Clinical trial NCT03112174
Conditions: Mantle-Cell Lymphoma
Keywords: PCYC MCL Non-Hodgkin's Lymphoma NHL ibrutinib venetoclax Pharmacyclics
Sponsor: Pharmacyclics LLC.
Start date: 2017-06-19; Completion date: 2024-06-27
Enrollment: 366 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 multinational, randomized, double-blind study is designed to compare the efficacy and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects with MCL.

Detailed description:

Arms: arm 1: Participants with a low or high risk of TLS enroll into the open-label Safety Run-in Period to receive concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramp up to a target dose of 400 mg once daily over a 5-week period. arm 2: Participants randomized to ibrutinib and venetoclax for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax is discontinued after 104 weeks of treatment, regardless of response assessment. arm 3: Participants randomized to ibrutinib and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo is discontinued after 104 weeks of treatment, regardless of response assessment. arm 4: Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule.
Interventions: intervention 1: Ibrutinib intervention 2: Venetoclax intervention 3: Placebo Oral tablet to match Venetoclax
Intervention descriptions: intervention 1: Administered orally once daily intervention 2: Administered orally once daily intervention 3: Administered orally once daily

Protocol documents:
Prot_000.pdf: 
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PROTOCOL
TITLE:
Phase 3 Study of Ibrutinib in Combination with Venetoclax in 
Subjects with Mantle Cell Lymphoma
PROTOCOL NUMBER:
PCYC-1143-CA
STUDY DRUG:
Ibrutinib 
IND NUMBER:
102,688
EudraCT NUMBER:
2017-000129-12
SPONSOR MEDICAL 
MONITOR:
 MD, PhD
Pharmacyclics LLC
Phone:
Email:
SPONSOR:
Pharmacyclics LLC, an AbbVie company
1000 Gateway Boulevard
South San Francisco, CA 94080
United States of America
DATE FINAL:
16 December 2016
Amendment 0.1
16 May 2017 (UK only)
Amendment 1
17 November 2017
Amendment 2
7 November 2019
Amendment 2.1 
27 April 2020 (France only)
Amendment 3
25 March 2021
Amendment 4:
16 September 2022
Confidentiality Statement
This document contains confidential information of Pharmacyclics LLC that must not be disclosed to 
anyone other than the recipient study staff and members of the institutional review board/ethics 
committee. This information cannot be used for any other purpose other than the evaluation or 
conduct of the clinical study without the prior written consent of Pharmacyclics LLC.
NCT03112174




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TABLE OF CONTENTS
PROTOCOL APPROVAL PAGE ...........................................................................................2
TABLE OF CONTENTS..........................................................................................................3
LIST OF APPENDICES...........................................................................................................8
LIST OF IN-TEXT TABLES AND FIGURES........................................................................9
SYNOPSIS...............................................................................................................................10
ABBREVIATIONS .................................................................................................................22
1
BACKGROUND....................................................................................................25
1.1
Mantle Cell Lymphoma ...........................................................................................25
1.1.1
Disease Background ................................................................................................25
1.1.2
Current Treatment Options.......................................................................................25
1.2
Ibrutinib Overview...................................................................................................26
1.2.1
Summary of Nonclinical Data..................................................................................27
1.2.1.1
Pharmacology..........................................................................................................27
1.2.1.2
Safety Pharmacology and Toxicology......................................................................27
1.2.2
Summary of Clinical Data........................................................................................28
1.2.2.1
Pharmacokinetics and Product Metabolism..............................................................28
1.2.3
Summary of Clinical Safety.....................................................................................28
1.2.3.1
Monotherapy Studies ...............................................................................................28
1.2.3.2
Combination Studies................................................................................................29
1.2.4
Risks........................................................................................................................30
1.2.4.1
Bleeding-related Events...........................................................................................30
1.2.4.2
Leukostasis..............................................................................................................30
1.2.4.3
Infections.................................................................................................................30
1.2.4.4
Cytopenias...............................................................................................................30
1.2.4.5
Interstitial Lung Disease (ILD) ................................................................................31
1.2.4.6
Cardiac Arrhythmias and Cardiac Failure.................................................................31
1.2.4.7
Tumor Lysis Syndrome............................................................................................31
1.2.4.8
Non-melanoma Skin Cancer ....................................................................................31
1.2.4.9
Lymphocytosis ........................................................................................................31
1.2.4.10
Cerebrovascular Accidents.......................................................................................32
1.2.4.11
Diarrhea...................................................................................................................32
1.2.4.12
Rash ........................................................................................................................32
1.2.4.13
Hypertension ...........................................................................................................32
1.3
Venetoclax Overview...............................................................................................33
1.3.1
Summary of Nonclinical Data..................................................................................33
1.3.2
Summary of Venetoclax Clinical Data .....................................................................34
1.3.2.1
Clinical Pharmacokinetics........................................................................................34
1.3.2.2
Summary of Clinical Safety.....................................................................................34
1.3.3
Risks........................................................................................................................35
1.3.3.1
Tumor Lysis Syndrome............................................................................................35
1.3.3.2
Neutropenia .............................................................................................................36
1.3.3.3
Serious Infections ....................................................................................................36
1.4
Study Rationale .......................................................................................................36


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1.4.1
Rationale for the Ibrutinib and Venetoclax Combination..........................................36
1.4.2
Dose Rationale.........................................................................................................37
1.4.3
Rationale for the Safety Run-in Period.....................................................................38
1.4.4
Rationale for the Design of the Treatment Arms ......................................................39
1.4.5
Rationale for the PFS Assumption of 23 Months in the Ibrutinib and Venetoclax 
Relapsed/Refractory Treatment Arm........................................................................39
1.4.6
Rationale for MRD Testing......................................................................................39
1.4.7
Rationale for Treatment-naive Open-label Arm, Inclusion of Patients with a 
TP53 Mutation and Exclusion of Blastoid Variant ...................................................40
1.4.8
Sample Size Considerations for Treatment-naive Open-label Arm Including 
Patients with a TP53 Mutation .................................................................................41
2
STUDY OBJECTIVES..........................................................................................42
2.1
Safety Run-in Period................................................................................................42
2.1.1
Primary Objective....................................................................................................42
2.1.2
Secondary Objectives...............................................................................................42
2.2
Randomization Phase...............................................................................................42
2.2.1
Primary Objective....................................................................................................42
2.2.2
Secondary Objectives...............................................................................................42
2.2.3
Exploratory Objectives ............................................................................................43
2.3
Treatment-naive Open-label Arm.............................................................................43
2.3.1
Primary Objective....................................................................................................43
2.3.2
Secondary Objectives...............................................................................................43
2.3.3
Exploratory Objectives ............................................................................................44
3
STUDY DESIGN ...................................................................................................44
3.1
Overview of Study Design.......................................................................................44
3.1.1
Safety Run-in Period................................................................................................44
3.1.2
Randomization Phase...............................................................................................48
3.1.3
Treatment-naive Open-label Arm.............................................................................50
4
SUBJECT SELECTION .......................................................................................51
4.1
Eligibility Criteria for SRI and Randomization Phase...............................................51
4.1.1
Inclusion Criteria .....................................................................................................51
4.1.2
Exclusion Criteria ....................................................................................................53
4.2
Eligibility Criteria for the Treatment-naive Open-label Arm ....................................55
4.2.1
Inclusion Criteria for the Treatment-naive Open-label Arm......................................55
4.2.2
Exclusion Criteria for the Treatment-naive Open-label Arm.....................................56
5
TREATMENT OF SUBJECTS.............................................................................58
5.1
Treatment Allocation and Blinding ..........................................................................58
5.1.1
Safety Run-in Period................................................................................................58
5.1.2
Randomization Phase...............................................................................................58
5.1.2.1
Randomization.........................................................................................................58
5.1.2.2
Blinding...................................................................................................................59
5.1.3
Replacement of Subjects..........................................................................................59
5.1.4
Treatment-naive Open-label Arm.............................................................................59
5.2
Study Treatment ......................................................................................................60
5.2.1
SRI and Randomized Phase .....................................................................................60
5.2.2
Treatment-naive Open-label Cohort.........................................................................61


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5.3
Study Medication.....................................................................................................61
5.3.1
Ibrutinib...................................................................................................................61
5.3.1.1
Formulation/Packaging/Storage ...............................................................................61
5.3.1.2
Dose and Administration .........................................................................................61
5.3.1.3
Overdose .................................................................................................................62
5.3.1.4
Dose Modification for Adverse Reactions................................................................62
5.3.1.5
Leukocytosis/Leukostasis ........................................................................................64
5.3.1.6
Dose Modification for Hepatic Impaired Subjects....................................................64
5.3.2
Venetoclax...............................................................................................................65
5.3.2.1
Formulation/Packaging/Storage ...............................................................................65
5.3.2.2
Venetoclax Toxicity Management............................................................................66
5.3.2.3
Dose and Administration .........................................................................................67
5.3.2.4
Overdose .................................................................................................................67
5.3.2.5
Dose Modification for Adverse Reactions................................................................68
5.3.2.6
Dose Modification for Hepatic Impaired Subjects....................................................69
5.4
Criteria for Permanent Discontinuation of Study Drug.............................................69
6
CONCOMITANT MEDICATIONS/PROCEDURES..........................................69
6.1
Permitted Concomitant Medications ........................................................................69
6.2
Medications to be Used with Caution.......................................................................70
6.2.1
CYP3A Inhibitors/Inducers......................................................................................70
6.2.1.1
Concomitant Use with Ibrutinib ...............................................................................70
6.2.1.2
Concomitant Use with Venetoclax/placebo ..............................................................70
6.2.2
Drugs that May have Their Plasma Concentration Altered by Ibrutinib....................71
6.2.3
Drugs That May Have Their Plasma Concentrations Altered by Venetoclax ............72
6.2.4
Antiplatelet Agents and Anticoagulants ...................................................................72
6.2.4.1
Concomitant Use with Ibrutinib ...............................................................................72
6.2.4.2
Concomitant Use with Venetoclax...........................................................................72
6.2.5
Prohibited Concomitant Medications and Products for Ibrutinib and/or 
Venetoclax/placebo..................................................................................................72
6.3
Guidelines for Ibrutinib Management with Surgeries or Procedures.........................73
6.3.1
Minor Surgical Procedures.......................................................................................73
6.3.2
Major Surgical Procedures.......................................................................................73
7
STUDY EVALUATIONS......................................................................................74
7.1
Description of Procedures........................................................................................74
7.1.1
Assessments ............................................................................................................74
7.1.1.1
ICF ..........................................................................................................................74
7.1.1.2
Confirm Eligibility...................................................................................................74
7.1.1.3
Medical History and Demographics .........................................................................74
7.1.1.4
Prior and Concomitant Medications .........................................................................74
7.1.1.5
Adverse Events........................................................................................................74
7.1.1.6
Physical Examination...............................................................................................75
7.1.1.7
Eye-related Symptom Assessment ...........................................................................75
7.1.1.8
ECOG......................................................................................................................75
7.1.1.9
Vital Signs...............................................................................................................75
7.1.1.10
Tumor Lysis Syndrome (TLS) Risk Assessment ......................................................75
7.1.1.11
B-Symptoms............................................................................................................76


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7.1.2
Laboratory...............................................................................................................76
7.1.2.1
Hematology.............................................................................................................76
7.1.2.2
Chemistry (Serum)...................................................................................................76
7.1.2.3
Coagulation Studies.................................................................................................76
7.1.2.4
Hepatitis Serologies .................................................................................................76
7.1.2.5
Serum β2-microglobulin ..........................................................................................77
7.1.2.6
Urinalysis ................................................................................................................77
7.1.2.7
Pregnancy Test ........................................................................................................77
7.1.3
Diagnostics/Procedures............................................................................................77
7.1.3.1
ECG ........................................................................................................................77
7.1.3.2
CT/MRI and PET.....................................................................................................77
7.1.3.3
Endoscopy...............................................................................................................79
7.1.3.4
Tumor Tissue...........................................................................................................79
7.1.3.5
Bone Marrow Biopsies for Evaluation of Bone Marrow Involvement ......................79
7.1.3.6
Bone Marrow Aspirate and Peripheral Blood for Minimal Residual Disease (MRD) 
Assessment..............................................................................................................80
7.1.3.7
Bone Marrow Aspirate and Peripheral Blood for Biomarker Assessment .................80
7.1.4
Pharmacokinetics/Biomarkers..................................................................................81
7.1.4.1
Pharmacokinetics for Safety Run-in and Randomization Phase ................................81
7.1.4.2
Pharmacokinetics Treatment-naive Open-label Arm ................................................82
7.1.4.3
Exploratory Biomarkers...........................................................................................83
7.1.5
Patient-Reported Outcomes......................................................................................83
7.1.5.1
FACT-Lym for Safety Run-in and Randomization Phase.........................................83
7.1.5.2
EQ-5D-5L for SRI, Randomization Phase and Treatment-naive Open-label Arm.....84
7.1.6
Medical Resource Utilization (MRU).......................................................................84
7.2
Efficacy Evaluations................................................................................................84
7.2.1
Overall Response Assessments ................................................................................84
7.2.2
Survival...................................................................................................................85
7.3
Sample Collection and Handling..............................................................................85
8
STUDY PROCEDURES........................................................................................85
8.1
Screening Phase.......................................................................................................85
8.1.1
Screening/Consenting Visit......................................................................................85
8.2
Treatment Phase ......................................................................................................86
8.2.1
Treatment Visits for Standard Ramp-up Schedule for SRI, Randomization 
Phase, and Treatment-naive (TN) Open-label Arm...................................................87
8.2.1.1
Week 1 Day 1 and Week 2 Day 1 ............................................................................87
8.2.1.2
Week 1 Day 2 and Week 2 Day 2 ............................................................................88
8.2.1.3
Week 1 Day 3 and Week 2 Day 3 (Hospitalized Subjects Only)...............................88
8.2.1.4
Weeks 3, 4, and 5 Day 1 for Standard Ramp-up Schedule........................................89
8.2.1.5
Week 6 Day 1..........................................................................................................90
8.2.1.6
Week 8 Day 1 (± 1 Day) and Week 10 Day 1 (± 1 Day)...........................................91
8.2.1.7
Week 13 and beyond (±7 Days) ...............................................................................91
8.2.2
Response Evaluation................................................................................................92
8.2.3
End-of-Treatment Visit............................................................................................93
8.3
Follow-up Phase ......................................................................................................93
8.3.1
Response Follow-up ................................................................................................93


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8.3.2
Long-term Follow-up...............................................................................................93
9
SUBJECT COMPLETION AND WITHDRAWAL.............................................94
9.1
Completion..............................................................................................................94
9.2
Withdrawal from Study Treatment...........................................................................94
9.3
Withdrawal from Study............................................................................................94
10
STATISTICAL METHODS AND ANALYSIS....................................................95
10.1
Analysis Population.................................................................................................95
10.1.1
Safety Run-in Period Evaluable Population..............................................................95
10.1.2
Safety Population.....................................................................................................96
10.1.3
Intent-to-Treat Population in Randomization Phase..................................................96
10.1.4
All-Treated Population for Treatment-naive Open-label Arm...................................96
10.1.5
Additional Analysis Population................................................................................96
10.2
Endpoints.................................................................................................................96
10.2.1
Safety Run-in Period................................................................................................96
10.2.2
Randomization Phase Primary Endpoint ..................................................................96
10.2.3
Randomization Phase Secondary Endpoints.............................................................97
10.2.4
Randomization Phase Exploratory Endpoints...........................................................98
10.2.5
Treatment-naive Open-label Arm Primary Endpoint ................................................98
10.2.6
Treatment-Naive Open-Label Arm Secondary Endpoints.........................................98
10.2.7
Treatment-naive Open-label Arm Exploratory Endpoints.........................................98
10.3
Sample Size Determination (Randomization Phase).................................................98
10.4
Sample Size Determination (Treatment-naive Open-label Arm)...............................99
10.5
Efficacy Analysis...................................................................................................100
10.5.1
Randomization Phase.............................................................................................100
10.5.1.1
Analysis for Primary Efficacy Endpoint.................................................................100
10.5.1.2
Analysis for Secondary Efficacy Endpoints............................................................100
10.5.2
Treatment-naive Open-label Arm...........................................................................101
10.5.2.1
Analysis for the Primary Efficacy Endpoint ...........................................................101
10.5.2.2
Analysis for Secondary Efficacy Endpoints............................................................102
10.6
Safety Analysis......................................................................................................102
10.7
Pharmacokinetic Analysis......................................................................................103
10.7.1
Ibrutinib.................................................................................................................103
10.7.2
Venetoclax.............................................................................................................103
10.8
Biomarker Analyses...............................................................................................104
11
ADVERSE EVENT REPORTING .....................................................................104
11.1
Definitions.............................................................................................................104
11.1.1
Adverse Events......................................................................................................104
11.1.2
Serious Adverse Events .........................................................................................105
11.1.3
Severity Criteria (Grade 1-5)..................................................................................106
11.1.4
Causality (Attribution)...........................................................................................107
11.2
Unexpected Adverse Events...................................................................................107
11.3
Special Reporting Situations ..................................................................................107
11.4
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators ..........................................................................................................108
11.4.1
Assessment of Adverse Events...............................................................................108
11.4.2
Adverse Event Reporting Period............................................................................108


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11.4.3
Expediting Reporting Requirements for Serious Adverse Events ...........................109
11.4.4
Pregnancy..............................................................................................................109
11.4.5
Other Malignancies................................................................................................110
11.4.6
Eye-Related Adverse Events..................................................................................110
11.4.7
Adverse Events of Special Interest (AESI).............................................................110
11.4.7.1
Major Hemorrhage.................................................................................................110
12
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS.........111
12.1
Regulatory and Ethical Compliance .......................................................................111
12.2
Institutional Review Board (IRB), Research Ethics Board (REB) and 
Independent Ethics Committee (IEC) Approval .....................................................111
12.3
Informed Consent ..................................................................................................111
12.4
Quality Control and Quality Assurance..................................................................112
12.5
Protected Subject Health Information Authorization ..............................................112
12.6
Study Files and Record Retention ..........................................................................112
12.7
Case Report Forms and Record Maintenance .........................................................113
12.8
Investigational Study Drug Accountability.............................................................114
12.9
Study Monitoring/Audit Requirements...................................................................114
12.10
Investigator Responsibilities ..................................................................................115
12.11
Sponsor Responsibilities........................................................................................115
12.12
Financial Disclosure ..............................................................................................115
12.13
Liability and Clinical Trial Insurance.....................................................................116
12.14
Protocol Amendments............................................................................................116
12.15
Publication of Study Results ..................................................................................116
12.16
Study Discontinuation............................................................................................117
12.17
Study Completion..................................................................................................117
13
REFERENCES ....................................................................................................118
14
APPENDICES......................................................................................................123
LIST OF APPENDICES
Appendix A.
Schedule of Assessments – Standard Ramp-up Schedule...............................124
Appendix B.
Schedule of Assessments – Treatment-naive Open-label Arm .......................127
Appendix C.
ECOG Status Scores .....................................................................................130
Appendix D.
Sample List of Cautionary Medications.........................................................131
Appendix E.
Revised Criteria for Response Assessment for Malignant Lymphoma ...........133
Appendix F.
Child-Pugh Score for Subjects with Liver Impairment...................................136
Appendix G.
Howard Criteria for Laboratory and Clinical TLS* (Howard et al, NEJM 2011)
.....................................................................................................................137
Appendix H.
Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of Tumor Lysis Syndrome (TLS).................................................138
Appendix I.
FACT-Lym questionnaire (version 4)............................................................142
Appendix J.
EQ-5D-5L.....................................................................................................146


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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1.
Ibrutinib Dose Modifications........................................................................63
Table 2.
Ibrutinib Dose Modifications for Cardiac Failure or Cardiac 
Arrhythmias .................................................................................................64
Table 3.
Ibrutinib Dose Reduction Levels ..................................................................64
Table 4.
Identity of Venetoclax/Placebo Drug Product...............................................65
Table 5.
Recommended Dose Modifications for Venetoclax/placebo-related 
Toxicities .....................................................................................................68
Table 6.
Dose Modification for Toxicity During Venetoclax/placebo Treatment ........69
Table 7.
Management of Potential Ibrutinib and Venetoclax/placebo Interactions 
with CYP3A Inhibitors.................................................................................71
Table 8.
Ibrutinib and Venetoclax PK Samples Schedule at the Target Dose..............81
Table 9.
Pharmacokinetic Sample Schedule for Ibrutinib and Venetoclax or 
placebo on the PK Days ...............................................................................81
Table 10.
Pharmacokinetic Sample Schedule for Treatment-naive Open-label Arm .....82
FIGURES
Figure 1.
Study Schematic – Safety Run-in Period ......................................................11
Figure 2.
Standard Ramp-up Schedule.........................................................................13
Figure 3.
Randomization Phase Schematic ..................................................................14
Figure 4.
Venetoclax Ramp-up Schedule for Treatment-naive Open-label Arm...........15
Figure 5.
Study Schema for Treatment-naive Open-label Arm.....................................16
Figure 6.
Study Schematic – Safety Run-in Period ......................................................45
Figure 7.
Standard Ramp-up Schedule.........................................................................46
Figure 8.
Randomization Phase Schematic ..................................................................49
Figure 9.
Study Design: Treatment-naive Open-label Arm ..........................................50
Figure 10.
Venetoclax Standard Ramp-up Schedule ......................................................50


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SYNOPSIS
Study Title:
Phase 3 study of ibrutinib in combination with venetoclax in subjects with 
mantle cell lymphoma (MCL) 
Protocol Number:
PCYC-1143-CA 
Study Phase:
3
Study Duration:
Estimated to be 5 years
Investigational 
Product and 
Reference Therapy:
Ibrutinib will be supplied as 140 mg hard gelatin capsules or 560 mg tablets for 
oral (PO) administration.
Venetoclax will be supplied as 10 mg, 50 mg, and 100 mg tablets for oral (PO) 
administration.
Objectives:
(Safety Run-in [SRI] 
Period and 
Randomization Phase)
Safety Run-in Period
Primary Objective:
To evaluate the occurrence of tumor lysis syndrome (TLS) and dose-limiting 
toxicities (DLTs) with the concurrent administration of ibrutinib and venetoclax.
Secondary Objectives:
To evaluate response (partial and complete response), progression-free survival 
(PFS), duration of response (DOR), and overall survival (OS).
Randomization Phase 
Primary Objective:
To evaluate whether the combination of ibrutinib and venetoclax will result in 
prolongation of PFS compared to ibrutinib and placebo in subjects with relapsed 
or refractory MCL.
Secondary Objectives:

To evaluate whether the combination of ibrutinib and venetoclax will 
increase the complete response (CR) rate, the overall response rate 
(ORR), the minimal residual disease (MRD) negative remission rate in 
subjects who were MRD positive at screening and achieve CR, OS, 
DOR, and time-to-next treatment (TTNT) compared to ibrutinib and 
placebo.

To evaluate the frequency, severity, and relatedness of adverse events 
(AEs); frequency, severity and management of TLS; AEs requiring dose 
reductions and/or discontinuation of study drug, or leading to death. 

To determine the pharmacokinetics (PK) of ibrutinib and venetoclax.

To evaluate whether the combination of ibrutinib and venetoclax will 
improve quality of life using a Health-related quality of life 
questionnaire (FACT-Lym, etc.), compared to ibrutinib and placebo.
Objectives:
(Treatment-naive 
Open-label Arm)
Primary Objective:
To evaluate the complete response (CR) rate with the combination of ibrutinib 
and venetoclax in subjects with treatment-naive MCL
Secondary Objectives:

To evaluate the overall response rate (ORR), the duration of response 
(DOR) and duration of CR 

To evaluate the minimal residual disease (MRD)-negative remission 
rate in subjects who achieve CR who were MRD positive at screening


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
To evaluate progression-free survival (PFS), overall survival (OS), and 
time-to-next treatment (TTNT) with the combination of ibrutinib and 
venetoclax

To evaluate the frequency, severity, and relatedness of adverse events 
(AEs); frequency, severity and management of TLS; AEs requiring dose 
reductions and/or discontinuation of study drug, or leading to death

To determine the pharmacokinetics (PK) of ibrutinib and venetoclax
Exploratory Objectives:

To evaluate biomarkers in relationship to efficacy outcomes

To evaluate whether the combination of ibrutinib and venetoclax will
improve quality of life using a health-related quality of life 
questionnaire (EQ-5D-5L, etc.)
Study Design:
1. Safety Run-in 
Period
2. Randomization 
Phase
3. Treatment-naive 
Open-label Arm
This Phase 3 multinational, randomized, double-blind study is designed to 
compare the efficacy and safety of the combination of ibrutinib and venetoclax 
vs. ibrutinib and placebo in subjects with MCL. 
Approximately 287 subjects will be enrolled. In the treatment-naive open-label 
arm, approximately 75 subjects will be enrolled.
1. Safety Run-in Period
The study will start with an open-label Safety Run-in Period to evaluate the 
occurrence of tumor lysis syndrome (TLS) and DLTs with the concurrent 
administration of ibrutinib and venetoclax. TLS and DLT occurrence will be 
assessed during the venetoclax Ramp-up Period for a minimum of 5 weeks.
Up to 27 subjects may be enrolled during the Safety Run-in Period (Figure 1):
Figure 1.
Study Schematic – Safety Run-in Period
PD = progressive disease; WC = withdrawal of consent
Tumor Lysis Syndrome (TLS) Categories
Two TLS risk categories will be evaluated separately and in parallel:

Increased risk for TLS – Subjects with high tumor burden (at least one 
lesion > 10 cm; or at least one lesion > 5 cm and circulating 
lymphocytes > 25,000 cells/mm3) and/or with baseline creatinine 
clearance (CrCl) < 60 mL/min. During the Safety Run-in Period, 
subjects at increased risk for TLS will be hospitalized for a minimum of 
24 hours (and up to 48 hours at the discretion of the investigator) at the 
start of the 20 mg ramp-up dose and again at the start of the 50 mg 
ramp-up dose of venetoclax for monitoring and prophylaxis of TLS.

Low risk for TLS – Subjects not meeting the criteria described above
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 


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TLS events are defined as follows: 

Clinical TLS – any event that meets Howard criteria (Appendix G) with 
the following exceptions: 
o
For the purpose of TLS assessment during the Safety Run-in Period, 
only those increases in serum creatinine > 1.0 mg/dL from 
pre-treatment baseline will be considered clinical TLS.
o
In subjects with renal dysfunction at baseline (CrCl < 60 mL/min), 
clinical TLS is defined as the presence of laboratory TLS plus either 
seizures, cardiac dysrhythmia, or death.

Laboratory TLS – any event that meets Howard criteria (Appendix G) 
for laboratory TLS, that does not resolve within 72 hours despite 
protocol required management
Dose-Limiting Toxicities (DLT) 
A DLT is defined as any Grade 3 or higher non-TLS AE at least possibly related 
to study drug (ibrutinib and/or venetoclax) and occurring during the DLT 
assessment period with the following clarifications:
Non-Hematologic DLTs:

Grade ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum 
medical supportive care and persisting > 5 days

Grade 3 fatigue persisting > 7 days

Grade 3 infection is not a DLT, however an infection with life-
threatening consequences or requiring urgent intervention (Grade 4) 
will be considered a DLT

Treatment delay of any study drug > 7 days for toxicity 
Hematologic DLTs:

Grade 3 neutropenia is not a DLT; however, Grade 4 neutropenia
(ANC < 500/mm3) lasting for > 7 days is a DLT 

Grade 3 or 4 neutropenia complicated by fever ≥38.5°C or infection 

Grade 4 thrombocytopenia (< 25,000/mm3) that persists for > 7 days 

Grade 3 or 4 thrombocytopenia associated with Grade 2 or greater 
bleeding

Grade 3 anemia is not a DLT; however, Grade 4 anemia is a DLT

Treatment delay of any study drug > 7 days for hematologic toxicity
Initially, 6 subjects at low risk for TLS and 12 subjects at increased risk for TLS 
will receive ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and 
gradually ramped up to a target dose of 400 mg once daily over a 5-week period 
(see Figure 2 below). TLS events and DLTs will be assessed during the 
venetoclax Ramp-up Period for a minimum of 5 weeks. 


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Figure 2.
Standard Ramp-up Schedule
Subjects at Low Risk for TLS
Evaluation of TLS
Three additional subjects will be dosed, if 1 out of 6 subjects at low risk for TLS 
experiences a laboratory TLS event and no subjects experience a clinical TLS 
event. If 0 out of 6 or ≤1 out of 9 subjects experience a laboratory TLS event 
and no subjects experience a clinical TLS event, the Randomization Phase will 
start using the standard ramp-up schedule for subjects at low risk for TLS. 
If ≥2 out of 6-9 subjects at low risk for TLS experience a laboratory TLS event 
or any subject experiences a clinical TLS event, the Randomization Phase will 
start with a 4-week ibrutinib lead-in followed by the standard Ramp-up 
Schedule (Figure 2) for subjects in both TLS risk categories.
Evaluation of DLTs
With respect to DLTs, if < 2 out of 6 or < 3 out of 9 subjects experience DLT(s) 
during the DLT assessment period, the Randomization Phase will commence 
using the standard Ramp-up Schedule for subjects at low risk for TLS 
(Figure 2). However, if ≥3 out of 9 subjects experience DLT(s), the 
Randomization Phase will commence with a 4-week ibrutinib lead-in followed 
by the standard Ramp-up Schedule for subjects in both TLS risk categories 
(Figure 2).
The Safety Review Committee (SRC) will evaluate TLS and DLT data during 
the Safety Run-in Period prior to initiation of the Randomization Phase.
Subjects at Increased Risk for TLS
Evaluation of TLS 
If < 3 out of the 12 subjects at increased risk for TLS experience a laboratory 
TLS event and no subjects experience a clinical TLS event, enrollment of 
increased-risk TLS subjects to the Randomization Phase will commence using 
the standard Ramp-up Schedule for subjects at increased risk for TLS 
(Figure 2).
However, if ≥3 out of the 12 increased risk subjects experience a laboratory 
TLS event or any of these subjects experience a clinical TLS event, at least 
6 subjects at increased risk for TLS should be treated with the 4-week ibrutinib 
lead-in and assessed for safety either in an external study or within this study. If 
≤2 out of these 6 subjects experience a laboratory TLS event and no subjects 
experience a clinical TLS event, the Randomization Phase will commence with 
a 4-week ibrutinib lead-in followed by the standard Ramp-up Schedule for 
subjects at increased risk of TLS (Figure 2).
 
