrolled in the study. Returned study drug(s) must not be dispensed again, even to
the same participant. Study drug(s) may not be relabeled or reassigned for use by other participants.
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. Further guidance and information for the final
disposition of unused study drugs are provided in the SIPPM. Refer to Section 10.13
(Appendix 13) for further guidance on study procedures after the end of eCRF data collection and
database closure.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Procedures for Randomization
Prior to randomization, physician will designate the comparator treatment to be used if participant
is randomized to Treatment Arm B.
Phase 2 Part: Participants will be randomly assigned to 1:1:1:1 to Treatment Arm A1
(ibrutinib 560mg QD +rituximab), A2 (ibrutinib 420 mg QD +rituximab), A3 (ibrutinib 140 mg
BID +rituximab) or Treatment Arm B (physician’s choice of lenalidomide +rituximab or
bortezomib +rituximab) based on a computer-generated randomization schedule prepared before
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the study by or under the supervision of the sponsor.
Randomization will be stratified by sMIPI score (low/intermediate vs high), prior lines of therapy
(1 prior line with POD24 [POD within 24 months of diagnosis] vs 1 prior line with POD>24 [POD
>24 months after diagnosis] vs >1 prior line), and geographical region (US/EU vs ROW).
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 participant. The requestor
must use his or her own user identification and personal identification number when contacting
the IWRS, and will then give the relevant participant details to uniquely identify the participant.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.4. 
Study Treatment Compliance
The study drugs are to be prescribed only by the principal investigator or a qualified physician
listed as a sub-investigator on required delegation documents. Study drugs may not be used for
any purpose other than that outlined in this protocol, including other human studies, patients not
in any study, animal investigations, or in vitro testing.
Rituximab will be administered as an IV infusion and bortezomib will be administered as an IV
injection or SC by qualified study-site personnel. The details of each administration will be
recorded in the CRF; date, start and stop time of the infusions, dose, and volume infused. The site
pharmacist will maintain a log of all rituximab/bortezomib vials prepared for infusion and/or SC
administration. Drug supplies for each participant will be inventoried and accounted for throughout
the study.
Ibrutinib and lenalidomide will be self-administered orally by the participants. The investigator or
the site pharmacist will maintain a log of all ibrutinib and lenalidomide dispensed and returned.
Drug supplies for each participant will be inventoried and accounted for throughout the study. Site
personnel are to instruct the participant to bring any unused ibrutinib or lenalidomide to the site at
the beginning of each treatment cycle to check dosing compliance. Instructions for proper self-
administration and ibrutinib and lenalidomide storage conditions will be provided. Precautions
associated with the use of ibrutinib and lenalidomide and prohibited concomitant medications will
be reviewed. Site staff will provide additional instruction to reeducate any participant who is not
compliant with the ibrutinib and lenalidomide schedule.
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. Instructions
regarding accountability for study drug are provided in the SIPPM. Refer to Section 10.13
(Appendix 13) for further guidance on study procedures after the end of eCRF data collection.
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6.5. 
Dose Modification
Any dose/dosage adjustment must be overseen by medically qualified study site personnel
(principal or sub-investigator unless an immediate safety risk appears to be present), and recorded
in the ‘Dosage Administration’ page of the CRF.
Always follow local labels if dose modification guidelines are more restrictive than the
recommended guidelines presented in this protocol.
6.5.1. 
Ibrutinib
Ibrutinib interruption and/or dose reduction may be required for toxicities related to ibrutinib.
Ibrutinib may be held for a maximum of 28 consecutive days. For any hold beyond 28 days, contact
medical monitor prior to restarting. The actions described in Table 5 and Table 6 should be taken
for the following potentially drug-related toxicities:
 
Grade 2 cardiac failure (Table 7 and Table 8).
 
ANC <500 cells/µL for more than 7 days. See Section 6.7.1 for instructions regarding the use
of growth factor support.
 
Platelets <50,000 cells/µL in the presence of clinically significant bleeding.
 
Platelets <25,000 cells/µL.
 
Grade 3 or greater non-hematological toxicity.
Adverse events that do not meet the criteria above but are persistent and considered by the
investigator to be potentially manageable by dose modification, may also be managed per the
instructions in Table 5 and Table 6 for non-cardiac events, and Table 7 and Table 8 for cardiac
events.
Table 5: 
Recommended Dose Modifications for Non-cardiac Events for Participants who Started
Ibrutinib at 560 mg QD or 420 mg QD
Occurrence 
Action
Firsta 
Hold study drug until recovery to Grade ≤1 or baseline; may restart at original
dose level
Second 
Hold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose
level lower
Third 
Hold study drug until recovery to Grade ≤1 or baseline; may restart at 2 dose
levels lower from the original dose level
Fourth  
Discontinue study drug
a. 
When resuming treatment, restart at the same or lower dose based on benefit-risk evaluation. If the toxicity
reoccurs, reduce daily dose by 140 mg
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Table 6: 
Recommended Dose Modifications for Non-cardiac Events for Participants who Started
Ibrutinib at 140 mg BID
Occurrence 
Action
Firsta 
Hold study drug until recovery to Grade ≤1 or baseline; may restart at original
dose level
Seconda 
Hold study drug until recovery to Grade ≤1 or baseline; may restart at original
dose level
Third 
Hold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose
level lower from the original dose level (ie, 140 mg QD)
Fourth  
Discontinue study drug
a. 
When resuming treatment, restart at the same or lower dose based on benefit-risk evaluation.
Table 7: 
Recommended Dose Modifications for Events of Cardiac Failure or Cardiac Arrhythmias for
Participants who Started Ibrutinib at 560 mg QD or 420 mg QD
Event 
Toxicity Occurrence 
Dose Modification After Recovery
Grade 2 cardiac failure 
First 
Hold study drug until recover to Grade ≤1
or baseline, may restart at 1 dose level
lower from the original dose level
Second 
Hold study drug until recover to Grade ≤1
or baseline, may restart at 2 dose levels
lower from the original dose level
Third 
Discontinue ibrutinib
Grade 3 cardiac 
arrhythmias 
First 
Hold study drug until recovery to Grade ≤1
or baseline, may restart 1 dose level lower
from the original dose levela
Second 
Discontinue ibrutinib
Grade 3 or 4 cardiac failure 
Grade 4 cardiac 
arrhythmias
First
Discontinue ibrutinib
a. 
Evaluate the benefit-risk before resuming treatment.
Table 8: 
Recommended Dose Modifications for Events of Cardiac Failure or Cardiac Arrhythmias for
Participants who Started Ibrutinib at 140 mg BID
Event 
Toxicity Occurrence 
Dose Modification After Recovery
Grade 2 cardiac failure
First 
Hold study drug until recover to Grade ≤1
or baseline, may restart at 1 dose level
lower (140 mg QD)
Second 
Discontinue ibrutinib
Grade 3 cardiac 
arrhythmias 
First 
Hold study drug until recover to Grade ≤1
or baseline, may restart 1 dose level lower
(140 mg QD)a
Second 
Discontinue ibrutinib
Grade 3 or 4 cardiac failure 
Grade 4 cardiac 
arrhythmias
First
Discontinue ibrutinib
a. 
Evaluate the benefit-risk before resuming treatment.
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Hepatic impairment
Ibrutinib is metabolized in the liver, and therefore, subjects with chronic hepatic impairment
(Child-Pugh class A, B, or C) should have the dose of ibrutinib modified as indicated below. Refer
to Section 10.8 (Appendix 8) for Child-Pugh classification.
For participants with mild liver impairment (Child-Pugh class A), the recommended dose of
ibrutinib is 140 mg QD (Arm A1 and A2) or 70 mg QD (Arm A3). Patients with Child-Pugh class
B or C at screening are not eligible to participate in this study. For participants who develop
moderate liver impairment while on study (Child-Pugh class B), the recommended dose of
ibrutinib is 70 mg QD for Arm A1 and A2. Participants in Arm A3 who develop moderate liver
impairment (Child-Pugh class B) while on study should interrupt treatment until recovery to
Child-Pugh class A or better and may restart with 70 mg QD. It is not recommended to administer
ibrutinib to participants with severe hepatic impairment (Child-Pugh class C). Therefore, for
participants who develop severe hepatic impairment (Child-Pugh Class C), ibrutinib must be held
until resolved to moderate impairment (Child-Pugh Class B) or better. Monitor participants for
signs of ibrutinib toxicity and follow dose modification guidance as needed.
For dose modifications of ibrutinib related to concomitant medication use, see Section 6.7.2. For
dose modifications of ibrutinib during the perioperative period for surgeries or invasive
procedures, see Section 6.7.4. Doses of rituximab, lenalidomide, and bortezomib should be
reduced or held in accordance with the dose modification guidelines in their respective product
labels as described below.
6.5.2. 
Rituximab
There will be no dose reductions for rituximab. Rituximab should be held for any Grade 4 toxicity
or for any rituximab-related, unmanageable Grade 3 AEs. Rituximab should be held until the AE
returns to baseline or resolves completely. Detailed dosing and medical management instructions
for infusion reactions and cytokine release syndrome are provided in the product label
(RUXIENCE® USPI 2021; RUXIENCE® SmPC 2022).
6.5.3. 
Lenalidomide
Treatment is continued, modified or discontinued based upon clinical and laboratory findings (see
lenalidomide product label [Lenalidomide Accord SmPC 2022; or refer to local label if locally
sourced]).
Hematologic toxicities
Dose modification guidelines as summarized in Table 9 are recommended to manage Grade 3 or 4
neutropenia or thrombocytopenia considered to be related to lenalidomide.
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Table 9: 
Lenalidomide Dose Modifications for Hematologic Toxicities
Platelet Counts
Thrombocytopenia During Treatment in MCL
When Platelets 
Recommended Course
<50,000/µL
Interrupt lenalidomide and follow complete blood counts
weekly
≥50,000/µL
Resume lenalidomide at 5 mg less than the previous dose.
If previous dose was 5 mg, reduce dose to 2.5 mg daily or
5 mg every other daya
Do not dose below 2.5 mg daily or 5 mg every other daya
Absolute Neutrophil count (ANC)
Neutropenia during treatment in MCL
When Neutrophils 
Recommended Course
<1000/µL for at least 7 days 
OR  
<1,000/µL with an associated
temperature at least 38.5 degrees Celsius
OR
<500/µL
Interrupt lenalidomide treatment and follow complete blood
counts weekly
≥1,000/µL
Resume lenalidomide at 5 mg less than the previous dose
If previous dose was 5 mg, reduce dose to 2.5 mg daily or
5 mg every other daya
Do not dose below 2.5 mg daily or 5 mg every other daya
ANC absolute neutrophil counts; MCL mantle cell lymphoma
a. 
If using locally sourced lenalidomide, refer to local label for lowest dose level allowed.
Renal impairment
Adjustments to the dose of lenalidomide is recommended to provide appropriate drug exposure in
participants with moderate or severe renal impairment, because lenalidomide is primarily excreted
unchanged by the kidney. Lenalidomide dose adjustment should be instituted for participants with
a CrCl <60 mL/min. The recommended doses for participants with MCL and renal impairment are
shown in Table 10. To be enrolled in the study, participants must have CrCl ≥30 mL/min. If during
treatment a participant’s renal status changes, the dose should be adjusted. In the event of a dose
adjustment, lenalidomide doses may be re-escalated at the investigator’s discretion.
Table 10: 
Recommended Lenalidomide Dosage for Participants with Renal Impairment
Moderate renal impairment-CrCl 30 to
<60 mL/min
Lenalidomide should be given at a dose of 10 mg
daily
Severe renal impairment-CrCl <30 mL/min (not
requiring dialysis)
Lenalidomide should be given at a dose of 15 mg
every 48 hours
End-stage renal disease- CrCl <30 mL/min
(requiring dialysis)
Lenalidomide should be given at a dose of 5 mg
daily. Administer dose after dialysis
CrCl  creatinine clearance
Tumor lysis syndrome
Lenalidomide may be continued (maintain dose) in patients with laboratory tumor lysis syndrome
(TLS) or Grade 1 clinical TLS, or at the physician’s discretion, reduce dose by 1 level and continue
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lenalidomide. Vigorous IV hydration should be provided and appropriate medical management
according to the local standard of care, until correction of electrolyte abnormalities. Rasburicase
therapy may be needed to reduce hyperuricemia. Hospitalization of the participant will be at
physician’s discretion.
In participants with Grade 2 to 4 clinical TLS, interrupt lenalidomide and obtain a chemistry panel
weekly or as clinically indicated. Vigorous IV hydration should be provided and appropriate
medical management according to the local standard of care, until correction of electrolyte
abnormalities. Rasburicase therapy and hospitalization will be at physician’s discretion. When the
TLS resolves to Grade 0, restart lenalidomide at next lower dose per physician’s discretion.
Tumor flare reaction
At the physician’s discretion, lenalidomide may be continued in patients with Grade 1 or 2 tumor
flare reaction (TFR) without interruption or modification. At the physician’s discretion, therapy
with non-steroidal anti-inflammatory drugs (NSAIDs), limited duration corticosteroids, and/or
narcotic analgesics may be administered. In participants with Grade 3 or 4 TFR, withhold
treatment with lenalidomide and initiate therapy with NSAIDs, corticosteroids and/or narcotic
analgesics. When TFR resolves to ≤Grade 1, restart lenalidomide treatment at the same dose level
for the rest of the cycle. Participants may be treated for management of symptoms per the guidance
for treatment of Grade 1 and 2 TFR.
Skin rash
Lenalidomide interruption or discontinuation should be considered for Grade 2 or 3 skin rash.
Lenalidomide must be discontinued for angioedema, anaphylactic reaction, Grade 4 rash,
exfoliative or bullous rash, or if Stevens-Johnson syndrome, toxic epidermal necrolysis or drug
reaction with eosinophilia and systemic symptoms is suspected, and should not be resumed
following discontinuation from these reactions.
Other toxicities
For other Grade 3 or 4 toxicities judged to be related to lenalidomide, hold treatment and restart at
the physician’s discretion at next lower dose level when toxicity has resolved to Grade ≤2.
For full safety information for lenalidomide, refer to the product label (Lenalidomide Accord
SmPC 2022 [or local label if locally sourced]).
6.5.4. 
Bortezomib
Dose adjustments should be based on the highest grade of toxicity that is ascribed to bortezomib.
Bortezomib treatment should be withheld at the onset of any Grade 3 nonhematological or Grade 4
hematological toxicities excluding neuropathy as described in the product label (VELCADE USPI
2021; VELCADE® SmPC 2021). Once the symptoms of the toxicity have resolved, bortezomib
therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose;
1 mg/m2/dose reduced to 0.7 mg/m2/dose) (Table 11). If the toxicity is not resolved, or if it recurs
at the lowest dose, discontinuation of bortezomib must be considered unless the benefit of
treatment clearly outweighs the risk.
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Table 11: 
Bortezomib Dose Modifications
Starting Dose 
First Dose Reduction
Second Dose
Reduction
Third Dose Reduction
Bortezomib 1.3 mg/m2 
Bortezomib 1.0 mg/m2 
Bortezomib 0.7 mg/m2 
Discontinue bortezomib
Neuropathic pain and/or peripheral neuropathy
Starting bortezomib SC may be considered for participants with pre-existing or at high risk of
peripheral neuropathy. Participants with pre-existing severe neuropathy should be treated with
bortezomib only after careful risk-benefit assessment. Participants experiencing new or worsening
peripheral neuropathy during bortezomib therapy may require a decrease in the dose and/or a less
dose-intense schedule.
For dose or schedule modification guidelines for participants who experience bortezomib-related
neuropathic pain and/or peripheral neuropathy see Table 12.
Table 12: 
Recommended Dose Modification for Bortezomib-related Neuropathic Pain and/or
Peripheral Sensory of Motor Neuropathy
Severity of Neuropathy  
Posology Modification
Grade 1 (asymptomatic: loss of deep tendon
reflexes or paresthesia) with no pain or loss of
function
None
Grade 1 with pain or Grade 2 (moderate
symptoms: limiting instrumental ADLa
Reduce bortezomib to 1.0 mg/m2
OR
Change bortezomib treatment schedule to
1.3 mg/m2 once per week
Grade 2 with pain or Grade 3 (severe symptoms;
limiting self care ADLb
Withhold bortezomib treatment until symptoms of
toxicity have resolved. When toxicity resolves
re-initiate bortezomib treatment and reduce dose
to 0.7 mg/m2 once per week
Grade 4 (life-threatening consequences; urgent
intervention indicated) and/or severe autonomic
neuropathy
Discontinue bortezomib
ADL Activities of Daily Living
a. 
Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.
b. 
Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications
and not bedridden.
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Hematologic toxicities
Dose modification guidelines for hematologic toxicities are shown in Table 13.
Table 13: 
Bortezomib Dose Modifications for Hematologic Toxicities
Toxicity  
Posology Modification or Delay
Hematological toxicity
≥Grade 3 neutropenia with
fever, Grade 4 neutropenia
lasting more than 7 days, a
platelet count <10,000/µL
Bortezomib therapy should be withheld for up to 2 weeks until the
participant has an ANC ≥750 cells/µL and a platelet count
≥25,000 cells/µL
 
If , after bortezomib has been held, the toxicity does not
resolve, as defined above, then bortezomib must be
discontinued
 
If toxicity resolves, ie, participant has an ANC ≥750 cells/µL
and a platelet count ≥25,000 cells/µL, bortezomib may be
reinitiated at a dose reduced by 1 dose level (from 1.3 mg/m2
to 1 mg/m2, or from 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2
If platelet counts <25,000
cells/µL, or ANC <750 cells/µL
on a bortezomib dosing day
(other than Day 1 of each cycle
Bortezomib therapy should be withheld
Grade ≥3 non-hematological
toxicities considered to be
related to bortezomib
Bortezomib therapy should be withheld until symptoms of the
toxicity have resolved to Grade 2 or better. Then, bortezomib may
be reinitiated at a dose reduced by 1 dose level (from 1.3 mg/m2 to 1
mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For bortezomib-related
neuropathic pain and/or peripheral neuropathy, hold and/or modify
bortezomib as outlined in Table 12
ANC absolute neutrophil count
Hepatic impairment
Participants with mild hepatic impairment do not require a dose adjustment and should be treated
per the recommended dose. Participants with moderate or severe hepatic impairment should be
started on bortezomib at a reduced dose of 0.7 mg/m2 per injection during the first treatment cycle,
and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be
considered. The recommended modification guidelines for participants with hepatic impairment is
shown in Table 14.
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Table 14: 
Recommended Starting Dose Modification for Bortezomib in Participants with Hepatic
Impairment
Grade of
Hepatic 
Impairmenta
Bilirubin Level
SGOT (AST)
Levels
Modification of Starting Dose
Mild
≤1 x ULN  
More than ULN  
None
More than 1 x to 1.5 x ULN  Any  
None
Moderate 
More than 1.5 x to 3 x ULN  Any  
Reduce bortezomib to 0.7 mg/m2
in the first treatment cycle.
Consider dose escalation of
1.0 mg/m2 or further dose
reduction to 0.5 mg/m2 in
subsequent cycles based on
participant tolerability
Severe 
More than 3 x ULN  
Any  
AST aspartate aminotransferase; NCI National Cancer Institute; SGOT serum glutamic oxaloacetic transaminase;
ULN upper limit of normal
a. Based on NCI Organ Dysfunction Working Group classifications for categorizing hepatic impairment (mild, moderate,
severe).
For full safety information for bortezomib refer to the product label (VELCADE USPI 2021;
VELCADE® SmPC 2021).
6.6. 
Treatment of Overdose
There is no specific experience in the management of ibrutinib overdose in participants. One
healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a
dose of 1,680 mg of ibrutinib.
There is no specific experience in the management of lenalidomide overdose in participants. In
dose-ranging studies in healthy subjects, some were exposed to up to 200 mg, and in single-dose
studies, some subjects were exposed to up to 400 mg. Pruritis, urticaria, rash, and elevated liver
transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was
neutropenia and thrombocytopenia.
There is no known specific antidote for bortezomib overdosage. In humans, fatal outcomes
following the administration of more than twice the recommended therapeutic dose have been
reported, which were associated with the acute onset of symptomatic hypotension and
thrombocytopenia.
Limited experience with doses higher than the approved dose of IV rituximab formulation is
available from clinical trials in humans. The highest IV dose of rituximab tested in humans to date
is 5,000 mg (2,250 mg/m2), tested in a dose escalation study in patients with CLL. No additional
safety signals were identified.
The sponsor does not recommend a specific intervention for an overdose. In the event of an
overdose, the investigator or treating physician should provide supportive care and:
 
Contact the sponsor’s medical monitor immediately.
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 
Evaluate the participant to determine, in consultation with the sponsor medical monitor,
whether study drug(s) should be interrupted, or the dose reduced.
 
Closely monitor the participant for AEs, SAEs, and laboratory abnormalities until study
treatment(s) can no longer be detected systemically (at least 7 days).
 
Obtain a plasma sample for PK analysis if requested by the sponsor’s medical monitor
(determined on a case-by-case basis).
 
Document the prescribed dose, the quantity of the excess dose as well as the duration of the
overdosing in the CRF. Refer to Section 10.3.4, Special Reporting Situations [Appendix 3]).
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the sponsor’s medical monitor based on the clinical evaluation of the participant.
6.7. 
Concomitant Therapy
Pre-study therapies up to 30 days before first dose of study treatment must be recorded at
screening. Concomitant therapies must be recorded throughout the study beginning with start of
the first dose of study treatment to 30 days after the last dose of study treatment or until the start
of subsequent anti-lymphoma therapy, whichever is first. All therapies (prescription or over-the-
counter medications, including vaccines, vitamins, herbal supplements; non-pharmacologic
therapies such as electrical stimulation, acupuncture, special diets, exercise regimens, or other
specific categories of interest) different from the study treatment must be recorded in the CRF.
Modification of an effective preexisting therapy should not be made for the explicit purpose of
entering a participant into the study.
As of implementation of Protocol Amendment 1, only concomitant therapy related to SAE, or
≥Grade 3, up to 30 days after the last dose of study treatment or until the start of subsequent
anti-lymphoma therapy, whichever occurs first, needs to be recorded.
For participants who continue to receive study treatment after the end of the eCRF collection and
clinical database closure, only SAEs and pregnancy information will be documented in the
participant file/source notes and reported to the sponsor’s Global Medical Safety database only
until the end of the study (see Section 4.4) and as described in Section 10.13 (Appendix 13).
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6.7.1. 
Permitted Concomitant Medications
The participant should receive full supportive care during study participation (including fluids and
electrolyte replacement, and antibiotics when appropriate). Use of neutrophil growth factors
(filgrastim and pegfilgrastim) or red blood cell growth factors is permitted per the American
Society of Clinical Oncology (ASCO) guidelines or per the institution’s guidelines (Smith 2006).
Transfusions may be given in accordance with institutional policy. Use of anti-microbial
prophylaxis (eg, pneumocyctis jirovecii pneumonia prophylaxis with sulfamethoxazole and
trimethoprim or equivalent), and vaccines, per the institution’s guidelines is strongly
recommended, especially in participants who are at increased risk for opportunistic infections. It
is strongly recommended that anti-viral prophylaxis recommendations are followed per rituximab
and bortezomib product labels.
Localized, hormonal, or bone sparing treatment for non-B-cell malignancies, and localized
radiotherapy for medical conditions other than the underlying B-cell malignancies may be
considered with approval from the medical monitor. Short courses (<14 days) of corticosteroids
for non‑cancer related medical reasons (eg, joint inflammation, asthma exacerbation, and
infusion -related reactions) or treatment for autoimmune cytopenias are permitted at doses not
exceeding 100 mg/day of prednisone or equivalent. Systemic use of corticosteroids in excess of
prednisone 20 mg/day or its equivalent for >14 days is prohibited unless reviewed and approved
by the sponsor’s medical monitor. Corticosteroids are permitted as premedication for
administration of rituximab or for the management of hypersensitivity as per institutional policy.
6.7.2. 
Medications to be Used with Caution
6.7.2.1. 
CYP3A Inhibitors/Inducers
Concomitant use With Ibrutinib
Ibrutinib is metabolized primarily by CYP3A4. Concomitant use of ibrutinib and drugs that
strongly or moderately inhibit CYP3A can increase ibrutinib exposure, and strong CYP3A
inhibitors should be avoided. The recommended ibrutinib dose modifications for coadministration
with CYP3A inhibitors is provided below (Table 15). 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. Always follow local labels if dose
modification guidelines are more restrictive than the recommended guidelines presented in this
protocol.
If antivirals for the treatment of COVID-19 that are strong CYP3A inhibitors (eg. Paxlovid) are
indicated, ibrutinib should be interrupted for the duration of the treatment (see Section 10.10
[Appendix 10] and Table 15).
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Table 15: 
Recommended Ibrutinib Dose Modifications for Co-administration with CYP3A Inhibitors
Co-administered Drug
Recommended Ibrutinib Dose for the Duration of the
Inhibitor Usea
 