  
 


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Evaluation of DLTs
If < 4 out of the 12 subjects at increased risk for TLS experience DLT(s) during 
the DLT assessment period, the Randomization Phase will commence using the 
standard Ramp-up Schedule. However, if ≥4 out of the 12 subjects experience 
DLT(s), the Randomization Phase will commence with a 4-week ibrutinib 
lead-in followed by the standard Ramp-up Schedule for subjects at increased 
risk of TLS.
The SRC will evaluate TLS and DLT data during the Safety Run-in Period prior 
to the Randomization Phase.
Subjects in either TLS risk category who experience a laboratory or clinical 
TLS event will be managed according to standard institutional practice. 
For subjects who experience laboratory TLS, dosing of venetoclax will be 
withheld per protocol and may be resumed when all laboratory abnormalities 
have returned to baseline. Dose reduction of venetoclax is not allowed for 
subjects enrolled in the Safety Run-in Period. Once venetoclax dosing is 
resumed, the applicable ramp-up week will re-start at the same dose level.
Those subjects incurring clinical TLS (regardless of TLS risk category) must be 
documented and discussed with the study medical monitor to determine whether 
the risk-benefit ratio justifies the subject remaining on study.
Subjects will be treated with ibrutinib and venetoclax for approximately 
104 weeks followed by ibrutinib monotherapy until disease progression (PD), 
unacceptable toxicity or withdrawal of consent. Venetoclax will be discontinued 
after 104 weeks of treatment regardless of response assessment. Subjects who 
discontinue study treatment for any reason will be followed for progression (if 
not progressed before treatment discontinuation), subsequent anti-cancer 
therapy and survival status until study closure.
2. Randomization Phase 
The Randomization Phase portion of the study will follow a randomized, 
double-blind design (Figure 3). Ibrutinib and venetoclax/placebo will be 
administered using the Standard Ramp-up Schedule. 
Subject eligibility will be determined up to 28 days prior to randomization. 
Approximately 260 eligible subjects will be randomized at a 1:1 ratio to 
ibrutinib and venetoclax or ibrutinib and placebo. Randomization will be 
stratified by number of prior lines of therapy, ECOG performance status (PS), 
and by TLS risk category.
Figure 3.
Randomization Phase Schematic
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Initially, subjects at increased risk of TLS will be hospitalized for a minimum of 
24 hours (and up to 48 hours at the discretion of the investigator) at the start of 
the 20 mg ramp-up dose and again at the start of the 50 mg ramp-up dose of 
venetoclax for monitoring and prophylaxis of TLS. The data monitoring 
committee (DMC) will review unblinded safety data during the course of the 
study to determine whether continued hospitalization of these subjects during 
ramp-up remains warranted.
Subjects will be treated with either ibrutinib and venetoclax or ibrutinib and 
placebo for approximately 104 weeks, followed by ibrutinib monotherapy until 
PD, unacceptable toxicity or withdrawal of consent. Venetoclax/placebo will be 
discontinued after 104 weeks of treatment, regardless of response assessment.
Subjects who discontinue study treatment for any reason will be followed for 
progression (if not progressed before treatment discontinuation), subsequent 
anticancer therapy, and survival status until study closure.
3. Treatment-naive Open-label Arm
A separate open-label arm is designed to explore the efficacy and safety of the 
combination of ibrutinib and venetoclax in subjects with treatment-naive MCL 
(Figure 5).
In the treatment-naive open-label arm, approximately 75 subjects will be 
enrolled and treated with ibrutinib 560 mg and venetoclax 400 mg. Among 
them, approximately 50 subjects ≥65 years and approximately 25 subjects with 
a TP53 mutation will be enrolled.
Ibrutinib and venetoclax will be administered using the 5-week ramp-up 
schedule shown in Figure 4. Treatment-naive MCL patients will use the same 
dose and schedule as established in the Safety Run-in for the Randomization 
Phase of the study. Therefore, there will be no Safety Run-in for the treatment-
naive cohort.
Note: Sponsor may hold enrollment for patients in the treatment-naive open-
label arm to ensure that at least 25 patients with a TP53 mutation are enrolled.
Figure 4.
Venetoclax Ramp-up Schedule for Treatment-naive 
Open-label Arm
 
  
 
 
 
 
 
 
 


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Figure 5.
Study Schema for Treatment-naive Open-label Arm
PD = progressive disease; WC = withdrawal of consent
Subject eligibility will be determined up to 28 days prior to the first dose of 
study drug.
Subjects in the protocol-defined increased risk for tumor lysis syndrome (TLS) 
group will be hospitalized for a minimum of 24 hours (and up to 48 hours at the 
discretion of the investigator) at the start of the 20 mg and 50 mg ramp-up dose 
of venetoclax for monitoring and prophylaxis of TLS; subjects in the low-risk 
for TLS group may be hospitalized at the discretion of the investigator.
Subjects will be treated with ibrutinib and venetoclax for approximately 
104 weeks (2 years), followed by ibrutinib monotherapy until PD, unacceptable 
toxicity or withdrawal of consent or study closure. Venetoclax will be 
discontinued after 104 weeks (2 years) of treatment, regardless of response 
assessment.
CT and PET or PET/CT: A CT scan (with contrast unless contraindicated) of the 
neck, chest, abdomen, and pelvis and any other disease sites (eg, extremity) and 
a PET scan are required for the pretreatment tumor assessment within 28 days of 
the 1st dose. Thereafter, CT scans will be done for tumor assessments on 
Week 13 Day 1 (±7 days); every 12 weeks for the remainder of the 1st year; 
every 16 weeks during the 2nd and 3rd years; and every 24 weeks thereafter until 
PD. PET or PET/CT is mandatory for all subjects at the Week 13 visit 
(+/- 7 days), the Week 25 visit (+/- 7 days) for subjects in SD or PR who did not 
achieve CR at Week 13, and at the 1-year visit (Week 49 +/- 7 days) for all 
subjects, as well as at any other time point to confirm a CR. Other PET or 
PET/CT scans that are NOT mandatory can be performed within a 30-day 
window of the visit. 
Subjects who discontinue study treatment for any reason other than progressive 
disease will be followed for disease progression from the first dose of study 
drug every 12 weeks for the remaining of the 1st year; every 16 weeks during the 
2nd and 3rd years; and every 24 weeks thereafter until subsequent anticancer 
therapy, and survival status until study closure.
Population:
SRI and Randomization Phase: Subjects with relapsed/refractory mantle cell 
lymphoma 
Treatment-naive Open-label Arm: Subjects with treatment-naive mantle cell 
lymphoma
Centers:
Multiple, US and ex-US 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 


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Inclusion Criteria:
SRI and 
Randomization Phase)
Refer to Section 4.1
for the complete and 
detailed list of 
inclusion/exclusion 
criteria.
Disease-Related (see Section 4.1.1 for details)

Pathologically confirmed MCL (in tumor tissue), 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)

At least 1 measurable site of disease that is ≥2.0 cm in the longest 
diameter and measurable in 2 perpendicular dimensions per CT

At least 1, but no more than 5, prior treatment regimens for MCL 
including at least 1 prior rituximab/anti-CD20 containing regimen

Failure to achieve at least partial response (PR) with, or documented 
disease progression after, the most recent treatment regimen

Subjects must have adequate fresh or paraffin embedded tissue
Laboratory (see Section 4.1.1 for details)

Adequate hematologic function

Adequate hepatic and renal function
Demographic 

Men and women ≥18 years of age

Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
of ≤2
Exclusion Criteria:
(SRI and 
Randomization Phase)
Disease-Related (see Section 4.1.2 for details)

History or current evidence of central nervous system lymphoma
Concurrent Conditions (see Section 4.1.2 for details)

Concurrent enrollment in another therapeutic investigational study or 
prior therapy with ibrutinib or other BTK inhibitors

Prior treatment with venetoclax or other BCL2 inhibitors

Anticancer therapy including chemotherapy, radiotherapy, small 
molecule and investigational agents ≤21 days prior to receiving the first 
dose of study drug

Treatment with any of the following within 7 days prior to the first 
dose of study drug:
o
moderate or strong cytochrome P450 3A (CYP3A) inhibitors
o
moderate or strong CYP3A inducers
Inclusion Criteria: 
(Treatment-naive 
Open-label Arm)
1. Pathologically confirmed treatment-naive MCL (tumor tissue), 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).

A report from the local laboratory is acceptable if available; however, it 
must be reviewed and approved by the central pathology laboratory to 
verify the above criteria prior to enrollment.

If the report from the local laboratory is not available, a tumor block or 
slides must be sent to the central pathology laboratory for confirmation 
of the MCL diagnosis prior to enrollment


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2. Men and women ≥18 years of age with a TP53 mutation1
3. At least 1 measurable site of disease that is ≥2.0 cm in the longest diameter 
and measurable in 2 perpendicular dimensions per CT
4. Subjects must have adequate fresh or paraffin-embedded tissue
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
6. Adequate hematologic function independent of transfusion and growth factor 
support for at least 7 days prior to first dose, with the exception of pegylated 
G-CSF (pegfilgrastim) and darbepoeitin which require at least 14 days prior 
to the first dose defined as: 

Absolute neutrophil count (ANC) > 1000 cells/mm3 (1.0 x 109/L)

Platelet count > 50,000 cells/mm3 (50 x 109/L)

Hemoglobin > 8.0 g/dL
7. Adequate hepatic and renal function defined as:

Serum aspartate transaminase (AST) or alanine transaminase (ALT) 
≤3.0 x upper limit of normal (ULN)

Estimated Creatinine Clearance (CrCl) ≥30 mL/min (Cockcroft-Gault)

Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin)
8. Prothrombin time (PT) or International normal ratio (INR) < 1.5 x upper limit 
of normal (ULN) and PTT (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 ≤3.0
9. Male and female subjects of reproductive potential who agree to use 
both a highly effective method of birth control (eg, implants, 
injectables, combined oral contraceptives, some intrauterine devices 
[IUDs], complete abstinence2, or sterilized partner) and a barrier 
method (eg, condoms, cervical ring, sponge, etc) during the period of 
therapy and for 90 days after the last dose of study drug
Exclusion Criteria: 
(Treatment-naive 
Open-label Arm)
1. Blastoid variant of MCL
2. History or current evidence of central nervous system lymphoma
3. Concurrent enrollment in another therapeutic investigational study or prior 
therapy, including ibrutinib or other BTK inhibitors
4. Prior treatment with venetoclax or other BCL2 inhibitors
                                               
1 TP53 test by local or central lab
2 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
http://www hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf


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5. History of other malignancies, except:

Malignancy treated with curative intent and with no known active 
disease present for ≥3 years before the first dose of study drug and felt 
to be at low risk for recurrence by treating physician

Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease

Adequately treated carcinoma in situ without evidence of disease
6. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of 
study drug
7. Clinically significant infection requiring IV systemic treatment that was 
completed ≤14 days before the first dose of study drug
8. Any uncontrolled active systemic infection
9. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia)
10. History of stroke or intracranial hemorrhage within 6 months prior to 
enrollment
11. Known history of human immunodeficiency virus (HIV) or active with 
hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are 
positive for hepatitis B core antibody, or hepatitis C antibody must have a 
negative polymerase chain reaction (PCR) result before enrollment. Those 
who are hepatitis B surface antigen (HBsAg) or PCR positive will be 
excluded.
12. Major surgery within 4 weeks of the first dose of study drug.
13. Any life-threatening illness, medical condition, or organ system dysfunction 
that, in the investigator’s opinion, could compromise the subject’s safety or 
put the study outcomes at undue risk
14. Currently active, clinically significant cardiovascular disease, such as 
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined 
by the New York Heart Association Functional Classification; or a history 
of myocardial infarction, unstable angina, or acute coronary syndrome 
within 6 months prior to randomization
15. Unable to swallow capsules or tablets, or malabsorption syndrome, disease 
significantly affecting gastrointestinal function, or resection of the stomach 
or small bowel, symptomatic inflammatory bowel disease or ulcerative 
colitis, or partial or complete bowel obstruction
16. Treatment with any of the following within 7 days prior to the first dose of 
study drug:

Moderate or strong cytochrome P450 3A (CYP3A) inhibitors 
(Appendix D)

Moderate or strong CYP3A inducers (Appendix D)
17. Administration or consumption of any of the following within 3 days prior 
to the first dose of study drug:

grapefruit or grapefruit products

Seville oranges (including marmalade containing Seville oranges)

star fruit
18. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects 
with known risk factors (as defined by high tumor burden and/or diminished 
renal function, as detailed in “Study Design” section above) for TLS


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19. Subjects with chronic liver disease with hepatic impairment Child-Pugh 
class B or C
20. Female subject who is pregnant, breastfeeding or is considering becoming 
pregnant during the study or for approximately 90 days after the last dose of 
study drug
21. Male subject who is considering fathering a child or donating sperm during 
the study or for approximately 90 days after the last dose of study drug
22. Unwilling or unable to participate in all required study evaluations and 
procedures
23. Unable to understand the purpose and risks of the study and to provide a 
signed and dated informed consent form (ICF) and authorization to use 
protected health information (in accordance with national and local subject 
privacy regulations)
24. Known hypersensitivity to the active ingredient or other components of one 
or more study drugs
Study Treatment: 
(Safety Run-in and 
Randomization Phase)
Ibrutinib: 
560 mg of ibrutinib dosed orally once daily. Ibrutinib may be supplied either as 
560 mg tablet (maximum of 1 tablet dosed once daily) or as 140 mg capsules 
(maximum of 4 capsules dosed once daily)
Venetoclax: 
Orally once daily venetoclax started either concurrently with ibrutinib using the 
standard Ramp-up Schedule
Placebo:
Oral matching placebo for venetoclax started concurrently with ibrutinib using 
the standard Ramp-up Schedule
Study Treatment: 
(Treatment-naive
Open-label Arm)
Ibrutinib: 
560 mg of ibrutinib dosed orally once daily. Ibrutinib may be supplied either as 
a 560 mg tablet (maximum 1 tablet dosed once daily) or as 140 mg capsules 
(maximum of 4 capsules dosed once daily)
Important: If using tablets, please ensure that patients do not take more than 
one 560 mg tablet per day.
Venetoclax: 
Orally once daily venetoclax started concurrently with ibrutinib using the 
Venetoclax Standard Ramp-up Schedule (Figure 4).
Concomitant 
Therapy:
Caution is advised when administering moderate or strong CYP3A inhibitors or 
inducers or P-gp inhibitors. Refer to Section 6 for information on concomitant 
therapy.
Sample Size 
Determination: 
(SRI and 
Randomization Phase)
Safety Run-in Period
Sample size determination for the Safety Run-in Period follows the standard 
dose escalation convention as described in the DLT and TLS assessment 
section. Up to 27 subjects may be enrolled in the Safety Run-in Period for 
evaluation.


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Randomization Phase 
The primary efficacy endpoint of PFS will be determined by investigator 
assessment. Approximately 260 subjects will be enrolled and randomized at a 
1:1 ratio. With a targeted HR of 0.61 (corresponding to an improvement in 
median PFS from 14 months to 23 months), 134 PFS events will provide at least 
80% power at a 1-sided overall significance level of 0.025. Overall survival will 
be analyzed at the time of the primary analysis of PFS when the superiority 
boundary for PFS is crossed. Details are presented in Section 10 of the protocol.
Sample Size 
Determination: 
(Treatment-naive
Open-label Arm)
A sample size of 75 treatment-naive subjects is needed to exclude a 35% CR 
rate at a 1-sided significance level of 0.025 with approximately 80% power, 
assuming a target CR rate of 51%. 
For the subpopulation with a TP53 mutation, a sample size of 48 subjects is 
needed to exclude a 25% CR rate with approximately 80% power, assuming a 
target CR rate of 45%. The TP53 population could be a mix of treatment-naive 
MCL subjects and/or R/R MCL subjects with a TP53 mutation.
Statistical 
Methods/Data 
Analysis:
(SRI and 
Randomization 
Phase)
Endpoints for the Safety Run-in Period will be summarized descriptively and 
separately from the Randomization Phase data. 
The primary endpoint in the Randomization Phase, PFS, will be compared 
between treatment arms using the stratified log-rank test. The hazard ratio will 
be estimated using a stratified Cox proportional hazard model. Details are 
presented in Section 10 of the protocol.
Statistical 
Methods/Data 
Analysis:
(Treatment-naive 
Open-label Arm)
The CR rate is the primary endpoint for the open-label arm and will be 
estimated based on exact binomial distribution. The confidence interval will be 
provided. Details are presented in Section 10 of the protocol.


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ABBREVIATIONS
AE 
adverse event 
AESI
Adverse Events of Special Interest (AESI)
ALT 
alanine aminotransferase 
AML
acute myeloid leukemia
ANC
absolute neutrophil count 
ASCO
American Society of Clinical Oncology
AST 
aspartate aminotransferase 
AUC
area under the concentration-time curve
BCL-2
B-cell lymphoma 2
BCR 
B-cell receptor 
BCRP
Breast Cancer Resistance Protein
BTK 
Bruton’s tyrosine kinase 
BUN
blood urea nitrogen
CI
confidence interval
CLL
chronic lymphocytic leukemia 
Cmax
maximum observed plasma concentration
CR 
complete response rate
CrCl
creatinine clearance
CFR
Code of Federal Regulations
CRF
case report form (paper or electronic as appropriate for this study)
cGVHD
chronic graft vs. host disease
CMH
Cochran-Mantel-Haenszel
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
DOR
duration of response
ECOG
Eastern Cooperative Oncology Group
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
electronic data capture
EMR
electronic medical records
EOT
End of treatment
EQ5-D
European Quality of Life- 5 Dimensions
EU
European Union
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded tumor tissue
FL
follicular lymphoma
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor


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HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDPE
high density polyethylene
HIV
human immunodeficiency virus
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator's Brochure
IV
Intravenous
IC50 
concentration that inhibits a process by 50%
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MDS
myelodysplastic syndrome
MRD
minimal residual disease
MRI
Magnetic Resonance Imaging
MRU
Medical Resource Utilization
MTD
maximum tolerated dose
NCI-ODWG
National Cancer Institute Organ Dysfunction Working Group
NHL
Non-Hodgkin’s Lymphoma
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PET
Positron Emission Tomography
PFS
Progression free survival
P-gp
P-glycoprotein
PK
Pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PR 
partial response 
PRO
patient-reported outcome(s)
PS
performance status
aPTT
activated partial thromboplastin time
PT
prothrombin time 
QTc 
QT interval corrected for heart rate 
REB
Research Ethics Board
RP3D
Recommended Phase 3 Dose 


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SAE 
serious adverse event
SAP
Statistical Analysis Plan
SCARs
severe cutaneous adverse reactions 
SJS
Stevens-Johnson syndrome 
SLL
small lymphocytic lymphoma 
SmPC
Summary of product characteristics
SRI
Safety Run-in
t1/2
half-life
Tmax
time to maximum plasma concentration 
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
TN
treatment-naive
TTNT
time-to-next treatment
ULN
upper limit of normal
USPI
United States Prescribing Information
WC
withdrawal of consent


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1
BACKGROUND
1.1
Mantle Cell Lymphoma
1.1.1
Disease Background
Mantle cell lymphoma (MCL) is a distinct clinical-pathologic entity within the non-Hodgkin’s 
lymphomas (NHL). Initially termed “centrocytic lymphoma” in the Kiel Classification system 
(Lennert 1981), MCL has subsequently been shown to harbor the translocation t(11,14)(q13;q32), 
which results in constitutive overexpression of cyclin D1 (Zucca 1994). These features are now 
considered requisite for the diagnosis of the disease.
Mantle cell lymphoma accounts for about 6-9% of all NHL cases in the Western world. The annual 
incidence of MCL has increased during recent decades to 1-2/100,000. MCL occurs more 
frequently in older adults (Zhou 2008). Most patients with MCL are men (median age: 65 years) 
who present with advanced stage disease (ie, Stage III or IV) and most cases follow an aggressive 
clinical course (Dreyling 2014). The typical presentation is with generalized lymphadenopathy, 
and extranodal involvement frequently occurs in the gastrointestinal tract, spleen, bone marrow, 
and liver; less common extranodal sites are skin, lungs, and breast or soft tissues. Though the 
clinical course of MCL may be somewhat indolent at diagnosis, the course invariably becomes 
aggressive over time. Unlike other NHLs, MCL is considered incurable with standard therapies 
and is associated with a poor prognosis and a relatively short median overall survival (OS) 
(Lenz 2004). There is no curative therapy for MCL. A few patients may achieve long-term, 
disease-free survival after allogeneic stem cell transplantation (Goy 2011), but in general, the 
disease is characterized by a series of relapses with a median OS of 4 to 5 years. A number of 
MCL prognostic variables have been identified, including the presence or absence of extranodal 
disease, age, lactate dehydrogenase (LDH) levels, performance status, and Ki-67 proliferative 
index (Hoster 2008).
1.1.2
Current Treatment Options
Current initial therapy for the treatment of MCL includes cyclophosphamide, doxorubicin, 
vincristine, and prednisone (CHOP) or hyperfractionated cyclophosphamide, vincristine, 
doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (Hyper-CVAD), 
often in combination with rituximab (R-CHOP or R-Hyper CVAD). In recent years, treatment 
with bendamustine and rituximab has gained increasing use following studies showing that this 
combination significantly prolongs PFS, while maintaining a favorable safety profile among 
patients with previously untreated MCL (Robinson 2008, Rummel 2005). 
For patients who relapse after initial therapy, chemoimmunotherapy treatment options involve 
the use of rituximab in combination with one or more of the following: bendamustine, cladribine, 
fludarabine, cyclophosphamide, mitoxantrone, etoposide and procarbazine. (Dreyling 2013, 
NCCN 2016). In cases of early relapses or in patients with refractory disease, newer targeted 
approaches should be strongly considered. Three non-cytotoxic drugs, ibrutinib, bortezomib and 


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lenalidomide, are FDA approved for previously treated patients with MCL in the US. In the 
European Union, approved treatment in the relapsed and refractory MCL setting was limited to 
temsirolimus until the approval of ibrutinib in 2014. Based on registration trials, the ORR for 
these drugs are 68% (21% CR) with ibrutinib, 33% (8% CR) with bortezomib, 28% (8% CR) 
with lenalidomide, and 22% (2% CR) with temsirolimus, with a median PFS of 13.9, 6.5, 4 and 
4.8 months, respectively (Campo 2015). These drugs are being combined with rituximab and 
incorporated into standard therapeutic and maintenance regimens showing some improved 
efficacy (Ghielmini 2009). Despite the fact that results from ibrutinib showed marked 
improvement over temsirolimus (Dreyling 2016), the median PFS of approximately 14 months 
underscores the need to improve further on the dismal outcome for relapsed MCL patients. 
However, new strategies are needed that may substantially improve outcomes for R/R MCL 
patients and may in long-term obviate intensive chemotherapy and/or transplantation in younger 
MCL patients and chemotherapy in older patients with MCL (Campo 2015). Based on the 
preliminary data showing a CR rate of 70% with an acceptable safety profile observed in an 
ongoing study of ibrutinib and venetoclax in patients with relapsed or refractory MCL 
(Tam 2016) coupled with the durability of responses observed with ibrutinib monotherapy and 
venetoclax monotherapy in patients with relapsed or refractory MCL who achieved CR observed 
with each (Rule 2016, Gerecitano 2015), the combination of ibrutinib and venetoclax is expected 
to induce deep and durable responses in patients with relapsed/refractory MCL.
1.2
Ibrutinib Overview
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of Bruton’s tyrosine kinase (BTK) co-developed by Pharmacyclics LLC and Janssen 
Research & Development LLC for the treatment of B-cell malignancies.
Ibrutinib has been approved in many regions, including the United States (US) and European 
Union (EU), for indications including the treatment of patients with MCL who have received at 
least 1 prior therapy, patients with chronic lymphocytic leukemia (CLL)/small lymphocytic 
lymphoma (SLL) including CLL/SLL with a deletion of the short arm of chromosome 
17 (del17p), patients with Waldenström’s macroglobulinemia (WM), patients with marginal zone 
lymphoma (MZL) who require systemic therapy and have received at least one prior 
anti-CD20-based therapy, and cGVHD after failure of one or more lines of systemic therapy.
For the most up-to-date and comprehensive nonclinical and clinical information regarding 
ibrutinib background, safety, efficacy, in vitro and in vivo preclinical activity, and toxicology of 
ibrutinib, always refer to the latest version of the ibrutinib Investigator's Brochure (IB) and/or the 
applicable regional labeling information.


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1.2.1
Summary of Nonclinical Data
1.2.1.1
Pharmacology
Ibrutinib was designed as a selective and covalent inhibitor of BTK (Pan 2007). In vitro, 
ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM). The irreversible binding of 
ibrutinib to Cys-481 in the active site of BTK results in sustained inhibition of BTK catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this position. 
When added directly to human whole blood, ibrutinib inhibits signal transduction from the BCR 
and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM stimulation followed 
by CD69 expression (Herman 2011).
Ibrutinib arrested cell growth and induced apoptosis in human B-cell lymphoma cell lines in 
vitro and inhibited tumor growth in vivo in xenograft models (Herman 2011). Ibrutinib also 
inhibited adhesion and migration of MCL cells in co-culture and reduced tumor burden in lymph 
node and bone marrow in a murine model of MCL dissemination and progression (Chang 2013a, 
Chang 2013b)
For more detailed and comprehensive information regarding nonclinical pharmacology, please 
refer to the current ibrutinib IB.
1.2.1.2
Safety Pharmacology and Toxicology
No treatment-related effects were observed in the central nervous system or respiratory system in 
rats at any dose tested. Further, no treatment-related corrected QT interval (QTc) prolongation 
effect was observed at any tested dose in a cardiovascular study using telemetry-monitored dogs. 
Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the 
greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues 
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without 
inflammation). Additional toxicity findings seen in only one species with no observed human 
correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally 
decreased trabecular and cortical bone (rat) and corneal dystrophy (dog). In studies in pregnant 
rats and rabbits, ibrutinib administration was associated with malformations (teratogenicity) at 
ibrutinib doses that result in approximately 14 and 2 times the exposure (area under the 
concentration-time curve [AUC]) in patients administered the dose of 560 mg daily, respectively. 
Fetal loss and reduced fetal body weights were also seen in treated pregnant animals. 
Carcinogenicity studies have not been conducted with ibrutinib. In vitro and in vivo genetic 
toxicity studies showed that ibrutinib is not genotoxic. No effects on fertility or reproductive 
capacities were observed in a study in male and female rats.
For the most up-to-date and comprehensive information regarding nonclinical safety 
pharmacology and toxicology, please refer to the current ibrutinib IB.


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1.2.2
Summary of Clinical Data
1.2.2.1
Pharmacokinetics and Product Metabolism
Following oral administration of ibrutinib at doses ranging from 420 to 840 mg/day, exposure to 
ibrutinib increased proportionally with substantial inter-subject variability. The mean terminal 
plasma elimination half-life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median time to 
maximum plasma concentration (Tmax) of 2 hours. Despite the doubling in mean systemic 
exposure when dosed with food, the favorable safety profile of ibrutinib allows dosing with or 
without food. Ibrutinib is extensively metabolized primarily by cytochrome P450 (CYP) 3A4. 
The on-target effects of the main metabolite PCI-45227 are not considered clinically relevant. 
Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose exposure 
implying non-clinically relevant accumulation. Less than 1% of ibrutinib is excreted in the urine. 
Ibrutinib exposure is not altered in patients with creatinine clearance (CrCl) > 30 mL/min. 
Patients with severe renal impairment or patients on dialysis have not been studied. Following 
single-dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects 
with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) 
hepatic impairment compared to subjects with normal liver function. A higher proportion of 
Grade 3 or higher adverse reactions were reported in patients with B-cell malignancies 
(CLL, MCL and WM) with mild hepatic impairment based on NCI organ dysfunction working 
group (NCI-ODWG) criteria for hepatic dysfunction compared to patients with normal hepatic 
function.
For the most recent and the most comprehensive information regarding pharmacokinetics (PK) 
and product metabolism, please refer to the current ibrutinib IB.
1.2.3
Summary of Clinical Safety
A brief summary of safety data from monotherapy and combination therapy studies is provided 
below. For the most up to date and most comprehensive safety information regarding ibrutinib, 
please refer to the current ibrutinib IB. Additional safety information may be available for 
approved indications in regional prescribing labels where the study is conducted (eg, USPI, 
SmPC).
1.2.3.1
Monotherapy Studies 
Pooled safety data from a total of 1578 subjects treated with ibrutinib monotherapy in 20 studies 
in B-cell malignancies that have completed primary analysis or final analysis as of 
12 November 2018 are summarized below.


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The most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1578) included:
Most frequently reported 
TEAEs ³15%
Most frequently reported Grade 
3 or 4 TEAEs ³3%
Most frequently reported Serious 
TEAEs ³2%
Diarrhea
Neutropenia
Pneumonia
Fatigue
Pneumonia
Atrial fibrillation
Nausea
Thrombocytopenia
Pyrexia
Cough
Anemia
Febrile neutropenia
Anemia
Hypertension
Pyrexia
Diarrhea
Upper respiratory tract infection
Atrial fibrillation
Neutropenia
Oedema peripheral
Thrombocytopenia
1.2.3.2
Combination Studies
Pooled safety data from a total of 1449 subjects treated with various therapies in combination 
with ibrutinib from 13 studies conducted in subjects with B-cell malignancies are briefly 
summarized below. Therapies used in combination with ibrutinib in these studies included BR 
(bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and rituximab), 
ofatumumab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone).
The most frequently reported TEAEs in subjects receiving ibrutinib in combination therapy 
(N=1449) included:
Most frequently reported 
TEAEs ³20%
Most frequently reported Grade 
3 or 4 TEAEs ³3%
Most frequently reported Serious 
TEAEs ³2%
Diarrhea
Neutropenia
Febrile neutropenia
Neutropenia
Anemia
Pneumonia
Nausea
Febrile neutropenia
Atrial fibrillation
Fatigue
Thrombocytopenia
Pyrexia
Neutrophil count decreased
Anemia
Neutropenia
Anemia
Thrombocytopenia
Pneumonia
White cell count decreased
Leukopenia
Pyrexia
Platelet count decreased
Diarrhea
Hypertension
Atrial fibrillation
Hyponatraemia
Diarrhea


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1.2.4
Risks
1.2.4.1
Bleeding-related Events
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, 
and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
subdural intracranial hemorrhage, and hematuria. Subjects with congenital bleeding diathesis 
have not been studied. 
In an in vitro platelet function study, inhibitory effects of ibrutinib on collagen‑induced platelet 
aggregation were observed, refer to Section 6.2.4. 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 or symptoms of bleeding. See Section 6.2.4 for guidance on concomitant use of 
anticoagulants, antiplatelet therapy and/or supplements.
Supplements such as fish oil and vitamin E preparations should be avoided. Ibrutinib should be 
held at least 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of 
bleeding. See Section 6.3 for guidance on ibrutinib management with surgeries or procedures. 
Subjects with congenital bleeding diathesis have not been studied. 
1.2.4.2
Leukostasis
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high 
number of circulating white blood cells (> 400,000/µL) may confer increased risk. For subject 
and ibrutinib management guidance, refer to Section 5.3.1.5.
1.2.4.3
Infections 
Infections (including sepsis, bacterial, viral, or fungal infections) were observed in subjects 
treated with ibrutinib therapy. Some of these reported infections have been associated with 
hospitalization and death. Consider prophylaxis according to standard of care in patients who are 
at increased risk for opportunistic infections (see Section 6.1). Although causality has not been 
established, cases of progressive multifocal leukoencephalopathy (PML) have occurred in 
subjects treated with ibrutinib. Subjects should be monitored for symptoms (fever, chills, 
weakness, confusion), and appropriate therapy should be instituted as indicated.
1.2.4.4
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Monitor complete blood counts monthly.


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1.2.4.5
Interstitial Lung Disease (ILD)
Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. 
Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt 
ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines as needed (see 
Section 5.3.1.4).
1.2.4.6
Cardiac Arrhythmias and Cardiac Failure 
Atrial fibrillation, atrial flutter, and cases of ventricular tachyarrhythmia and cardiac failure 
including some fatal events, have been reported in subjects treated with ibrutinib, particularly in 
subjects with cardiac risk factors, hypertension, acute infections, and a previous history of 
cardiac arrhythmia. At baseline and then periodically, monitor subjects clinically for cardiac 
arrhythmia and cardiac failure. Subjects who develop arrhythmic symptoms (eg, palpitations, 
lightheadedness, syncope, chest discomfort or new onset of dyspnea) should be evaluated 
clinically and, if indicated, have an ECG performed. For cardiac arrhythmias or cardiac failure 
which persist, consider the risks and benefits of ibrutinib treatment and follow the protocol dose 
modification guidelines (see Section 5.3.1.4).
1.2.4.7
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis 
syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take 
appropriate precautions. 
1.2.4.8
Non-melanoma Skin Cancer
Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects 
for the appearance of non-melanoma skin cancer.
1.2.4.9
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 most subjects (66%) with CLL/small 
lymphocytic lymphoma (SLL). This effect has also been observed in some subjects (35%) with 
MCL treated with ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and 
should not be considered progressive disease in the absence of other clinical findings. In both 
disease types, lymphocytosis typically occurs during the first month of ibrutinib therapy and 
typically resolves within a median of 8 weeks in subjects with MCL and 14 weeks in subjects 
with CLL/SLL (range 0.1 to 104 weeks). When ibrutinib was administered in combination with 
BR or with obinutuzumab in subjects with CLL/SLL, lymphocytosis was infrequent (7% with 
ibrutinib + BR versus 6% with placebo + BR and 7% with ibrutinib + obinutuzumab versus 1% 


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with chlorambucil + obinutuzumab). Lymphocytosis was not observed with WM treated with
ibrutinib. 
For subject and ibrutinib management guidance, refer to Section 5.3.1.5.
1.2.4.10 Cerebrovascular Accidents
Although causality has not been established, cases of cerebrovascular accident, transient 
ischemic attack, and ischemic stroke including fatalities have been reported with the use of 
ibrutinib in the post-marketing setting, with and without concomitant atrial fibrillation and/or 
hypertension. Regular monitoring and appropriate treatment of conditions that can contribute to 
the occurrence of these events is recommended.
1.2.4.11 Diarrhea
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and 
combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, 
and constipation. These events are rarely severe and are generally managed with supportive 
therapies including antidiarrheals and antiemetics. Subjects should be monitored carefully for 
gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration. Medical 
evaluation should be made to rule out other etiologies such as Clostridium difficile or other 
infectious agents. Should symptoms be severe or prolonged follow the protocol dose 
modification guidelines (see Section 5.3.1.4).
1.2.4.12 Rash
Rash has been commonly reported in subjects treated with either single agent ibrutinib or in 
combination with chemotherapy. Rash occurred at a higher rate in the ibrutinib arm than in the 
ofatumumab arm in Study 1112. Most rashes were mild to moderate in severity. Isolated cases of 
severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have 
been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs 
and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be 
observed closely for rashes and treated symptomatically, including interruption of the suspected 
agent as appropriate. In addition, hypersensitivity-related events including erythema, urticaria, 
and angioedema have been reported.
1.2.4.13 Hypertension
Hypertension has been commonly reported in subjects treated with ibrutinib. Monitor subjects 
for new onset of hypertension or hypertension that is not adequately controlled after starting 
ibrutinib. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive 
treatment as appropriate.