Mild CYP3A inhibitors 
No dose adjustment required
 
Moderate CYP3A inhibitors 
280 mg QD is for participants who started on 560 mg
QD or 420 mg QD;
140 mg QD for participants who started on 140 mg BID
 
Voriconazole
 
Posaconazole at doses less than or
equal to suspension 200 mg BID
140 mg QD for participants who started on 560 mg QD
or 420 mg QD
70 mg QD where available for participants who started
on 140 mg BID or interrupt ibrutinib for the duration of
the inhibitor use
 
Other strong CYP3A inhibitors
 
Posaconazole at higher dosesb
Avoid concomitant use and consider alternative with less
CYP3A inhibitory potential
If these inhibitors will be used short-term (such as
anti-infectives for seven days or less), interrupt ibrutinib
If the benefit outweighs the risk, and long-term dosing
with a CYP3A inhibitor is required (more than seven
days), reduce ibrutinib dose to 140 mg QD for the
duration of the inhibitor use
BID twice daily; CYP cytochrome P450; IV intravenous, QD once daily
a
Monitor for adverse reactions to ibrutinib and interrupt or modify dose as recommended (see Section 6.5.1).
b
Posaconazole at higher doses (posaconazole suspension 200 mg three times daily or 400 mg twice daily, posaconazole IV
injection 300 mg once daily, posaconazole delayed release tablets 300 mg once daily).
Concomitant use With Bortezomib
 
Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib which
may decrease bortezomib efficacy. Avoid coadministration with strong CYP3A4 inducers. 
 
Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib which
may increase the risk of bortezomib toxicities. Participants should be monitored for signs of
bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in
combination with strong CYP3A4 inhibitors.
Concomitant use With Lenalidomide
 
Lenalidomide undergoes limited metabolism and does not inhibit or induce CYP3A4
isoenzymes.
Examples of inhibitors, inducers, and substrates can be found at:
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers
and
http://medicine.iupui.edu/clinpharm/ddis/main-table/
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6.7.2.2. 
Antiplatelet Agents and Anticoagulants
Concomitant use With ibrutinib
 
The concomitant use of warfarin or a vitamin K antagonist with ibrutinib should be avoided.
Supplements such as fish oil and vitamin E preparations should be avoided. Participants
requiring the initiation of anticoagulation therapy during the course of the study should have
treatment with ibrutinib held, the sponsor’s medical monitor should be contacted, and ibrutinib
should not be restarted until the patient is clinically stable and the re-initiation of ibrutinib is
approved by the sponsor’s medical monitor.  Participants should be observed closely for signs
and symptoms of bleeding.
6.7.2.3. 
Drugs That may Have their Plasma Concentration Altered by Ibrutinib
 
In vitro studies indicated that ibrutinib is a mild P-glycoprotein (P-gp) inhibitor. Ibrutinib is
not expected to have systemic drug-drug interactions with P-gp substrates. However, it cannot
be excluded that ibrutinib could inhibit intestinal P-gp after a therapeutic dose. There are no
clinical data available. Therefore, to avoid a potential interaction in the GI tract, narrow
therapeutic range P-gp substrates such as digoxin should be taken at least 6 hours before or
after ibrutinib.
6.7.2.4. 
Drugs That may Increase the Risk for Thrombosis
Concomitant use With Lenalidomide
 
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as
estrogen containing therapies, should be used with caution after taking a benefit-risk
assessment in participants receiving lenalidomide.
6.7.3. 
Prohibited Concomitant Medications
 
Any non-study protocol-related chemotherapy, anticancer immunotherapy, experimental
therapy, or radiotherapy other than the outlined in the study regimen.
 
Administration of live attenuated and replication-competent viral vector vaccines are
prohibited and must only be administered ≥30 days after the last dose of ibrutinib
(see Section 10.10 [Appendix 10]). Recommendations for COVID-19 vaccination are
included in Section 10.10 (Appendix 10).
 
Corticosteroids for the treatment of the underlying malignancy are prohibited. See
Section 6.7.1 for further details on concomitant use of ibrutinib and corticosteroids.
 
Participants may not consume grapefruit or grapefruit products, Seville oranges (including
marmalade containing Seville oranges), blood oranges, pomelos, tangelos, and star fruit
within the 3-day period prior to the first ibrutinib and bortezomib administration and until the
last day of treatment is completed due to possible CYP3A mediated metabolic interaction.
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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6.7.4. 
Guidelines for Ibrutinib Management with Surgeries or Procedures
The following guidance should be applied during the perioperative period for participants 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 held at least 7 days prior to the intervention and should be held at least 7 days after the
procedure, and restarted at the discretion of the investigator when the surgical site is
reasonably healed without serosanguineous drainage or the need for drainage tubes.
 
For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or
paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should not
be restarted for at least 3 days after the procedure. For bone marrow biopsies that are
performed while the participant is on ibrutinib, it is not necessary to hold ibrutinib for these
procedures.
 
For emergency procedures, ibrutinib should be held after the procedure until the surgical site
is reasonably healed, for at least 7 days after the urgent surgical procedure.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Treatment
A participant's study treatment must be discontinued if:
 
The participant withdraws consent to receive study intervention
 
The participant experiences overt disease progression or relapse
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention
 
The participant becomes pregnant
 
A serious protocol violation has occurred, as determined by the principal investigator or the
sponsor
If a participant discontinues study treatment before the onset of disease progression, end of
treatment and post-treatment assessments should be obtained and follow-up of scheduled
assessments should be continued. Refer to Section 8.2.1 for instructions regarding the
post-treatment efficacy assessments and Section 8.2.2.1 for instructions on the progressive disease
form. The reason(s) a participant discontinues treatment will be recorded on the eCRF. Refer to
Section 10.13 (Appendix 13) for further guidance on study procedures after the end of eCRF data
collection.
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7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Loss to follow-up
 
Withdrawal of consent
 
The sponsor discontinues the study (see Section 10.2.12 [Appendix 2])
When a participant withdraws before study completion, the reason for withdrawal is to be
documented in the CRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent then no additional assessments are allowed. Refer to Section 10.13
(Appendix 13) for further guidance on study procedures after the end of eCRF data collection.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply (eg, consult with family members, contacting the participant’s other physicians,
medical records, database searches, use of locator agencies at study completion), as local
regulations permit.
7.2.1. 
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Section 10.2.4:
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.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if the participant repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 
Before a participant is deemed lost to follow up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls,
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emails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods. These contact attempts, and any contact with the appropriate
family members, if applicable, should be documented in the participant’s medical records.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participant to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
8.1. 
Study Procedures
8.1.1. 
Overview
For the Phase 2 part of the study, there are 2 phases: a Screening Phase, and a Treatment Phase.
The frequency and timing of assessments and procedures to be performed during the study are
outlined in the Schedule of Activities (Table 1) and further discussed within this section.
Assessments/procedures should be completed on the day indicated; if this is not possible because
of a weekend, holiday, or emergency, the assessment/procedure should be completed within 48
hours of the scheduled day. During treatment, the clinical laboratory samples can be taken on the
day of or day prior to dosing, provided the results are available before any study treatment is
administered.
Repeat or unscheduled samples may be taken for safety reasons. Serum or urine pregnancy tests
should be performed for females of childbearing potential, as determined necessary by the
investigator or required by local regulation to establish the absence of pregnancy at any time during
their participation in the study. For participants who continue to receive study treatment after the
end of the eCRF collection and clinical database closure, Section 10.13 (Appendix 13) describes
the study procedures to be followed.
8.1.2. 
Screening Phase
The Screening Phase will be up to 30 days prior to randomization. All participants (or their legally
acceptable representative) must sign an ICF prior to the conduct of any study-related procedures.
During this phase, eligibility criteria will be reviewed by the investigator and a complete clinical
evaluation will be performed as specified in the Schedule of Activities. Screening procedures will
be performed up to 30 days before randomization.
Eligibility criteria will be reviewed and a complete clinical and disease history evaluation will be
performed. Laboratory tests noted in the inclusion criteria must be performed within 14 days prior
to randomization and the results within the limits specified in the inclusion criteria.
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 participant’s routine
clinical evaluation and not specifically for this study can be used after signed informed consent
has been obtained provided the assessments fulfill the study requirements and are performed within
30 days prior to randomization.
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8.1.3. 
Open-label Treatment Phase
The Treatment Phase will extend from randomization until study treatment discontinuation.
Participants should start study drug treatment within 72 hours after randomization. The last
measurements taken before randomization will be defined as the baseline values. These values
should be consistent with the values in the inclusion and exclusion criteria in order for the
participant to receive treatment. The sponsor recommends disease evaluations be performed per
standard of care. Response assessments will be performed preferably using Lugano Criteria
(Cheson 2014). Participants with confirmed progressive disease will discontinue study treatment.
Safety data collection will be limited to SAEs, Grade ≥3 AEs, and AEs leading to treatment
discontinuation; and concomitant medications related to SAEs and Grade ≥3 AEs, and will be
recorded in the eCRF. Refer to Section 10.13 (Appendix 13) for further guidance on study
procedures after the end of eCRF data collection.
8.2. 
Efficacy
8.2.1. 
Efficacy Assessments
Eligible participants must have at least 1 measurable site of disease by radiological assessment
(Cheson 2014). Efficacy evaluations will be conducted as specified in the Schedule of Activities
(Table 1) and may include the following: CT scans, MRI, PET using [18F]-FDG, bone marrow
aspirate and biopsy, endoscopy, physical examination, per standard of care.
To determine whether continued study treatment is warranted, investigators should monitor and
assess participants for response to treatment or disease progression per standard of care preferably
using the Lugano Criteria (Cheson 2014). Disease status and date of disease progression should be
documented. Refer to Section 10.13 (Appendix 13) for further guidance on study procedures after
the end of eCRF data collection.
8.2.2. 
Efficacy Criteria
8.2.2.1. 
Assessment of Disease Response and Progressive Disease
Assessment of disease response and progressive disease will be based on Lugano criteria
(Cheson 2014). For all participants with disease progression by the investigator, the investigator
should notify the sponsor medical monitor promptly when becoming aware of the progression
including after database closure.
8.2.2.2. 
Definition of Measurable and Assessable Disease
Measurable sites of disease are defined as lymph nodes, lymph node masses, or extranodal sites of
lymphoma. Each measurable site of disease must be clearly measurable in 2 perpendicular
dimensions, as determined by imaging evaluation. Eligible participants must have at least
1 measurable site of disease ≥2 cm in the long axis. All other measurable sites of disease must be
greater than 1.5 cm in the long axis for lymph nodes and greater than 1.0 cm in the long axis for
extranodal lesions.
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Up to 6 measurable sites of disease will be followed as target lesions for each participant.
Measurable sites of disease should be chosen such that they are from as disparate regions of the
body as possible and are representative of the participant’s overall disease burden. If there are
lymph nodes or lymph node masses in the mediastinum or retroperitoneum larger than 1.5 cm, at
least 1 lymph node mass from each region should always be included.
Sites of disease that are not measurable as defined above will be considered assessable. Assessable
disease includes any site of disease that would be difficult to follow quantitatively with
measurement, including pleural effusions, ascites, bone lesions, abdominal masses, and other
lesions that cannot be confirmed and followed by imaging. Assessable sites of disease will be
followed as non-target lesions. In addition, if more than 6 sites of disease are measurable, these
other sites of measurable disease may be included as non-target lesions.
8.2.2.3. 
Response Categories
The response categories being used to assess efficacy are based on the Lugano Criteria
(Cheson 2014) as further described in Table 16.
Table 16: 
Response Assessments Based on the Lugano Criteria
Response 
category
Criteria
Complete 
Response 
For an overall response of CR, all the following criteria must be met:
 
Score of 1, 2, or 3 on the 5-point scale, with or without a residual mass, on the most
recent post-baseline PET scan
 
Any organ enlargement must have regressed to normal
 
If the bone marrow biopsy or aspirate was positive by morphology or
immunohistochemistry at baseline, a repeat bone marrow biopsy must be negative by
morphology, or if indeterminate by morphology, it must be negative by
immunohistochemistry
 
If an endoscopy was positive by morphology or immunohistochemistry at baseline, a
repeat endoscopy must be negative by morphology, or if indeterminate by
morphology, it must be negative by immunohistochemistry
 
No new lesions
Partial Response 
An overall response of PR requires the following:
If a post-baseline PET scan is available at the current or a previous timepoint:
 
A score of 4 or 5 with reduced uptake compared with baseline, with or without
residual masses of any size, on the most recent post-baseline PET scan. Residual
uptake in the bone marrow higher than uptake in normal marrow but reduced
compared with baseline (including diffuse uptake compatible with reactive changes
from chemotherapy) is allowed.
 
No criteria for progressive disease are met
If no post-baseline PET scan is available:
 
A ≥50% decrease in the sum of the product of the diameters of up to 6 target
measurable nodes and extranodal sites
 
When a lesion is too small to measure on CT, assign 5 mm x 5 mm as the default
value
 
When no longer visible, 0 x 0 mm
 
For a node greater than 5 mm x 5 mm, but smaller than normal, use actual
measurement for calculation
 
Nonmeasured lesions are absent/normal or regressed, but no increase
 
Spleen, if enlarged at baseline, must have regressed by >50% in length beyond
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Table 16: 
Response Assessments Based on the Lugano Criteria
Response 
category
Criteria
normal
 
No new lesions
Stable Disease 
An overall response of stable disease is defined as follows:
If a post-baseline PET scan is available at the current or a previous timepoint:
 
A score 4 or 5 with no significant change in FDG uptake from baseline, on the most
recent post-baseline PET scan
 
No criteria for progressive disease are met
If no post-baseline PET scan is available:
 
<50% decrease from baseline in sum of the product of the diameters of up to 6
dominant, measurable nodes and extranodal sites
 
No criteria for progressive disease are met
Progressive 
Disease 
Progressive disease requires at least 1 of the following:
 
Progression of 1 or more target nodes or extranodal lesions based on the product of
the perpendicular diameters. An individual node/lesion must be abnormal with:
 
LDi >1.5 cm, and
 
increased by ≥50% from perpendicular diameters nadir. And
 
an increase in LDi or SDi from nadir of 0.5 cm for lesions ≤2 cm or 1.0 cm for
lesions >2 cm
 
New or clear progression of preexisting nonmeasured lesions
 
Regrowth of previously resolved lesions
 
A new node >1.5 cm in any axis
 
A new extranodal site >1.0 cm in any axis; if ≤1.0 cm in any axis, its presence must
be unequivocal and must be attributable to lymphoma
 
New or recurrent splenomegaly. In the setting of prior splenomegaly, the splenic
length must increase by >50% of the extent of its prior increase beyond baseline (eg,
a 15-cm spleen must increase to >16 cm). If no prior splenomegaly, must increase by
at least 2 cm from baseline
 
Assessable disease of any size unequivocally attributable to lymphoma
 
New or recurrent bone marrow involvement
 
PET score 4 or 5 with an increase in intensity of uptake from baseline and/or new
FDG-avid foci consistent with lymphoma rather than another etiology (eg, infection,
inflammation). If uncertain regarding etiology of new lesions, biopsy or interval scan
may be considered.
Note: For any new nodes or extranodal lesions meeting the size criteria for progressive disease by CT or MRI, a PET or
biopsy should be performed when possible, and will not be considered progressive disease if the PET score is ≤3 or if the
biopsy is negative for MCL.
8.3. 
Safety Assessments
All participants who receive treatment will be considered evaluable for toxicity. Safety evaluations
should be performed as clinically indicated and can include physical examinations and relevant
clinical laboratory tests. Participants should be periodically monitored for atrial fibrillation. ECGs
should also be performed at the investigator’s discretion, particularly in participants with
arrhythmic symptoms (eg, palpitations, lightheadedness, or new onset dyspnea).
Adverse events should be monitored and evaluated by the investigator according to routine practice
guidelines. All SAEs occurring during the study must be reported to the sponsor by study-site
personnel within 24 hours of their knowledge of the event. The sponsor will collect SAE data by
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the SAE reporting process. SAEs, Safety data collection will be limited to Grade ≥3 AEs, and AEs
leading to treatment discontinuation, (irrespective of toxicity grade); and concomitant medications
related to SAEs and Grade ≥3 AEs.
For participants who continue to receive study treatment after the end of the eCRF collection and
clinical database closure, only SAEs and pregnancy information will be documented in the
participant file/source notes and reported to the sponsor’s Global Medical Safety database only
until the end of the study (see Section 4.4) and as described in Section 10.13 (Appendix 13). Details
on initial pregnancy reporting can be found in Section 8.4.5. The study will include the following
evaluations of safety and tolerability according to the timepoints provided in the Schedule of
Activities (Table 1).
8.3.1. 
Adverse Events
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study. Adverse events
will be followed by the investigator as specified in Section 10.3, Adverse Event Reporting
(Appendix 3) and graded according to the NCI CTCAE, Version 5.0.
8.3.2. 
Clinical Laboratory Tests
All laboratory tests should be performed at the laboratory facilities associated with the
investigational site. Laboratory certificates or accreditation and normal ranges of the laboratory
facility at the site must be submitted to the sponsor before the enrollment of any participant at the
site. If the participant has the laboratory assessments conducted at a laboratory facility other than
the one associated with the investigational site, the investigator must submit to the sponsor
laboratory certificates or accreditation and normal ranges for that facility as well. The laboratory
reports must be filed with the source documents.
Blood samples to assess the safety of study treatment will be collected. Required laboratory tests
must be performed within 48 hours of the scheduled visit. For Day 1, Cycle 1 only, clinical
laboratory tests do not need to be repeated if the Screening tests were performed within 5 days of
the first dose of study agent.
A complete blood cell count, including white blood cell count with differential count, platelet
count, hemoglobin, and hematocrit should be performed every week for the first 8 weeks of
lenalidomide treatment.
The investigator must review the laboratory report, document this review, and record any clinically
relevant changes occurring during the study in the AE section of the CRF. For example, laboratory
abnormalities leading to an action regarding any study treatment (dose reduction, 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 AE, the following laboratory values
should be reported in the laboratory section of the CRF: the value indicative of the onset of each
toxicity grade; the most abnormal value observed during the AE, and the value supporting recovery
to Grade ≤1 or to baseline values. Details of the clinical laboratory assessments to be performed
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are provided in Section 10.1 (Appendix 1). Repeat or unscheduled blood sampling may be taken
for safety reasons or technical issues. Refer to Section 10.13 (Appendix 13) for further guidance
on study procedures after the end of eCRF data collection.
8.3.3. 
Vital Signs
Temperature, pulse/heart rate, and blood pressure will be recorded at the timepoints shown in
Table 1. 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). If an abnormal
heart rhythm is suspected, further investigation (ECG and/or Holter monitor) is required per
investigator’s discretion. Vital signs that are considered to be clinically relevant by the investigator
are to be documented as AEs.
8.3.4. 
Physical Examination
Physical examinations will be performed at the timepoints shown in Table 1. The Screening
physical examination will include, at a minimum, participant’s weight, height, general appearance,
examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal
system, lymphatic system, and nervous system. A limited symptom-directed physical examination
is required at Screening.
8.3.5. 
Electrocardiograms
Twelve-lead ECGs will be performed for all participants during Screening and at end of treatment.
ECGs should also be performed at the investigator’s discretion, particularly in participants with
arrhythmic symptoms (eg, palpitations, lightheadedness or new onset dyspnea). Abnormalities
noted at screening should be included in the medical history.
During the collection of ECGs, participants should be in a quiet setting without distractions
(eg, television, cell phones). Participants should rest in a supine position for at least 5 minutes
before ECG collection and should refrain from talking or moving arms or legs.
8.3.6. 
ECOG Performance Status
The ECOG performance status scale will be used at Screening to confirm eligibility (Oken 1982).
ECOG performance status scale is provided in Section 10.5 (Appendix 5).
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and PQCs, from clinical studies are crucial for the protection of participants, 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.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study. As of
implementation of Protocol Amendment 1, safety data collection will be limited to SAEs, Grade
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≥3 AEs, AEs leading to treatment discontinuation; and concomitant medications related to SAEs
and Grade ≥3 AEs will be recorded in the eCRF as specified in the protocol (Section 10.3). See
Section 6.7 for concomitant medication safety reporting.
Further details on AEs, SAEs, and PQCs can be found in Section 10.3: Adverse Events, Serious
Adverse Events, Product Quality Complaints, and Other Safety Reporting: Definitions and
Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF is obtained until completion of the participant's last study-related
procedure, which may include contact for follow-up of safety.
All AEs with an onset date after the signing of the ICF and up to 30 days after study treatment
discontinuation must be recorded on specific AE pages of the CRF.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study site personnel immediately, but no later than 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study treatment, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
All SAEs occurring after signature of the ICF up to 30 days after study treatment discontinuation
must be reported on AE pages in the CRF and on an SAE form, regardless of the investigator-
attributed causal relationship with study treatment or study mandated procedures.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the CRF, which must be completed and reviewed by a physician
from the study site and transmitted to the sponsor immediately but no later than within 24 hours.
The initial and follow-up reports of an SAE should be transmitted electronically or by facsimile
(fax). Telephone reporting should be the exception and the reporter should be asked to complete
the appropriate form(s) first.
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
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Solicited Adverse Events
Solicited AEs are predefined local at the injection site and systemic events for which the participant
is specifically questioned.
Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
Adverse events and the special reporting situation of pregnancy will be followed by the
investigator as specified in Section 10.3: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting (Appendix 3).
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs 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. A SUSAR will be reported to regulatory authorities
unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR summary,
unless otherwise specified.
8.4.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using an SAE reporting form. If a participant becomes
pregnant during the study, a determination regarding study treatment discontinuation must be made
by the investigator in consultation with the sponsor.
Follow-up information regarding the outcome of the pregnancy for female participants who
become pregnant, or where the pregnancy was the result of male participant and his partner, and
any postnatal sequelae in the infant will be required. After the end of eCRF data collection and
clinical database closure, pregnancy reporting will continue as described above and in
Section 10.13 (Appendix 13).
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Lenalidomide
Lenalidomide is a thalidomide analog and is contraindicated for use during pregnancy. Birth
defects have been observed in preclinical studies of lenalidomide similar to thalidomide in humans.
Because of the embryofetal risk of lenalidomide, investigators should comply, and all participants
receiving lenalidomide must adhere to the global lenalidomide pregnancy prevention program or
equivalent local lenalidomide pregnancy prevention program applicable in their region.
Investigators should comply with the lenalidomide Global PPP or with the respective
country/territory-specific Lenalidomide Risk Minimization Program (ie, pregnancy prevention
program) as implemented in the post-marketing setting and ensure that all participants adhere to
these programs. When no Lenalidomide Risk Minimization Program exists, participants receiving
lenalidomide must adhere to the lenalidomide Global PPP. Therefore, strict monitoring for
pregnancy must be conducted during Screening and throughout the Treatment Phase, as specified
in the Schedule of Activities. If pregnancy occurs, study treatment should be discontinued
immediately and the participant should be referred to an obstetrician experienced in reproductive
toxicity for further evaluation and counseling. The sponsor will collect information on the outcome
of the pregnancy and health of the baby for 1 year after birth or until the outcome of an adverse
pregnancy event is known or resolved.
If the centrally supplied generic lenalidomide is approved in a country/territory, the locally
approved PPP for the product should be used.  If the protocol is more stringent than the local PPP,
the pregnancy prevention measures described in the protocol should be followed, but the
country/territory-specific regulations implemented for lenalidomide in the post-marketing setting
for the product need to be fulfilled.  If the centrally supplied lenalidomide is not approved in a
country/territory, the global PPP should be used.
8.4.6. 
Disease-related Events and Disease-related Outcomes Not Qualifying
as Adverse Events or Serious Adverse Events
All events that meet the definition of a serious adverse event will be reported as serious adverse
events, regardless of whether they are protocol-specific assessments.
Expected progression of disease, which is part of the natural course of the disease under study,
should not be considered or reported as an adverse event (or serious adverse event).
However, if determined by the investigator to be more likely related to the study treatment,
protocol design, or protocol procedures than being expected from the underlying disease, the
treatment-invoked progression (ie, the treatment-invoked signs/symptoms of such progression)
should be reported per the usual reporting requirements.
Death that is attributed by the investigator explicitly to progression of disease should not be
considered nor reported as an adverse event (or serious adverse event).
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However, if determined by the investigator to be more likely related to the study treatment,
protocol design, or protocol procedures than being expected from the underlying disease, the
treatment-invoked death due to progression should be reported per the usual reporting
requirements.
Progression of disease and death due to disease progression should be documented on the
appropriate CRF forms (eg, the Disease Progression form and the Death form).
Signs or symptoms of disease progression that are of clinical significance, such as spinal cord
compression, vena cava superior syndrome, major vessel rupture, efflux obstruction or organ
failure, should be documented on the appropriate CRF forms.
8.5. 
Pharmacokinetics
Upon  implementation of Protocol Amendment 1, venous blood samples for ibrutinib analysis
already collected (ibrutinib treatment arm only) may be used for further development of the
existing population-based PK model. No further blood samples will be collected from participants
for PK evaluation upon implementation of protocol Amendment 1.
8.5.1. 
Evaluations
Plasma samples may  be analyzed to determine concentrations of ibrutinib using a validated,
specific, and sensitive LC-MS/MS method by or under the supervision of the sponsor.
8.5.2. 
Pharmacokinetic Parameters
Population PK analysis of plasma concentration-time data of ibrutinib may be performed using
nonlinear mixed-effects modeling (NONMEM), with the aim of providing estimates of PK
parameters (eg, oral clearance, apparent clearance [CL/F] and apparent volume of distribution at
steady state [V/F]) or metrics of systemic exposure (eg, area under the plasma concentration-time
curve within the dosing interval [AUCss] and Ctrough). Model-derived plasma concentrations or
metrics of exposure parameters (eg, AUC) may be subjected to further analyses to explore PK
correlation between exposure and relevant clinical information.
8.6. 
Pharmacodynamic Evaluations
Upon  implementation of Protocol Amendment 1, venous blood samples for ibrutinib analysis
already collected may be used for BTK and/or Interleukin-2-inducible T-cell kinase (ITK) occupancy
(free and total) evaluation. No further blood samples will be collected from participants for PD
evaluation upon implementation of protocol Amendment 1.
8.7. 
Biomarkers
8.7.1. 
Biomarker Assessments
A portion of the formalin-fixed paraffin-embedded (FFPE) tumor block or slides collected for
confirmation of diagnosis may be evaluated for biomarker assessments (eg, Ki-67, TP53, and other
genes). A buccal swab should be submitted with tumor samples. Only 1 set of buccal swab is
needed.
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8.7.2. 
Formalin-Fixed Paraffin-Embedded Tumor Tissue and Lymph Node
Biopsies
FFPE tumor block or slides from the most recent dated tumor tissue biopsy (archival) or a newly
obtained biopsy will be collected at study entry and evaluated for biomarker assessment. A portion
of the slides will also be used to confirm eligibility prior to enrollment if the report from the local
laboratory is not available prior to randomization or the central laboratory is not able to confirm
MCL diagnosis based on the local laboratory report. If central laboratory is not able to confirm
diagnosis from the archived tissue sample, a fresh tissue sample is required.
Expression and mutation patterns may be investigated within the FFPE tissue to determine whether
characterization of the FFPE sample could predict response or resistance to study treatment in r/r
MCL. The FFPE tissue may be subjected to immunohistochemistry, gene expression profiling, and
DNA analysis or other similar technologies.
8.8. 
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form. Instructions for the collection, handling, storage, and shipment of samples are
found in the Laboratory Manual that will be provided. Collection, handling, storage, and shipment
of samples must be under the specified, and where applicable, controlled temperature conditions
as indicated in the Laboratory Manual. Archival tumor tissue and fresh biopsies collected in this
study will be sent to a central laboratory designated by the sponsor. General requirements for
suitable archival tumor tissue sample can also be found in the laboratory manual. Refer to the
Schedule of Activities (Table 1) for the timing and frequency of all sample collections.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
Study protocol
 