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1.3
Venetoclax Overview
Venetoclax (VENCLEXTA®) is a potent, orally administered inhibitor of B-cell lymphoma 2 
(BCL-2) co-developed by AbbVie Inc and Genentech Inc for the treatment of B-cell 
malignancies.
Venetoclax has been granted accelerated approval in the US based on overall response rate in the 
US for the treatment of patients with CLL with 17p deletion, as detected by an FDA approved 
test, who have received at least one prior therapy. In the EU, venetoclax in combination with 
rituximab is indicated for the treatment of adult patients with CLL who have received at least 
1 prior therapy. Monotherapy is indicated for the treatment of CLL in the presence of 17p del or 
TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway 
inhibitor, or in the absence of 17p del or TP53 mutation in adult patients who have failed both 
chemoimmunotherapy and a B-cell receptor pathway inhibitor. Similarly, the Australian 
Therapeutic Goods Administration approved venetoclax for the treatment of patients with 
relapsed/refractory CLL with 17p deletion, and for patients without 17p deletion who have no 
other suitable treatment options.
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway. The Bcl-2 
oncogene was first identified in follicular lymphoma (FL) where the t(14;18) chromosomal 
translocation results in significant over-expression of the protein in B-cells. The Bcl-2 family of 
genes encodes a family of closely related proteins that possess either pro-apoptotic or 
anti-apoptotic activity and share up to four Bcl-2 Homology (BH) domains (Willis 2003, 
Cory 2002, Borner 2003, Cory 2003). Bcl-2 overexpression is a major contributor to the 
pathogenesis of some types of lymphoid malignancies.
Venetoclax (also known as ABT-199) is a novel, orally available, small molecule Bcl-2 family 
protein inhibitor that binds with high affinity (Ki < 0.010 nM) to Bcl-2 and with lower affinity to 
other Bcl-2 family proteins Bcl- xL and Bcl-w (> 4,000-fold and > 2,000- to > 20,000-fold lower 
affinity than to Bcl-2, respectively) (Souers 2013). Selective inhibition by venetoclax disrupts 
Bcl-2 signaling and rapidly induces multiple hallmarks of apoptotic cell death in 
Bcl-2-dependent human tumor cell lines (venetoclax Investigator’s Brochure [IB]). Importantly, 
venetoclax inhibition of Bcl-2 is independent of p53 activity.
1.3.1
Summary of Nonclinical Data
In vitro, venetoclax demonstrated broad cell killing activity against a panel of lymphoma and 
leukemia cells including B-cell follicular lymphomas (FLs), mantle cell lymphomas (MCLs), 
diffuse large B-cell lymphomas (DLBCLs), and acute myeloid leukemias (AMLs). Venetoclax 
was especially potent against cell lines expressing high levels of Bcl-2. Leukemia and lymphoma 
cell lines bearing the t(14;18) translocation were significantly more sensitive to venetoclax than 
nonmutated lines. A detailed discussion of the non-clinical toxicology, metabolism, and 
pharmacology can be found in the venetoclax IB.


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1.3.2
Summary of Venetoclax Clinical Data
1.3.2.1
Clinical Pharmacokinetics
Following multiple oral administrations under fed conditions, maximum plasma concentration of 
venetoclax was reached 5-8 hours after dose. Venetoclax steady state AUC increased 
proportionally over the dose range of 150-800 mg. Food can increase venetoclax exposure 
(3.4-fold with a low-fat meal and 5.1- to 5.3-fold with a high-fat meal). Venetoclax should be 
administered with a meal. The population estimate for the terminal elimination half-life of 
venetoclax was approximately 26 hours. In vitro studies demonstrated that venetoclax is 
predominantly metabolized by CYP3A4/5. Less than 0.1% of venetoclax is excreted renally. 
Venetoclax exposures in subjects with mild or moderate renal impairment are similar to those 
with normal renal function. The PK of venetoclax has not been studied in subjects with severe 
renal impairment (CrCl < 30 mL/min) or subjects on dialysis. Venetoclax exposures are similar 
in subjects with mild and moderate hepatic impairment and normal hepatic function based on the 
NCI Organ Dysfunction Working Group criteria. Mild hepatic impairment was defined as 
normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total 
bilirubin > 1.0 to 1.5 times ULN, moderate hepatic impairment as total bilirubin > 1.5 to
3.0 times ULN, and severe hepatic impairment as total bilirubin > 3.0 times ULN. The PK of 
venetoclax has not been studied in subjects with severe hepatic impairment.
For the most comprehensive information regarding PK and product metabolism, please refer to 
the current venetoclax IB.
1.3.2.2
Summary of Clinical Safety
Doses administered in venetoclax clinical studies have ranged from 20 mg to 1200 mg.
As of 28 November 2018, on the basis of open-label and unblinded data available in the clinical 
databases for company-sponsored studies in the venetoclax oncology development program, a 
total of 2543 adult subjects (1313 CLL/SLL, 361 AML, 218 MM, 570 NHL, and 59 MDS, 
20 ALL, 1 rhabdomyosarcoma, and 1 Evans tumor in the pooled analysis dataset across all 
monotherapy and combination therapy oncology studies in the venetoclax development program 
have been exposed to at least 1 dose of venetoclax. An additional 20 pediatric subjects 
(< 18 years of age; 5 ALL, 10 AML, 3 neuroblastoma, other solid tumors) have been exposed to 
at least 1 dose of venetoclax. 
As of 28 November 2018, a total of 576 NHL subjects treated with venetoclax in the oncology 
clinical program had open-label or unblinded safety data available, including 136 subjects who 
received venetoclax monotherapy, and 440 subjects who received venetoclax in combination 
with other agents including rituximab, BR, R-CHOP, or G-CHOP. Fifty additional subjects 
received BR in Study BO29337. Of the 576 NHL subjects treated with venetoclax, 570 subjects 
are included in the pooled analyses across all studies, and data from the remaining 6 subjects 


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who crossed over to venetoclax treatment in Study BO29337 are excluded from the pooled 
analyses.
Overall for NHL, when treated with venetoclax as a single agent or in combination with other 
therapies, the most common adverse events were nausea, neutropenia, and diarrhea. 
Approximately three-fourths of subjects experienced ≥ Grade 3 adverse events, and the most 
common events were neutropenia, thrombocytopenia, and anaemia. The most common SAEs 
were febrile neutropenia, neutropenia, and pneumonia. Of the fatal events in the NHL program, 
the majority were adverse events of malignant neoplasm progression. Findings from the analysis 
based on the exposure-adjusted incidence rates were consistent with the findings from the 
analysis based on the subject incidence rates. Many of the adverse events reported in the current 
NHL studies are consistent with underlying disease or concomitant medical conditions, as well 
as other combination agents used to treat NHL patients. Safety in combination agents appears to 
be consistent with that observed in monotherapy trials and combination backbone regimen.
The incidence of TLS in NHL studies is low with reports of 2 cases (1.9%) of laboratory TLS in 
monotherapy Study M12-175, 4 cases of laboratory TLS (2.5%) in combination Study BO29337 
(1 subject venetoclax + R, 3 subjects venetoclax + BR), and 4 cases of laboratory TLS (1.5%) in 
combination Study GO27878 (venetoclax + R-CHOP or G-CHOP). All cases of TLS resolved, 
and none led to discontinuation of study drug. No cases of clinical TLS were reported. 
Neutropenia has a similar frequency in the NHL clinical program as in CLL with higher 
frequency in NHL combination studies. Serious adverse events of neutropenia and febrile 
neutropenia, albeit in small numbers, occurred in higher frequency in combination studies. 
Infections, including serious, were observed in the NHL clinical program, with similar incidence 
in monotherapy and combination studies.
For the most comprehensive venetoclax safety and efficacy data, please refer to the most current 
venetoclax IB.
1.3.3
Risks
1.3.3.1
Tumor Lysis Syndrome 
Tumor lysis syndrome (TLS) is an important identified risk for venetoclax in oncology studies, 
especially in CLL and MCL. As a result of on-target effects, the potential for TLS was identified 
early in the program.
TLS in CLL and MCL
The risk is during the first 5 weeks of ramp-up period. A low starting dose followed by gradual 
dose ramp-up allows for the tumor size to be gradually reduced and has been effective in 
reducing the risk of TLS. Venetoclax should be initiated with the 20 mg dose and gradually 
ramp-up/titrate up to 400 mg target dose over 5 weeks. In general, before initiating venetoclax, a 
subject's risk for developing TLS should be assessed based on extent of disease, renal function, 
and known propensity and risk factors for TLS in that tumor type. Prophylaxis with hydration 


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and uric-acid reducing agents is recommended as appropriate. Clinical chemistries should be 
corrected. Choice of initial dose and ramp up to reach the final dose is based on the risk 
assessment in the indications. Monitor clinical chemistries and manage electrolyte abnormalities 
promptly, as clinically indicated.
1.3.3.2
Neutropenia
Neutropenia is an important identified risk for venetoclax. Clinical data from the oncology 
studies suggest that the neutropenia adverse events are observed among subjects who receive 
venetoclax as a single agent or in combination with other therapeutic agents, with slightly higher 
frequency observed in some combination studies. Serious adverse events of neutropenia or 
neutropenia events that lead to discontinuations are few across the entire venetoclax oncology 
program. For the oncology studies, neutropenia management guidelines are provided in the 
protocol. Granulocyte colony stimulating factors can be used for supportive measures, however 
the guidance for their use in non- CLL indications, especially in AML, is per routine local 
oncology practice, as well as protocol-specific.
1.3.3.3
Serious Infections
Serious infection is an important identified risk for venetoclax. Infections have been reported in 
the oncology clinical studies; however, these events are confounded by the underlying disease, 
comorbidities, and other immunosuppressive medications. To date, no clear relationship has been 
noted between serious infectious events and neutropenia. The types of infectious events observed 
generally have been consistent with those anticipated in the elderly population of heavily 
pretreated subjects with hematologic malignancies and are similar across all indications. 
Infections are closely monitored in venetoclax program across all indications. Patients should be 
advised to report fever and should be assessed for further management as per standard medical 
practice. In the oncology studies, recommendations are included in the protocol regarding the 
need for anti-infective prophylaxis per standard of care (eg, National Comprehensive Cancer 
Network guidelines [NCCN] for oncology subjects).
1.4
Study Rationale 
1.4.1
Rationale for the Ibrutinib and Venetoclax Combination
Several in vitro studies have shown ibrutinib and venetoclax to be an active combination. In one 
study, MCL cell lines and leukemic patient cells were exposed to ibrutinib, venetoclax and the 
combination for 72 hours. The combination substantially increased induction of apoptosis 
compared to each agent alone (combo: 23%, ibrutinib: 3.8%, venetoclax: 3.0%) (Portell 2014). 
A separate study using MCL cell lines confirmed the synergistic effect of ibrutinib and 
venetoclax on proliferation inhibition and apoptosis through perturbation of the BTK, AKT and 
BCL2 pathways (Zhao 2015) providing further mechanistic rationale for co-targeting of these 
two oncogenic pathways. 


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Supportive in vivo data is derived from a CCMCL1/NSG mouse model where the ibrutinib and 
venetoclax combination was tested. The combination produced apoptosis of MCL tumor cells, 
which was associated with a down-regulation of SOX11 and PAX5. Simultaneous down-
regulation of MCL1 via ibrutinib and targeting of BCL2 was hypothesized to contribute to the in 
vitro synergism and in vivo activity observed in this report (Zhao 2013).
With respect to venetoclax monotherapy activity, in clinical trial M12-175, venetoclax was tested 
in 28 subjects with relapsed/refractory MCL at target doses of 200 to 1200 mg. The ORR was 
found to be 75% with a CR rate of 21% (Gerecitano 2015). Based on these data and prior 
ibrutinib studies, the ongoing AIM Trial (ABT-199 and ibrutinib in MCL) is evaluating the 
combination of ibrutinib at 560 mg and venetoclax at a target dose of 400 mg in subjects with 
relapsed and refractory MCL. This study is using a 4-week venetoclax ramp-up after 4 weeks of 
ibrutinib monotherapy. Twenty-one subjects have completed response assessments at the 
primary endpoint landmark of 16 weeks; 10 subjects achieved confirmed CR (including MRD 
clearance), 4 subjects achieved unconfirmed CR, and 4 subjects achieved PR (Tam 2017). These 
results display a high initial response rate for the ibrutinib and venetoclax combination.
Two other studies evaluating the combination of ibrutinib and venetoclax (one of which will also 
explore the addition of anti-CD20 therapy to the doublet) in subjects with relapsed/refractory 
MCL have started enrollment, though no toxicity or safety data have yet been reported 
(Portell 2016, Le Gouill 2016). 
1.4.2
Dose Rationale
As of 28 November 2015, safety data are available from 346 NHL subjects treated with 
venetoclax (128 from monotherapy studies and 218 from combination studies). The venetoclax 
Phase 1 dose escalation study M12-175 included 106 subjects with relapsed/refractory NHL 
treated in 8 dose cohorts with escalated doses from 100 mg to 1200 mg. The primary objectives 
of this study were to assess the safety profile, characterize the PK, and determine the maximum 
tolerated dose (MTD) of venetoclax monotherapy. Two dose-limiting toxicities (DLTs) (Grade 3 
febrile neutropenia and Grade 4 neutropenia) were observed, both at the 600 mg dose level, and 
the MTD was not reached. The most frequent all-grade AEs were: nausea (46.1%), diarrhea 
(42.2%), fatigue (35.2%), and vomiting (20.3%), and the most frequent Grade ≥3 AEs were 
anemia (14.1%) and neutropenia (12.5%).
In the PCYC-1143-CA study, ibrutinib will be administered at 560 mg/day (approved dose for 
MCL) in combination with venetoclax at a target dose of 400 mg. This dose combination has 
previously been administered in an ongoing dose-escalation study in subjects with relapsed or 
refractory MCL (Portell 2016) with low/intermediate risk for TLS. In the AIM study using a 
4-week venetoclax ramp-up (50, 100, 200 and 400 mg) after 4 weeks of ibrutinib monotherapy at 
560 mg, 16 subjects with relapsed or refractory MCL (Tam 2017) were dosed and have 
completed the ramp-up with TLS events reported in two subjects with high tumor burden, 
leading to revision of the protocol venetoclax starting dose from 50 mg to 20 mg per day. 


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Subsequently, 8 additional subjects have been treated using the revised schedule with no cases of 
TLS encountered. Common AEs (≥25%) were diarrhea, fatigue, nausea and/or vomiting, upper 
respiratory tract infection, gastroesophageal reflux, neutropenia, cough, and dyspnea. The most 
frequent Grade 3-4 AE was neutropenia, and no Grade 5 AEs have been reported. The ORR was 
71%, and the CR rate was 63%. All CR subjects were confirmed by PET, endoscopy (if baseline 
gut involvement was present) and bone marrow aspirate, including MRD clearance (assessed by 
flow cytometry with minimum sensitivity of 10-4). 
These preliminary data suggest that the combination had an acceptable safety profile without 
unexpected toxicities and resulted in high rates of deep remission.
1.4.3
Rationale for the Safety Run-in Period
Among the 106 subjects with relapsed/refractory NHL enrolled in the M12-175 study, 2 cases 
(1.9%) of laboratory TLS were observed during the Ramp-up Period at the 200 mg and 300 mg 
dose levels in subjects with bulky disease (tumor > 10 cm) with MCL (n=28) and DLBCL 
(n=41), respectively. To mitigate the risk of TLS observed in Cohort 1 in study M12-175, a 
Ramp-up Schedule of 3-4 weeks was used for subsequent cohorts.
The concurrent administration of ibrutinib and venetoclax in subjects at increased risk of TLS 
has not been investigated. In an ongoing dose-escalation study in subjects with relapsed/ 
refractory MCL (Portell 2016), the concurrent administration of 420 mg of ibrutinib and 400 mg 
of venetoclax to subjects with low/intermediate risk for TLS observed no cases of TLS, despite 
the fact that the ramp-up started at 100 mg of venetoclax and was only of 3 weeks duration 
(100, 200 and 400 mg). In the AIM MCL study, 560 mg of ibrutinib was administered 4 weeks 
prior to the administration of venetoclax. This was based on the rationale that the ibrutinib 
lead-in will reduce the risk of TLS. However, some subjects with high tumor burden did not 
respond to the ibrutinib lead-in and initiated venetoclax with increased, rather than reduced, 
tumor burden (Tam 2016). Therefore, given that the frequency of TLS in the setting of MCL has 
been reported to be low and to prevent early progression with single-agent ibrutinib, the 
concomitant administration of ibrutinib and venetoclax is warranted to initially evaluate the 
safety profile for the combination. 
During the Safety Run-in Period, 12 subjects at increased risk for TLS (ie, subjects with high 
tumor burden and/or baseline creatinine clearance [CrCl] < 60 mL/min) and 6-9 subjects at low 
risk for TLS (not meeting these criteria) will receive ibrutinib at 560 mg plus venetoclax starting 
at 20 mg and ramped-up to a target dose of 400 mg over a 5-week period.
Depending on the number of TLS events and DLTs in each of the TLS risk categories, the 
Randomization Phase will start with either the concurrent administration of ibrutinib and 
venetoclax using the 5-week standard Ramp-up Schedule (see Section 3) or with a 4-week 
ibrutinib lead-in followed by the initiation of venetoclax using the 5-week standard Ramp-up 
Schedule.


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During the Safety Run-in Period, subjects at increased risk for TLS will be hospitalized for a 
minimum of 24 hours (and up to 48 hours at the discretion of the investigator) at the start of the 
20 mg ramp-up dose and again at the start of the 50 mg ramp-up dose of venetoclax for 
monitoring and prophylaxis of TLS. During the Randomization Phase, an independent Data 
Monitoring Committee (DMC) will review unblinded safety data to determine whether continued 
hospitalization of these subjects during ramp-up remains warranted.
1.4.4
Rationale for the Design of the Treatment Arms 
The comparison between the ibrutinib and venetoclax combination with ibrutinib and placebo 
will evaluate the ability of the combined treatment to increase the complete response rate and 
progression-free survival (PFS) compared to ibrutinib monotherapy. Ibrutinib has shown a higher 
ORR and CR rate as monotherapy among treatments approved for relapsed or refractory MCL, 
(Campo 2015) and therefore serves as an appropriate control arm for this study. 
1.4.5
Rationale for the PFS Assumption of 23 Months in the Ibrutinib and Venetoclax 
Relapsed/Refractory Treatment Arm
The primary endpoint in this study is PFS, with a null hypothesis of hazard ratio (HR) ≥1 for the 
ibrutinib and venetoclax group relative to ibrutinib and placebo group and an alternative 
hypothesis of HR of 0.61 corresponding to an improvement in median PFS from 14 months to 
23 months. The PFS of 14 months for the ibrutinib + placebo group is based on results from 
previous studies with ibrutinib monotherapy in subjects with relapsed/refractory MCL 
(PCYC-1104-CA, MCL2001 and MCL3001), and the assumption of a PFS of 23 months for the 
ibrutinib and venetoclax group is based on the 24-month PFS rate estimated from subjects who 
achieved a CR in these studies. 
In the pooled analysis of ibrutinib studies PCYC-1104-CA, MCL2001 and MCL3001, the ORR 
and CR rate were 65.7% and 20.0%, respectively. Importantly, the estimated 24-month PFS was 
70% in the subjects who achieved a CR, compared to 19% in subjects who failed to achieve a 
CR (Rule 2016). In the venetoclax phase I trial, the CR rate in subjects with MCL was 21% 
(Gerecitano 2015), and no subjects with CR had experienced relapse. Therefore, based on these 
studies, subjects with a CR are likely to have better PFS. In addition, based on the preliminary 
efficacy results of the AIM study (Tam 2016, Tam 2017) for ibrutinib and venetoclax treatment, 
if the CR rate in the 1143 trial exceeds 55%, then under the exponential distribution assumption 
for PFS, the median PFS with the combination is predicted to be ≥23 months.
1.4.6
Rationale for MRD Testing
The prognostic impact of MRD was analyzed in 259 patients with MCL treated within 
2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). 
After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved MRD 
negativity (by allele specific RT-PCR with sensitivity of at least 10-4) based on blood and/or 


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bone marrow (BM) analysis. MRD negativity resulted in a significantly improved duration of 
response (DOR 87% vs 61% patients in remission at 2 years, P = 0.004) (Pott 2010).
Whether MRD-negative remissions with non-chemo regimens will also translate into improved 
clinical outcomes in MCL is not yet known. The prognostic significance of MRD negativity by 
flow cytometry and clonoSEQ will be assessed. The correlation between assays and the 
correlation between peripheral blood and bone marrow MRD findings will also be determined.
1.4.7
Rationale for Treatment-naive Open-label Arm, Inclusion of Patients with a TP53 
Mutation and Exclusion of Blastoid Variant
In the AIM study that included 24 patients with relapsed/refractory MCL (23 patients) or 
treatment-naive MCL with a TP53 mutation (1 patient), patients were treated open-label with 
ibrutinib 560 mg and venetoclax 400 mg (Tam 2018). Patients had a median age of 68 years and 
had received 0 - 6 prior lines of therapy. Fifty percent of patients (n=12) had aberrations of 
TP53. The complete response rate according to PET was 62% at Week 16 (primary endpoint) 
and 71% overall. For patients with a TP53 mutation, the CR rate was 50% with and without PET, 
and the ORR was 58% without PET and 50% with PET. MRD clearance was confirmed by flow 
cytometry in 67% of patients. In a time-to-event analysis, 78% of the patients with a response 
were estimated to have an ongoing response at 15 months (Tam 2018). Tumor lysis syndrome 
occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 
83% of patients), fatigue (in 75%), and nausea or vomiting (in 71%). In this study and compared 
to historical controls, treatment with ibrutinib and venetoclax was consistent with improved 
outcomes in patients with MCL who had been predicted to have poor outcomes with current 
therapy (Tam 2018). Based on these encouraging results including 1 treatment-naive MCL 
patient with a TP53 mutation who responded, it is of interest to explore the combination of 
ibrutinib and venetoclax in treatment-naive MCL in patients that are ≥65 years of age and 
transplant-ineligible and in patients with a TP53 mutation. In treatment-naive MCL, the standard 
of care for patients that are ≥65 years of age and transplant-ineligible is BR or a variety of other 
options based on fitness level. The reported overall response rates with different therapeutic 
approaches for treatment-naive MCL patients with varying fitness levels (BR, R-CHOP, 
VR-CHOP, VR-CAP, FCR, R-CHOP/R-DHAP, R-Hyper CVAD) vary from 75 – 94% (Flinn 
2014, Lenz 2005, Robak 2015, Kluin-Nelemans 2012, Hermine 2016, Rummel 2014, Chen 
2017, Merli 2012, Rummel 2013, Rummel 2017); the corresponding CR rates vary from 35 –
72%, and for BR, one of the most commonly used therapies used in the transplant-ineligible and 
less fit treatment-naive MCL population, are approximately around 50% (Flinn 2014, Rummel 
2005, Rummel 2014, Chen 2017, Rummel 2017). Based on the encouraging results in patients 
with a TP53 mutation, it is of interest to explore the combination of ibrutinib and venetoclax in 
treatment-naive MCL in patients with a TP53 mutation, which is a population that is chemo-
insensitive and therefore has limited treatment options (Eskelund 2017, Delfau-Larue 2015, 
Halldorsdottir 2011, Ferrero 2017, Obr 2018). For patients with a TP53 mutation, the available 
literature focuses on PFS and OS outcomes (Eskelund 2017, Delfau-Larue 2015, 
Halldorsdottir 2011, Ferrero 2017, Obr 2018), and CR rates are underreported; it is hypothesized 


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that CR rates for MCL with a TP53 mutation are below the CR rates around 50% reported for 
BR in treatment-naive MCL. In the AIM study (Tam 2018), the CR rate for subjects with TP53 
aberrations (mutations and deletions, n=12) is 50%; in the PHILEMON study, where R/R MCL 
patients received a combination of ibrutinib, rituximab and lenalidomide, similar proportions of 
patients with and without a TP53 mutation had an overall response and CR; when correcting for 
other prognostic factors, no PFS difference was seen between patients with and without a TP53 
mutation (Jerkeman 2018). These encouraging data support the use of ibrutinib and venetoclax in 
patients with a TP53 mutation.
The randomized portion for R/R MCL has a PFS endpoint. For treatment-naive MCL, the 
endpoint of CR rate was chosen, also considering the small sample size (n=75). Durable CRs 
may represent clinical benefit and can be assessed earlier (compared to PFS).
In summary, exploring the combination of ibrutinib and venetoclax in treatment-naive MCL 
patients with or without a TP53 mutation is of interest with the goal to explore CR rates and 
other efficacy and safety parameters that can be achieved with this combination in comparison 
with historical CR rates and efficacy and safety data. 
The R/R MCL population in this study is inclusive of MCL patients with blastoid variant; 
blastoid variant and MCL with a TP53 mutation are considered high-risk MCL populations. 
Since favorable outcomes in younger/fit/transplant-eligible patients with blastoid variant were 
observed with high-dose chemotherapy, high-dose consolidation and stem cell transplant 
(Dreyling 2018), contrasting young/fit/transplant-eligible patients with TP53 mutations who do 
not benefit from intensive chemotherapy and often relapse early (Eskelund 2017, 
Delfau-Larue 2015), MCL patients with blastoid variant are excluded from the open-label 
treatment-naive arm, and the focus is on the population with a TP53 mutation as the high-risk 
group for treatment-naive subjects. 
1.4.8
Sample Size Considerations for Treatment-naive Open-label Arm Including 
Patients with a TP53 Mutation
A sample size of 75 treatment-naive subjects is needed to exclude a 35% CR rate at a 1-sided 
significance level of 0.025 with approximately 80% power, assuming a target CR rate of 51%.
For the subpopulation with a TP53 mutation, a sample size of 48 subjects is needed to exclude a 
25% CR rate with approximately 80% power, assuming a target CR rate of 45%. The TP53 
population could be a mix of treatment-naive MCL subjects and/or R/R MCL subjects with a 
TP53 mutation.
Based on a historical CR rate of approximately 50% with BR (Flinn 2014, Rummel 2005, 
Rummel 2014, Chen 2017, Rummel 2017) in transplant-ineligible treatment-naive MCL 
subjects, the success criteria were set at excluding a CR rate of 40% for the transplant-ineligible 
treatment-naive MCL patients ≥65 years. Since the CR rates for MCL patients with TP53 
mutations are estimated to be lower (Eskelund 2017), the success criteria were set at excluding a 


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25% CR rate for the MCL patients with a TP53 mutation. In combination, for the entire cohort of 
75 treatment-naive MCL patients, which contain at least one third of patients (n=25) with a TP53 
mutation, the success criteria were set at excluding a 35% CR rate.
2
STUDY OBJECTIVES
2.1
Safety Run-in Period
2.1.1
Primary Objective
To evaluate the occurrence of TLS and DLTs with the concurrent administration of ibrutinib and 
venetoclax.
2.1.2
Secondary Objectives
To evaluate response (partial and complete response), PFS, DOR, and OS.
2.2
Randomization Phase
2.2.1
Primary Objective
To evaluate whether the combination of ibrutinib and venetoclax will result in prolongation of 
PFS compared to ibrutinib and placebo in subjects with relapsed or refractory MCL.
2.2.2
Secondary Objectives

To evaluate whether the combination of ibrutinib and venetoclax will increase the 
CR rate, the overall response rate (ORR), the minimal residual disease (MRD) 
negative remission rate in subjects who were MRD positive at screening and
achieve CR, OS, DOR, and time-to-next treatment (TTNT) compared to ibrutinib 
and placebo.

To evaluate the frequency, severity, and relatedness of AEs; frequency, severity and 
management of TLS; AEs requiring dose reductions and/or discontinuation of study 
drug, or leading to death.

To determine the PK of ibrutinib and venetoclax.

To evaluate whether the combination of ibrutinib and venetoclax will improve 
quality of life using a Health-related quality of life questionnaire (FACT-Lym) 
compared to ibrutinib and placebo.


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2.2.3
Exploratory Objectives 

To determine the prognostic significance of MRD negative remission by comparing 
the correlation to the efficacy outcomes in the two treatment arms.

To evaluate whether the combination of ibrutinib and venetoclax will decrease 
MRD positive relapse in subjects who achieve MRD negative remission compared 
to ibrutinib and placebo.

To evaluate the correlation of MRD negative remission in blood vs. bone marrow.

To evaluate the correlation of MRD negative remission determined by flow 
cytometry and clonoSEQ.

To evaluate PFS2: time from randomization to death or next disease progression 
(defined as the earliest of disease progression after the first subsequent anti-cancer 
therapy or start of the second subsequent therapy).

To identify alterations in genes or proteins associated with sensitivity or resistance 
to the ibrutinib and venetoclax combination.

To evaluate patient-reported outcomes as measured by European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire EuroQoL Five-
Dimension (EQ-5D-5L)

To evaluate medical resource utilization (MRU) (eg, requirements of 
hospitalizations, emergency department visits, transfusions, and use of 
hematopoietic growth factors)
2.3
Treatment-naive Open-label Arm
2.3.1
Primary Objective
To evaluate the complete response (CR) rate with the combination of ibrutinib and venetoclax in 
subjects with treatment-naive MCL
2.3.2
Secondary Objectives

To evaluate the overall response rate (ORR), the duration of response (DOR) and 
duration of CR 

To evaluate the minimal residual disease (MRD)-negative remission rate in subjects 
who were MRD positive at screening and achieve CR

To evaluate progression-free survival (PFS), overall survival (OS), and time-to-next 
treatment (TTNT) with the combination of ibrutinib and venetoclax

To evaluate the frequency, severity, and relatedness of adverse events (AEs); 
frequency, severity and management of TLS; AEs requiring dose reductions and/or 
discontinuation of study drug, or leading to death

To determine the pharmacokinetics (PK) of ibrutinib and venetoclax


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2.3.3
Exploratory Objectives

To evaluate biomarkers in relationship to efficacy outcomes

To evaluate whether the combination of ibrutinib and venetoclax will improve 
quality of life using a health-related quality of life questionnaire (EQ-5D-5L)
3
STUDY DESIGN 
3.1
Overview of Study Design
This Phase 3 multinational, randomized, double-blind study is designed to compare the efficacy 
and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects 
with MCL.
Approximately up to 287 subjects with R/R MCL will be enrolled.
A separate open-label arm is designed to explore the efficacy and safety of the combination of 
ibrutinib and venetoclax in subjects with treatment-naive MCL.
In the treatment-naive open-label arm, approximately 75 subjects will be enrolled and treated 
with ibrutinib 560 mg and venetoclax 400 mg. Among them, approximately 50 subjects 
≥65 years and approximately 25 subjects with a TP53 mutation will be enrolled. Treatment-
naive MCL patients will use the same dose and schedule as established in the Safety Run-in for 
the Randomization Phase of the study. Therefore, there will be no Safety Run-in for the 
treatment-naive cohort.
3.1.1
Safety Run-in Period
The study will start with an open-label Safety Run-in Period to evaluate the occurrence of TLS 
and DLTs with the concurrent administration of ibrutinib and venetoclax. TLS and DLT 
occurrence will be assessed during the venetoclax Ramp-up Period for a minimum of 5 weeks.
Up to 27 subjects may be enrolled during the Safety Run-in Period (Figure 6).


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Figure 6.
Study Schematic – Safety Run-in Period
PD = progressive disease; WC = withdrawal of consent
Tumor Lysis Syndrome (TLS) Categories
Two TLS risk categories will be evaluated separately and in parallel:

Increased risk for TLS – Subjects with high tumor burden (at least one lesion 
> 10 cm; or at least one lesion > 5 cm and circulating lymphocytes 
> 25,000 cells/mm3) and/or with baseline creatinine clearance (CrCl) < 60 mL/min. 
During the Safety Run-in Period, subjects at increased risk for TLS will be 
hospitalized for a minimum of 24 hours (and up to 48 hours at the discretion of the 
investigator) at the start of the 20 mg ramp-up dose and again at the start of the 
50 mg ramp-up dose of venetoclax for monitoring and prophylaxis of TLS.

Low risk for TLS – Subjects not meeting the criteria described above.
TLS events are defined as follows: 

Clinical TLS – any event that meets Howard criteria (Appendix G) with the 
following exceptions: 
o
For the purpose of TLS assessment during the Safety Run-in Period, only those 
increases in serum creatinine > 1.0 mg/dL from pre-treatment baseline will be 
considered clinical TLS.
o
In subjects with renal dysfunction at baseline (CrCl < 60 mL/min), clinical TLS 
is defined as the presence of laboratory TLS plus either seizures, cardiac 
dysrhythmia, or death. 

Laboratory TLS – any event that meets Howard criteria (Appendix G) for laboratory 
TLS, that does not resolve within 72 hours despite protocol required management.
Dose-Limiting Toxicity (DLT)
A DLT is defined as any Grade 3 or higher non-TLS AE at least possibly related to study drug 
(ibrutinib and/or venetoclax) and occurring during the DLT assessment period with the following 
clarifications:
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 




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Subjects at Low Risk for TLS
Evaluation of TLS
Three additional subjects will be dosed if 1 out of 6 subjects at low risk for TLS experiences a 
laboratory TLS event and no subjects experience a clinical TLS event. If 0 out of 6 or ≤1 out of 
9 subjects experience a laboratory TLS event and no subjects experience a clinical TLS event, 
the Randomization Phase will start using the standard Ramp-up Schedule for subjects at low risk 
for TLS.
If ≥2 out of 6-9 subjects at low risk for TLS experience a laboratory TLS event, or any subject 
experiences a clinical TLS event, the Randomization Phase will start with a 4-week ibrutinib 
lead-in followed by the standard Ramp-up Schedule (Figure 7) for subjects in both TLS risk 
categories.
Evaluation of DLTs
With respect to DLTs, if < 2 out of 6 or < 3 out of 9 subjects experience DLT(s) during the DLT 
assessment period, the Randomization Phase will commence using the standard Ramp-up 
Schedule for subjects at low risk for TLS (Figure 7). However, if ≥3 out of 9 subjects experience 
DLT(s), the Randomization Phase will commence with a 4-week ibrutinib lead-in followed by 
the standard Ramp-up Schedule for subjects in both TLS risk categories (Figure 7).
The Safety Review Committee (SRC) will evaluate TLS and DLT data after 6-9 subjects in the 
low TLS risk category have completed the TLS/DLT assessment period (the Ramp-up Period 
with a minimum of 5 weeks). Members of SRC will include the Sponsor (Medical Monitor or 
designee, Drug Safety Representative and Biostatistician) as well as participating investigators.
Subjects at Increased Risk for TLS
Evaluation of TLS
With respect to TLS only, if < 3 out of the 12 subjects at increased risk for TLS experience a 
laboratory TLS event and no subjects experience a clinical TLS event, enrollment of 
increased-risk TLS subjects to the Randomization Phase will commence using the standard 
Ramp-up Schedule for subjects at increased risk for TLS (Figure 7).
However, if ≥3 out of the 12 increased risk subjects experience a laboratory TLS event or any of 
these subjects experience a clinical TLS event, at least 6 subjects at increased risk for TLS 
should be treated with the 4-week ibrutinib lead-in and assessed for safety in either in an external 
study or within this study. If ≤2 out of these 6 subjects experience a laboratory TLS event and
no subjects experience a clinical TLS event, the Randomization Phase will commence with a 
4-week ibrutinib lead-in followed by the standard Ramp-up Schedule for subjects at increased 
risk of TLS (Figure 7).