Ibrutinib Investigator’s Brochure
 
Package inserts for lenalidomide, bortezomib, and rituximab
 
Lugano Criteria (Cheson 2014)
 
Site investigational product and procedures manual
 
Laboratory manual and supplies (for samples and image acquisition)
 
IWRS instructions and guidance and supplies
 
NCI-CTCAE Version 5.0
 
Electronic data capture manual and CRF completion guidelines
 
Participant information materials
 
Sample ICF
 
Participant wallet (study) card
 
Imaging Manual
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9. 
STATISTICAL CONSIDERATIONS
Due to the early termination of the study, an IDMC to monitor safety data, and to review efficacy
data, is no longer required. Data will be summarized, and descriptive statistics will be presented.
9.1. 
Safety Analyses
All safety analyses will use data for the safety population. The baseline value for safety assessment
is defined as the value collected at the time closest to, but prior to, the start of study drug
administration. The safety parameters to be evaluated are the incidence, intensity, and type of AEs,
clinically significant changes in the participant’s physical examination findings, vital signs
measurements, and clinical laboratory results. 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 AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs are AEs that
occur after the first dose of study treatment, through the Treatment Phase, and for 30 days
following the last dose of study treatment; any AE that is considered study treatment-related
regardless of the start date of the event; or any event that is present at baseline but worsens in
severity or is subsequently considered treatment-related bythe investigator. Any new or worsening
AE occurring at or after the initial administration of study treatment through the day of last dose
plus 30 days, or prior to the start of a subsequent anticancer therapy, whichever is earlier, or any
follow-up AE (linked to an existing TEAE) with onset date and time beyond 30 days after the last
dose of study treatment but prior to the start of subsequent therapy, or any AE that is considered
treatment-related regardless of the start date of the event, is considered to be treatment-emergent.
All reported AEs with onset during the treatment phase (ie, treatment-emergent AEs, and AEs that
have worsened since baseline) will be included in the analysis. For each AE, the percentage of
participants who experience at least 1 occurrence of the given event will be summarized by
treatment group.
Parameters with predefined NCI-CTCAE Version 5.0 toxicity grades will be summarized. Change
from baseline to the worst AE grade experienced by the participant during the study will be
provided as shift tables
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue treatment due to an AE, or who experience a severe or an
SAE.
Clinical Laboratory Tests
Hematology and serum chemistry laboratory data up to 30 days after last dose or the End of
Treatment visit date, or until start of a subsequent anticancer therapy, whichever is later, will be
reported in International System of Units (SI).
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Summary statistics (mean, standard deviation, median and range) will be calculated for the raw
data and for changes from baseline at each timepoint of assessment as well as for the changes from
baseline to the last value.
Graphical displays of over-time summaries and shift tables will be presented for the following key
laboratory parameters: hemoglobin, white blood cell count, neutrophils, platelets, AST, ALT, total
bilirubin, creatinine, alkaline phosphatase, and electrolytes (sodium, potassium, calcium, and
phosphate). The same analysis may be applied to other laboratory parameters.
Shift tables will summarize by cycle the number of participants with each baseline NCI CTCAE
grade and changes to the maximum NCI CTCAE grade in the cycle (up to 30 days after last dose
or the End of Treatment visit date, whichever is later).
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. 
Appendix 1: Clinical Laboratory Tests
The following tests will be performed by the local laboratory according to the Schedule of
Activities (Table 1):
 
Hematology
-hemoglobin  
-ANC
-white blood cell count 
-absolute lymphocyte count
-platelet count
 
Coagulation Studies
 
aPTT (activate partial thromboplastin time)
 
international normalized ratio (INR) and/or prothrombin time
 
Serum Chemistry Panel
-sodium  
-AST
-potassium  
-ALT
-creatinine 
-uric acid
-lactic acid dehydrogenase
-total bilirubin  
-alkaline phosphatase
-albumin  
-calcium
-phosphate
 
Screening for Hepatitis B and C will include the following evaluations: Hepatitis B surface
antigen, Hepatitis B surface antibody, Hepatitis B core antibody, and Hepatitis C antibody.
Participants who test positive for Hepatitis B core antibody must have Hepatitis B DNA by
PCR performed and confirmed as negative prior to randomization. Participants who test
positive for Hepatitis C antibody are eligible if previously treated and achieved a sustained
viral response, defined as a negative viral load for Hepatitis C after completion of the
treatment for hepatitis.
 
Where endemic, screening for active or chronic persistent HEV infection is required.
Participants who test positive for anti-Hep E antibody must have Hepatitis E RNA by PCR
performed (serum or stool) and confirmed as negative prior to randomization.
 
Pregnancy test (serum beta-human chorionic gonadotropin  [β-hCG] or urine): for female
participants of childbearing potential only.
The actual date of assessment and, if required, the actual time of the assessment of laboratory
samples will be recorded in the source documentation and in the CRF or laboratory requisition
form. Refer to Section 10.13 (Appendix 13) for further guidance on study procedures after the end
of eCRF data collection.
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10.2. Appendix 2: Regulatory, Ethical, and Study Oversight Considerations
10.2.1. 
Regulatory and Ethical Considerations
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- or territory-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 participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers (LTMs), Clinical Trial Managers
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional
Review Boards (IECs/IRBs) per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
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 participants, 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) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
In situations where a departure from the protocol is unavoidable during the study, 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 must 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
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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.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country/territory, if applicable. A study may not be initiated until all local
regulatory requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study treatment 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, participant 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 chairperson or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
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
participant:
 
Completed investigator financial disclosure forms from all subinvestigators, where required
 
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
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 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
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 participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants 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 participants
 
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
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study treatment
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 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants 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 participants, 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 ofthe study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Country/Territory Selection
This study will only be conducted in those countries/territories where the intent is to launch or
otherwise help ensure access to the developed product if the need for the product persists, unless
explicitly addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical
Design Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.2.2. 
Informed Consent Process
Each participant (or their legally acceptable representative) must give consent according to local
requirements after the nature of the study has been fully explained. The ICF(s) must be signed
before performance of any study-related activity. The ICF(s) that is/are used must be approved by
both the sponsor and by the reviewing IEC/IRB and be in a language that the participant can read
and understand. The informed consent must be in accordance with principles that originated in the
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and
sponsor policy. Informed consent may be obtained remotely. Refer to the monitoring guidelines
(or other equivalent documents).
Before enrollment in the study, the investigator or an authorized member of the study site personnel
must explain to potential participants or their legally acceptable representative the aims, methods,
reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Participants 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 participant will receive for the treatment
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of his or her disease. Participants 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 participant 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 participant, to the extent permitted
by the applicable law(s) or regulations. By signing the ICF the participant 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 participant agrees to allow his or her study
physician to recontact the participant for the purpose of obtaining consent for additional safety
evaluations, and subsequent disease-related treatments, if needed.
The participant or their 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 must be appropriately recorded by means of either the participant's or his or her legally
acceptable representative’s personally dated signature. After having obtained the consent, a copy
of the ICF must be given to the participant.
If the participant is unable to read or write, an impartial witness must be present for the entire
informed consent process (which includes reading and explaining all written information) and
must personally date and sign the ICF after the oral consent of the participant is obtained.
10.2.3. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants 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 participants confidential.
The informed consent obtained from the participant (or their legally acceptable representative)
includes information about, and where required per applicable regulations, explicit consent for the
processing of personal data and for the investigator/institution to allow direct access to his or her
original medical records (source data/documents) for study-related monitoring, audit, IEC/IRB
review, and regulatory inspection. The informed consent also provides information to address the
lawful transfer of the data to other entities and to other countries/territories.
The participant 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, or make requests
concerning his or her personal data in accordance with applicable data protection law. Reasonable
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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.
In the event of a data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
Exploratory DNA, pharmacodynamics, biomarker, PK and immunogenicity  research is not
conducted under standards appropriate for the return of data to participants. 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 participants 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.
10.2.4. 
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 and co-medications in
the protocol, if applicable, to understand B cell NHL and MCL, to understand differential
intervention responders, and to develop tests/assays related to ibrutinib and co-medications in the
protocol, if applicable and B cell NHL and MCL. 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. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
10.2.5. 
Publication Policy/Dissemination of Clinical Study Data
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 pharmacogenetic or 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.
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The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of
pharmacogenetic or 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 participant 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 sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the interim results of clinical studies as required by law. The
disclosure of the study results will be performed after the end of study in order to ensure the
statistical analyses are relevant.
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10.2.6. 
Data Quality Assurance
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 may review the CRF for accuracy and completeness during
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved
with the investigator or designee, as appropriate. After upload of the data into the study database
they will be verified for accuracy and consistency with the data sources.
10.2.7. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in the 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 ofthe participant's source documents. Data must be entered into
the CRF in English. The CRF must be completed as soon as possible after a participant visit and
the forms must be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires [see
Section 10.9, Appendix 9, for the FACT-Lym questionnaire]) will be completed by the same
individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to
a CRF are needed after the initial entry into the CRF, this can be done in either of the following
ways:
 Investigator and study site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
Refer to Section 10.13 (Appendix 13) for further guidance after the end of eCRF data collection.
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10.2.8. 
Source Documents
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:
participant 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 AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention or withdrawal from the
study, if applicable.
The author of an entry in the source documents must be identifiable. Given that PROs are reports
of a patient's health condition that come directly from the patient, without interpretation by a
clinician or anyone else, the responses to PRO measures entered by study participants into source
records cannot be overridden by site staff or investigators.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, 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 participant interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource 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 eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
CRF. Refer to Section 10.13 (Appendix 13) for further guidance on source documentation after
the end of eCRF data collection.
10.2.9. 
Monitoring
The sponsor will use a combination of monitoring techniques (eg, 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 may compare the data entered into the CRF with the source
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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. Refer to Section 10.13 (Appendix 13) for further guidance on monitoring of
participants who continue study treatment after the end of eCRF data collection.
10.2.10. 
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. Participant 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 must immediately notify the sponsor if he or she has been
contacted by a regulatory agency concerning an upcoming inspection.
10.2.11. 
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 participant, 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
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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.
10.2.12. 
Study and Site Start and Closure
First Act of Recruitment
The first participant screened is considered the first act of recruitment and it becomes the study
start date.
Study/Site Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed. The investigator may initiate study site closure
at any time, provided there is reasonable cause and sufficient notice is given in advance of the
intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development
Following implementation of Protocol Amendment 1, the eCRF data collection period will end,
and the clinical database will be closed as soon as possible but no later than when the last study
participant has completed the first 6 cycles of study treatment, or switched to ibrutinib
monotherapy 560 mg QD (unless ibrutinib dose was reduced for toxicity reasons). The sponsor
will ensure that participants benefiting from treatment will be able to continue receiving study
treatment after the end of eCRF data collection. Refer to Section 10.13 (Appendix 13) for further
guidance on data collection and reporting procedures for participants who continue study treatment
after the end of the eCRF data collection. The study is considered completed when all participants
still receiving study treatment have transitioned to commercial or alternative access to study
treatment, have stopped receiving study treatment, or upon a decision by the sponsor to terminate
the study, whichever occurs earlier.
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10.3. 
Appendix 3: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of participants, 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.
10.3.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have
a causal relationship with the intervention. An AE 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 Council 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 SAEs, AEs, Grade ≥3 AEs, AEs leading to treatment
discontinuation, and concomitant medications related to SAEs and Grade ≥3 AEs, starting with
the signing of the ICF (refer to All Adverse Events under Section 10.3.5, Time Period and
Frequency for Collecting Adverse Events and Serious Adverse Events Information, for time of last
AE recording (Appendix 3). For participants who continue to receive study treatment after the end
of the eCRF collection and clinical database closure, only SAEs and pregnancy information will
be documented in the participant file/source notes and reported to the sponsor’s Global Medical
Safety database only until the end of the study (see Section 4.4) and as described in Section 10.13
(Appendix 13).
All SAEs, AEs, Grade ≥3 AEs, AEs leading to treatment discontinuation, regardless of
seriousness, severity, or presumed relationship to study treatment, must be recorded using medical
terminology in the source document and the eCRF. 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 AE to study therapy. All
measures required for AE management must be recorded in the source document and reported
according to sponsor instructions.
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Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for
Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening (The participant 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*
Note: Events that do not qualify as an AE cannot be reported as an SAE, even if the conditions for
seriousness are met. In particular, this is the case for events due to disease progression leading to
death, hospitalization, etc.
* 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 may not result in death or hospitalization but may jeopardize the participant or
may require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious. This also includes the situation when treatment -invoked
signs and symptoms of disease progression are determined by the investigator to be more likely
related to the study treatment than being expected from the underlying disease.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study treatment 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).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For ibrutinib, the expectedness of an AE will be determined by
whether or not it is listed in the IB. For the nonsponsored investigational medicinal products  with
a marketing authorization, the expectedness of an AE will be determined by whether or not it is
listed in the VELCADE USPI or SmPC (VELCADE® USPI 2021; VELCADE® SmPC 2021),
(Lenalidomide Accord SmPC 2022 [or local label if locally sourced]) or the RUXIENCE USPI or
SmPC (RUXIENCE® USPI 2021; RUXIENCE® SmPC 2022).
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10.3.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is assessed by the Investigator. The following
selection must be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.3.3. 
Severity Criteria
An assessment of severity grade will be made by the investigator according to the NCI-CTCAE
Version 5.0. Any AEs or SAEs not listed in the NCI-CTCAE Version 5.0 should be evaluated for
severity/intensity by using the standard definitions as follows:
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate
instrumental ADL.*
Grade 3
Severe or medically significant but not immediately life threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care ADL.**
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to adverse event.
* 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the
telephone, managing money, etc.
** 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking
medications, and not bedridden.
ADL=activities of daily living
Notes: A semi-colon indicates ‘or’ within the description of the grade.
The investigator must use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.3.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
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 
Overdose of a sponsor study intervention, lenalidomide, bortezomib, or rituximab
 
Suspected abuse/misuse of a sponsor study intervention, lenalidomide, bortezomib, or
rituximab
 
Accidental or occupational exposure to a sponsor study intervention, lenalidomide,
bortezomib, or rituximab
 
Any failure of expected pharmacologic action (ie, lack of effect if used according to the local
label) of a sponsor study treatment (to be reported as a PQC for marketed products
 
Unexpected therapeutic or clinical benefit from use of a sponsor study treatment
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson product (with or without patient exposure to the Johnson & Johnson
medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors), lenalidomide, bortezomib, or rituximab
 
Exposure to a sponsor study treatment, ibrutinib, lenalidomide, bortezomib, or rituximab from
breastfeeding
 
Reporting of participant pregnancy or participant partner(s) pregnancy
Special reporting situations must be recorded in the CRF. Any special reporting situation that
meets the criteria of an SAE must be recorded on the SAE page of the CRF. Refer to Section 10.13
(Appendix 13) for further guidance after the end of eCRF data collection.
10.3.5. 
Procedures
All AEs, regardless of seriousness, severity, or presumed relationship to study treatment, must be
recorded using medical terminology in the source document and the CRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the CRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant 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 personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
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Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon the
participant's discontinuation from 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 intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as an SAE, except hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
 
For convenience the investigator may choose to hospitalize the participant for the duration of
the intervention period.
 
Expected progression of disease, which is part of the natural course of the disease under study,
should not be considered an AE (or SAE). However, if determined by the investigator to be
more likely related to the study treatment, protocol design, or protocol procedures, than the
underlying disease, the clinical signs or symptoms of progression and the possibility that the
study treatment is enhancing disease progression, should be reported per the usual reporting
requirements.
For reporting of death that is attributed by the investigator explicitly to progression of disease, see
Section 8.4.6.
For reporting signs or symptoms of disease progression, see Section 8.4.6.
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form and
safety report form of the CRF, which must be completed and reviewed by a physician from the
study site, and transmitted in a secure manner to the sponsor within 24 hours. The initial and
follow-up reports of an SAE should be transmitted in a secure manner electronically or by
facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to
complete the appropriate form(s) first.
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10.3.6. 
Other Malignancies
In addition to AE reporting, all new malignant tumors, including solid tumors, skin malignancies
and hematologic malignancies, are to be reported for the duration of study treatment.
10.3.7. 
Product Quality Complaint Handling
Definition
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, reliability, or performance of a distributed product, including its labeling, drug delivery
system, or package integrity. A PQC may have an impact on the safety and efficacy of the product.
In addition, it includes any technical complaints, defined as any complaint that indicates a potential
quality issue during manufacturing, packaging, release testing, stability monitoring, dose
preparation, storage or distribution of the product or the drug delivery system.
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.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.3.8. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who must be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
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10.4. 
Appendix 4: Contraceptive Guidance and Lenalidomide Global / Local
PPP/REMS Programs
Participants must follow contraceptive measures as outlined in Section 5.1 (Inclusion Criteria) and
Section 5.3. Pregnancy information will be collected and reported as noted in Section 8.4.5.
Definitions
Female Participant of Childbearing Potential
A female participant is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile (see below).
 