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Evaluation of DLTs
With respect to DLTs, if < 4 out of the 12 subjects at increased risk for TLS experience DLT(s) 
during the DLT assessment period, the Randomization Phase will commence using the standard 
Ramp-up Schedule. However, if ≥4 out of the 12 subjects experience DLT(s), the 
Randomization Phase will commence with a 4-week ibrutinib lead-in followed by the standard 
Ramp-up Schedule for subjects at increased risk of TLS.
The SRC will evaluate TLS and DLT data after all 12 subjects in the increased TLS risk category 
have completed the TLS and DLT assessment period prior to the Randomization Phase, and if 
required, after an additional 6 subjects have completed the TLS and DLT assessment period (the 
Ramp-up Period with a minimum of 5 weeks) after the 4-week ibrutinib lead-in.
Subjects in either TLS risk category who experience a laboratory or clinical TLS event will be
managed according to standard institutional practice.
For subjects who experience laboratory TLS, dosing of venetoclax will be withheld per protocol 
and may be resumed when all laboratory abnormalities have returned to baseline. Dose reduction 
of venetoclax is not allowed for subjects enrolled in the Safety Run-in Period. Once venetoclax 
dosing is resumed, the applicable ramp-up week will re-start at the same dose level.
Those subjects incurring clinical TLS (regardless of TLS risk category) must be documented and 
discussed with the study medical monitor to determine whether the risk-benefit ratio justifies the 
subject remaining on study.
Subjects will be treated with ibrutinib and venetoclax for approximately 104 weeks followed by 
ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Venetoclax will 
be discontinued after 104 weeks of treatment regardless of response assessment.
Subjects who discontinue study treatment for any reason will be followed for progression (if not 
progressed before treatment discontinuation), subsequent anti-cancer therapy and survival status 
until study closure.
3.1.2
Randomization Phase
The Randomization Phase portion of the study will follow a randomized, double-blind design. 
Ibrutinib and venetoclax/placebo will be administered using the Ramp-up Schedule that was 
determined to be appropriate for each TLS risk category. The Data Monitoring Committee 
(DMC) will review the safety recommendations made by the SRC and will be responsible for 
giving recommendations on continuing, modifying, or stopping the Randomization Phase of the 
trial (Figure 8).
Subject eligibility will be determined up to 28 days prior to randomization. Approximately 
260 eligible subjects will be randomized at a 1:1 ratio to ibrutinib and venetoclax or ibrutinib and 


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placebo. Randomization will be stratified by number of prior lines of therapy, ECOG PS, and by 
TLS risk category.
Figure 8.
Randomization Phase Schematic
Initially, subjects at increased risk of TLS will be hospitalized for a minimum of 24 hours (and 
up to 48 hours at the discretion of the investigator) at the start of the 20 mg ramp-up dose and 
again at the start of the 50 mg ramp-up dose of venetoclax for monitoring and prophylaxis of 
TLS. The DMC will review unblinded safety data during the course of the study to determine 
whether continued hospitalization of these subjects during ramp-up remains warranted.
Subjects will be treated with either ibrutinib and venetoclax or ibrutinib and placebo for 
approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or 
withdrawal of consent. Venetoclax/placebo will be discontinued after 104 weeks of treatment 
regardless of response assessment.
Subjects who discontinue study treatment for any reason will be followed for progression (if not 
progressed before treatment discontinuation), subsequent anti-cancer therapy, and survival status 
until study closure.
The independent Data Monitoring Committee (DMC) will review unblinded safety data 
including all deaths and any progression associated with safety 6-9 months after initiation of the 
Randomization Phase to evaluate the safety of the combination of ibrutinib and venetoclax and to 
confirm continued dosing with the combination is warranted. In addition, the DMC will review 
TLS data in the course of the study to ascertain whether the continued hospitalization of subjects 
with high tumor burden and/or creatinine clearance < 60 mL/min during ramp-up is needed. The 
make-up of the DMC, responsibilities, authorities, and procedure will be detailed in a separate 
DMC charter.
The rationale for the study concept is provided in Section 1.4.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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CT and PET or PET/CT: A CT scan (with contrast unless contraindicated) of the neck, chest, 
abdomen, and pelvis and any other disease sites (eg, extremity) and a PET scan are required for 
the pretreatment tumor assessment within 28 days of the 1st dose. Thereafter, CT scans will be 
done for tumor assessments on Week 13 Day 1 (±7 days); every 12 weeks for the remainder of 
the 1st year; every 16 weeks during the 2nd and 3rd years; and every 24 weeks thereafter until PD. 
PET or PET/CT is mandatory for all subjects at the Week 13 visit (+/- 7 days), the Week 25 visit 
(+/- 7 days) for subjects in SD or PR who did not achieve CR at Week 13, and at the 1-year visit 
(Week 49 +/- 7 days) for all subjects, as well as at any other time point to confirm a CR. Other 
PET or PET/CT scans that are NOT mandatory can be performed within a 30-day window of the 
visit. For MRI refer to Section 7.1.3.2.
Subjects who discontinue study treatment for any reason will be followed for disease 
progression, subsequent anticancer therapy, and survival status until study closure.
4
SUBJECT SELECTION
4.1
Eligibility Criteria for SRI and Randomization Phase
4.1.1
Inclusion Criteria
Prior to enrollment, each potential subject must satisfy all of the following inclusion criteria. 
These criteria must continue to be met by the subject prior to first dose of study treatment.
Disease-Related
1. Pathologically confirmed MCL (tumor tissue), 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)

A report from the local laboratory is acceptable if available; however, it must be 
reviewed and approved by the central pathology laboratory to verify the above 
criteria prior to randomization (for Randomization Phase subjects only).

If the report from the local laboratory is not available prior to randomization (for 
Randomization Phase subjects only), the tumor block or slides must be sent to the 
central pathology laboratory for confirmation of the MCL diagnosis.
2. At least 1 measurable site of disease that is ≥2.0 cm in the longest diameter and measurable 
in 2 perpendicular dimensions per CT
3. At least 1, but no more than 5, prior treatment regimens for MCL including at least 1 prior 
rituximab/anti-CD20 containing regimen
4. Failure to achieve at least partial response (PR) with, or documented disease progression 
after, the most recent treatment regimen
5. Subjects must have adequate fresh or paraffin embedded tissue (Section 7.1.3.4).


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Laboratory
6. Adequate hematologic function independent of transfusion and growth factor support for at 
least 7 days prior to first dose (Safety Run-in Period) or to randomization (for the 
Randomization Phase), with the exception of pegylated G-CSF (pegfilgrastim) and 
darbepoeitin which require at least 14 days prior to the first dose (Safety Run-in Period) or to 
randomization (for the Randomization Phase), defined as: 

Absolute neutrophil count (ANC) > 1000 cells/mm3 (1.0 x 109/L)

Platelet count > 50,000 cells/mm3 (50 x 109/L)

Hemoglobin > 8.0 g/dL
Note: Subjects in the Randomization Phase with bone marrow involvement may be enrolled 
without meeting the above hematologic function criteria after documented discussion with the 
medical monitor.
7. Adequate hepatic and renal function defined as:

Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤3.0 x upper 
limit of normal (ULN)

Estimated Creatinine Clearance (CrCl) ≥30 mL/min (Cockcroft-Gault)

Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin)
8. Prothrombin time (PT)/International normal ratio (INR) < 1.5 x upper limit of normal (ULN) 
and PTT (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 ≤3.0.
Demographic
9. Men and women ≥18 years of age
10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2


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Ethical/Other
11. Male and female subjects of reproductive potential who agree to use both a highly effective 
method of birth control (eg, implants, injectables, combined oral contraceptives, some 
intrauterine devices [IUDs], complete abstinence3, or sterilized partner) and a barrier method 
(eg, condoms, cervical ring, sponge, etc) during the period of therapy and for 90 days after 
the last dose of study drug.
4.1.2
Exclusion Criteria
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria (These criteria must continue to be not met by the subject until first dose of study 
treatment):
Disease-Related
1. History or current evidence of central nervous system lymphoma
Concurrent Conditions
2. Concurrent enrollment in another therapeutic investigational study or prior therapy with 
ibrutinib or other BTK inhibitors
3. Prior treatment with venetoclax or other BCL2 inhibitors
4. Anticancer therapy including chemotherapy, radiotherapy, small molecule and 
investigational agents ≤ 21 days (or at least 5 drug half-lives, whichever is shorter) prior to 
first administration of study treatment and/or monoclonal antibody ≤3weeks (or at least 
5 drug half-lives, whichever is shorter) prior to receiving the first dose of study drug
5.
History of other malignancies, except: 

Malignancy treated with curative intent and with no known active disease present 
for ≥3 years before the first dose of study drug and felt to be at low risk for 
recurrence by treating physician

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease

Adequately treated carcinoma in situ without evidence of disease
6. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug
                                               
3 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
http://www hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf


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7. Clinically significant infection requiring IV systemic treatment that was completed ≤14 days 
before the first dose of study drug
8. Any uncontrolled active systemic infection
9. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to 
Common Terminology Criteria for Adverse Event (CTCAE, v4.03), Grade 0 or 1, or to the 
levels dictated in the inclusion/exclusion criteria with the exception of alopecia
10. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia)
11. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
12. Prior stem cell transplant that requires ongoing immunosuppressive therapy or clinical graft 
vs host disease (GVHD)
13. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus 
(HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, 
hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative 
polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will 
be excluded.
14. Major surgery within 4 weeks of the first dose of study drug.
15. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk
16. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable angina, 
or acute coronary syndrome within 6 months prior to randomization
17. Unable to swallow capsules or tablets, or malabsorption syndrome, disease significantly 
affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
18. Treatment with any of the following within 7 days prior to the first dose of study drug:

moderate or strong cytochrome P450 3A (CYP3A) inhibitors (see Appendix D for 
examples)

moderate or strong CYP3A inducers (see Appendix D for examples) 
19. Administration or consumption of any of the following within 3 days prior to the first dose 
of study drug:

grapefruit or grapefruit products

Seville oranges (including marmalade containing Seville oranges)

star fruit
20. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects with known risk 
factors (as defined by high tumor burden and/or diminished renal function, as detailed in 
“Study Design” section above) for TLS


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21. Subjects with chronic liver disease with hepatic impairment Child-Pugh class B or C 
(Appendix F)
22. Female subject who is pregnant, breastfeeding or is considering becoming pregnant during 
the study or for approximately 90 days after the last dose of study drug
23. Male subject who is considering fathering a child or donating sperm during the study or for 
approximately 90 days after the last dose of study drug
24. Unwilling or unable to participate in all required study evaluations and procedures
25. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information 
(in accordance with national and local subject privacy regulations)
26. Known hypersensitivity to the active ingredient or other components of one or more study 
drugs
4.2
Eligibility Criteria for the Treatment-naive Open-label Arm
4.2.1
Inclusion Criteria for the Treatment-naive Open-label Arm
1. Pathologically confirmed treatment-naive MCL (tumor tissue), 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)

A report from the local laboratory is acceptable if available; however, it must be 
reviewed and approved by the central pathology laboratory to verify the above 
criteria prior to enrollment

If the report from the local laboratory is not available, a tumor block or slides must 
be sent to the central pathology laboratory for confirmation of the MCL diagnosis 
prior to enrollment
2. Men and women ≥18 years of age with a TP53 mutation4
3. At least 1 measurable site of disease that is ≥2.0 cm in the longest diameter and measurable 
in 2 perpendicular dimensions per CT
4. Subjects must have adequate fresh or paraffin-embedded tissue
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2
6. Adequate hematologic function independent of transfusion and growth factor support for at 
least 7 days prior to first dose, with the exception of pegylated G-CSF (pegfilgrastim) and 
darbepoeitin which require at least 14 days prior to the first dose defined as: 

Absolute neutrophil count (ANC) > 1000 cells/mm3 (1.0 x 109/L)
                                               
4 TP53 test by local or central lab


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
Platelet count > 50,000 cells/mm3 (50 x 109/L)

Hemoglobin > 8.0 g/dL
7. Adequate hepatic and renal function defined as:

Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤3.0 x upper 
limit of normal (ULN)

Estimated Creatinine Clearance (CrCl) ≥30 mL/min (Cockcroft-Gault)

Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin)
8. Prothrombin time (PT) or International normal ratio (INR) < 1.5 x upper limit of normal 
(ULN) and PTT (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 ≤3.0
9. Male and female subjects of reproductive potential who agree to use both a highly effective 
method of birth control (eg, implants, injectables, combined oral contraceptives, some 
intrauterine devices [IUDs], complete abstinence5, or sterilized partner) and a barrier method 
(eg, condoms, cervical ring, sponge, etc) during the period of therapy and for 90 days after 
the last dose of study drug
4.2.2
Exclusion Criteria for the Treatment-naive Open-label Arm
1. Blastoid variant of MCL
2. History or current evidence of central nervous system lymphoma
3. Concurrent enrollment in another therapeutic investigational study or prior therapy, including 
ibrutinib or other BTK inhibitors
4. Prior treatment with venetoclax or other BCL2 inhibitors
5. History of other malignancies, except:

Malignancy treated with curative intent and with no known active disease present 
for ≥3 years before the first dose of study drug and felt to be at low risk for 
recurrence by treating physician

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence 
of disease

Adequately treated carcinoma in situ without evidence of disease
                                               
5 Complete abstinence is a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
http://www hma.eu/fileadmin/dateien/Human_Medicines/01 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf


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6. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug
7. Clinically significant infection requiring IV systemic treatment that was completed ≤14 days 
before the first dose of study drug
8. Any uncontrolled active systemic infection
9. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia)
10. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
11. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus 
(HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, or 
hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before 
enrollment. Those who are hepatitis B surface antigen (HBsAg) or PCR positive will be 
excluded.
12. Major surgery within 4 weeks of the first dose of study drug.
13. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk
14. Currently active, clinically significant cardiovascular disease, such as uncontrolled 
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart 
Association Functional Classification; or a history of myocardial infarction, unstable angina, 
or acute coronary syndrome within 6 months prior to randomization
15. Unable to swallow capsules or tablets, or malabsorption syndrome, disease significantly 
affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic 
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
16. Treatment with any of the following within 7 days prior to the first dose of study drug:

Moderate or strong cytochrome P450 3A (CYP3A) inhibitors (Appendix D)

Moderate or strong CYP3A inducers (Appendix D)
17. Administration or consumption of any of the following within 3 days prior to the first dose 
of study drug:

grapefruit or grapefruit products

Seville oranges (including marmalade containing Seville oranges)

star fruit
18. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects with known risk 
factors (as defined by high tumor burden and/or diminished renal function, as detailed in 
“Study Design” section above) for TLS
19. Subjects with chronic liver disease with hepatic impairment Child-Pugh class B or C
20. Female subject who is pregnant, breastfeeding or is considering becoming pregnant during 
the study or for approximately 90 days after the last dose of study drug


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21. Male subject who is considering fathering a child or donating sperm during the study or for 
approximately 90 days after the last dose of study drug
22. Unwilling or unable to participate in all required study evaluations and procedures
23. Unable to understand the purpose and risks of the study and to provide a signed and dated 
informed consent form (ICF) and authorization to use protected health information 
(in accordance with national and local subject privacy regulations)
24. Known hypersensitivity to the active ingredient or other components of one or more study 
drugs
5
TREATMENT OF SUBJECTS
5.1
Treatment Allocation and Blinding
5.1.1
Safety Run-in Period
Up to 27 subjects may be enrolled during the Safety Run-in Period. Initially, 6-9 subjects at low 
risk for TLS and 12 subjects at increased risk for TLS will receive ibrutinib at 560 mg once daily 
and open-label venetoclax at a starting dose of 20 mg once daily and gradually ramped up to a 
target dose of 400 mg once daily over a 5-week period. TLS events and DLT occurrence will be 
assessed during the venetoclax Ramp-up Period for a minimum of 5 weeks. Depending on the 
occurrence of TLS events and DLTs, a minimum of 6 additional subjects at increased risk for 
TLS may be treated with the 4-week ibrutinib lead-in during the Safety Run-in Period.
Subjects dosed in the Safety Run-in Period will continue on open-label ibrutinib at 560 mg once 
daily and open-label venetoclax at a target dose of 400 mg for up to approximately 104 weeks, 
followed by ibrutinib monotherapy until disease progression, unacceptable toxicity or 
withdrawal of consent.
5.1.2
Randomization Phase
The Randomization Phase portion of the study will follow a randomized, double-blind design. 
After written informed consent has been obtained and eligibility has been established, the study 
site will obtain the subject’s identification number and treatment assignment from the Interactive 
Response Technology (IRT) System.
5.1.2.1
Randomization
Approximately 260 eligible subjects will be randomized at a 1:1 ratio to ibrutinib and venetoclax 
or ibrutinib and placebo treatment arms. Randomization will be stratified by number of prior 
lines of therapy (1-2, ≥3), ECOG PS (0-1, 2), and by TLS category (low risk, increased risk for 
TLS). Subjects will be dosed within 3 days of randomization.
Subjects will continue treatment with either ibrutinib and venetoclax or ibrutinib and placebo for 
at least 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or 


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withdrawal of consent. Venetoclax/placebo will be discontinued after 104 weeks of treatment, 
regardless of response assessment.
A stratified, permuted-block randomization will be implemented in order to obtain a balanced 
assignment to each treatment within levels of the stratification factors.
5.1.2.2
Blinding
Subjects, investigators, and the Sponsor’s study team members will remain blinded to treatment 
assignment. The investigator will not be provided with randomization codes nor the treatment 
received. The codes will be maintained within the IRT System, which has the functionality to 
allow the investigator to break the blind for an individual subject if necessary to appropriately 
manage or treat the subject. Data that may potentially unblind the treatment assignment (ie, study 
drug plasma concentrations) will be handled with special care to ensure that the integrity of the 
blind is maintained and the potential for bias is minimized.
Telephone contact with the Sponsor or its designee will be available 24 hours per day, 7 days per 
week. In the event the blind is broken, the Sponsor must be informed as soon as possible. The 
date and time of the unblinding must be documented within the IRT System, in the appropriate 
section of the eCRF and in the source document. The confirmation received from the IRT 
System indicating the code break must be retained with the subject's source documents in a 
secure manner. A subject whose treatment assignment has been unblinded may continue the 
study treatment if the subject is expected to continue to receive clinical benefit. The subject 
should continue to return for scheduled study visits. The single-blind (ie, subject remains blinded 
to treatment assignment) should be maintained, provided the subject’s safety is not 
compromised.
5.1.3
Replacement of Subjects
Subjects who miss ≥20% of the planned doses of ibrutinib or venetoclax for reasons other than 
toxicity (eg, non-compliance, withdrawal of consent, disease progression) during the TLS and 
DLT assessment period (venetoclax ramp-up during the Safety Run-in Period), or subjects who 
do not complete the TLS and DLT assessment period for any reason other than TLS or a DLT 
will be replaced.
Randomized subjects will not be replaced in the Randomization Phase.
5.1.4
Treatment-naive Open-label Arm
In the treatment-naive open-label arm, approximately 75 subjects will be enrolled and treated 
with ibrutinib 560 mg and venetoclax 400 mg. Among them, approximately 50 subjects 
≥65 years and approximately 25 subjects with a TP53 mutation will be enrolled. Ibrutinib and 
venetoclax will be administered using the 5-week ramp-up schedule.
Subject eligibility will be determined up to 28 days prior to the first dose of study drug.


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After written informed consent has been obtained and eligibility has been established, the study 
site will obtain the subject’s identification number from the Interactive Response Technology 
(IRT) System.
Subjects in the protocol-defined increased-risk for tumor lysis syndrome (TLS) group will be 
hospitalized for a minimum of 24 hours (and up to 48 hours at the discretion of the investigator) 
at the start of the 20 mg and 50 mg ramp-up dose of venetoclax for monitoring and prophylaxis 
of TLS; subjects in the low-risk for TLS group may be hospitalized at the discretion of the 
investigator.
Subjects will be treated with ibrutinib and venetoclax for approximately 104 weeks (2 years), 
followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. 
Venetoclax will be discontinued after 104 weeks (2 years) of treatment, regardless of response 
assessment.
Subjects who discontinue study treatment for any reason will be followed for disease 
progression, subsequent anticancer therapy, and survival status until study closure.
5.2
Study Treatment
5.2.1
SRI and Randomized Phase
Ibrutinib

Orally once daily ibrutinib 560 mg (4 x 140 mg capsules OR 1 x 560 mg tablet) 
continuously 
Note: Dose modification of ibrutinib for AEs is specified in Section 5.3.1.4, Section 5.3.1.6, and 
Section 6.2.1.1.
Important: If using tablets, please ensure that patients do not take more than one 560 mg tablet per 
day.
Venetoclax

Orally once daily venetoclax at a target dose of 400 mg (4 X 100 mg)
Note: Dose modification of venetoclax/placebo for AEs is specified in Section 5.3.2.5 and 
Section 6.2.1.2.
Placebo

Oral once daily matching placebo for venetoclax at a target dose of 400 mg 
(4 X 100 mg)
Note: Dose modification of venetoclax/placebo for AEs is specified in Sections 5.3.2.5 and 
Section 6.2.1.2.


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5.2.2
Treatment-naive Open-label Cohort
Ibrutinib

Orally once daily ibrutinib 560 mg (4 x 140 mg capsules OR 1 x 560 mg tablet) 
continuously 
Note: Dose modification of ibrutinib for AEs is specified in Section 5.3.1.4, Section 5.3.1.6, and 
Section 6.2.1.1.
Important: If using tablets, please ensure that patients do not take more than one 560 mg 
tablet per day.
Venetoclax 

Orally once daily venetoclax at a target dose of 400 mg (4 X 100 mg) dosed 
concurrently with ibrutinib
Note: Dose modification of venetoclax/placebo for AEs is specified in Section 5.3.2.5 and 
Section 6.2.1.2.
5.3
Study Medication
5.3.1
Ibrutinib
5.3.1.1
Formulation/Packaging/Storage
Ibrutinib is provided either as hard gelatin capsules each containing 140 mg of ibrutinib, or as 
film coated tablets each containing 560 mg of ibrutinib. All formulation excipients are 
compendial and are commonly used in oral formulations. Refer to the ibrutinib IB for a list of 
excipients.
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with 
labels bearing the appropriate label text as required by governing regulatory agencies and child-
resistant packaging. The ibrutinib tablets 560 mg will be packaged in blisters.
Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
dose modifications for subjects on ibrutinib tablets, study drug storage, preparation and handling.
Study drug labels will contain information to meet the applicable regulatory requirements.
5.3.1.2
Dose and Administration
Ibrutinib 560 mg (4 x 140 mg capsules or 1 x 560 mg tablet) is administered orally once daily. 
The ibrutinib capsules or tablet are/is to be taken with venetoclax/placebo tablets at 
approximately the same time each day with a meal and water. The capsules or tablet should be 
swallowed intact and subjects should not attempt to open capsules, break the tablet or dissolve 


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them in water. The use of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges 
should be avoided for the duration of the study (Appendix D).
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the same day 
with a return to the normal schedule the following day. The subject should not take extra 
capsules to make up the missed dose.
For subjects starting with the concurrent administration of ibrutinib and venetoclax using the 
standard Ramp-up Schedule, ibrutinib will be delivered in the clinic on Days 1, 2 (all subjects) 
and 3 (hospitalized subjects) of Weeks 1 and 2; on Days 1 of the remaining weeks during the 
venetoclax Ramp-up Period (see Section 8.2); and on the PK sample collection day (see 
Section 7.1.4.1 and Section 7.1.4.2). Otherwise, ibrutinib dosing is typically done on an 
outpatient basis.
Ibrutinib will be dispensed to subjects at each dispensing visit. Study drug may not be shipped to 
the subject without approval from the Sponsor and may not be dispensed to anyone other than 
the subject. Unused ibrutinib dispensed during previous visits must be returned to the site and 
drug accountability records (Section 12.8) updated at each visit. Returned drug must not be 
redispensed to anyone and must not be destroyed without prior written approval of Clinical 
Monitor/CRA and /or the Sponsor. Study drugs can only be destroyed after full accountability 
and reconciliation by the Clinical Monitor/CRA unless required by local institutional policy.
5.3.1.3
Overdose
There is no specific experience in the management of ibrutinib overdose in patients. No MTD 
was reached in the Phase 1 study in which subjects received up to 12.5 mg/kg/day 
(1400 mg/day). Healthy subjects were exposed up to a single dose of 1680 mg. One healthy 
subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 
1680 mg. Subjects who ingested more than the recommended dosage should be closely 
monitored and given appropriate supportive treatment.
Refer to Section 11.3 for further information regarding special reporting situations as a result of 
overdose. 
5.3.1.4
Dose Modification for Adverse Reactions
Ibrutinib interruption and/or dose reduction may be required for toxicities related to ibrutinib. 
The dose of study drug must be modified according to the dose modification guidance in Table 1
and Table 2 if any of the following ibrutinib related toxicities occur:

Grade 3 or greater neutropenia with infection or fever

Grade 4 neutropenia (ANC < 500/µL) for more than 7 days. See Section 6.1 for 
instructions regarding the use of growth factor support.


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
Grade 3 thrombocytopenia (platelets < 50,000/µL) in the presence of Grade ≥2 
bleeding

Grade 4 thrombocytopenia (platelets < 25,000/µL)

Grade 3 or greater non-hematological toxicity (Note: Table 2 recommendations for 
Grade 3 or greater cardiac failure and cardiac arrhythmias)

Grade 2 cardiac failure (Table 2)

Any other Grade 4 or unmanageable Grade 3 toxicity
If clinically indicated, the use of anticoagulants or antiplatelet agents may be considered for the 
thromboprophylaxis of atrial fibrillation (Section 6.2.4 and Section 1.2.4.6). 
For other AEs including grade 2 AEs that are deemed per the investigator potentially manageable 
by dose reduction, these can be managed with a one dose level dose reduction.
In the event that the investigator feels deviation from the recommendations above is required, 
please consult the medical monitor to discuss for approval.
Dose changes must be recorded in the Dose Administration eCRF.
Table 1.
Ibrutinib Dose Modifications
Hematologic AEs
Occurrence
Action to be Taken
First
Withhold ibrutinib until recovery to an ANC ≥750/µL or platelets > 25,000/µL with no 
evidence of Grade ≥2 bleeding; may restart at original dose level
Subsequent
Withhold ibrutinib until recovery to an ANC ≥750/µL or platelets > 25,000/µL with no 
evidence of Grade ≥2 bleeding; may restart at 1 dose level lower* (refer to Table 3)
Other Hematologic and Non-Hematologic AEs (for Events not Specified in Table 2)
Occurrence
Action to be Taken
First
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at original dose levela
Second
Withhold ibrutinib until recovery to Grade ≤1 or baseline; restart at 1 dose level lower*
(3 capsules [ie 420 mg daily]) (refer to Table 3)
Third
Withhold ibrutinib until recovery to Grade ≤1 or baseline; restart at 1 dose level lower
(2 capsules [ie 280 mg daily]) (refer to Table 3)
Fourth
Discontinue ibrutinib
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.
* Dose reduction due to a TLS event or a DLT is not applicable for Safety Run-in subjects.
Note: Do not dose below 280 mg daily except in case of required concomitant administration of strong or moderate CYP3A 
inhibitors or moderate hepatic impairment; refer to Section 5.3.1.6 and Section 6.2.1.


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Table 2.
Ibrutinib Dose Modifications for Cardiac Failure or Cardiac Arrhythmias
Events
Occurrence
Action
Grade 2 cardiac failure
First
Hold study drug until recovery to Grade ≤ 1 or baseline; 
restart at 1 dose level lower (3 capsules [ie, 420 mg daily])
Second
Hold study drug until recovery to Grade ≤ 1 or baseline; 
restart at 1 dose level lower (2 capsules [ie, 280 mg daily])
Third
Discontinue study drug
Grade 3 cardiac 
arrhythmias
First
Hold study drug until recovery to Grade ≤ 1 or baseline; 
restart at 1 dose level lower (3 capsules [ie, 420 mg daily])a
Second
Discontinue study drug
Grade 3 or 4 cardiac failure
Grade 4 cardiac 
arrhythmias
First
Discontinue study drug
a Evaluate the benefit-risk before resuming treatment.
Table 3.
Ibrutinib Dose Reduction Levels
Starting Dose Level
560 mg
Dose Reduction Level 1
420 mg
Dose Reduction Level 2
280 mg
Dose Reduction Level 3
140 mg
Dose Reduction Level 4
Discontinue
For required dose modification for hepatic impairment refer to Section 5.3.1.6 and for 
concomitant treatment with CYP3A inhibitors refer to Section 6.2.1.
5.3.1.5
Leukocytosis/Leukostasis
A high number of circulating white blood cells (> 400,000/µL) may confer increased risk of 
leukostasis; these subjects should be closely monitored. Administer supportive care such as 
hydration and/or leukapheresis as indicated. Ibrutinib may be temporarily held, and the medical 
monitor should be contacted.
5.3.1.6
Dose Modification for Hepatic Impaired Subjects
Ibrutinib is metabolized in the liver, and therefore subjects with clinically significant chronic 
hepatic impairment at the time of Screening (Child-Pugh class B or C) are excluded from study 
participation. See Appendix F for Child-Pugh classification.

For subjects with existing chronic mild hepatic impairment (Child-Pugh class A) at 
enrollment, the starting dose has to be adjusted to a level of 280 mg daily (two 
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
For subjects who develop mild hepatic liver impairment while on study (Child-Pugh 
class A), the recommended dose reduction for ibrutinib is to a level of 280 mg daily 
(two capsules) unless lower doses had already been implemented.

For subjects who develop moderate hepatic impairment while on study (Child-Pugh 
class B), the recommended dose reduction is to a level of 140 mg daily (one 
capsule).

Subjects who develop severe hepatic impairment (Child-Pugh class C) must hold 
study drug until resolved to moderate impairment (Child-Pugh class B) or better.
Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study 
should be managed per standard dose modification guidelines in Section 5.3.1.4.
5.3.2
Venetoclax
5.3.2.1
Formulation/Packaging/Storage
The individual study drug information is presented in Table 4.
Table 4.
Identity of Venetoclax/Placebo Drug Product
Study Drug
Trademark
Formulation
Route of 
Administration
Manufacturer
Venetoclax/placebo
N/A
10 mg tablet
Film coated
Oral
AbbVie
Venetoclax/placebo
N/A
50 mg tablet
Film coated
Oral
AbbVie
Venetoclax/placebo
N/A
100 mg tablet
Film coated
Oral
AbbVie
Packaging and Labeling
The venetoclax/placebo tablets will be packaged in blister packs during the initial dose ramp-up 
period and in high density polyethylene (HDPE) plastic bottles thereafter to accommodate the 
study design. Each container will be labeled as required per country requirements. Labels must 
remain affixed to the container.
Storage and Disposition of Study Drug
The venetoclax/placebo supplied in this study is for investigational use only, and must only be 
used within this study. All study drug must be maintained under adequate security and stored 
under conditions specified on the label until dispensed for subject use or returned to the Sponsor 
or representative.
The tablets must be stored at a controlled room temperature of 15° to 25°C (59° to 77°F).


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5.3.2.2
Venetoclax Toxicity Management
Prophylaxis and Management of Tumor Lysis Syndrome 
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the Ramp-up 
Period. Changes in electrolytes consistent with TLS that require prompt management can occur 
as early as 6-8 hours following the first dose of venetoclax and at each dose increase. The risk of 
TLS is a continuum based on multiple factors, including comorbidities. Subjects with high tumor 
burden are at a greater risk of TLS when initiating venetoclax. Reduced renal function further 
increases the risk. The risk may decrease as tumor burden decreases with venetoclax treatment.
Tumor burden assessments, including radiographic evaluation (eg, CT scan) should be 
performed at Screening as well as blood chemistry assessments (creatinine, uric acid, potassium, 
phosphorus, calcium, and albumin, if available) in all subjects. Pre-existing abnormalities should 
be corrected prior to initiation of treatment with venetoclax.
The prophylaxis measures listed below should be followed and more intensive measures 
(including hospitalization) should be employed as overall risk increases:
Hydration: Ensure adequate hydration (1.5-2 L) 48 hours prior to initiating therapy with 
venetoclax and throughout the Ramp-up Period, especially on the first day of each ramp-up dose. 
Administer intravenous (IV) fluids as indicated based on overall risk of TLS or for those who 
cannot maintain adequate oral hydration.
Anti-hyperuricemic agents: Administer allopurinol within 72 hours prior to initiation of 
venetoclax; consider continuing through the Ramp-up Period. Rasburicase is recommended for 
subjects at high risk, especially those with high tumor burden.
Laboratory Assessments:
Pre-dose: Assess blood chemistries prior to initiating venetoclax to evaluate kidney function and 
correct pre-existing abnormalities. Reassess blood chemistries before starting each subsequent 
ramp-up dose of venetoclax.
Post-dose: For hospitalized subjects, monitor blood chemistries 4, 8, 12, 24 and, as needed, 
48 hours after the venetoclax dose. For outpatient subjects, monitor blood chemistries at 
6-8 hours and at 24 hours after the venetoclax dose. Electrolyte abnormalities should be 
corrected promptly (see Appendix H for Recommendations for Initial Management of 
Electrolyte Abnormalities and Prevention of Tumor Lysis). The next dose of venetoclax should 
not be administered until the 24-hour blood chemistry results have been evaluated. The same 
monitoring schedule should be followed when starting each subsequent ramp-up dose.


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Hospitalization: Based on investigator assessment, subjects with high tumor burden (at least one 
lesion > 10 cm; or at least one lesion > 5 cm and circulating lymphocytes > 25,000 cells/mm3) 
and/or CrCl < 60 mL/min, are at greater risk of TLS and require hospitalization the first 
24-48 hours of treatment at the 20 mg and the 50 mg ramp-up doses of venetoclax for more 
intensive prophylaxis and monitoring. Consider hospitalization for subsequent ramp-up doses 
based on reassessment of risk. During the course of the study, the DMC will review unblinded 
TLS data to determine whether continued hospitalization of these subjects is warranted.
5.3.2.3
Dose and Administration
Venetoclax/placebo tablets should be taken orally once daily with a meal and water at 
approximately the same time each day with ibrutinib capsules. Venetoclax/placebo tablets should 
be swallowed whole and not chewed, crushed, or broken prior to swallowing. If the subject 
misses a dose of venetoclax/placebo within 8 hours of the time it is usually taken, the subject 
should take the missed dose as soon as possible on the same day and resume the normal daily 
dosing schedule. If a subject misses a venetoclax/placebo dose by more than 8 hours, the subject 
should not take the missed dose and resume the usual dosing schedule the following day. The use 
of strong CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be avoided for 
the duration of the study (Appendix D).
For subjects starting with the concurrent administration of ibrutinib and venetoclax using the 
standard Ramp-up Schedule, venetoclax/placebo will be delivered in the clinic on Days 1, 2 (all 
subjects) and 3 (hospitalized subjects) of Weeks 1 and 2; on Days 1 of the remaining weeks 
during the Ramp-up Period (see Section 8.2); and on the PK sample collection day (see 
Section 7.1.4.1 and Section 7.1.4.2). Otherwise, venetoclax dosing will be done on an outpatient 
basis. Subjects should strictly adhere to the Ramp-up Schedule. In the event of TLS, dosing of 
venetoclax will be withheld and/or modified per the protocol and may be resumed at the 
investigator’s discretion, when all laboratory abnormalities have returned to baseline. If 
venetoclax is resumed at the same dose level, the 7-day count should be re-started. In cases of 
vomiting after taking venetoclax/placebo, no additional dose (tablets) should be taken that day. 
The next dose should be taken at the usual time the following day.
5.3.2.4
Overdose
There is no specific antidote for venetoclax/placebo. For subjects who experience overdose, 
closely monitor and provide appropriate supportive treatment; during the Ramp-up Period, 
interrupt venetoclax/placebo and monitor carefully for signs and symptoms of TLS along with 
other toxicities. Based on the venetoclax (assume for placebo) large volume of distribution and 
extensive protein binding, dialysis is unlikely to result in significant removal of venetoclax 
(assume for placebo).
Refer to Section 11.3 for further information regarding special reporting situations as a result of 
overdose.


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5.3.2.5
Dose Modification for Adverse Reactions
Venetoclax/placebo dosing interruption and/or dose reduction may be required. See Table 5 for 
dose modifications for hematologic and other toxicities related to venetoclax/placebo. For 
subjects who have had a dosing interruption greater than 1 week during the Ramp-up Period or
greater than 2 weeks when at target dose, reassess for risk of TLS to determine if reinitiation 
with a reduced dose is necessary (eg, all or some levels of the dose Ramp-up Schedule).
Dose reduction of venetoclax is not allowed for subjects enrolled in the Safety Run-in Period 
(see Section 3.1.1).
Table 5.
Recommended Dose Modifications for Venetoclax/placebo-related 
Toxicities
Event
Occurrence
Action
Tumor Lysis Syndrome
Blood chemistry changes 
or symptoms suggestive 
of TLS
Any
Withhold the next day’s dose. If resolved within 
24-48 hours of last dose, resume at the same dose.
For any blood chemistry changes requiring more than 
48 hours to resolve, resume at a reduced dose* 
(see Table 6) 
For any events of clinical TLS, resume at a reduced dose 
following resolution (see Table 6)*
Non-Hematologic Toxicities
Grade 3 or 4 non-
hematologic toxicities 
1st occurrence 
Interrupt venetoclax/placebo
Once the toxicity has resolved to Grade 1 or baseline level, 
venetoclax/placebo therapy may be resumed at the same 
dose. No dose modification is required. 
2nd and subsequent 
occurrences 
Interrupt venetoclax/placebo.
Follow dose reduction guidelines in Table 6 when resuming 
treatment with venetoclax/placebo after resolution. A larger 
dose reduction may occur at the discretion of the 
investigator.*
Hematologic Toxicities
Grade 3 or 4 neutropenia 
with infection or fever; or 
Grade 4 hematologic 
toxicities (except 
lymphopenia) 
1st occurrence 
Interrupt venetoclax/placebo.
To reduce the infection risks associated with neutropenia, 
granulocyte-colony stimulating factor (G-CSF) may be 
administered with venetoclax/placebo if clinically 
indicated. Once the toxicity has resolved to Grade 1 or 
baseline level, venetoclax/placebo may be resumed at the 
same dose. 
2nd and subsequent 
occurrence 
Interrupt venetoclax/placebo.
Consider using G-CSF as clinically indicated.
Follow dose reduction guidelines* in Table 6 when 
resuming venetoclax/placebo after resolution. Additional 
dose reductions may occur at the discretion of the 
investigator
* Dose reduction due to a TLS event or a DLT is not applicable for Safety Run-in Period subjects. 


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Consider discontinuing venetoclax/placebo for subjects who require dose reductions to less than 
100 mg for more than 2 weeks.
If the dose of venetoclax/placebo is reduced, at the investigator’s discretion, the dose of 
venetoclax/placebo may be re-escalated after 2 months of a dose reduction in the absence of a 
recurrence of the toxicity that led to the reduction. Dose changes must be recorded in the Dose 
Administration eCRF.
Table 6.
Dose Modification for Toxicity During Venetoclax/placebo Treatment
Dose at Interruption
Restart Dosea
400 mg
300 mg
300 mg
200 mg
200 mg
100 mg
a Continue the reduced dose for at least 1 week before increasing the dose. 
5.3.2.6
Dose Modification for Hepatic Impaired Subjects
No dose adjustment is recommended in subjects with mild or moderate hepatic impairment based 
on results of the population pharmacokinetic analysis. A recommended dose has not been 
determined for subjects who develop severe hepatic impairment.
5.4
Criteria for Permanent Discontinuation of Study Drug
Investigators are encouraged to keep a subject who is experiencing clinical benefit in the study 
unless significant toxicity puts the subject at risk or routine noncompliance puts the study 
outcomes at risk. Subjects who discontinue either ibrutinib or venetoclax/placebo (but not both) 
for tolerability issues may continue in the study as long as they are receiving at least one study 
drug. For a complete list of criteria for permanent discontinuation of study treatment, refer to 
Section 9.2.
An End-of-Treatment Visit (Section 8.2.3) is required for all subjects except for those subjects 
who have withdrawn full consent.
6
CONCOMITANT MEDICATIONS/PROCEDURES
6.1
Permitted Concomitant Medications
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.


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Usage of antimicrobial prophylaxis in accordance with standard practice (eg, ASCO guidelines 
[Flowers 2013]) is permitted and should be considered in patients who are at increased risk for 
opportunistic infections.
Use of neutrophil growth factors (filgrastim and pegfilgrastim) red blood cell growth factors 
(erythropoietin) and transfusion is permitted in accordance with institutional policy (eg, ASCO 
Guidelines [Smith 2006]). 
In addition, short courses (≤14 days) of steroid treatment for non-cancer related medical reasons 
(eg, joint inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at 
doses that are clinically indicated are permitted.
6.2
Medications to be Used with Caution
6.2.1
CYP3A Inhibitors/Inducers
6.2.1.1
Concomitant Use with Ibrutinib
Ibrutinib is metabolized primarily by CYP3A4. Avoid concomitant use of systemic strong or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.

If a strong CYP3A inhibitor must be used, reduce ibrutinib dose to 140 mg or 
withhold treatment for the duration of inhibitor use. Subjects should be monitored 
for signs of ibrutinib toxicity.

If a moderate CYP3A inhibitor must be used, reduce ibrutinib to 140 mg for the 
duration of the inhibitor use. Avoid grapefruit and Seville oranges during 
ibrutinib/placebo treatment, as these contain moderate inhibitors of CYP3A (see 
Section 6.2.1.1).

No dose adjustment is required in combination with mild inhibitors.
Table 7 summarizes the recommended dose modifications with moderate and strong CYP3A 
inhibitors. Avoid concomitant use of systemic strong CYP3A inducers (eg, carbamazepine, 
rifampin, phenytoin, and St. John’s Wort). Consider alternative agents with less CYP3A 
induction.
A list of common CYP3A inhibitors and inducers is provided in Appendix D. For further 
information, please refer to the current ibrutinib IB and examples of inhibitors, inducers, and 
substrates can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is 
continually revised and should be checked frequently for updates.
6.2.1.2
Concomitant Use with Venetoclax/placebo
Concomitant use of venetoclax/placebo with strong CYP3A inhibitors at initiation and during the 
Ramp-up Period increases the risk for TLS. Concomitant use of venetoclax/placebo with strong 
CYP3A inhibitors at initiation (7 days prior to first dose) and during the Ramp-up Period is 


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contraindicated. For subjects who have completed the Ramp-up Period and are on a steady daily 
dose of venetoclax/placebo, reduce the venetoclax/placebo dose by at least 75% when strong 
CYP3A inhibitors must be used concomitantly.
Avoid concomitant use of moderate CYP3A inhibitors with venetoclax. Consider alternative 
treatments. If a moderate CYP3A inhibitor must be used, reduce the doses of venetoclax/placebo 
by at least 50%. Monitor subjects more closely for signs of toxicities. Table 7 summarizes the 
recommended dose modifications with moderate and strong CYP3A inhibitors.
Resume the venetoclax/placebo dose that was used prior to initiating the CYP3A inhibitor 2 to 
3 days after discontinuation of the inhibitor.
Avoid concomitant use of venetoclax/placebo with strong CYP3A inducers (eg, carbamazepine, 
phenytoin, rifampin, St. John’s Wort) or moderate CYP3A inducers (eg, bosentan, efavirenz, 
etravirine, modafinil, nafcillin). Consider alternative treatments with less CYP3A induction.
A list of common CYP3A inhibitors and inducers is provided in Appendix D. For further 
information, please refer to the current venetoclax IB.
A sample list of cautionary medications that fall into these categories is provided in Appendix D.
Table 7.
Management of Potential Ibrutinib and Venetoclax/placebo Interactions 
with CYP3A Inhibitors
Venetoclax/placebo
Ibrutinib
Inhibitors
Initiation and 
Ramp-up Period
Target Daily Dose 
(After Ramp-up)
At any time
Strong CYP3A 
inhibitor
Contraindicated
Avoid inhibitor use, consider 
alternative agent. If must be 
used, reduce the venetoclax 
dose by at least 75%
Avoid inhibitor use, consider 
alternative agent. If must be used, 
withhold ibrutinib for duration of 
inhibitor use, or reduce ibrutinib to 
140 mg
Moderate CYP3A 
inhibitor
Avoid inhibitor use, consider alternative agent. If 
must be used, reduce the venetoclax dose by at least 
50%
Avoid inhibitor use, consider 
alternative agent. If must be used, 
reduce ibrutinib to 140 mg
6.2.2
Drugs that May have Their Plasma Concentration Altered by Ibrutinib
In vitro studies indicated that ibrutinib is a mild 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 is no clinical data available. 
Therefore, to avoid a potential interaction in the GI tract, narrow therapeutic range P-gp 
substrates such as digoxin should be taken at least 6 hours before or after ibrutinib.


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6.2.3
Drugs That May Have Their Plasma Concentrations Altered by Venetoclax
Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and weak 
OATP1B1 inhibitor in vitro. To avoid a potential interaction in the gastrointestinal tract, 
coadministration of narrow therapeutic index P-gp substrates such as digoxin with venetoclax 
should be avoided. If a narrow therapeutic index P-gp substrate must be used, it should be taken 
at least 6 hours before venetoclax. 
A list of medications that are P-gp substrates is provided in Appendix D. For further information, 
please refer to the current venetoclax IB.
6.2.4
Antiplatelet Agents and Anticoagulants
6.2.4.1
Concomitant Use with Ibrutinib
Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet 
function, and supplements such as fish oil and vitamin E preparations should be avoided during 
treatment with ibrutinib. Bleeding events of any grade, including bruising and petechiae, 
occurred in patients treated with ibrutinib and the mechanism for the bleeding events is not well 
understood. Subjects with congenital bleeding diathesis have not been studied. Ibrutinib should 
be held at least 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk 
of bleeding (see Section 6.3).
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation), 
consider the risks and benefits of continuing ibrutinib treatment. If therapeutic anticoagulation is 
clinically indicated, treatment with ibrutinib/placebo should be held and not be restarted until the 
subject is clinically stable and has no signs of bleeding. No dose reduction is required when 
study drug is restarted. Subjects should be observed closely for signs and symptoms of bleeding.
6.2.4.2
Concomitant Use with Venetoclax
In a drug-drug interaction study in three healthy subjects, administration of a single 400 mg dose 
of venetoclax with 5 mg warfarin resulted in 18% to 28% increase in Cmax and AUC∞of 
R-warfarin and S-warfarin. Because venetoclax was not dosed to steady state, it is recommended 
that the international normalized ratio (INR) be monitored closely in subjects receiving warfarin.
6.2.5
Prohibited Concomitant Medications and Products for Ibrutinib and/or 
Venetoclax/placebo
Any non-study protocol-related chemotherapy, anticancer immunotherapy, experimental therapy, 
or radiotherapy are prohibited while the subject is receiving ibrutinib treatment.
Corticosteroids for the treatment of the underlying malignancy are prohibited (refer to 
Section 6.1 for further guidance).


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The Sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Subjects may not consume grapefruit or grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or star fruit within the 3-day period prior to the first 
ibrutinib and venetoclax administration and until the last day of treatment is completed due to 
possible CYP3A mediated metabolic interaction.
Do not administer live attenuated vaccines prior to, during, or after treatment with venetoclax. 
The safety and efficacy of immunization with live or attenuated viral vaccines during or
following venetoclax therapy have not been studied. Advise subjects that vaccinations may be 
less effective.
6.3
Guidelines for Ibrutinib Management with Surgeries or Procedures 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects who 
require surgical intervention or an invasive procedure while receiving ibrutinib: 
6.3.1
Minor Surgical Procedures
For minor procedures (such as a central line placement, skin or needle biopsy, lumbar puncture 
[other than shunt reservoir access], thoracentesis, or paracentesis) ibrutinib should be held for at 
least 3 days prior to the procedure and should not be restarted for at least 3 days after the 
procedure. For bone marrow biopsies that are performed while the subject is on ibrutinib, it is not 
necessary to hold ibrutinib.
6.3.2
Major Surgical Procedures
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be 
held at least 7 days prior to the intervention (except for emergency procedures) and should be 
held at least 7 days after the procedure and restarted at the discretion of the investigator when the 
surgical site is reasonably healed without serosanguineous drainage or the need for drainage 
tubes.


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7
STUDY EVALUATIONS
7.1
Description of Procedures
7.1.1
Assessments
7.1.1.1
ICF
The subject must read, understand, and sign the Institutional Review Board/Research Ethics 
Board/Independent Ethics Committee (IRB/REB/IEC) approved ICF confirming his or her 
willingness to participate in this study before any study-specific screening procedures are 
performed. Subjects in the US must also grant permission to use protected health information per 
the Health Insurance Portability and Accountability Act (HIPAA). In addition, subjects must sign 
all approved ICF amendments per the site IRB/REB/IEC guidelines during the course of the 
study.
7.1.1.2
Confirm Eligibility
All necessary procedures and evaluations must be performed to document that the subject meets 
all of the inclusion criteria and none of the exclusion criteria until first dose of study drug 
(Section 4).
7.1.1.3
Medical History and Demographics
The subject’s relevant medical history through review of medical records and by interview will 
be collected and recorded. Concurrent medical signs and symptoms must be documented to 
establish baseline severities. A disease history, including the date of initial diagnosis and list of 
all prior anticancer regimens, dates administered, and responses and DOR to these treatments, 
will also be recorded.
7.1.1.4
Prior and Concomitant Medications
All medications at least 14 days prior to the first dose through 30 days after the last dose of study 
drug will be documented. 
7.1.1.5
Adverse Events
The accepted regulatory definition for an AE is provided in Section 11.1. The occurrence of an 
AE at the time the ICF is signed until first dose should be recorded under medical history in the 
eCRF form. All medical occurrences after the first dose with study drug/treatment until 30 days 
after the last dose of study drug that meet the AE definition must be recorded as AEs in the 
eCRF. Laboratory abnormalities and changes in vital signs are considered to be AEs only if they 
result in dose reduction or treatment discontinuations, necessitate therapeutic medical 
intervention, meet protocol specific criteria or if the investigator considers them to be AEs. 
Additional important requirements for AE and SAE reporting are explained in Section 11.4.


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7.1.1.6
Physical Examination
The Screening and End-of-Treatment physical examination will include, at a minimum, the 
general appearance of the subject, height (Screening only) and weight, and examination of the 
skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, 
nervous system, and lymphatic system.
A limited symptom-directed physical examination may be required at selected timepoints as 
outlined in Section 8.
7.1.1.7
Eye-related Symptom Assessment
The subjects will be asked about eye-related symptoms.
If there are any eye-related symptoms of severity Grade ≥2 at Screening or if the subject 
develops any eye-related symptoms of severity Grade ≥2 while on study treatment, an 
ophthalmologic evaluation/consult must be performed, and the outcome must be reported on the 
ophthalmologic eCRF.
7.1.1.8
ECOG
The ECOG performance index is provided in Appendix C.
7.1.1.9
Vital Signs
Vital signs will include blood pressure, heart rate, and body temperature. Vital signs will be 
assessed after the subject has rested in the sitting position for ≥3 minutes.
7.1.1.10 Tumor Lysis Syndrome (TLS) Risk Assessment
At Screening, all study subjects will be assessed for risk of developing TLS. The risk of TLS is a 
continuum based on multiple factors, including comorbidities. Subjects at increased risk are 
defined as having at least one lesion > 10 cm; or at least one lesion > 5 cm and circulating 
lymphocytes > 25,000 cells/mm3 and/or have reduced renal function CrCl < 60 mL/min. The risk 
may decrease as tumor burden decreases with venetoclax treatment.
Blood chemistry (creatinine, uric acid, potassium, phosphorus, calcium, and albumin if available) 
assessments will be performed in all subjects within 72 hours prior to initiating venetoclax 
treatment.
Subjects with high tumor burden at baseline and/or CrCl < 60 mL/min will be hospitalized 
during the first 24-48 hours of treatment at the 20 mg (Week 1) and the 50 mg (Week 2) 
venetoclax dose. Blood chemistry (creatinine, uric acid, potassium, phosphorus, calcium, and 
albumin if available) should be monitored pre-dose and 4±1, 8±1, 12±1, 24±2 and, as needed, 
48±2 hours after the venetoclax dose. (Hospitalization for subjects lacking immediate access to a 


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facility capable of correcting TLS promptly or for subjects who are otherwise considered at risk 
for TLS should be discussed with the medical monitor). For all other subjects, blood chemistry 
will be monitored pre-dose, 6-8 and 24±2 hours after the venetoclax dose at the 20 mg and the 50 
mg dose levels.
During the remaining ramp-up weeks (weeks 3-5), for subjects at increased risk for TLS at 
baseline, blood chemistries will be monitored at pre-dose and 6-8 hours after each dose increase.
Appropriate venetoclax dosing and management of subjects throughout their study treatment is 
guided by their individual risk for developing TLS. Risk-based TLS prophylaxis and 
management measures are described in Section 5.3.2.2.
7.1.1.11 B-Symptoms
B-symptoms include fever > 38°C for at least 3 consecutive days, drenching night sweats or 
weight loss > 10% since the last disease assessment.
7.1.2
Laboratory
All laboratory tests will be collected by local lab.
7.1.2.1
Hematology
Hematology parameters will include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils.
7.1.2.2
Chemistry (Serum)
Blood chemistry parameters will include sodium, potassium, chloride, blood urea nitrogen 
(BUN)/Urea, creatinine, glucose, calcium, and albumin, if available, total protein, AST, ALT, 
alkaline phosphatase, total bilirubin, LDH, phosphorus, uric acid, magnesium and bicarbonate.
7.1.2.3
Coagulation Studies
Measurement of PT, INR and aPTT will be performed at Screening using a local laboratory. INR 
should be followed more closely in subjects on warfarin therapy.
7.1.2.4
Hepatitis Serologies
Hepatitis serologies include hepatitis C antibody, hepatitis B surface antigen, and hepatitis B 
core antibody. If hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody is 
positive, then PCR to quantitate hepatitis B DNA or hepatitis C RNA must be performed and 
must be negative prior to randomization/enrollment. This applies to the SRI and Randomization 
Phase only. Treatment-naive open-label arm subjects with a positive hepatitis B surface antigen 
test are excluded from the trial.


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7.1.2.5
Serum β2-microglobulin
One blood sample(s) for β2-microglobulin will be taken during the screening period.
7.1.2.6
Urinalysis
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.
7.1.2.7
Pregnancy Test
Serum or urine pregnancy test will be required at Screening by local laboratory only for women 
of childbearing potential. A serum or urine pregnancy test will also be performed on Day 1 prior 
to first dose. If positive, pregnancy must be ruled out by ultrasound, at least 3 weeks after a 
positive urine pregnancy test, to be eligible. This test may be performed more frequently if 
required by local regulatory authorities.
7.1.3
Diagnostics/Procedures
7.1.3.1
ECG
A single 12-lead ECG will be done at Screening and at the EOT visit. Subjects should be in a 
supine position and resting for at least 10 minutes before obtaining the ECG. During the 
treatment period, ECGs may be performed at the investigator’s discretion, particularly in subjects 
with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea.
During visits in which both ECGs and blood draws are performed, ECGs should be performed 
first.
Abnormalities noted at the Screening ECG should be included in the medical history.
7.1.3.2
CT/MRI and PET
SRI and Randomized Phase
Pretreatment tumor assessment will be performed within 28 days before the first dose of study 
drug.
A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis and any 
other disease sites and a PET scan are required for the pretreatment tumor assessment. CT scans 
with contrast will be done for tumor assessments on Week 13 Day 1 (±7 days); every 12 weeks 
for the remainder of the first year; every 16 weeks during the second and third years; and every 
24 weeks thereafter until PD. In subjects with positive PET at baseline, PET or PET/CT is 
mandatory to confirm a CR. Disease assessments may be repeated as clinically indicated to 
confirm response or progression.


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Lesions that have been irradiated cannot be included in the tumor assessment unless unequivocal 
tumor progression has been documented in these lesions after radiation therapy. There must be 
radiographically measurable disease at Screening (at least one lymph node ≥2.0 cm in the 
longest diameter). Up to 6 measurable lymph nodes (target lesions > 1.5 cm in the longest 
diameter), clearly measurable in 2 perpendicular dimensions, will be followed as target lesions 
for each subject. Measurable sites of disease should be chosen such that they are representative 
of the subject’s disease. In addition, selection of target lesions should be from as disparate 
regions of the body as possible when these areas are significantly involved. If additional lesions 
are present but are not included in the target lesion assessment, they can be added as non-target 
lesions and followed throughout the study.
Information on extranodal involvement (eg, gastric or ocular disease) will also be recorded. 
Lesions in anatomical locations that are not well visualized by CT may be measured by MRI 
instead and should continue to be measured by MRI until disease progression.
In the case where CT contrast is contraindicated, an alternative would be MRI of the abdomen 
and pelvis with MRI contrast and CT of the chest and neck without CT contrast. In this case, 
neck nodes cannot be used as target lesions.
NOTE: PET/CT hybrid scanners may be used to acquire the required CT images only if the CT 
produced by the scanner is of diagnostic quality, adheres to the specified slice thickness/scan 
parameters, and includes the use of intravenous (IV) contrast. Additionally, the CT images must 
be separated from the PET data prior to submitting the data and cannot be transmitted as fused 
CT/PET images.
If using a hybrid machine to acquire both PET and CT, the PET must be performed prior to the 
CT with IV contrast as to not compromise PET results.
If a CT with contrast scan indicates suspected CR, a confirmatory PET scan may be performed 
within 30 days.
For subjects who remain stable with PR for > 6 months with residual lymph node lesions 
> 1.5 cm that remain relatively unchanged, a PET scan may be performed to determine if CR has 
been achieved and MRD testing should be implemented.
De-identified copies of all scans and radiology reports (including those from screening) must be 
provided to the Sponsor or designee (eg, central imaging vendor). At the Sponsor’s discretion, 
the Sponsor or its designee may conduct an independent review of the investigator responses.
Treatment-naive Open-label Arm
CT and PET or PET/CT scans (with contrast unless contraindicated) of the neck, chest, 
abdomen, and pelvis and any other disease sites (eg, extremity) and a PET scan are required for 
the pretreatment tumor assessment within 28 days of the 1st dose. Thereafter, CT scans will be 


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done for tumor assessments on Week 13 Day 1 (±7 days); every 12 weeks for the remainder of 
the 1st year; every 16 weeks during the 2nd and 3rd years; and every 24 weeks thereafter until PD. 
PET or PET/CT is mandatory for all subjects at the Week 13 visit (+/- 7 days), the Week 25 visit 
(+/- 7 days) for subjects in SD or PR who did not achieve CR at Week 13, and at the 1-year visit 
(Week 49 +/- 7 days) for all subjects, as well as at any other time point to confirm a CR. Other 
PET or PET/CT scans that are NOT mandatory can be performed within a 30-day window of the 
visit. For MRI refer to Section 7.1.3.2.
7.1.3.3
Endoscopy
Endoscopy is optional at baseline but is required and must be negative to confirm CR (preferably 
within 30 days of the initial documentation of CR) in subjects with known endoscopy-positive 
GI involvement at baseline.
7.1.3.4
Tumor Tissue
Approximately 20 slides of fresh or most recent dated FFPE archival tumor biopsy tissue will be 
collected at study entry and evaluated for biomarker assessment. An optional fresh tumor biopsy 
may be collected at the time of disease progression.
Confirmation of MCL diagnosis is required prior to enrollment; a report from the local 
laboratory is acceptable. The diagnosis of MCL from the local laboratory must include 
morphology and expression of either cyclin D1 in association with other relevant markers 
(eg, CD20 and CD5) or evidence of t(11;14)(q13;q32) as assessed by cytogenetics or fluorescent 
in situ hybridization (FISH). The report containing this information must be sent to the central 
laboratory and the sponsor for confirmation of the diagnosis prior to enrollment.
For subjects who do not have this report available, the formalin-fixed paraffin embedded (FFPE) 
tumor tissue block or slides must be sent to the central laboratory and confirmation of MCL 
diagnosis must be obtained from the central laboratory prior to enrollment.
7.1.3.5
Bone Marrow Biopsies for Evaluation of Bone Marrow Involvement
A unilateral bone marrow biopsy must be collected at Screening up to 28 days prior to the first 
administration of study drug to be evaluated for bone marrow involvement, unless prior bone 
marrow biopsy is obtained within 90 days prior to study treatment. Additional bone marrow 
biopsy will be collected in subjects with documented CR.
Bone marrow involvement must be assessed locally prior to enrollment. A local pathology report 
must be available for review. If a local pathology report is not available, bone marrow 
involvement will be assessed at the central lab. For subjects that meet CR criteria, if a local 
pathology report is not available, a bone marrow biopsy will need to be tested to ensure there is 
no lymphoma involvement in the bone marrow to confirm CR.


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If the subject’s physical examination findings, laboratory evaluations, radiographic 
evaluations and endoscopy (if applicable) suggest that CR has been achieved in all other 
response parameters, a bone marrow biopsy must be obtained for subjects with bone marrow 
involvement at baseline (by standard pathology) to confirm the CR. If the response parameters 
indicate a suspected CR, a bone marrow biopsy may be collected within 30 days to confirm CR.
7.1.3.6
Bone Marrow Aspirate and Peripheral Blood for Minimal Residual Disease 
(MRD) Assessment
Minimal residual disease assessment will be performed by flow cytometry at Screening for every 
subject to detect a dominant clone in peripheral blood or bone marrow aspirate. MRD negativity 
will be assessed by flow cytometry both in the peripheral blood and the bone marrow aspirate 
collected at documented CR. Thereafter subjects should be followed with peripheral blood MRD 
analyses by flow cytometry every 12 weeks (±7 days) for the remaining first year; every 
16 weeks during the second and third years; and every 24 weeks thereafter until PD. 
MRD-negative remission is defined as undetectable MRD at documented CR in subjects who 
were MRD positive at screening as assessed by flow cytometry in bone marrow (BM) aspirate 
and/or peripheral blood and a consecutive peripheral blood sample 12 weeks later.
If the MRD assessment is positive in bone marrow at CR, a repeat bone marrow aspirate is 
required 24 weeks later if the subject remains in CR to evaluate MRD status in the bone marrow.
If peripheral blood becomes positive for MRD, a bone marrow sample will not be necessary; 
however, equivocal cases should be discussed with the medical monitor to determine the need 
for repeat bone marrow testing.
MRD-positive relapse is defined as a detectable increase in disease after a MRD-negative 
remission, as assessed by flow cytometry of a peripheral blood or BM aspirate sample.
7.1.3.7
Bone Marrow Aspirate and Peripheral Blood for Biomarker Assessment
Bone marrow aspirates and peripheral blood samples will be stored for exploratory biomarker 
analysis. ClonoSEQ (Adaptive Biotechnologies), a highly sensitive and exploratory MRD 
detection assay, will also be used for retrospective assessment of MRD in a subset of collected 
samples of bone marrow and peripheral blood to compare MRD negativity as determined by 
flow cytometry. If the ClonoSeq technology assay is not available for use or a technically 
superior assay for MCL MRD has emerged at the time of testing, an alternative molecular MRD 
assay with equivalent or better analytical performance may be used for analysis.


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7.1.4
Pharmacokinetics/Biomarkers
7.1.4.1
Pharmacokinetics for Safety Run-in and Randomization Phase
Ibrutinib and venetoclax should be dosed together at the same time with 8 ounces of water and a 
meal. It is anticipated that steady state will be reached after 1 week of administration of the 
highest venetoclax dose. Ibrutinib and venetoclax PK samples will be collected at steady state on 
the PK days as shown in Table 8 at the time points listed in Table 9.
Table 8.
Ibrutinib and Venetoclax PK Samples Schedule at the Target Dose
Dosing Schedule
PK Day
Standard ramp-up
Week 6 Day 1
Pharmacokinetics of ibrutinib and venetoclax when dosed in combination will be determined at 
time-points specified in Table 9 below.
Table 9.
Pharmacokinetic Sample Schedule for Ibrutinib and Venetoclax or 
placebo on the PK Days
Study Drugs
Pre-dose 
PKa
Doseb
Time after ibrutinib and venetoclax dose
1 hour
(± 15 
min)
2 hour 
(± 15 min)
4 hour 
(± 30 min)
6 hour
(± 30 min)
8 hour
(± 1 h)
Ibrutinib and 
Venetoclax or 
Placebo*
X
X
X
X
X
X
X
a Predose samples should be collected 30 minutes prior to the administration of ibrutinib and venetoclax or placebo 
b Ibrutinib/venetoclax or placebo should be dosed the same time within 30 minutes after completion of the meal.
Example: 
Predose PK 
7:00 am
Breakfast7:00 to 7:30 am
Dose 
7:30 am
1 hr PK
8:30 am
2 hr PK
9:30 am 
4 hr PK
11:30 am
6 hr PK
1:30 pm
8 hr PK
3:30 pm
* Unscheduled PK sampling schedule based on Medical Monitor request, e.g. dose modification (at least 7 days after dose
modification)
Refer to the laboratory binder for instructions on collecting and processing these samples. On the 
day of the sampling visit, the clinical staff will instruct the subject to not take a dose before 
arrival at the clinic. Study drug intake will be observed by clinic staff. The actual time (versus 
requested time) that each sample is drawn must be recorded using a 24-hour format. The same 
clock should be used for recording the time of dosing. In the event that medical management is 
needed, use of concomitant medications should be recorded. In the case of ibrutinib or 


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venetoclax/placebo dose holds or modifications prior to the above time points, please consult 
with medical monitor to determine the most appropriate time at which to obtain PK blood 
samples.
For subjects who must start a moderate or strong CYP3A inhibitor while on treatment with 
ibrutinib or venetoclax, additional PK blood samples for the evaluation of ibrutinib and 
venetoclax exposure is requested at least one week after the initiation of the concomitant CYP3A 
inhibitor. PK samples will be collected at the time points described above.
7.1.4.2
Pharmacokinetics Treatment-naive Open-label Arm
Ibrutinib and venetoclax should be dosed together at the same time with 8 ounces of water and a 
meal. It is anticipated that steady state will be reached after 1 week of administration of the 
highest venetoclax dose. Ibrutinib and venetoclax PK samples will be collected at steady state on 
the PK days as shown at the time points listed in Table 10.
Table 10.
Pharmacokinetic Sample Schedule for Treatment-naive Open-label Arm
Study Arm
Week
Study 
Day
Predosea
Time Point Postdose
Doseb
1h
(± 15 
min)
2h
(±15min)
4h
(± 30 
min)
6h
(±30 
min)
8h
(±1 h)
Treatment-
naive 
Open-
label*
4
7
X
X
X
X
X
X
X
6
1
X
X
X
X
X
X
X
13 & 
beyond
(+/- 7 
days)
X
X
X
X
a Predose samples should be collected 30 minutes prior to the administration of ibrutinib and venetoclax 
b Ibrutinib and venetoclax should be dosed the same time within 30 minutes after completion of the meal.
* Unscheduled PK sampling schedule based on Medical Monitor request, e.g. dose modification (at least 7 days after dose 
modification)
Refer to the laboratory binder for instructions on collecting and processing these samples. On the 
day of the sampling visit, the clinical staff will instruct the subject to not take a dose before 
arrival at the clinic. Study drug intake will be observed by clinic staff. The actual time (versus 
requested time) that each sample is drawn must be recorded using a 24-hour format. The same 
clock should be used for recording the time of dosing. In the event that medical management is 
needed, use of concomitant medications should be recorded. In the case of ibrutinib or 
venetoclax dose holds or modifications prior to the above time points, please consult with 
medical monitor to determine the most appropriate time at which to obtain PK blood samples.
For subjects who must start a moderate or strong CYP3A inhibitor while on treatment with 
ibrutinib or venetoclax, additional PK blood samples for evaluation of ibrutinib and venetoclax 
exposure is requested at least one week after the initiation of the concomitant CYP3A inhibitor. 
PK samples will be collected at the time points described above.