Participant of child-bearing potential (even if they have amenorrhea) must:
 
Practice true abstinence; or
 
Practice ≥1 highly effective method of contraception. Contraception must begin 4 weeks
before initiating study treatment, and continue during the Treatment Phase, during dose
interruptions and continuing for at least 4 weeks after the last dose of study treatment.
Best practice is for the pregnancy test, prescribing and/or dispensing to take place on the
same day.
Female Participant Not of Childbearing Potential
Female participants in the following groups are considered NOT to have child-bearing potential
and do not need to undergo pregnancy testing or receive contraceptive advice.
 
Age ≥50 years and naturally amenorrhoeic for ≥1 year. Please note amenorrhea following
cancer therapy does not rule out child-bearing potential.
 
Premature ovarian failure confirmed by a specialist gynecologist.
 
Previous bilateral salpingo-oophorectomy or hysterectomy
 
XY genotype, Turner syndrome, uterine agenesis
Treating physicians are advised to refer their patient for a gynecological opinion if at all unsure as
to whether a woman meets the criteria for being of non-childbearing potential.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female
participant experiences menarche) or the risk of pregnancy changes (eg, a female participant who
is not heterosexually active becomes active), a female participant must begin a highly effective
method of contraception, as described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered. Best practice is
for the pregnancy test, prescribing and dispensing to take place on the same day. If not established
on effective contraception, the patient must be referred to an appropriately trained healthcare
professional for contraceptive advice in order that contraception can be initiated.
Contraceptive (birth control) use by male or female participants must be consistent with local
regulations regarding the acceptable methods of contraception for those participating in clinical
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studies. Typical use failure rates may differ from those when used consistently and correctly. Use
must be consistent with local regulations regarding the use of contraceptive methods for
participants in clinical studies.
In the event of pregnancy whilst on treatment with Lenalidomide
 
Stop treatment immediately
 
Refer patient to an obstetrician experienced in reproductive toxicity for further evaluation and
counselling.
 
Notify the study sponsor/Medical Monitor within 24 hours of awareness using the appropriate
pregnancy notification form. A determination regarding study treatment discontinuation must
be made by the investigator in consultation with the sponsor.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions of the medicinal product is important. It allows continued
monitoring of the benefit/risk balance of the medicinal product. All adverse events (AEs) must be
reported to the sponsor. The sponsor assumes responsibility for appropriate reporting of AEs 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.
Because of the embryo-fetal risk of lenalidomide, all participants receiving lenalidomide must be
enrolled in the lenalidomide PPP/REMS applicable in their region. Investigators should comply
with the lenalidomide Global PPP or with the respective country/territory-specific Lenalidomide
Risk Minimization Program (ie, PPP), as implemented in the post-marketing setting and ensure
that all participants adhere to these programs. When no Lenalidomide Risk Minimization Program
exists, participants must adhere to the Global lenalidomide PPP.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the vasectomized partner is
the sole sexual partner of the female participant of childbearing potential and the absence of sperm in the
vasectomized partner has been confirmed. If not, additional highly effective method of contraception must
be used. Spermatogenesis cycle is approximately 74 days.)
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USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of
ovulationb
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
 oral
 injectable
 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 treatment. 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 participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of
action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier
methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use must be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study treatment.
c) Male condom and female condom must not be used together (due to risk of failure with friction).
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10.5. 
Appendix 5: ECOG Performance Status Score
Grade 
Eastern Cooperative Oncology Group (ECOG) Performance Status
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a
light or sedentary nature, eg, light housework, office work
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and
about more than 50% of waking hours
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 
Dead
Source: Oken 1982
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10.6. 
Appendix 6: Calculating the Simplified MIPI for MCL
For each prognostic factor, 0-3 points are given to each subject and points are summed up to a maximum
of 11. Subjects with 0-3 points in sum are classified as low risk, subjects with 4-5 points as intermediate
risk, and subjects with 6-11 points as high risk. ECOG performance status is weighted with 2 points if
subjects were unable to work or bedridden (ECOG 2-4). LDH is weighted according to the ratio to the ULN
(Hoster 2008).
Points 
Age, year 
ECOG  
LDH/ULN  
WBC, /uL
0 
< 50 
0-1 
< 0.67 
< 6700
1 
50-59 
- 
0.67-0.99 
6700-9999
2 
60-69 
2-4  
1.0-1.49 
10000-14999
3 
70 
- 
1.5 
15000
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10.7. 
Appendix 7: New York Heart Association Classification of Functional
Capacity
The following table presents the New York Heart Association Classification of Functional Capacity and
Objective Assessment:
Class 
Patient Symptoms
I 
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue,
palpitation, dyspnea (shortness of breath).
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results
in fatigue, palpitation, dyspnea (shortness of breath).
III 
Marked limitation of physical activity. Comfortable at rest. Less-than-ordinary activity
causes fatigue, palpitation, or dyspnea.
IV  
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at
rest. If any physical activity is undertaken, discomfort increases.
Class 
Objective Assessment
A 
No objective evidence of cardiovascular disease. No symptoms and no limitation in ordinary
physical activity.
B 
Objective evidence of minimal cardiovascular disease. Mild symptoms and slight limitation
during ordinary activity. Comfortable at rest.
C 
Objective evidence of moderately severe cardiovascular disease. Marked limitation in
activity due to symptoms, even during less-than-ordinary activity. Comfortable only at rest.
D 
Objective evidence of severe cardiovascular disease. Severe limitations. Experiences
symptoms even while at rest.
Source: American Heart Association 2017.
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10.8. 
Appendix 8: Child-Pugh Score for Participants With Liver Impairment
Measure 
1 point 
2 points 
3 points
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3)
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8)
PT/INR  
<1.7 
1.71-2.30 
>2.30
Ascites 
None 
Mild 
Moderate to Severe
Hepatic encephalopathy  
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV
(or refractory)
Points 
Class
5-6 
A
7-9 
B
10-15 
C
Sources:
Child CG, Turcotte JG. Surgery and portal hypertension. In Child CG. The liver and portal hypertension. Philadelphia:Saunders.
1964; 50 64.
Pugh RN, Murray Lyon IM, Dawson L, et al. Transection of the oesophagus for bleeding oesophageal varices. The British
Journal of Surgery, 1973; 60:646 649.
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10.10. Appendix 10: Guidance on Study Conduct During the COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, isolation or quarantine by participants and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being unavailable, isolated, or reassigned to critical tasks.
The sponsor is providing options for study related participant management in the event of
disruption to the conduct of the study. This guidance does not supersede any local or government
requirements or the clinical judgement of the investigator to protect the health and well-being of
participants and site staff. If, at any time, a participant’s travel to the study site is considered to be
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes
necessary to discontinue participation in the study, the procedures outlined in the protocol for
discontinuing study intervention will be followed.
If, as a result of the COVID-19 pandemic, scheduled visits cannot be conducted in person at the
study site, they will be performed to the extent possible remotely/virtually or delayed until such
time that on-site visits can be resumed. At each contact, participants will be interviewed to collect
safety data. Key efficacy endpoint assessments should be performed if required and as feasible.
Participants will also be questioned regarding general health status to fulfill any physical
examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted after consultation with the participant, investigator, and the sponsor. Missed
assessments/visits will be captured in the clinical trial management system for protocol deviations.
Discontinuations of study interventions and withdrawal from the study should be documented with
the prefix “COVID-19-related” in the case report form (CRF).
Modifications made to the study conduct as a result of the COVID-19 pandemic should be
summarized in the clinical study report.
GUIDANCE SPECIFIC TO THIS PROTOCOL:
Testing for COVID-19 should be performed according to local guidance. If a participant has tested
positive for COVID-19, the following should be reported in the Electronic Data capture (eDC)
tool:
 
all cases of COVID-19, regardless of severity or causality (including asymptomatic COVID-
19) up to the End of Treatment visit +30 days
 
all medications given to prevent (including vaccines) or treat COVID-19 up to the End of
Treatment visit + 30 days
If a participant has tested positive for COVID 19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for administration of study treatment, performing.
study assessments, and follow-up.
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JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
105
Status: Approved, Date: 08 June 2023
Participant Visits and Assessments
 
For participants who are unable to come to the site for Disease Evaluation visits, the visit
should be postponed and rescheduled as soon as possible.
 
For participants who are unable to come to the site for Cycle visits, contact (eg, telephone,
videoconference, or other channels) with the participant should be made in advance, to collect
information on the participant’s current health status and any new or ongoing AEs and
concomitant medications. The remote method that is used for contact with the participant must
be allowable per local regulations and fully documented in the participant source record.
Home health nursing can be done via site contact with a visiting nurse service independent of
the sponsor, if permitted by local regulations. Protocol specified laboratory assessments and
physical examinations should be obtained locally, if possible. Where local laboratories are
used, it is important to ensure appropriate documentation of laboratory reference ranges. After
reviewing all available information, and if the investigator assesses that continued treatment
is acceptable, contact the site manager to discuss alternative solutions for the provision of
study treatment to participants (see alternatives below). The remote contact with the
participant, the local laboratory results, and the sponsor discussion should be documented in
the participant source record. Similarly, at a minimum, a comment must be entered in the
Comments CRF clearly designating as “COVID19 related” and acknowledging the discussion
between the investigator and the sponsor.
 
If the participant is not willing or able to go to a local clinic/laboratory, remote contact
(eg, telephone, videoconference, or other channels) with the participant is recommended, as
well as a thorough review of the participant’s medical history, prior labs, and most recent
disease evaluation. The remote method chosen must be allowable per local regulations and
fully documented in the participant source record. If appropriate, treatment should be
interrupted until new laboratory assessments are made. However, if the investigator assesses
that continued treatment is acceptable despite the absence of new laboratory tests, contact the
site manager to discuss alternative solutions for the provision of study medication to
participants (see possible alternatives below). Proper documentation of all discussions and
decisions should be made in the participant source record and in the Comments CRF.
 
If any change in participant status is identified that may impact the participant’s safety, then
study treatment should be interrupted until the participant can be assessed. Any changes in
study treatment (dose, frequency, interruption) needs to be clearly documented as
“COVID-19-related”. When conditions improve, travel restrictions are lifted, and the
participant is willing and able to come to the clinic, participants should be scheduled for an
in-clinic, follow-up visit.
 
All deviations from protocol-required assessments should be documented in detail within the
participant’s source record and should be clearly designated as “COVID-19-related”. It must
be documented if a visit is conducted remotely. Source documentation should detail how each
assessment was collected (eg, remote vs. on-site, central vs. local laboratory, vital signs taken
at home by caretaker vs. delegated in-home nursing).
 
Consenting and re-consenting of participants will be performed as applicable for the measures
taken (including also remote consenting by phone or video consultation) and according to
local guidance for informed consent applicable during the COVID-19 pandemic
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
106
Status: Approved, Date: 08 June 2023
Study Drug Supply
If a participant is unable to travel to the site for a scheduled visit where study drug would be
dispensed, the following alternate measures should be discussed with the study monitor and may
be considered to ensure continuity of treatment, upon sponsor’s approval:
 
A caregiver or family member may pick up study drug on behalf of the participant if first
discussed and agreed by the participant. The conversation with the participant must be
documented in the participant source records. The participant must name the individual who
will pick up study drug on their behalf. This is necessary for site staff to confirm the study
drug is provided to the appropriate individual, ensure proper chain of custody of study drug,
and to maintain participant privacy. Identification of who will pick up the study drug must be
confirmed and documented in the participant source record.
 
Investigative site staff may deliver study drug directly to the participant’s home. The chain of
custody and transit conditions must be clearly documented within the participant source
record.
 