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7.1.4.3
Exploratory Biomarkers
Blood samples and a buccal swab will be collected and sent to the central laboratory at selected 
time points specified in the Schedule of Assessments (Appendix A and Appendix B).
Approximately 20 slides of fresh or most recent dated FFPE archival tumor biopsy tissue will be 
collected at study entry. An optional fresh tumor biopsy may be collected at the time of disease 
progression. A bone marrow aspirate and a bone marrow biopsy will be collected based on 
Section 7.1.3.5 and Section 7.1.3.6. Tumor cells from peripheral blood, bone marrow and/or 
tumor tissue may be studied for genomic alterations, as well as gene and/or protein expression 
profiling. Non-cancer cell genes derived from the buccal swab will only be used as a control for 
the cancer gene mutation analysis. In addition to the markers known to be involved in MCL 
prognosis, inhibition of BCR signaling and BCL-2 pathways may also be explored. These efforts 
may identify biomarkers that could support the understanding of the disease or assist with future 
development of treatment options.
Bone marrow aspirate and peripheral blood samples will be stored for exploratory biomarker 
analysis by clonoSEQ. Samples collected in this study may be stored at a biorepository for up to 
10 years (or according to local regulations) for additional research as new assays are developed 
for ibrutinib, venetoclax and MCL. Samples will only be used to better understand the effects 
ibrutinib and venetoclax in MCL; sensitivity and/or resistance to the investigational treatment 
regimen in this study.
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.
7.1.5
Patient-Reported Outcomes
7.1.5.1
FACT-Lym for Safety Run-in and Randomization Phase
The FACT-Lym questionnaires (Appendix I) will be administered in this study. The FACT-Lym 
was originally developed to assess functional status and well-being of patients with NHL 
(Eremenco 2004). Reliability and validity have been assessed in NHL (Webster 2005) and more 
recently construct validity has been supported in subjects with relapsed/refractory MCL 
(Carter 2008).
The FACT-Lym consists of the Functional Assessment of Chronic Illness Therapy - General 
(FACT-G) and a lymphoma-specific additional concerns subscale (Lym).
Responses to all items are rated on a 5-point scale ranging from 0 “not at all” to 4 “very much”. 
The recall period is the past 7 days. The lymphoma subscale includes 15 items and scores range 
from 0 to 60. Two summary scores may also be calculated: the FACT-Lym total score (FACT-G 
plus Lym) and the FACT-Lym trial outcome index (TOI) score (physical well-being+functional 


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well-being+lymphoma). Higher scores represent better functional status and well-being for all 
subscales and summary scales.
The subscale of most interest in this study will be the Lym subscale. Carter (Carter 2008) and 
Cella et al. (Cella 2005) reported a minimal important change score for the Lym subscale in a 
relapsed/refractory MCL population range from approximately 2.9 to 5.4. Therefore, a 5-point 
change in the Lym subscale was selected as a conservative estimate of clinically meaningful 
deterioration in lymphoma symptoms. Time to complete the FACT-Lym is approximately 7 to 
12 minutes. All translations not currently available will be completed according to best practice 
guidelines for translating PRO instruments to the local language(s) (Wild 2005).
The FACT-Lym questionnaire (Appendix I) will be administered at the beginning of the clinic 
visits prior to any procedures or physician interactions to prevent influencing subject 
perceptions. The questionnaires will be administered on Week 1 Day 1, Week 13 Day 1 
(±7 days); every 4 weeks for the remainder of the first year; every 8 weeks during the second and 
third years; and every 12 weeks thereafter until disease progression.
7.1.5.2
EQ-5D-5L for SRI, Randomization Phase and Treatment-naive Open-label Arm
The EQ-5D-5L (Appendix J) is a standardized instrument used to measure health outcome 
(EuroQol Group 1990) and consists of a 5-item questionnaire and a “thermometer” visual analog 
scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The 
scores for the 5 dimensions are used to compute a single utility score ranging from 0 to 1, 
representing the general health status of the individual. The 5 dimensions evaluated are mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. The questionnaire will be 
administered on the same visit schedule as the FACT-Lym.
7.1.6
Medical Resource Utilization (MRU)
Medical resource utilization including hospitalizations, emergency department visits, and 
hematopoietic growth factor use will be collected for each treatment arm throughout the study 
treatment period.
7.2
Efficacy Evaluations
7.2.1
Overall Response Assessments
Overall response assessments will include physical examinations, recording of symptoms, 
hematological test results, bone marrow aspirate or bone marrow biopsy, CT/PET radiological 
evaluations and endoscopy per the schedule of assessments (Appendix A and Appendix B). 
Response assessments will be performed according to the Revised Criteria for Response 
Assessment of Malignant Lymphoma (Cheson 2014), as assessed by investigators (Appendix E) 
until disease progression or withdrawal of consent from the study.


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7.2.2
Survival
After progression, survival status will be assessed approximately every 12 weeks until death, 
withdrawal by subject, or study terminated by Sponsor, whichever comes first. Data on the 
subsequent lines of anticancer therapy will be captured. Survival sweeps will be conducted at the 
time of the final analysis. All subjects who are on study and not known to have died prior to the 
survival sweep will be contacted at that time.
7.3
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in source documents for 
transcription to the eCRF or laboratory requisition form. Refer to the Schedule of Assessments 
(Appendix A and Appendix B) for the timing and frequency of all sample collections.
Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual.
8
STUDY PROCEDURES
8.1
Screening Phase
Screening procedures will be performed up to 28 days before the first dose of ibrutinib and 
venetoclax/placebo, unless otherwise specified, and may be performed over more than 1 visit. 
All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any 
study-specific screening procedures are performed. After signing the ICF, Screening, and being 
deemed eligible for entry, subjects will be enrolled in the study.
8.1.1
Screening/Consenting Visit
The following procedures will be performed at the Screening Visit within 28 days prior to 
enrollment unless otherwise noted:

Review of eligibility criteria

Medical history including demographic information and prior treatments for MCL 
(if applicable)

Collection of pathology report for cytogenetics/FISH documenting MCL diagnosis 
(if available)

Collection of approximately 20 slides of fresh or most recent dated FFPE archival 
tumor biopsy tissue, OR tumor biopsy obtained by core needle biopsy prior to 
randomization

Document bone marrow disease involvement (bone marrow biopsy must be 
obtained at Screening or up to 90 days before the first dose of study drug for disease 
confirmation)


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
Record concomitant medications (including chemotherapy, radiation, over-the-
counter drugs, vitamins, and herbs)

Perform a complete physical examination, including height (may use prior height 
measurement if available in source documents), weight and examination of the skin, 
eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, 
lymphatic system, and nervous system

B-symptom assessment

Obtain vital signs (including blood pressure, heart rate, and body temperature) after 
the subject has rested in the sitting position for ≥3 minutes.

Evaluation of ECOG PS

Determination of Medical Resource Utilization (MRU)

Obtain a single 12-lead ECG after the subject has been in a supine position and 
resting for at least 10 minutes.

AEs (record as Medical History on eCRF)

Obtain bone marrow biopsy and aspirate (within 28 days prior to first dose) as 
described in Section 7.1.3.5

Obtain blood specimens for the following laboratory tests
o
Hematology
o
Blood chemistry (including creatinine clearance)
o
Coagulation panel (PT/INR, aPTT)
o
Hepatitis Serologies
o
Serum β2-microglobulin
o
Urinalysis
o
Obtain serum or urine pregnancy test for women of childbearing potential only

Imaging by CT and/or other modality as described in Section 7.1.3.2.

TLS risk assessment and prophylaxis within 72 hours of first dose of venetoclax
o
Serum creatinine, uric acid, potassium, phosphorus, calcium, and albumin, if available
o
Determination of level of risk and need for hospitalization
o
Hydration: subject education
o
Prescription of allopurinol (and rasburicase for high risk subjects)
8.2
Treatment Phase
Following completion of the Screening Visit and once eligibility has been confirmed (per 
inclusion/exclusion criteria), subjects will initiate study treatment (see Section 5.2 for ibrutinib 
and venetoclax dosing).


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Refer to the Schedule of Assessments (Appendix A and Appendix B) for a complete list of 
procedures to be performed at each scheduled study visit.
8.2.1
Treatment Visits for Standard Ramp-up Schedule for SRI, Randomization Phase, 
and Treatment-naive (TN) Open-label Arm
8.2.1.1
Week 1 Day 1 and Week 2 Day 1
Pre-dose (within 72 hours prior to the first venetoclax dose and before each dose increase)

Confirmation of eligibility (per inclusion/exclusion criteria) at week 1 only.

Update medical history at week 1 only

AEs

Concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins, and herbs)

Physical examination

Vital signs

ECOG PS (Week 1 Day 1 only)

PRO at week 1 only

Determination of Medical Resource Utilization (MRU)

TLS risk assessment and prophylaxis

Hospitalization of subjects with high tumor burden

Laboratory Tests
o
Hematology
o
Blood chemistry
o
Serum or urine pregnancy test (for women of childbearing potential only) 
(Week 1 Day 1 only)
o
MRD peripheral blood (Week 1 Day 1 only)
o
Biomarker blood sample (Week 1 Day 1 only)
o
Buccal Swab (Week 1 Day 1 only)
Dosing – Week 1 Day 1 and Week 2 Day 1
The dose of venetoclax or placebo should not be administered until the blood chemistry results 
have been evaluated.

In-clinic administration of venetoclax or placebo with a meal

In-clinic administration of ibrutinib


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Post-dose

For hospitalized subjects, serum creatinine, uric acid, potassium, phosphorus, 
calcium, and albumin, if available should be monitored at 4±1, 8±1, 12±1 hours, 
after the venetoclax/placebo dose.

For all outpatient subjects, serum creatinine, uric acid, potassium, phosphorus, 
calcium, and albumin, if available should be monitored at 6-8 hours after the 
venetoclax/placebo dose.

Any changes in these parameters should be managed promptly and treatment 
modified before any further venetoclax/placebo is administered.
8.2.1.2
Week 1 Day 2 and Week 2 Day 2
Pre-dose

AEs

Concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins, and herbs)

Vital signs

Laboratory Tests
o
Blood chemistry (creatinine, uric acid, potassium, phosphorus, calcium, and 
albumin, if available) 

TLS risk assessment and prophylaxis

Determination of Medical Resource Utilization (MRU)
Dosing – Week 1 Day 2 and Week 2 Day 2
The dose of venetoclax/placebo should not be administered until the 24-hour blood chemistry 
monitoring results have been evaluated.

In-clinic administration of venetoclax/placebo with a meal

In-clinic administration of ibrutinib
8.2.1.3
Week 1 Day 3 and Week 2 Day 3 (Hospitalized Subjects Only)
Pre-dose

AEs

Concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins, and herbs)

Laboratory Tests
o
Blood chemistry monitoring (creatinine, uric acid, potassium, phosphorus, 
calcium, and albumin, if available)


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
TLS risk assessment and prophylaxis

Determination of Medical Resource Utilization (MRU)
Dosing – Week 1 Day 3 and Week 2 Day 3
The dose of venetoclax/placebo should not be administered until the blood chemistry monitoring 
results have been evaluated.

In-clinic administration of venetoclax/placebo with a meal

In-clinic administration of ibrutinib
Dosing – Week 1 Day 3 and Week 2 Day 3
The dose of venetoclax or placebo should not be administered until the blood chemistry 
monitoring results have been evaluated.

In-clinic administration of venetoclax or placebo with a meal

In-clinic administration of ibrutinib
8.2.1.4
Weeks 3, 4, and 5 Day 1 for Standard Ramp-up Schedule
Pre-dose

AEs

Concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins, and herbs)

Physical examination

Vital signs

ECOG PS (Week 3 Day 1 only)

Determination of Medical Resource Utilization (MRU)

TLS risk assessment and prophylaxis

Laboratory Tests
o
Hematology
o
Blood chemistry

Pharmacokinetics (only for TN open-label arm, on Week 4 Day 7). Pre-dose (± 30 min);


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Dosing
The dose of venetoclax or placebo should not be administered until the blood chemistry results 
have been evaluated.

In-clinic administration of venetoclax or placebo with a meal

In-clinic administration of ibrutinib
Post-dose

Blood chemistry monitoring (creatinine, uric acid, potassium, phosphorus, calcium, 
and albumin, if available) 

Post-dose 1 hour (±15 min), 2 hours (±15 min), 4 hours (±30 min), 6 hours 
(±30 min) and 8 hours (±1 hour) after the administration of ibrutinib and venetoclax
o
For subjects with high tumor burden, serum creatinine, uric acid, potassium, 
phosphorus, calcium, and albumin, if available should be monitored at 6-8 hours 
after the start of the venetoclax or placebo dose at each ramp-up dose level. Any 
changes in these parameters should be managed promptly and treatment 
modified before any further venetoclax or placebo is administered.
8.2.1.5
Week 6 Day 1
Pre-dose

AEs

Concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins, and herbs)

Physical examination

Vital signs

ECOG PS

Determination of Medical Resource Utilization (MRU)

TLS risk assessment and prophylaxis

Laboratory Tests
o
Hematology
o
Blood chemistry
o
PK samples for ibrutinib and venetoclax or placebo 
Dosing 

In-clinic administration of venetoclax or placebo with a meal

In-clinic administration of ibrutinib


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Post-dose

PK samples for ibrutinib and venetoclax or placebo 1 hour (±15 min), 2 hours 
(±15 min), 4 hours (±30 min), 6 hours (±30 min) and 8 hours (±1 hour) after the 
administration of ibrutinib and venetoclax or placebo (see Section 7.1.4)
8.2.1.6
Week 8 Day 1 (± 1 Day) and Week 10 Day 1 (± 1 Day)

AEs

Concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins, and herbs)

Physical examination

Vital signs

Determination of Medical Resource Utilization (MRU)

TLS risk assessment and prophylaxis

Laboratory Tests
o
Hematology
o
Blood chemistry
Dosing

In-clinic administration of venetoclax or placebo with a meal

In-clinic administration of ibrutinib
8.2.1.7
Week 13 and beyond (±7 Days)

AEs

Concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins, and herbs)

PRO at response assessment visits (see Section 7.1.5 for all timepoints 
[Appendix I])

Physical examination

Vital signs

ECOG PS

Determination of Medical Resource Utilization (MRU)

TLS risk assessment and prophylaxis

Response Assessments


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
For TN open-label arm only
o
Week 13 mandatory PET scan for all subjects.
o
Week 25 mandatory PET scan for subjects in SD and PR at Week 13.
o
Week 49, mandatory PET scan for all subjects

Laboratory Tests
o
Hematology
o
Blood chemistry

For TN open-label arm only
o
Week 13 Day 1: Pharmacokinetics. Pre-dose (±30 min); Post-dose 1 hour 
(±15 min), 2 hours (±15 min) after the administration of ibrutinib and 
venetoclax
After Week 13, clinic visits are scheduled every 4 weeks for one year; every 8 weeks during the 
second and third years; and every 12 weeks thereafter until treatment discontinuation. At each 
clinic visit subject should be supplied with enough study drug to last until the next clinic visit.
8.2.2
Response Evaluation 
Response assessment visits should occur on Week 13 Day 1, then every 12 weeks for the first 
year; every 16 weeks during the second and third years; and every 24 weeks thereafter until PD. 
In addition, response assessments can be performed as clinically indicated to confirm response or 
progression.

CT/PET/MRI/endoscopy

Overall response assessment

B-symptoms

Laboratory Tests
o
Hematology
o
MRD BMA (at CR only)
o
Biomarker BMA (at CR only)
o
MRD peripheral blood
o
Biomarker peripheral blood
o
Bone marrow biopsy (at CR only, if baseline is positive for lymphoma or 
missing)

Determination of Medical Resource Utilization (MRU)


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8.2.3
End-of-Treatment Visit 

AEs

Concomitant medications (including chemotherapy, radiation, over-the-counter 
drugs, vitamins, and herbs)

ECG

Determination of Medical Resource Utilization (MRU)

Laboratory Tests
o
Hematology
o
Blood chemistry
o
Urinalysis
o
Serum or urine pregnancy test for women of childbearing potential only
o
MRD peripheral blood
o
Biomarker blood

Physical Exam

Vital signs
8.3
Follow-up Phase
Once a subject has completed the End-of-Treatment Visit, they will enter the Follow-up Phase.
8.3.1
Response Follow-up
Subjects who discontinue treatment for reasons other than PD will participate in the response 
follow-up. From the time of first dose (Safety Run-in Period and TN open-label arm) or 
randomization (for Randomization Phase), these subjects will be followed every 12 weeks for the 
first year; every 16 weeks during the second and third years; and every 24 weeks thereafter until 
PD. Once subjects progress (for subjects who have not withdrawn consent), they will start the 
Long-term Follow-up.
8.3.2
Long-term Follow-up
Subjects in Long-term Follow-up will be contacted approximately every 12 weeks (±14 days) by 
clinic visit or telephone to assess survival and the use of alternative anticancer therapy. Subjects 
will be contacted until death, subject withdrawal, or study termination by the Sponsor, whichever 
occurs first.


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9
SUBJECT COMPLETION AND WITHDRAWAL
9.1
Completion
A subject will be considered to have completed the study, if he or she has died before the end of 
the study, has not been lost to follow up, or has not withdrawn consent before the end of the 
study.
9.2
Withdrawal from Study Treatment
Study treatment will be discontinued in the event of any of the following events:

Progressive disease including clinical progression

Unacceptable toxicity: an intercurrent illness or AE that prevents further ibrutinib or 
venetoclax administration

Withdrawal of consent for treatment by subject

Investigator decision (such as chronic noncompliance, significant protocol 
deviation, clinical deterioration, or best interest of the subject)

Study termination by Sponsor

Subject becomes pregnant
All subjects, regardless of reason for discontinuation of study treatment will undergo an 
End-of-Treatment Visit and, if applicable, be followed for progression and survival.
The investigator should notify the Sponsor within 24 hours if a subject discontinues study 
treatment (ibrutinib and/or venetoclax/placebo) due to disease progression and should provide
documentation of disease progression for review by the medical monitor. If a subject shows 
signs of disease progression on physical examination or laboratory assessment, the subject may 
continue study treatment until disease progression is confirmed. These subjects should stay in the 
study to be followed for survival.
9.3
Withdrawal from Study
Withdrawal from study (including all follow-up) will occur under the following circumstances:

Withdrawal of consent for follow-up observation by the subject

Lost to follow-up

Study termination by Sponsor

Death
If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject. The measures taken to follow up should be documented.


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When a subject withdraws before completing the study, the following information should be 
documented in the source documents:

Reason for withdrawal;

Whether the subject withdraws full consent (ie, withdraws consent to treatment and 
all further contact) or partial consent (ie, withdraws consent to treatment but agrees 
to participate in follow-up visits).
10 STATISTICAL METHODS AND ANALYSIS 
Statistical analysis will be done by the Sponsor or under the authority of the Sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details including alpha allocation, study power consideration, secondary 
endpoint ranking, analysis populations, and detailed analysis plan will be provided in a separate 
Statistical Analysis Plan (SAP). The SAP may supersede the protocol specifics, provided 
modifications to the protocol are justified and clearly documented.
The study consists of an open-label Safety Run-in portion and a double-blind Randomization 
Phase portion for subjects with relapsed/refractory MCL. The Safety Run-in portion is to 
evaluate the occurrence of TLS and DLTs with the concurrent administration of ibrutinib and 
venetoclax. The double-blind portion is to evaluate the efficacy and safety of the combination of 
ibrutinib and venetoclax in comparison to the combination of ibrutinib and placebo. Endpoints 
from the Safety Run-in Period will be summarized descriptively and separately from the 
Randomization Phase data. Endpoints from the Randomization Phase portion will be 
summarized and analyzed as described in the later sections.
The study includes a separate open-label arm for treatment-naive subjects: A total of 
approximately 75 subjects, with approximately 50 subjects ≥65 years of age and approximately 
25 subjects with a TP53 mutation. Endpoints for the Treatment-naive Open-label arm will be 
summarized and analyzed as described in Section 10.5.2.
10.1 Analysis Population
10.1.1 Safety Run-in Period Evaluable Population
Subjects who miss ≥20% of the planned doses of ibrutinib or venetoclax for reasons other than 
toxicity (eg, non-compliance, withdrawal of consent, disease progression) during the TLS and 
DLT assessment period, or subjects who do not complete the TLS and DLT assessment period for 
any reason other than TLS or a DLT will be considered non-evaluable and will need to be 
replaced.


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10.1.2 Safety Population
The Safety Population consists of all subjects treated with at least one dose of any study drug 
(ibrutinib or venetoclax) in the double-blind portion. The safety population will be used for the 
analysis of safety data.
Subjects receiving at least one dose of study drug in the Treatment-naive Open-label arm will be 
included in the All-Treated population described in Section 10.2.5.
10.1.3 Intent-to-Treat Population in Randomization Phase
The Intent-to-Treat (ITT) Population consists of all subjects randomized into the Randomization 
Phase portion of the study, with subjects grouped according to the treatment assigned at 
randomization. It will be used for the analysis of Randomization Phase efficacy data.
10.1.4 All-Treated Population for Treatment-naive Open-label Arm
The All-Treated Population for the open-label arm consists of treatment-naive subjects who 
received at least one dose of study drug (ibrutinib or venetoclax) and will be used as the primary 
population for the efficacy and safety analyses.
10.1.5 Additional Analysis Population
Additional analysis populations will be defined in the SAP.
10.2 Endpoints
10.2.1 Safety Run-in Period

Frequency of TLS and DLTs

Frequency, severity, and relatedness of AEs

Frequency of AEs causing study drug discontinuation, or dose reductions or leading 
to death

Response (CR, PR), DOR, and PFS

OS
Unless indicated otherwise, the safety and efficacy data from the Safety Run-in portion will be 
summarized descriptively including all treated subjects and separately from the double-blind 
portion of the study. Details will be specified in the SAP. 
10.2.2 Randomization Phase Primary Endpoint
The primary efficacy endpoint of the Randomization Phase portion of this study is PFS, defined 
as the duration from the date of randomization to the date of investigator-assessed disease 


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progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or 
death from any cause, whichever occurs first.
10.2.3 Randomization Phase Secondary Endpoints 
Efficacy:

Complete response rate (CR) based on the best overall response per investigator 
assessment according to the Revised Response Criteria for Malignant Lymphoma 
(Cheson 2014).

Overall response rate (ORR), defined as CR or PR per investigator assessment 
according to the Revised Response Criteria for Malignant Lymphoma 
(Cheson 2014).

MRD-negative remission rate in subjects who achieve CR per investigator 
assessment. A MRD-negative remission is defined as undetectable MRD at 
documented CR in subjects who were MRD positive at screening as assessed by 
flow cytometry in bone marrow and/or peripheral blood, with requirement of 
confirmation of MRD negativity in the subsequent peripheral blood 12 weeks later. 
OS, defined as the time from randomization to death from any cause.

DOR, defined for subjects who achieve an overall response as the time from the 
first occurrence of response (CR or PR) to disease progression or death, whichever 
occurs first.

TTNT, defined as the duration from the date of randomization to the start date of 
any anti-lymphoma treatment subsequent to study treatment.
Safety:

Frequency, severity, and relatedness of AEs

Frequency, severity and management of TLS

Frequency of AEs requiring discontinuation of study drug or dose reductions, or 
leading to death
Pharmacokinetics:

Pharmacokinetics of ibrutinib at steady state

Pharmacokinetics of venetoclax at steady state
Patient Reported Outcomes (PRO):

Time to worsening in FACT-Lym subscale of the health-related quality of life 
questionnaire (FACT-Lym)


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10.2.4 Randomization Phase Exploratory Endpoints

Patient-reported outcomes by EQ-5D-5L

Medical resource utilization (MRU)
10.2.5 Treatment-naive Open-label Arm Primary Endpoint
The primary efficacy endpoint of the treatment-naive open-label arm is the complete response 
(CR) rate based on the best overall response according to the Revised Response Criteria for 
Malignant Lymphoma (Cheson 2014).
10.2.6 Treatment-Naive Open-Label Arm Secondary Endpoints

Overall response rate (ORR), defined as CR or PR according to the Revised 
Response Criteria for Malignant Lymphoma (Cheson 2014)

Duration of Response (DOR), defined for subjects who achieve an overall response 
as the time from the first occurrence of response (CR or PR) to disease progression 
or death, whichever occurs first

Duration of CR, defined for subjects who achieve CR as the time from the first 
occurrence of CR to disease progression or death, whichever occurs first

MRD-negative remission rate in subjects who were MRD positive at screening and
achieve CR. MRD-negative remission is defined the same as described in 
Section 10.2.3.

PFS, defined as the time from the date of the first dose of study treatment to the date 
of disease progression using the Revised Response Criteria for Malignant 
Lymphoma (Cheson 2014), or death from any cause, whichever occurs first

OS, defined as the time from the date of the first dose of study treatment to death 
from any cause

TTNT, defined as the duration from the date of the first dose of study treatment to 
the start date of any anti-lymphoma treatment subsequent to study treatment
10.2.7 Treatment-naive Open-label Arm Exploratory Endpoints

Identification of biomarkers that are predictive of response (or resistance) to study 
treatment

Patient-reported outcome by EQ-5D-5L
10.3 Sample Size Determination (Randomization Phase)
The Randomization Phase sample size will be powered based on the primary endpoint of PFS. 
Approximately 260 subjects will be randomized at a 1:1 ratio.


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The null hypothesis is hazard ratio (HR) ≥1 for the ibrutinib and venetoclax group relative to 
ibrutinib and placebo group. The alternative hypothesis is HR < 1.
With a targeted HR of 0.61 (corresponding to an improvement in median PFS from 14 months to 
23 months), 134 PFS events will provide at least 80% power at a 1-sided overall significance 
level of 0.025. Assuming an enrollment rate of approximately 10-11 subjects per month (a rough 
estimate based on 3 pieces of enrollment rates), the accrual is projected to complete 
approximately 21 months from the first subject in. Detailed projection of the enrollment schedule 
will be provided in a separate document. The actual length of the study and the time to the final 
analysis will depend on the actual enrollment rate and the number of events that occur.
The sample size and power calculations for the study are based on a 1-sided log-rank test for PFS and 
were calculated using the software package, East 6.4.1 (Cytel Software Corp, Cambridge, MA).
OS will be analyzed at the time of the primary analysis of PFS when the superiority boundary for 
PFS is crossed. It is anticipated that 112 and 155 OS events in total will be observed at the interim 
analysis (at ~40 months) and at the final analysis (at ~57 months), respectively. This is based on the 
assumption that the median OS for the ibrutinib and placebo group is approximately 30 months 
(estimated based on data from subjects treated with ibrutinib monotherapy in MCL3001), and the 
hazard ratio is 0.65 (corresponding to a median OS of 46.2 months for the ibrutinib and venetoclax 
group). With 155 OS events, the study has ~76% power at a 1-sided overall significance level of 
0.025. At the interim analysis, if 112 OS events are observed, the information fraction will be 72.3%. 
The 1-sided alpha spending is 0.008 at the interim analysis based on a group sequential design with 
Lan-Demets spending function with O’Brien-Fleming boundary. This will ensure control of the 
overall type I error for the study. The exact alpha boundary will be calculated using the actual 
number of events observed at the interim analysis.
The calculations for OS are based on the software package, East 6.5 (Cytel Software Corp, 
Cambridge, MA).
10.4 Sample Size Determination (Treatment-naive Open-label Arm)
A sample size of 75 treatment-naive subjects is needed to exclude a 35% CR rate at a 1-sided 
significance level of 0.025 with approximately 80% power, assuming a target CR rate of 51%.
For the subpopulation with a TP53 mutation, a sample size of 48 subjects is needed to exclude a 
25% CR rate with approximately 80% power, assuming a target CR rate of 45%. The TP53 
population could be a mix of treatment-naive MCL subjects and/or R/R MCL subjects with a 
TP53 mutation.


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10.5 Efficacy Analysis 
10.5.1 Randomization Phase
10.5.1.1 Analysis for Primary Efficacy Endpoint
The primary efficacy endpoint of the Randomization Phase portion of this study is PFS, defined 
as the duration from the date of randomization to the date of investigator-assessed disease 
progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or 
death from any cause, whichever occurs first. PFS will be compared between treatment arms 
using the stratified log rank test. The HR for PFS will be estimated using a stratified Cox 
proportional hazards model. The 95% CI for the HR will be provided. The stratification factors 
will be the same as the randomization stratification factors: prior lines of therapy, ECOG PS, and 
the TLS categories. The stratification factors will be obtained at the time of randomization. 
Kaplan Meier estimates and associated plot will be generated. The median PFS for each 
treatment arm and the associated 95% CI will be constructed using the Brookmeyer-Crowley 
methodology (Brookmeyer 1982).
10.5.1.2 Analysis for Secondary Efficacy Endpoints
Details of the analysis methods, models, and multiplicity adjustments to control the overall 
Type 1 error rate will be specified in the SAP.
10.5.1.2.1 Complete Response Rate
CR rate is the proportion of subjects with CR as the best overall response by the time of analysis.
The CR rate will be compared between treatment arms using stratified Cochran-Mantel-Haenszel 
(CMH) test. The difference in CR rate between treatment arms and its 95% CI will be calculated 
using the normal approximation to the binomial distribution.
10.5.1.2.2 Overall Response Rate
Overall response rate (ORR) is the proportion of subjects with CR or PR. The analysis methods 
for ORR will be the same as those described in Section 10.5.1.2.1.
10.5.1.2.3 Minimal Residual Disease-Negative Remission Rate
The MRD-negative remission rate in subjects who were MRD positive at screening and achieve 
a CR will be calculated. The analysis methods of MRD-negative remission rate will be the same 
as those described in Section 10.5.1.2.1.
10.5.1.2.4 Overall Survival
The interim analysis for OS will be conducted at the primary analysis of PFS. Details for the 
interim and final analyses for OS will be specified in the SAP.


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In the Randomization Phase, OS will be compared between treatment arms using the stratified 
log rank test. All deaths will be considered as an event. Data for subjects who have not died by 
the time of analysis will be censored at the date of last contact. Methods for comparison of OS 
between treatment arms will be the same as the methods for the primary efficacy endpoint of 
PFS. 
10.5.1.2.5 Duration of Response
In the Randomization Phase, DOR will be summarized using Kaplan-Meier estimates for 
subjects who achieve an overall response. The censoring rule for DOR is the same as PFS.
10.5.1.2.6 Time-to-next Treatment
In the Randomization Phase, Time-to-next Treatment will be compared between treatment arms. 
Methods for comparison of TTNT between treatment arms will be the same as the methods for 
the primary efficacy endpoint of PFS.
10.5.1.2.7 Time to Worsening in FACT-Lym Subscale
In the Randomization Phase, time to worsening in FACT-Lym subscale of the health-related 
quality of life questionnaire (FACT-Lym) will be compared between treatment arms. Methods 
for comparison will be the same as the methods for the primary efficacy endpoint of PFS as 
appropriate.
10.5.2 Treatment-naive Open-label Arm
Analyses in the following sections will be conducted for treatment-naive subjects enrolled in the 
open-label arm. In addition, analyses on the subjects with a TP53 mutation will be conducted; 
R/R MCL subjects with a TP53 mutation may be included in the analyses. Analysis details will 
be specified in the SAP.
10.5.2.1 Analysis for the Primary Efficacy Endpoint
The primary efficacy endpoint of the treatment-naive open-label arm is the CR rate, defined as 
the proportion of subjects with a CR as the best overall response using the Revised Response 
Criteria for Malignant Lymphoma (Cheson 2014). 
The CR rate will be estimated, and the 95% CI will be calculated based on exact binomial 
distribution.