If no other alternative is feasible, direct-to-patient shipment of study drug from the site may
be considered with prior approval from the sponsor. Site staff need to obtain permission from
the participant and record this in the participant source record for direct-to-patient shipments.
It is important to note this process is not allowed by the health authorities in all
countries/territories and a specific approval process must be followed with the sponsor before
moving forward. If requested by the site, the sponsor will investigate local requirements and
confirm health authority requirements for direct-to-patient shipment. If approval is granted by
the sponsor, specific procedures including shipment conditions, preferred courier services,
and documentation requirements will be communicated by the sponsor to the site.
If a participant is able to come to the site for a Cycle visit but anticipates being unable to come to
the next Cycle visit, the investigator may dispense study treatment for the current cycle and an
additional cycle, after agreement with the sponsor’s medical monitor. Prior to continuing treatment
with the additional study treatment, the participant should obtain protocol-specified laboratory
assessments and physical examinations locally, if possible, and the investigator should conduct a
remote contact as described above. After reviewing all available information, if the investigator
assesses that continued treatment is acceptable, the participant may continue treatment using the
previously supplied additional study treatment. Proper documentation of all discussions and
decisions should be made in the participant source record and in the Comments CRF.
For participants who have reason to believe they have been exposed to COVID-19 but do
not yet have a confirmed diagnosis and/or are not showing symptoms of infection:
 
The investigator should consider the risk/benefit of continuing ibrutinib based on the
individual participant’s underlying condition and the potential risks associated with
COVID-19.
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
107
Status: Approved, Date: 08 June 2023
 
If the participant becomes symptomatic at any point, refer to guidance below for participants
with symptomatic COVID-19 infection.
For participants who have been diagnosed with COVID-19:
 
Investigators should instruct participants to notify them or study site staff immediately if they
are diagnosed with COVID-19, even if asymptomatic, so that appropriate treatment measures
can be determined.
 
The investigator should consider the risk/benefit of continuing ibrutinib based on the nature
and status of the participant’s underlying condition and the potential risks associated with
COVID-19.
 
As with all infections, the investigator should follow the protocol guidance which is to
interrupt therapy for Grade 3 or higher non-hematologic AE (see Section 6.5) and resume
once infection has resolved to Grade 1 or baseline (recovery). Given that severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) is a relatively new pathogen, a more
cautious approach would be appropriate, with interruption for confirmed cases of
SARS-CoV-2 infection of any grade.
 
Investigators should consider prophylaxis (eg, Evusheld, if available) and antiviral
medications (eg, Paxlovid, if available) for participants diagnosed with COVID-19 infection.
 
If available in the region, antivirals (eg, Paxlovid or other available agents) should be
considered early after COVID-19 diagnosis. Anti-viral treatment with Paxlovid is highly
recommended within the first 5 days after COVID-19 diagnosis. Participants may remain
asymptomatic or have minimal symptoms for a period of time prior to deteriorating.
Investigators should make participants aware that these drugs may potentially significantly
lower their risk of severe COVID-19. Note: for antivirals that are strong CYP3A inhibitors
(eg. Paxlovid), ibrutinib should be interrupted for the duration of the treatment (Table 15).
On-site Monitoring Visits
In case on-site monitoring visits are not possible, as per institution policies, the sponsor’s site
managers may contact the investigator to arrange remote monitoring visits. Additional on-site
monitoring visits may be needed in the future to catch up on source data verification.
All of the above measures are recommended for consideration on a temporary basis during the
COVID-19 pandemic to enable continuity of treatment and to ensure that participant assessments,
particularly those assessing relapse and safety, continue as outlined in the protocol without
imposing health risk to participants, their families, and site staff. Every effort should be made to
complete all protocol-required assessments. Investigators should use their clinical judgment and
risk/benefit assessment in determining if a participant can continue study treatment in the absence
of on-site clinic visits. If remote visits are not possible, or if in the investigator’s judgment,
appropriate safety monitoring is not feasible in a remote setting, the investigator should consider
temporarily interrupting study treatment (for a maximum of 28 consecutive days, unless reviewed
and approved by the sponsor) or discontinuing study treatment.
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
108
Status: Approved, Date: 08 June 2023
Recommendations for COVID-19 Vaccination for Ibrutinib Recipients
It is recommended that participants receive prophylactic COVID-19 vaccination when locally
available, at the discretion of investigator judgement or institutional practice, and in compliance
with the study protocol and local labels for the vaccine. Below is general guidance for
consideration.
All vaccines authorized for use (eg, full or conditional approval, or emergency use authorization
[EUA]), are allowable unless they are live, attenuated, or replicating viral vectors. Live attenuated
vaccines must be completed ≥4 weeks prior to randomization or initiated ≥30 days after last dose
of ibrutinib. There are no specific timing restrictions for inactivated vaccines, which include
vaccines which use alternative technology like mRNA or replication-incompetent viral vectors,
per protocol. Any vaccination, including COVID-19 vaccinations, must be recorded on the
Concomitant Medication page of the CRF.
No data are currently available to suggest that COVID-19 vaccines pose specific or additional
safety risk beyond other vaccines for MCL patients undergoing treatment.  Theoretically, a
diminished immune response may occur in immunocompromised patients, and therefore these
patients may have reduced vaccine effectiveness.
Several organizations and journals have published recommendations for COVID-19 vaccine
administration in cancer patients, including:
 
Garassino MC, et al. The ESMO call to action on COVID-19 vaccinations and patients with
cancer: Vaccinate. Monitor. Educate. Ann Oncol. 2021;32:579-581:
 
https://www.esmo.org/guidelines/cancer-patient-management-during-the-covid-19-
pandemic
 
Desai A, et al. COVID-19 vaccine guidance for patients with cancer participating in oncology
clinical trials. Nat Rev Clin Oncol. 2021;18:313-319:
 
https://www.nature.com/articles/s41571-021-00487-z
 
European Society for Blood and Marrow Transplantation:
 
https://www.ebmt.org/covid-19-and-bmt
 
American Society for Transplantation and Cellular Therapy (ASTCT):
 
https://www.hematology.org/covid-19/ash-astct-covid-19-vaccination-for-hct-and-car-t-
cell-recipients
 
Centers for Disease Control and Prevention (CDC):
 
https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html
 
National Comprehensive Cancer Network (NCCN):
 
https://www.nccn.org/covid-19/pdf/COVID-19_Vaccination_Guidance_V2.0.pdf
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
109
Status: Approved, Date: 08 June 2023
Based on guidance from the organizations listed above, the following measures should be
implemented to minimize participants’ risk of severe COVID-19 infection:
 
Participants should be reminded that the ongoing pandemic is still putting them at risk of
contracting COVID-19. Investigators should ask participants to continue to limit their risk of
exposure to infected individuals as much as possible and strictly adhere to prevention
measures such as proper masking, hand hygiene, social distancing, and avoiding travel and
public transportation to the largest extent possible.
 
Investigators should discuss with participants the importance of COVID-19 vaccines in the
prevention of severe illness, hospitalization, and death from COVID-19. For this reason, it is
strongly recommended that all participants receive a full COVID-19 vaccination series prior
to enrollment with repeated vaccination throughout study conduct per institutional practice or
investigator´s discretion  
. In addition, if not already vaccinated, caregivers, family, and
household contacts should be advised to receive COVID-19 vaccination as well.
 
Investigators should consider prophylaxis (eg, Evusheld, if available in the region) to reduce
participants’ risk of severe/fatal COVID.
NCT05564052


NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
111
Status: Approved, Date: 08 June 2023
10.12. Appendix 12: Calculated and Measured Creatinine Clearance
Cockcroft-Gault formula:
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault
formula:
CrCl (140 - age [in years]) x weight (kg) (x 0.85 for females)
(72 x serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, micromol/L),
use the following formula to convert SI units to conventional (mg/dL) units (Manual of
Laboratory and Diagnostic Tests, 2004):
• 
serum creatinine (micromol/L) divided by 88.4  serum creatinine (mg/dL)
Source: Cockcroft and Gault 1976
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
112
Status: Approved, Date: 08 June 2023
10.13. Appendix 13: Continuation of Study Treatment After the End of eCRF Data
Collection and Clinical Database Closure to the End of the Study
Protocol Amendment 1 will allow those participants who are benefiting from treatment to continue
receiving study treatment after the end of eCRF data collection and clinical database closure until
ibrutinib is commercially available, available from another source, or until the end of the study (as
defined in Section 10.2.12), whichever occurs earlier. Investigators are expected to transition their
participants to commercially available study treatment or alternative access to study treatment as
these become available.
The following limited schedule is applicable.
Documentation of assessments performed is required only in the participant file/source notes.
Dosage and Administration
Ibrutinib will be administered according to the regimen established in Protocol Amendment 1.
Dispensing of ibrutinib will occur every 6 months. Participants will be supplied with ibrutinib as
per local standard practice. For lenalidomide, refer to the product label (Lenalidomide Accord
SmPC 2022); follow local labels for dispensing instructions for other study drugs.
Treatment Period
The sponsor will ensure that participants benefiting from study treatment will be able to continue
receiving treatment after the end of eCRF data collection and clinical database closure until study
treatment is commercially available or available from another source, or study completion,
whichever occurs earlier.
Efficacy Evaluations
Investigators should monitor and assess participants for response to treatment or disease
progression according to local institutional practice. If investigators determine that a participant is
no longer benefiting from study treatment (ie, disease progression has occurred), the participant
should discontinue study treatment and study participation. The assessments and outcome should
be entered in the participant file/source notes. Notification of progressive disease to the medical
monitor should be via email.
Safety Evaluations
Once the eCRF data collection has ended, any test for safety (ie, hematology laboratory
assessments, chemistry laboratory assessments, pregnancy tests, assessment of vital signs) should
comply with standard local institution practice. These local test results should be entered in the
participant file/source notes, and do not need to be reported to the sponsor unless they meet the
SAE criteria.
Safety Reporting
Once the eCRF data collection has ended, serious adverse events that occur while the participant
is receiving study treatment and within 30 days after the last dose of study treatment or until the
start of a subsequent systemic anti-cancer therapy, if earlier will be reported to the sponsor’s global
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
113
Status: Approved, Date: 08 June 2023
medical safety database only via the same serious adverse event reporting process used over the
course of the study (see Section 10.3.5 [Serious Adverse Events]). Serious adverse events should
also be documented in the participant file/source notes.
Pregnancy reporting should continue as described in Section 8.4.5. The pregnancy should be
documented in the participant file/source notes.
Treatment Compliance
No study treatment will be recorded in diary cards after the end of eCRF data collection.
Biomarker
No biomarker specimens will be collected after clinical database closure.
Case Report Form Completion
No data will be collected in the eCRF after clinical database closure.
Monitoring
Once the clinical database will be closed after all participants completed Cycle 6, the sponsor will
no longer perform on-site monitoring visits, unless specifically required, but will perform remote
monitoring visits. At these remote visits, the sponsor will monitor the adequate reporting and
follow-up of SAEs and pregnancy information and ensure participants not benefiting from study
treatment stopped the study treatment. Documentation around drug receipt/dispensing/return will
be discussed with the site staff.
Source Documentation
At a minimum, the type and level of detail of source data collected should be consistent with that
commonly recorded at the site as a basis for standard medical care. This should include: participant
and study identification, study discussion, documentation of the informed consent process
including the date, dates of visits, drug receipt/dispensing/return records, study drug administration
information
NCT05564052


JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 08 June 2023
10.14. Appendix 14: Protocol Amendment History
The protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents.
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Clinical Protocol 54179060MCL3004 Amendment 1
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Status: Approved, Date: 08 June 2023
11. 
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JNJ-54179060  (ibrutinib) 
Clinical Protocol 54179060MCL3004 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 08 June 2023
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 08 June 2023
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development, LLC
Signature: electronic signature appended at the end of the protocol 
Date: 
08-June-2023
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT05564052


Signature
User 
Date 
Reason
 
08-Jun-2023
11:50:59
(GMT)
Document Approval
PPD
NCT05564052