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10.5.2.2 Analysis for Secondary Efficacy Endpoints
10.5.2.2.1 Analyses of ORR, DOR, Duration of CR, and MRD-Negative Remission Rate
The analysis method for the ORR and the MRD-negative remission rate will be the same as those 
described for the CR rate.
DOR and the duration of CR will be summarized using Kaplan-Meier estimates for subjects who 
achieve a response. 
10.5.2.2.2 Analyses of PFS, OS, and TTNT
Kaplan-Meier estimates will be provided for PFS, OS, and TTNT. Censoring conventions will be 
provided in the SAP.
10.6 Safety Analysis
The safety variables to be analyzed include exposure of study drugs, AEs, and clinical laboratory 
test results (hematology and chemistry). In general, continuous variables will be summarized 
using descriptive statistics (n, mean, median, standard deviation, standard error and range). 
Categorical variables will be summarized using frequencies and percentages. No formal 
statistical testing is planned. 
Adverse Events
Adverse event parameters to be evaluated are SOC, preferred terms, incidence, and intensity of 
AEs; the relationship of AEs to study treatment; and the action taken with respect to study 
treatment due to AEs.
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).
Treatment-emergent period is defined as the period of time from the first dose of study treatment, 
until the earlier of:

Thirty days following the last dose of ibrutinib or venetoclax, whichever occurs 
later
OR

The start date of a new anticancer therapy.
The TEAEs are those events that:

Are not present prior to the treatment-emergent period and occur during the 
treatment-emergent period,

The onset dates are missing and end dates are during the treatment-emergent period,


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
Are considered related to study drug by the investigator regardless of the start dates 
of the events, or

Are present prior to the treatment-emergent period but worsen in severity during the 
treatment-emergent period or are subsequently considered related to study drug by 
the investigator.
All treatment-emergent AEs will be included in the analysis. For each AE, the number and 
percentage of subjects who experience at least one occurrence of the given event will be 
summarized. The number and percent of subjects with TEAEs will be summarized according to 
intensity (CTCAE, v4.03) and drug relationship, as well as categorized by system organ class 
and preferred term. For analysis, only AEs with a causal relationship of “possibly related” and 
“related” will be considered as related to study drug. Summaries, listings, datasets, or subject 
narratives may be provided, as appropriate, for those subjects who die, who discontinue 
treatment due to an AE, or who experience a severe adverse reaction or a SAE.
Clinical Laboratory Tests
Laboratory tests will be summarized separately for hematology and serum chemistry. All 
laboratory values will be graded using the CTCAE v4.03. The worst toxicity grade for selected 
laboratory tests will be tabulated.
10.7 Pharmacokinetic Analysis
10.7.1 Ibrutinib
Ibrutinib and PCI-45227 bioanalytical data will be used in a noncompartmental PK analysis. 
Plasma concentrations below the lowest quantifiable concentration will be treated as zero in the 
summary statistics. All subjects and samples excluded from the analysis will be clearly 
documented in the PK report.
Descriptive statistics will be used to summarize ibrutinib and PCI-45227 concentrations at each 
sampling time point (including, but not limited to: Cmax, Tmax, AUClast, and t1/2) at each dosing 
interval.
10.7.2 Venetoclax
Venetoclax bioanalytical data will be used in a noncompartmental PK analysis. Plasma 
concentrations below the lowest quantifiable concentration will be treated as zero in the 
summary statistics. All subjects and samples excluded from the analysis will be clearly 
documented in the PK report.
Descriptive statistics will be used to summarize venetoclax concentrations at each sampling time 
point and PK parameters (including, but not limited to: Cmax, Tmax, and AUC) at each dosing 
interval.


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10.8
Biomarker Analyses 
Biomarker exploratory analyses are planned to identify biomarkers that are predictive of 
response (or resistance) to ibrutinib and venetoclax treatment. Descriptive statistics will be used 
to summarize these exploratory endpoints.
11 ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. The Sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures.
11.1 Definitions 
11.1.1 Adverse Events
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational study drug, whether or not considered related to the study drug (ICH-E2A 1995).
For the purposes of this clinical study, AEs include events which are either new or represent
detectable exacerbations of pre-existing conditions.
The term “disease progression” should not be reported as an AE term. As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported.
Adverse events may include, but are not limited to:

Subjective or objective symptoms provided by the subject and/or observed by the 
investigator or study staff including laboratory abnormalities of clinical significance

Any AEs experienced by the subject through the completion of final study 
procedures

AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with the 
underlying disease that were not present before the AE reporting period 

Complications that occur as a result of protocol-mandated interventions 
(eg, invasive procedures such as biopsies).


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The following are NOT considered AEs:

Pre-existing condition: A pre-existing condition (documented on the medical 
history CRF) is not considered an AE unless the severity, frequency, or character of 
the event worsens during the study period.

Per protocol, pre-planned, or elective hospitalization: Per-protocol 
hospitalizations for TLS prophylaxis and management are not considered SAEs, 
unless a hospitalization is prolonged beyond 3 days due to an AE. A hospitalization 
planned before signing the ICF is not considered an SAE, but rather a therapeutic 
intervention. However, if during the pre-planned hospitalization an event occurs, 
which prolongs the hospitalization or meets any other SAE criteria, the event will be 
considered an SAE. Surgeries or interventions that were under consideration, but 
not performed before enrollment in the study, will not be considered serious if they 
are performed after enrollment in the study for a condition that has not changed 
from its baseline level. Elective hospitalizations for social reasons, solely for the 
administration of chemotherapy, or due to long travel distances, are also not SAEs.

Diagnostic Testing and Procedures: Testing and procedures should not be 
reported as AEs or SAEs, but rather the cause for the test or procedure should be 
reported.

Asymptomatic Treatment-related Lymphocytosis: This event should also not be 
considered an AE. Subjects with treatment-related lymphocytosis should remain on 
study treatment and continue with all study-related procedures.
11.1.2 Serious Adverse Events
A SAE based on International Conference on Harmonisation (ICH) and EU Guidelines on 
Pharmacovigilance for Medicinal Products for Human Use is any untoward medical occurrence 
that at any dose:

Results in death (ie, the AE actually causes or leads to death)

Is life-threatening. Life-threatening is defined as an AE in which the subject was at 
risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it were more severe. If either the 
investigator or the Sponsor believes that an AE meets the definition of life-
threatening, it will be considered life-threatening.

Requires in-patient hospitalization > 24 hours or prolongation of existing 
hospitalization

Results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is an important medical event that may not result in death, be immediately 
life-threatening or require hospitalization, but may be considered an SAE when, 
based upon appropriate medical judgment, the event may jeopardize the subject or 


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subject may require intervention to prevent one of the other outcomes listed in this 
definition. Examples of such events are intensive treatment in an emergency 
department or at home for allergic bronchospasm, blood dyscrasias, or convulsion 
that does not result in hospitalization; or development of drug dependency or drug 
abuse
Given that the investigator’s perspective may be informed by having actually observed the event, 
and the Sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event, if either the Sponsor or the investigator believes that 
the event is serious, the event will be considered serious.
11.1.3 Severity Criteria (Grade 1-5)
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03 
(CTCAE v4.03) will be used for grading the severity (intensity). The CTCAE v4.03 displays 
Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. Should 
a subject experience any AE not listed in the CTCAE v4.03, the following grading system should 
be used to assess severity:

Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities

Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience 
or concern to the subject, and which may interfere with daily activities, but are 
usually ameliorated by simple therapeutic measures

Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activity, and require systemic drug 
therapy or other treatment

Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to 
be in imminent danger of death

Grade 5 (Death related to AE) – experiences which result in subject death


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11.1.4 Causality (Attribution)
The investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study medication caused the event) using the following definitions:
Not Related:
Another cause of the AE is more plausible; a temporal sequence cannot be 
established with the onset of the AE and administration of the 
investigational product; or, a causal relationship is considered biologically 
implausible.
Unlikely:
The current knowledge or information about the AE indicates that a 
relationship to the investigational product is unlikely.
Possibly 
Related:
There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the AE could also be 
attributed to concurrent or underlying disease, or the use of other drugs or 
procedures. Possibly related should be used when the investigational 
product is one of several biologically plausible AE causes.
Related:
The AE is clearly related to use of the investigational product.
11.2 Unexpected Adverse Events
An “unexpected” AE is an AE that is not listed in the ibrutinib IB/package insert or is not listed 
at the specificity or severity that has been observed. For example, hepatic necrosis would be 
“unexpected” (by virtue of greater severity) if the ibrutinib IB referred only to elevated hepatic 
enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
“unexpected” (by virtue of greater specificity) if the ibrutinib IB/package insert listed only 
cerebral vascular accidents. "Unexpected" also refers to AEs that are mentioned in the 
ibrutinib IB as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the study drug under 
investigation.
11.3 Special Reporting Situations
Special reporting situation on a Sponsor study may require expedited reporting and/or safety 
evaluation include, but are not limited to:

Overdose of any study drug

Suspected abuse/misuse of a study drug

Inadvertent or accidental exposure to a study drug

Medication error involving a product (with or without subject exposure to the study 
drug, eg, name confusion)
If any special reporting situation meets the criteria of an AE, it should be reported on the Serious 
Adverse Event Report Form. Please report all overdoses on a SAE form regardless of the 


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outcome. The Serious Adverse Event Report Form should be sent via email or fax to 
Pharmacyclics LLC Drug Safety or designee within 24 hours of awareness.
11.4 Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators
11.4.1 Assessment of Adverse Events
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation timepoints 
during the study. All AEs and SAEs, whether volunteered by the subject, discovered by study 
personnel during questioning, detected through physical examination, clinically significant 
laboratory test, or other means, will be recorded in the subject’s medical record and on the AEs 
CRF and, when applicable, on the Serious Adverse Event Report Form.
Each recorded AE or SAE will be described by its duration (ie, start and end dates), severity, 
regulatory seriousness criteria (if applicable), suspected relationship to the investigational 
product, and any actions taken.
11.4.2 Adverse Event Reporting Period
All AEs whether serious or non-serious, will be documented from the time the signed and dated 
ICF is obtained until 30 days following the last dose of study drug. SAEs will be reported to the 
Sponsor Drug Safety via an SAE reporting form and will be recorded in the eCRF from the time 
of ICF signing. Non-serious AEs will be recorded in the source documents from the time of ICF 
signing and will be recorded in the eCRF from the first dose of study drug.
Serious adverse events reported after 30 days following the last dose of study drug should also be 
reported if considered related to study drug. Resolution information after 30 days should be 
provided.
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical 
signs of disease progression may be reported (see Section 11.1.1).
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document. All records will need to capture the 
details of the duration and the severity of each episode, the action taken with respect to the study 
drug, investigator’s evaluation of its relationship to the study drug, and the event outcome. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (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.
All deaths should be reported with the primary cause of death as the AE term, as death is 
typically the outcome of the event, not the event itself. Autopsy and postmortem reports must be 


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forwarded to the Sponsor, or designee, as outlined above, if allowed per local regulatory 
guidelines.
If a death occurs within 30 days after the last dose of study drug, the death must be reported to 
the Sponsor as a SAE. 
11.4.3 Expediting Reporting Requirements for Serious Adverse Events
All SAEs (initial and follow-up information) will be reported on the Serious Adverse Event 
Report Form and sent via email or fax to Pharmacyclics LLC Drug Safety, or designee, within 
24 hours of the discovery of the event or information. Pharmacyclics LLC may request follow-up 
and other additional information from the investigator (eg, hospital admission/discharge notes 
and laboratory results). The contact information (phone, email and fax) for Pharmacyclics LLC 
Drug Safety can be found on the Serious Adverse Event Report Form and instructions.
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct.

It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow up 
after demonstration of due diligence with follow-up efforts)
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities 
and governing bodies according to the local regulations.
The investigator (or Sponsor where required) must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB.
11.4.4 Pregnancy
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested.
A female subject or female partner of a male subject must immediately inform the investigator if 
she becomes pregnant from the time of consent to 90 days after the last dose of study drug(s). 


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Any female subjects receiving study drug(s) who become pregnant must immediately 
discontinue study drug. The investigator should counsel the subject, discussing any risks of 
continuing the pregnancy and any possible effects on the fetus.
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. 
Any pregnancy occurring in a female subject or female partner of a male subject must be 
reported from the time of first dose up until 90 days after the last dose of study drug(s). Any 
occurrence of pregnancy must be recorded on the Pregnancy Report Form Part I and sent via 
email or fax to Pharmacyclics LLC Drug Safety, or designee, within 24 hours of learning of the 
event. All pregnancies will be followed for outcome, which is defined as elective termination of 
the pregnancy, miscarriage, or delivery of the fetus. For pregnancies with an outcome of live 
birth, the newborn infant will be followed until 30 days old by completing the Pregnancy Report 
Form Part II. Any congenital anomaly/birth defect noted in the infant must be reported as a SAE.
11.4.5 Other Malignancies
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any 
protocol-specified follow-up periods including post-progression follow-up for OS. If observed, 
enter data in the corresponding eCRF.
11.4.6 Eye-Related Adverse Events
New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was 
Grade 2 or higher at baseline and worsens should be evaluated by an ophthalmologist, whose 
findings should be reported on the ophthalmologic eCRF.
11.4.7 Adverse Events of Special Interest (AESI)
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities 
by the Sponsor. These events (regardless of seriousness) should be reported on the Serious 
Adverse Event Report Form and sent via email or fax to Pharmacyclics LLC Drug Safety, or 
designee, within 24 hours of awareness.
11.4.7.1 Major Hemorrhage
Major hemorrhage is defined as any of the following:

Any treatment-emergent hemorrhagic AEs of Grade 3 or higher*

Any treatment-emergent serious adverse events of bleeding of any grade

Any treatment-emergent central nervous system hemorrhage/hematoma of any 
grade
*All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 or higher 
AE per CTCAE v4.03.


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Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.4.7 above.
12 STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
12.1 Regulatory and Ethical Compliance
This clinical study was designed and will be implemented in accordance with the protocol, 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 
2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki.
12.2 Institutional Review Board (IRB), Research Ethics Board (REB) and Independent 
Ethics Committee (IEC) Approval
The investigator will submit this protocol, the ICF, IB, and any other relevant supporting 
information (eg, all advertising materials or materials given to the subject during the study) to the 
appropriate IRB/REB/IEC for review and approval before study initiation. Amendments to the 
protocol and ICF must also be approved by the IRB/REB/IEC before the implementation of 
changes in this study.
The investigator is responsible for providing the IRB/REB/IEC with any required information 
before or during the study, such as SAE expedited reports or study progress reports.
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) as 
well as country-specific national regulations and/or local laws.
The following documents must be provided to Pharmacyclics LLC or its authorized 
representative before entering subjects in this study: (1) a copy of the IRB/REB/IEC letter that 
grants formal approval; and (2) a copy of the IRB/REB/IEC-approved ICF.
12.3 Informed Consent
The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as 
country-specific national regulations and/or local laws. The ICF will document the study-specific 
information the investigator or his/her designee provides to the subject and the subject’s 
agreement to participate.
The investigator or designee (designee must be listed on the Delegation of Authority log) 
must explain in terms understandable to the subject the purpose and nature of the study, 
study procedures, anticipated benefits, potential risks, possible AEs, and any discomfort 
participation in the study may entail. This process must be documented in the subject’s source 
record. Each subject must provide a signed and dated ICF before any study-related (nonstandard 
of care) activities are performed. The original and any amended signed and dated consent forms 
must remain in each subject’s study file at the study site and be available for verification by 


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study monitors at any time. A copy of each signed consent form must be given to the subject at 
the time that it is signed by the subject.
12.4 Quality Control and Quality Assurance
Sponsor shall implement and maintain quality control and quality assurance procedures to ensure 
that the study is conducted and data are generated, documented and reported in compliance with 
the protocol, GCP, and applicable regulatory requirements. This study shall be conducted in 
accordance with the provisions of the Declaration of Helsinki (October 2008) and all revisions 
thereof, and in accordance with the Food and Drug Administration (FDA) regulations (21 CFR 
Parts 11, 50, 54, 56, and 312, Subpart D – Responsibilities of Sponsors and investigators) and 
with the ICH guidelines on GCP (ICH-E6 1996).
12.5 Protected Subject Health Information Authorization
Information on maintaining subject confidentiality in accordance to individual local and national 
subject privacy regulations must be provided to each subject as part of the informed consent 
process (refer to Section 7.1.1.1), either as part of the ICF or as a separate signed document 
(for example, in the US, a site-specific HIPAA consent may be used). The investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 
protected health information obtained during the study may be shared with Pharmacyclics LLC 
and its designees, regulatory agencies, and IRBs/REBs/IECs. As the study Sponsor, 
Pharmacyclics LLC will not use the subject’s protected health information or disclose it to a
third party without applicable subject authorization. It is the investigator’s or designee’s 
responsibility to obtain written permission to use protected health information from each subject. 
If a subject withdraws permission to use protected health information, it is the investigator’s 
responsibility to obtain the withdrawal request in writing from the subject and to ensure that no 
further data will be collected from the subject. Any data collected on the subject before 
withdrawal will be used in the analysis of study results.
During the review of source documents by the monitors or auditors, the confidentiality of the 
subject will be respected with strict adherence to professional standards and regulations.
12.6 Study Files and Record Retention
The investigator must keep a record of all subjects who have consented to enroll in the study. 
For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is to be 
recorded.
The investigator/study staff must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. Essential 
documentation includes, but is not limited to, the IB, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), regulatory approval letters (dated, where applicable), 
signed investigator agreements (eg, Form FDA 1572s or equivalent) and Financial Disclosures, 


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signed ICFs (including subject confidentiality information), drug dispensing and accountability 
records, shipping records of investigational product and study-related materials, signed 
(electronically), dated and completed case report forms (CRFs), and documentation of CRF 
corrections, SAE forms transmitted to Pharmacyclics LLC and notification of SAEs and related 
reports, source documentation, normal laboratory values, decoding procedures for blinded 
studies, curricula vitae for study staff, and all relevant correspondence and other documents 
pertaining to the conduct of the study.
All essential documentation will be retained by the investigator for at least 2 years after the date 
the last marketing application is approved for the drug for the indication for which it is being 
investigated and until there are no pending or contemplated marketing applications; or, if no 
application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.
The investigator must notify Pharmacyclics LLC and obtain written approval from 
Pharmacyclics LLC before destroying any clinical study documents or images (eg, scan, 
radiograph, ECG tracing) at any time. Should an investigator wish to assign the study records to 
another party or move them to another location, advance written notice will be given to 
Pharmacyclics LLC. Pharmacyclics LLC will inform the investigator of the date that study 
records may be destroyed or returned to Pharmacyclics LLC.
Pharmacyclics LLC must be notified in advance of, and Pharmacyclics LLC must provide 
express written approval of, any change in the maintenance of the foregoing documents if the 
investigator wishes to move study records to another location or assign responsibility for record 
retention to another party. If the investigator cannot guarantee the archiving requirements set 
forth herein at his or her study site for all such documents, special arrangements must be made 
between the investigator and Pharmacyclics LLC to store such documents in sealed containers 
away from the study site, so that they can be returned sealed to the investigator for audit 
purposes.
12.7 Case Report Forms and Record Maintenance
The CRFs will be used to collect the clinical study data and must be completed for each enrolled 
subject with all required study data accurately recorded such that the information matches the 
data contained in medical records (eg, physicians’ notes, nurses’ notes, clinic charts and other 
study-specific source documents). Authorized study site personnel (ie, listed on the Delegation of 
Authority log) will complete CRFs designed for this study according to the completion 
guidelines that will be provided. The investigator will ensure that the CRFs are accurate, 
complete, legible, and completed within a reasonable period of time. At all times, the 
investigator has final responsibility for the accuracy and authenticity of all clinical data.
The CRFs exist within an electronic data capture (EDC) system with controlled access managed 
by Pharmacyclics LLC or its authorized representative for this study. Study staff will be 
appropriately trained in the use of CRFs and application of electronic signatures before the start 


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of the study and before being given access to the EDC system. Original data and any changes of 
data will be recorded using the EDC system, with all changes tracked by the system and recorded 
in an electronic audit trail. The investigator attests that the information contained in the CRFs is 
true by providing electronic signature within the EDC system. After database lock, the 
investigator will receive a copy of the subject data (eg, paper, CD, or other appropriate media) 
for archiving at the study site.
12.8 Investigational Study Drug Accountability
Ibrutinib, venetoclax/placebo and any Pharmacyclics LLC supplied comparator used must be 
kept in a locked limited access room. The study drug must not be used outside the context of the 
protocol. Under no circumstances should the investigator or other site personnel supply ibrutinib, 
venetoclax/placebo or comparator to other investigators, subjects, or clinics or allow supplies to 
be used other than as directed by this protocol without prior authorization from 
Pharmacyclics LLC.
Accountability records for ibrutinib, venetoclax/placebo, and any Pharmacyclics LLC supplied 
comparator must be maintained and readily available for regular inspection by representatives of 
Pharmacyclics and are open to inspections by regulatory authorities at any time.
An Investigational Drug Accountability Log must be used for drug accountability. For additional 
details on investigational study drug management, please refer to the Pharmacy Manual.
12.9 Study Monitoring/Audit Requirements
Representatives of Pharmacyclics LLC or its designee will monitor this study until completion. 
Monitoring will be conducted through personal visits with the investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone. 
The purpose of monitoring is to ensure that the study is conducted in compliance with the 
protocol, standard operating procedures (SOPs), and other written instructions and regulatory 
guidelines, and to ensure the quality and integrity of the data. This study is also subject to 
reviews or audits.
To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor 
have access to all original source documents, including all electronic medical records (EMR) at 
reasonable times and upon reasonable notice. If access to the EMR cannot be granted to the 
monitor, the site must ensure that all certified copies of documents are available during 
monitoring visits for all screened and enrolled subjects. During the review of source documents, 
every effort will be made to maintain the anonymity and confidentiality of all subjects during 
this clinical study. However, because of the experimental nature of this treatment, the 
investigator agrees to allow the IRB/REB/IEC, representatives of Pharmacyclics LLC, its 
designated agents and authorized employees of the appropriate Regulatory Authority to inspect 
the facilities used in this study and, for purposes of verification, allow direct access to the 
hospital or clinic records of all subjects enrolled into this study. A statement to this effect will be 


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included in the informed consent and permission form authorizing the use of protected health 
information.
Pharmacyclics LLC or its authorized representative may perform an audit at any time during or 
after completion of this study. All study-related documentation must be made available to the 
designated auditor. In addition, a representative of the FDA or other Regulatory Agencies may 
choose to inspect a study site at any time before, during, or after completion of the clinical study. 
In the event of such an inspection, Pharmacyclics LLC will be available to assist in the 
preparation. All pertinent study data should be made available as requested to the Regulatory 
Authority for verification, audit, or inspection purposes.
12.10Investigator Responsibilities
A complete list of investigator responsibilities are outlined in the clinical trial research 
agreement and the investigator agreements (eg, Statement of Investigator Form FDA 1572s or 
equivalent), both of which are signed by the investigator before commencement of the study. In 
summary, the investigator will conduct the study according to the current protocol; will read and 
understand the IB; will obtain IRB/REB/IEC approval to conduct the study; will obtain informed 
consent from each study participant; will maintain and supply to the Sponsor or designee, 
auditors and regulatory agencies adequate and accurate records of study activity and drug 
accountability for study-related monitoring, audits, IRB/REB/IEC reviews and regulatory 
inspections; will report SAEs to the Sponsor or designee and IRB/ REB/IEC according to the 
specifics outlined in this protocol; will personally conduct or supervise the study; and will ensure 
that colleagues participating in the study are informed about their obligations in meeting the 
above commitments.
12.11
Sponsor Responsibilities
A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement 
and in the laws and regulation of the country in which the research is conducted. In summary, the 
Sponsor will select qualified investigators, provide them with the information they need to 
properly conduct the study, ensure adequate monitoring of the study, conduct the study in 
accordance with the general investigational plan and protocols and promptly inform 
investigators, health and regulatory agencies/authorities as appropriate of significant new adverse 
effects or risks with respect to the drug.
12.12
Financial Disclosure
A separate financial agreement will be made between each principal investigator and 
Pharmacyclics LLC or its authorized representative before the study drug is delivered.
For this study, each investigator and sub-investigator (as designated on the investigator 
agreements [eg, Form FDA1572 or equivalent]) will provide a personally signed Financial 
Disclosure Form in accordance with § 21 CFR 54. Each investigator will notify 


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Pharmacyclics LLC or its authorized representative of any relevant changes in financial 
disclosure information during the conduct of the study and for 1 year after the study has been 
completed.
12.13
Liability and Clinical Trial Insurance
In the event of a side effect or injury, appropriate medical care as determined by the 
investigator/designee will be provided.
The ICF will include a description of treatment in the event of a study-related injury and 
handling of the costs associated therewith, incorporating country-specific national regulations 
and/or local laws. Financial compensation for lost wages, disability or discomfort due to the 
study is not available.
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating sites 
at the time of study initiation.
12.14
Protocol Amendments
Pharmacyclics LLC will initiate any change to the protocol in a protocol amendment document. 
The amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised 
model ICF. Written documentation of IRB/REB/IEC and required site approval must be received 
by Pharmacyclics LLC before the amendment may take effect at each site. Additionally under 
this circumstance, information on any change in risk and/or change in scope must be provided to 
subjects already actively participating in the study, and they must read, understand and sign each 
revised ICF confirming willingness to remain in the trial.
No other significant or consistent change in the study procedures, except to eliminate an 
immediate hazard, shall be effected without the mutual agreement of the investigator and 
Pharmacyclics LLC.
12.15
Publication of Study Results
Pharmacyclics LLC may use the results of this clinical study in registration documents for 
Regulatory Authorities in the US or abroad. The results may also be used for papers, abstracts, 
posters, or other material presented at scientific meetings or published in professional journals or 
as part of an academic thesis by an investigator. In all cases, to avoid disclosures that could 
jeopardize proprietary rights and to ensure accuracy of the data, Pharmacyclics LLC reserves the 
right to preview all manuscripts and abstracts related to this study, allowing Pharmacyclics LLC 
sufficient time to make appropriate comments before submission for publication.
In most cases, the investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results. The medical monitor, study 
director and/or lead statistician may also be included in the list of authors. This custom can be 


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adjusted upon mutual agreement of the authors and Pharmacyclics LLC and in accordance with 
current standards for authorship as recorded in professional conference and journal submission 
instructions.
12.16
Study Discontinuation
The Sponsor reserves the right to terminate the study at any time. Should this be necessary, 
both the Sponsor and the investigator will arrange discontinuation procedures. In terminating the 
study, the Sponsor and the investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests.
12.17
Study Completion
The study is expected to be completed approximately 5 years from the first subject enrolled, the 
time all subjects have exited the study for any reason, or study termination at the Sponsor’s 
discretion, whichever occurs first.


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14 APPENDICES


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Appendix A.
Schedule of Assessments – Standard Ramp-up Schedule
Week
1
2
3
4
5
6
8
10
Week 13 
& 
beyonda
(±7 days)
Response 
Assessmentb
(±7 days)
EOTc
(±7 
days)
RFUd
LTFUw
Day
1
2
3
1
2
3
1
1
1
1
1 (±1 
day)
1 (±1 
day)
(±14 days)
Study Drug Administration
Ibrutinib 560 mg daily
Continuous
----
Venetoclax daily dose / placebo
20mg
50mg
100mg 200mg
400mg continuous target daily dose
----
Procedure
Screening
Day -28 to -1
Informed consent
X
Medical 
history/demographic/prior 
treatment
X
X
Confirm eligibility
X
X
Concomitant medicationse
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
AEsf
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
Physical examg
X
X
X
X
X
X X
X
X
X
X
Vital signs h
X
X
X
X
X
X
X
X X
X
X
X
X
ECOG
X
X
X
X
X
ECGi
X
X
Disease Assessment
CT/PET/MRI/endoscopyj
X
X
X
Tumor tissuek
X
(X)
Bone marrow biopsyx
X
(X)
B-symptoms
X
X
X
Overall response 
assessmentm
X
X
MRD Bone marrow 
aspiratel
X
(X)
MRD assessment in 
bloodn
X
X
X
TLS Risk Assessmento
X
X
X
X
X
X
X
X
X
X X
X
X
X
PROp
X
X
Medical resource 
utilization (MRU)
Hospitalizations, emergency department visits, hematopoietic growth factor use to be documented throughout 
study treatment period
Biomarker Bone marrow 
Aspiratel
X
(X)
Biomarker Peripheral Bloodu
X
X
X
X


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Week
1
2
3
4
5
6
8
10
Week 13 
& 
beyonda
(±7 days)
Response 
Assessmentb
(±7 days)
EOTc
(±7 
days)
RFUd
LTFUw
Day
1
2
3
1
2
3
1
1
1
1
1 (±1 
day)
1 (±1 
day)
(±14 days)
Study Drug Administration
Ibrutinib 560 mg daily
Continuous
----
Venetoclax daily dose / placebo
20mg
50mg
100mg 200mg
400mg continuous target daily dose
----
Procedure
Screening
Day -28 to -1
Hematologyq
X
X
X
X
X
X X
X
X
X
X
X
Blood chemistryr
X
X
X
X
X
X
X
X
X
X X
X
X
X
X
Urinalysiss
X
X
Serum or Urine Pregnancy
X
X
X
Hepatitis serologiest
X
Coagulation panel
X
Buccal Swab
X
Serum β2-microglobulin
X
PK blood samplingv
X
Survival status, incl. other 
malignanciesw
X
Subsequent Anticancer Therapy
X
X
Abbreviations:
EOT = End-of-Treatment Visit; RFU = Response Follow-up Visit; LTFU = Long-term Follow up; PRO = patient-reported outcome;
Footnotes:
a After week 13, study drug dispensing visits are scheduled every 4 weeks for one year; every 8 weeks during the 2nd and 3rd years; and every 12 weeks thereafter until treatment 
discontinuation.
b Response assessment visits are scheduled on Week 13 Day 1 (±7 days); every 12 weeks for the remainder of the 1st year; every 16 weeks during the 2nd and 3rd years, and every 
24 weeks thereafter until PD. In addition, response assessments can be performed as clinically indicated to confirm response or progression. 
c An EOT visit will occur 30 days (±7) from the last dose of study drug or prior to the start of a new anticancer treatment.
d Subjects who discontinue for reasons other than PD will have follow-up response assessments (based on Week 1 Day 1 for a subject) every 12 weeks (± 14 days) from the 
1st dose for the 1st year; every 16 weeks (± 14 days) during the 2nd and 3rd years; and every 24 weeks (± 14 days) thereafter until PD.
e Concomitant medications are collected from 30 days before the first dose through the 30 days after the last dose of study drug.
f See Section 11 for details regarding the reporting of AEs.
g A complete physical examination (at Screening and EOT) will include, at a minimum, the general appearance of the subject, height (may use prior height measurement if 
available in source documents) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, 
and nervous system. At other timepoints, a limited symptom-directed physical exam will be performed. The physical exam should include an eye-related symptom assessment.
h Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the subject has rested in the sitting position for ≥3 minutes.
iA single 12-lead ECG will be done at Screening and at the EOT visit. Subjects should be in a supine position and resting for at least 10 minutes before obtaining the ECG. During 
the treatment period, ECG’s may be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new 
onset dyspnea. 


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j
CT and PET or PET/CT: A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis and any other disease sites (eg, extremity) and a PET or 
PET/CT scan (CT should be of diagnostic quality) are required for the pretreatment tumor assessment within 28 days of the first dose. Thereafter, CT scans will be done for
tumor assessments on Week 13 Day 1 (±7 days); every 12 weeks for the remainder of the 1st year; every 16 weeks during the 2nd and 3rd years; and every 24 weeks thereafter 
until PD. PET or PET/CT is mandatory to confirm a CR. For MRI refer to Section 7.1.3.2.
k A total of up to 20 slides of fresh or the most recent dated FFPE archival tumor biopsy tissue will be required at study entry. An optional tumor biopsy should be collected at the 
time of disease progression if feasible.
l
A unilateral bone marrow aspirate will be done at Screening or up to 28 days before the 1st administration of study drug for MRD testing. A 2nd bone marrow aspirate will be 
performed in all subjects who achieve a CR. Subsequent bone marrow aspirates will be obtained as needed (ie, if MRD in BM at CR was positive, and subject remains CR) to 
confirm MRD-negative CR. 
m Response assessments will be completed by the investigator using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
n Blood will be drawn for MRD assessments at baseline, at documented complete response and onwards every 12 weeks (±7 days) for the remainder of the 1st year; every 
16 weeks during the 2nd and 3rd years; and every 24 weeks thereafter until PD. 
o Risk of TLS is to be re-assessed prior to each venetoclax dose ramp-up. Administration of prophylaxes as needed is to occur within 72 hours of dosing. Subjects with high tumor 
burden at baseline may be hospitalized for a minimum of the first 24 hours of treatment (and up to 48 hours at the discretion of the investigator) at the start of the 20 mg (ramp-
up dose) and the 50 mg dose levels and blood chemistry (creatinine, uric acid, potassium, phosphorus, calcium, and albumin, if available) should be monitored pre-dose and 4±1, 
8±1, 12±1, 24±2 and as needed 48±2 hours after the venetoclax dose. Additionally, for high-risk TLS subjects, post-dose blood chemistries will be monitored at pre-dose and 
6-8 hours after the venetoclax dose during ramp up of the 100 mg, 200 mg and 400 mg dose levels. For all other subjects, blood chemistry will be monitored pre-dose, 6-8 and 
24±2 hours after the venetoclax dose at the 20 mg and the 50 mg dose levels. 
p PRO questionnaires (FACT-Lym, EQ-5D-5L) should be completed prior to any assessments, and before being clinically evaluated by the study nurse or physician. The 
questionnaires will be administered on Week 1 Day 1, Week 13 Day 1 (±7 days); every 4 weeks for the remainder of the 1st year; every 8 weeks during the 2nd and 3rd years; and 
every 12 weeks thereafter until disease progression.
q Hematology includes complete blood count with differential and platelet counts. 
r Blood chemistry: Sodium, potassium, chloride, BUN, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, LDH, phosphate, uric 
acid, urea, magnesium and bicarbonate. Serum creatinine, uric acid, potassium, phosphorus and calcium should be assessed within 72 hours prior to the 1st venetoclax dose and 
before each dose increase.
s Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. 
t
Hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody will be evaluated. If hepatitis B core antibody or hepatitis B surface antigen or Hepatitis C 
antibody is positive, then PCR to quantitate hepatitis B DNA or hepatitis C RNA must be performed. DNA PCR needs to be confirmed negative (< 29 U) prior to enrollment in 
subjects who are hepatitis B core antibody or hepatitis B surface antigen positive. For subjects who are hepatitis C antibody positive, hepatitis C PCR needs to be confirmed 
negative prior to enrollment.
u Blood biomarker samples will be drawn at baseline, at documented complete response and onwards every 12 weeks (±7 days) for the remainder of the 1st year; every 16 weeks 
during the 2nd and 3rd years; and every 24 weeks thereafter until PD.
v PK samples will be drawn at protocol-specified timepoints: pre-dose (30min), 1hr (±15min), 2hrs (±15min), 4hrs (±30min), 6hrs (±30min), and 8hrs (±1hr) post dose.
w After progression, survival status, other malignancies and subsequent anticancer therapy will be collected approximately every 12 weeks (based on Week 1 Day 1 for a subject) 
until death, withdrawal by subject, loss to follow-up, or study terminated by Sponsor, whichever comes first.
x A unilateral bone marrow biopsy will be done at Screening or up to 28 days before the 1st administration of study drug for standard pathology. A 2nd bone marrow biopsy will be 
performed in subjects with positive bone marrow involvement at baseline by standard pathology who achieve a CR.


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Appendix B.
Schedule of Assessments – Treatment-naive Open-label Arm
Week
1
2
3
4
5
6
8
10
Week 13 
& 
beyonda
(±7 days)
Response 
Assessmentb
(±7 days)
EOTc
(±7 
days)
RFUd
LTFUw
Day
1
2
3
1
2
3
1
1
7
1
1
1 (±1 
day)
1 (±1 
day)
(±14 days)
Study Drug Administration
Ibrutinib 560 mg daily
Continuous
----
Venetoclax daily dose
20mg
50mg
100mg 200mg
400mg continuous target daily dose
----
Procedure
Screening
Day -28 to -1
Informed consent
X
Medical history/ demographic/
central lab pathology report 
confirmation or tissue test
X
X
Confirm eligibility*
X
X
Concomitant medicationse
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
AEsf
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
Physical examg
X
X
X
X
X
X
X
X
X
X
X
Vital signs h
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG
X
X
X
X
X
ECGi
X
X
Disease Assessment
CT/PET/MRI/endoscopyj
X
X
X
X
Tumor tissuek
X
(X)
Bone marrow biopsyx
X
(X)
B-symptoms
X
X
X
Overall response assessmentm
X
X
X
MRD Bone marrow aspiratel
X
(X)
MRD assessment in bloodn
X
X
X
TLS Risk Assessmento
X
X
X
X
X
X X
X
X
X
X
X
X
X
PROp
X
X
Medical resource utilization 
(MRU)
Hospitalizations, emergency department visits, hematopoietic growth factor use to be documented throughout study 
treatment period
Biomarker Bone marrow 
Aspiratel
X
(X)
Biomarker Peripheral Bloodu
X
X
X
X
Hematologyq
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistryr
X
X
X
X
X
X X
X
X
X
X
X
X
X
X


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Week
1
2
3
4
5
6
8
10
Week 13 
& 
beyonda
(±7 days)
Response 
Assessmentb
(±7 days)
EOTc
(±7 
days)
RFUd
LTFUw
Day
1
2
3
1
2
3
1
1
7
1
1
1 (±1 
day)
1 (±1 
day)
(±14 days)
Study Drug Administration
Ibrutinib 560 mg daily
Continuous
----
Venetoclax daily dose
20mg
50mg
100mg 200mg
400mg continuous target daily dose
----
Procedure
Screening
Day -28 to -1
Urinalysiss
X
X
Serum or Urine Pregnancy
X
X
X
Hepatitis serologiest
X
Coagulation panel
X
Buccal Swab
X
Serum β2-microglobulin
X
PK blood samplingv
X
X
X
Survival status, incl. other 
malignanciesw
X
Subsequent Anticancer Therapy
X
X
Abbreviations:
EOT = End-of-Treatment Visit; RFU = Response Follow-up Visit; LTFU = Long-term Follow up; PRO = patient-reported outcome; *TP53 mutation test by local or central lab
Footnotes:
a After week 13, study drug dispensing visits are scheduled every 4 weeks for 1 year; every 8 weeks during the 2nd and 3rd years; and every 12 weeks thereafter until treatment 
discontinuation.
b Response assessment visits are scheduled on Week 13 Day 1 (±7 days); every 12 weeks for the remainder of the 1st year; every 16 weeks during the 2nd and 3rd years, and every 
24 weeks thereafter until PD. In addition, response assessments can be performed as clinically indicated to confirm response or progression. PET scans will be performed at 
screening, at Week 13, Week 25, Week 49 and at suspected CR.
c An EOT visit will occur 30 days (±7) from the last dose of study drug or prior to the start of a new anticancer treatment.
d Subjects who discontinue for reasons other than PD will have follow-up response assessments (based on Week 1 Day 1 for a subject) every 12 weeks (± 14 days) from the 
1st dose for the 1st year; every 16 weeks (± 14 days) during the 2nd and 3rd years; and every 24 weeks (± 14 days) thereafter until PD.
e Concomitant medications are collected from 30 days before 1st dose through the 30 days after the last dose of study drug.
f See Section 11 for details regarding the reporting of AEs.
g A complete physical examination (at Screening and EOT) will include, at a minimum, the general appearance of the subject, height (may use prior height measurement if 
available in source documents) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, 
and nervous system. At other timepoints, a limited symptom-directed physical exam will be performed. The physical exam should include an eye-related symptom assessment.
h Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the subject has rested in the sitting position for ≥3 minutes.
I A single 12-lead ECG will be done at Screening and at the EOT visit. Subjects should be in a supine position and resting for at least 10 minutes before obtaining the ECG. 
During the treatment period, ECG’s may be performed at the investigator’s discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or 
new onset dyspnea. 


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j
CT and PET or PET/CT: A CT scan (with contrast unless contraindicated) of the neck, chest, abdomen, and pelvis and any other disease sites (eg, extremity) and a PET or 
PET/CT scan (CT should be of diagnostic quality) are required for the pretreatment tumor assessment within 28 days of the 1st dose. Thereafter, CT scans will be done for 
tumor assessments on Week 13 Day 1 (±7 days); every 12 weeks for the remainder of the 1st year; every 16 weeks during the 2nd and 3rd years; and every 24 weeks thereafter 
until PD. PET or PET/CT is mandatory for all subjects at the Week 13 visit (+/- 7 days), the Week 25 visit (+/- 7 days) for subjects in SD or PR who did not achieve CR at 
Week 13, and at the 1-year visit (Week 49 +/- 7 days) for all subjects, as well as at any other time point to confirm a CR. Other PET or PET/CT scans that are NOT mandatory 
can be performed within a 30-day window of the visit. For MRI refer to Section 7.1.3.2.
k A total of up to 20 slides of fresh or the most recent dated FFPE archival tumor biopsy tissue will be required at study entry. An optional tumor biopsy should be collected at the 
time of disease progression if feasible.
l
A unilateral bone marrow aspirate will be done at Screening or up to 28 days before the 1st administration of study drug for MRD testing. A 2nd bone marrow aspirate will be 
performed in all subjects who achieve a CR. Subsequent bone marrow aspirates will be obtained as needed (ie, if MRD in BM at CR was positive, and subject remains CR) to 
confirm MRD-negative CR. 
m Response assessments will be completed by the investigator using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
n Blood will be drawn for MRD assessments at baseline, at documented complete response and onwards every 12 weeks (±7 days) for the remainder of the 1st year; every 
16 weeks during the 2nd and 3rd years; and every 24 weeks thereafter until PD. 
o Risk of TLS is to be re-assessed prior to each venetoclax dose ramp-up. Administration of prophylaxes as needed is to occur within 72 hours of dosing. Subjects with high tumor 
burden at baseline may be hospitalized for a minimum of the first 24 hours of treatment (and up to 48 hours at the discretion of the investigator) at the start of the 20 mg (ramp-
up dose) and the 50 mg dose levels and blood chemistry (creatinine, uric acid, potassium, phosphorus, calcium, and albumin, if available) should be monitored pre-dose and 4±1, 
8±1, 12±1, 24±2 and as needed 48±2 hours after the venetoclax dose. Additionally, for high risk TLS subjects, post-dose blood chemistries will be monitored at pre-dose and 
6-8 hours after the venetoclax dose during ramp up of the 100 mg, 200 mg and 400 mg dose levels. For all other subjects, blood chemistry will be monitored pre-dose, 6-8 and 
24±2 hours after the venetoclax dose at the 20 mg and the 50 mg dose levels. 
p PRO questionnaires (EQ-5D-5L) should be completed prior to any assessments, and before being clinically evaluated by the study nurse or physician. The questionnaires will be 
administered on Week 1 Day 1, Week 13 Day 1 (±7 days); every 4 weeks for the remainder of the 1st year; every 8 weeks during the 2nd and 3rd years; and every 12 weeks 
thereafter until disease progression.
q Hematology includes complete blood count with differential and platelet counts. 
r Blood chemistry: Sodium, potassium, chloride, BUN, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, LDH, phosphate, uric 
acid, urea, magnesium and bicarbonate. Serum creatinine, uric acid, potassium, phosphorus and calcium should be assessed within 72 hours prior to the first venetoclax dose and 
before each dose increase.
s Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose. 
t
Hepatitis C antibody, hepatitis B surface antigen and hepatitis B core antibody will be evaluated. If hepatitis B core antibody or hepatitis B surface antigen or Hepatitis C 
antibody is positive, then PCR to quantitate hepatitis B DNA or hepatitis C RNA must be performed. DNA PCR needs to be confirmed negative (< 29 U) prior to enrollment in 
subjects who are hepatitis B core antibody or hepatitis B surface antigen positive. For subjects who are hepatitis C antibody positive, hepatitis C PCR needs to be confirmed 
negative prior to enrollment. Subjects who are Hepatitis B surface antigen positive are excluded from the trial.
u Blood biomarker samples will be drawn at baseline, at documented complete response and onwards every 12 weeks (±7 days) for the remainder of the 1st year; every 16 weeks 
during the 2nd and 3rd years; and every 24 weeks thereafter until PD.
v PK samples will be drawn at Week 4 Day 7 and Week 6 Day 1: pre-dose (±30min), 1hr (±15min), 2hrs (±15min), 4hrs (±30min), 6hrs (±30min), and 8hrs (±1hr) post dose. In 
addition, at Week 13: pre-dose (±30min), 1hr (±15min), 2hrs (±15min). Unscheduled PK sampling is allowed based on Medical Monitor request, e.g. dose modification (at least 
7 days after dose modification)
w After progression, survival status, other malignancies and subsequent anticancer therapy will be collected approximately every 12 weeks (based on Week 1 Day 1 for a subject) 
until death, withdrawal by subject, loss to follow-up, or study terminated by Sponsor, whichever comes first.
x A unilateral bone marrow biopsy will be done at Screening or up to 28 days before the first administration of study drug for standard pathology. A second bone marrow biopsy 
will be performed in subjects with positive bone marrow involvement at baseline by standard pathology who achieve a CR. 


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Appendix C.
ECOG Status Scores
Status
Eastern Cooperative Oncology Group (ECOG) Performance Status**
0
Fully active, able to carry on all predisease 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.
**Oken MM, Creech RH, Tormey DC, et al: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol. 5:649-655, 1982.
Available at: http://www.ecog.org/general/perf_stat html. Accessed January 4, 2008.






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Appendix E.
Revised Criteria for Response Assessment for Malignant 
Lymphoma
Site
PET-CT-based Response
CT-based Response
Complete Metabolic Response
(CMR)
Complete Radiologic Response
(ALL of the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3* with or without a residual 
mass on 5PS**.
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiological 
uptake or with activation within spleen or 
marrow, eg, with chemotherapy or myeloid 
colony stimulating factors, uptake may be 
greater than normal mediastinum and/or 
liver. In this circumstance, CMR may be 
inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiological uptake
Target nodes/nodal masses must regress 
to < 1.5 cm in LDi
No extralymphatic sites of disease
Non-measured lesion
Not applicable
Absent 
Organ enlargement
Not applicable
Regress to normal 
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if indeterminate, 
IHC negative
Partial Metabolic Response (PMR)
Partial Remission (PR) 
(ALL of the following)
Lymph nodes and 
extralymphatic sites
Score 4,5** with reduced uptake compared 
with baseline and residual mass(es) of any 
size.
At interim these findings suggest responding 
disease 
At end of treatment these findings indicate 
residual disease
> 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites
(When a lesion is too small to measure on 
CT, assign 5mm x 5mm as the default 
value. When no longer visible, 0x0 mm
For a node > 5mm x 5mm, but smaller 
than normal, use actual measurement for 
calculation.)
Non-measured lesion
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by > 50% in 
length beyond normal 
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed).
If there are persistent focal changes in the 
marrow in the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy, or an 
interval scan
Not applicable


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No Metabolic Response (NMR)
Stable disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 with no significant change in 
FDG uptake from baseline, at interim or 
end of treatment.
< 50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for PD are met 
Non-measured 
lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive Metabolic Disease (PMD)
Progressive disease requires at least 
ONE of the following
Individual target 
nodes/nodal masses, 
Extranodal lesions
Score 4, 5 with an increase in intensity of 
uptake from baseline and/or
New FDG-avid foci consistent with 
lymphoma at interim or end of treatment
assessment
PPD Progression: 
An individual node must be abnormal 
with: LDi > 1.5 cm AND Increase by 
≥50% from PPD nadir AND an increase 
in LDi or SDi from nadir
0.5 cm for lesions < 2 cm
1.0 cm for lesions > 2 cm 
In the setting of 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
New or recurrent splenomegaly 
Non-measured 
lesions
None
New or clear progression of pre-existing 
non-measured lesions 
New lesions
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.
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 less than 1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma.
Assessable disease of any size 
unequivocally attributable to lymphoma
Bone marrow
New or recurrent FDG avid foci
New or recurrent involvement
* Score 3 in many patients indicates a good prognosis with standard treatment, especially if at 
the time of an interim scan. However in trials involving PET where de-escalation is investigated, 
it may be preferable to consider score 3 as inadequate response (to avoid under-treatment).


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SPD – sum of the product of the perpendicular diameters for multiple lesions
LDi – Longest transverse diameter of a lesion
SDi – Shortest axis perpendicular to the LDi
PPD – Cross product of the LDi and perpendicular diameter
Measured dominant lesions – Up to 6 of the largest dominant nodes, nodal masses and 
extranodal lesions selected to be clearly measurable in 2 diameters. Nodes should preferably be 
from disparate regions of the body, and should include, where applicable, mediastinal and 
retroperitoneal areas. Non-nodal lesions include those in solid organs, eg, liver, spleen, kidneys, 
lungs, etc, gastrointestinal involvement, cutaneous lesions of those noted on palpation.
Non-measured lesions – Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal 
masses, and extranodal sites not selected as dominant, measurable or which do not meet the 
requirements for measurability, but are still considered abnormal. As well as truly assessable 
disease which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses and other lesions that cannot be confirmed and followed by imaging.
In Waldeyer’s ring or in extranodal sites, eg, gastrointestinal tract, liver, and bone marrow, FDG 
uptake may be greater than mediastinum with CMR, but should be no higher than surrounding 
normal physiologic uptake, eg, with marrow activation due to chemotherapy or myeloid growth 
factors.
**PET Five Point Scale (5-PS)
1. No uptake above background
2. Uptake < mediastinum 
3. Uptake > mediastinum, but < liver
4. Uptake moderately > liver
5. Uptake markedly higher than liver and/or new lesions
X. New areas of uptake unlikely to be related to lymphoma
Source: Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol.2014;32(27):3059-68. 


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Appendix F.
Child-Pugh Score for Subjects with Liver Impairment
Measure
1 point
2 points
3 points
Total bilirubin, μmol/L (mg/dL)
< 34 (< 2)
34-50 (2-3)
> 50 (> 3)
Serum albumin, g/L (g/dL)
> 35 (> 3.5)
28-35 (2.8-3.5)
< 28 (< 2.8)
PT/INR
< 1.7
1.71-2.30
> 2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed 
with medication)
Grade III-IV 
(or refractory)
Points
Class
5-6
A
7-9
B
10-15
C
Sources:
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia:Saunders. 1964. pp. 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: 646-9.


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Appendix G.
Howard Criteria for Laboratory and Clinical TLS*
(Howard et al, NEJM 2011)
Metabolic Abnormality
Criteria for Classification of 
Laboratory Tumor Lysis Syndrome
Criteria for Classification of 
Clinical Tumor Lysis Syndrome
Hyperuricemia
Uric acid > 8.0 mg/dL 
(475.8 μmol/liter) in adults or above 
the upper limit of the normal range for 
age in children
Hyperphosphatemia
Phosphorus > 4.5 mg/dL 
(1.5 mmol/liter) in adults or 
> 6.5 mg/dL (2.1 mmol/liter) in 
children
Hyperkalemia
Potassium > 6.0 mmol/liter 
Cardiac dysrhythmia or sudden death 
probably or definitely caused by 
hyperkalemia
Hypocalcemia
Corrected calcium < 7.0 mg/dL 
(1.75 mmol/liter) or ionized calcium 
< 1.12 (0.3 mmol/liter)†
Cardiac dysrhythmia, sudden death, 
seizure, neuromuscular irritability 
(tetany, paresthesias, muscle twitching, 
carpopedal spasm, Trousseau’s sign, 
Chvostek’s sign, laryngospasm, or 
bronchospasm), hypotension, or heart 
failure probably or definitely caused by 
hypocalcemia
Acute kidney injury‡
Not applicable
Increase in the serum creatinine level of 
0.3 mg/dL (26.5 μmol/liter) (or a single 
value > 1.5 times the upper limit of the 
age-appropriate normal range if no 
baseline creatinine measurement is 
available) or the presence of oliguria, 
defined as an average urine output of 
< 0.5 mL/kg/hr for 6 hr
* In laboratory TLS, two or more metabolic abnormalities must be present during the same 24-hour period within 3 days 
before the start of therapy or up to 7 days afterward. Clinical TLS requires the presence of laboratory TLS plus an increased 
creatinine level, seizures, cardiac dysrhythmia, or death.
† The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × 
(4 −albumin in grams per deciliter).
‡ Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 μmol per liter) or a 
period of oliguria lasting 6 hours or more. By definition, if acute kidney injury is present, the patient has clinical TLS. Data 
about acute kidney injury are from (Levin 2007).
Note: Only post-dose laboratory assessments will be considered when applying Howard Criteria for laboratory and clinical 
TLS.


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Appendix H.
Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS)
Section 1: First Dose of Venetoclax or Dose Escalation

Within the first 24 hours after either the first dose or dose escalation, if any 
laboratory criteria below are met, the patient should be hospitalized for monitoring 
and the investigator notified. No additional venetoclax doses should be administered 
until resolution. A rapidly rising serum potassium is a medical emergency.

Nephrology (or other acute dialysis service) should be contacted/consulted (per 
institutional standards to ensure emergency dialysis is available) on admission for 
any subject hospitalized prophylactically or in response to laboratory changes.

IV fluids (eg, D5 1/2 normal saline) should be initiated at a rate of at least 
1 mL/kg/hr rounded to the nearest 10 mL (target 150 to 200 mL/hr; not 
< 50 mL/hr). Modification of fluid rate should also be considered for individuals 
with specific medical needs.

Monitor for symptoms or signs of TLS (eg, fever, chills, tachycardia, nausea, 
vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, paresthesias, 
mental status changes, confusion, seizures). If any clinical features are observed, 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour 
STAT.

Vital signs should be taken at time of all blood draws or any Intervention.

The management recommendations below focus on the minimum initial responses 
required. If a diagnosis of TLS is established, ongoing intensive monitoring and 
multi-disciplinary management will be per institutional protocols
In addition to the recommendations in the table below:

For potassium increase ≥0.5 mmol/L from baseline, or any value > 5.0 mmol/L, 
recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour 
STAT and follow first guideline.

For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer phosphate 
binder and recheck potassium, phosphorus, uric acid, calcium and creatinine within 
1 hour STAT.


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Abnormality
Management Recommendations1,2
Hyperkalemia (including rapidly rising potassium)
Potassium ≥0.5 mmol/L increase from 
prior value (even if potassium within 
normal limits [WNL])

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT. If further ≥0.2 mmol/L increase in 
potassium, but still < upper limit of normal (ULN), manage as 
per potassium ≥ULN. Otherwise recheck in 1 hour.

Resume per protocol testing if change in potassium is 
< 0.2 mmol/L, and potassium < ULN, and no other evidence of 
tumor lysis.

At discretion of Investigator, may recheck prior to 
hospitalization. If stable or decreased, and still WNL, 
hospitalization is at the discretion of the Investigator. Potassium, 
phosphorus, uric acid, calcium and

Creatinine must be rechecked within 24 hours.
Potassium > upper limit of normal

Perform STAT ECG and commence telemetry.

Nephrology notification with consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer calcium gluconate 100 – 200 mg/kg IV slowly if 
there is ECG/telemetry evidence of life-threatening arrhythmias.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.
o
If potassium < ULN 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 1, 2 and 
4 hours, if no other evidence of tumor lysis.
Potassium ≥6.0 mmol/L (6.0 mEq/L) 
and/or symptomatic (eg, muscle 
cramps, weakness, paresthesias, nausea, 
vomiting, diarrhea)

Perform STAT ECG and commence telemetry.

Nephrology (or other acute dialysis service) assessment with 
consideration of initiating dialysis.

Administer Kayexalate 60 g (or Resonium A 60 g).

Administer furosemide 20 mg IV × 1.

Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV.

Administer sodium bicarbonate 1 to 2 mEq/kg IV push.
o
If sodium bicarbonate is used, rasburicase should not be 
used as this may exacerbate calcium phosphate precipitation.

Administer calcium gluconate 100 to 200 mg/kg IV slowly if 
there is ECG/telemetry evidence of life-threatening arrhythmias. 
Do not administer in same IV line as sodium bicarbonate.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine every hour STAT.
Hyperuricemia
Uric acid ≥8.0 mg/dL (476 μmol/L)

Consider rasburicase (0.2 mg/kg as an intravenous infusion over 
30 minutes).
o
If rasburicase is used, sodium bicarbonate should not be 
used as this may exacerbate calcium phosphate precipitation.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.


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Abnormality
Management Recommendations1,2
Uric acid ≥10 mg/dL (595 μmol/L)
OR
Uric acid ≥8.0 mg/dL (476 μmol/L) 
with 25% increase and creatinine 
increase ≥0.3 mg/dL (≥0.027mmol/L) 
from pre-dose level

Administer rasburicase (0.2 mg/kg as an intravenous infusion 
over 30 minutes).
o
When rasburicase is used, sodium bicarbonate should not be 
used as this may exacerbate calcium phosphate precipitation.

Consult nephrology (or other acute dialysis service).

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.

If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 4 hours later, 
if no other evidence of tumor lysis.
Hypocalcemia
Calcium ≤ 7.0 mg/dL (1.75 mmol/L)
AND
Patient symptomatic (eg, muscle 
cramps, hypotension, tetany, cardiac 
arrhythmias)

Administer calcium gluconate 50 to 100 mg/kg IV slowly with 
ECG monitoring.

Telemetry.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.

If calcium normalized 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 4 hours later, 
if no other evidence of tumor lysis. Calculate corrected calcium 
and check ionized calcium if albumin low
Hyperphosphatemia
Phosphorus ≥5.0 mg/dL 
(1.615 mmol/L) with ≥0.5 mg/dL 
(0.16 mmol/L) increase

Administer a phosphate binder (e.g., aluminum hydroxide, 
calcium carbonate, sevelamer hydroxide, or lanthanum 
carbonate).

Nephrology (or other acute dialysis service) notification (dialysis 
required for phosphorus ≥10 mg/dL). 

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 hour STAT.

If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, 
phosphorus, uric acid, calcium and creatinine 2 and 4 hours later, 
if no other evidence of tumor lysis.
Creatinine
Increase ≥ 25% from baseline

Start or increase rate of IV fluids.

Recheck potassium, phosphorus, uric acid, calcium and 
creatinine in 1 to 2 hours STAT.
Section 2: Ongoing Dosing of Venetoclax
Management of electrolyte changes from last value at intervals > 24 hours after either the first 
dose or dose escalation (eg, 48 or 72 hours) are as below.
Note: If the patient is hospitalized, no additional venetoclax doses should be administered until 
resolution.


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
For potassium, admit patient for any increase ≥1.0 mmol/L (1.0 mEq/L), or any 
level > upper limit of normal.
o
Refer to the management guidelines for electrolyte changes observed within the 
first 24 hours after either the first dose or dose escalation (see Table above).

If a smaller potassium increase is observed that does not meet the criteria for 
admission above, recheck potassium, phosphorus, uric acid, calcium and creatinine 
in 24 hours and confirm no evidence of tumor lysis prior to further venetoclax 
dosing.

For uric acid, calcium, phosphorus and creatinine, refer to the management 
guidelines for electrolyte changes observed within the first 24 hours after either the 
first dose or dose escalation (see Table above).
References
1. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult 
tumor lysis syndrome: an evidence-based review. J Clin Oncol.2008;26(16):2767-78.
2. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol. 2004;127(1):3-11.










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Appendix J.
EQ-5D-5L
 
 
 
 
 
 
 
    
 
 
 
   
 
 
 
 
 


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SAP_001.pdf: 
PCYC-1143-CA 
Statistical Analysis Plan 
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Statistical Analysis Plan 
 
 
 
 Phase 3 Study of Ibrutinib in Combination with Venetoclax in Subjects with Mantle Cell 
Lymphoma  
 
 
PCYC-1143-CA 
 
 
June 22, 2023 
Version 2.0 (Final) 
 
 
 
The information in this document is considered privileged and confidential by Pharmacyclics 
LLC, and may not be disclosed to others except to the extent necessary to obtain Institutional 
Review Board approval and informed consent, or as required by Federal and State Laws.  
Persons to whom this information is disclosed must be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
 
 
 
 
 
 
 
 
 
NCT03112174




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TABLE OF CONTENTS 
 
1 
INTRODUCTION ............................................................................................. 7 
1.1 
Study Design ..................................................................................................................7 
1.1.1 
Safety Run-in Period .........................................................................................7 
1.1.2 
Randomization Phase ........................................................................................8 
1.1.3 
Treatment Time and Follow-up Time...............................................................9 
1.2 
Endpoints .......................................................................................................................9 
1.3 
Statistical Hypotheses ..................................................................................................10 
1.4 
Sample Size Determination..........................................................................................10 
1.4.1 
PFS ..................................................................................................................10 
1.4.2 
OS ...................................................................................................................11 
1.5 
Planned Analysis ..........................................................................................................11 
1.5.1 
Primary PFS Analysis and Interim OS Analysis ............................................11 
1.5.2 
Final OS Analysis ...........................................................................................11 
1.6 
Testing Procedure and Level of Significance ..............................................................12 
1.6.1 
Adjustment of Multiplicity for Multiple Endpoints: ......................................12 
1.6.2 
Adjustment of Multiplicity for Multiple OS Analyses ...................................12 
1.7 
Blinding and Randomization Methods ........................................................................13 
1.7.1 
Blinding Method .............................................................................................13 
1.7.2 
Randomization Method ..................................................................................13 
2 
GENERAL ANALYSIS CONSIDERATION ............................................... 14 
2.1 
Analysis Sets ................................................................................................................14 
2.2 
Definition of Subgroups ...............................................................................................15 
3 
SUBJECT INFORMATION ........................................................................... 17 
3.1 
Subject Disposition ......................................................................................................17 
3.2 
Demographics, Baseline Characteristics, and Baseline Disease Characteristics .........17 
3.3 
Prior and Concomitant Medications ............................................................................17 
3.4 
Extent of Exposure to Study Treatment .......................................................................18 
3.5 
Prior and Subsequent Anti-Cancer Treatments............................................................19 
3.6 
Visit Impact of Logistical Restriction Due to COVID-19 ...........................................19 
4 
ANALYSIS FOR EFFICACY ENDPOINTS................................................ 20 
4.1 
Estimand of the Primary Efficacy Endpoint ................................................................20 
4.2 
Definitions and Analyses for Efficacy Endpoints ........................................................22 
5 
SAFETY ASSESSMENTS .............................................................................. 28 
5.1 
Data Summaries for COVID-19 ..................................................................................29 
5.2 
Safety Run-in ...............................................................................................................29 
6 
TREATMENT-NAÏVE COHORT ................................................................ 31 
7 
CHANGES IN THE PROTOCOL-PLANNED ANALYSES ..................... 32 
8 
APPENDICES .................................................................................................. 33 
8.1 
Algorithm for Defining 2 or more Consecutive Assessments Prior to the PFS Event 33 
 
 
 
 


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9 
REFERENCES ................................................................................................. 34 
 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BMA 
Bone Marrow Aspirate 
BOR 
Best Overall Response 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CRR 
Complete Response Rate 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECOG 
Eastern Cooperative Oncology Group 
FACT-Lym 
Functional Assessment of Chronic Illness Therapy – General (FACT-
G) and a lymphoma-specific additional concerns subscale (Lym) 
FWER 
Family Wise Error Rate 
IA 
Interim Analysis 
IDMC 
Independent Data Monitoring Committee 
ILD 
Interstitial Lung Disease 
IRC 
Independent Review Committee 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
HR 
Hazard Ratio 
KM 
Kaplan-Meier 
MCL 
Mantel Cell Lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIPI 
MCL International Prognostic Index 
MRD 
Minimal Residual Disease 
mOS 
Median Overall Survival 
mPFS 
Median Progression-free Survival 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NCI ODWG 
NCI Organ Dysfunction Working Group Liver Function Classification 
 
 
 
 


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NE 
Not Evaluable 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PA 
Primary Analysis 
PB 
Peripheral Blood 
PCYC 
Pharmacyclics 
PD 
Progressive Disease 
PDI 
Planned Dose Intensity 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic  
PR 
Partial Response 
PRO 
Patient Reported Outcome 
PS 
Performance Status 
PT 
Preferred Term 
QoL 
Quality of life 
RDI 
Relative Dose Intensity 
R/R 
Relapsed/Refractory 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCT 
Stem Cell Transplant 
SD 
Stable Disease 
SMQ 
Standardized MedDRA query 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SRI 
Safety Run-in 
TEAE 
Treatment-Emergent Adverse Event 
TLS 
Tumor Lysis Syndrome 
TN 
Treatment Naive 
TTNT 
Time to Next Treatment 
 
 
 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) is based on Protocol Amendment 4 dated September 25, 2022 
and defines key elements including variable definitions and statistical methods for analysis of 
data in evaluation of efficacy and safety for subjects with the Relapsed/Refractory (R/R) mantle 
cell lymphoma (MCL) who are enrolled in the study PCYC-1143-CA. 
Study PCYC-1143-CA also contains a separate arm treatment-naïve (TN) MCL cohort which has 
completed enrollment; an SAP addendum will be provided for the treatment-naïve (TN) MCL 
cohort at the appropriate time prior to the primary analysis. Subject demographics and disease 
characteristics and relevant safety data will be summarized for subjects with TN MCL who are 
enrolled at the time of the primary analysis for the subjects with R/R MCL. 
The analyses of exploratory biomarkers and pharmacokinetics (PK) data are not in the scope of 
this document. Throughout this SAP, "study treatment" and "study drug" are used 
interchangeably, and both are referring to ibrutinib and venetoclax or placebo. 
Analysis methods specified in this document take precedence over those described in the 
protocol, should there be any differences. Any changes in the protocol will be documented in 
Section 7, Changes in the Protocol Planned Analysis. This SAP will be finalized before 
unblinding of the study results. 
1.1 
Study Design 
This Phase 3, multinational, randomized, double-blind study is designed to compare the efficacy 
and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in R/R 
subjects with MCL. 
Approximately 287 subjects with R/R MCL (up to 27 SRI [Safety Run-in] subjects and 
260 randomized subjects) will be enrolled. 
A separate open-label cohort is designed to explore the efficacy and safety of the combination of 
ibrutinib and venetoclax in approximately 75 subjects with TN MCL (approximately 50 subjects 
≥65 years of age and approximately 25 subjects with a TP53 mutation). There will be no Safety 
Run-in period for this cohort. 
1.1.1 Safety Run-in Period  
The study will start with an open-label SRI period for subjects with R/R MCL to evaluate the 
occurrence of Tumor Lysis Syndrome (TLS) and dose-limiting toxicities (DLTs) with the 
concurrent administration of ibrutinib and venetoclax. The TLS and DLT occurrence will be 
assessed during the venetoclax Ramp-up Period for a minimum of 5 weeks (Figure 1). Up to 
27 subjects may be enrolled during the SRI period. 
 
 
 
 


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1.1.2 Randomization Phase 
The Randomization Phase of the study will follow a randomized, double-blind design. Ibrutinib 
and venetoclax/placebo will be administered using the Standard Ramp-up Schedule (without 
ibrutinib lead-in) that was determined to be appropriate for each TLS risk category in the Safety 
Run-in Phase. The Independent Data Monitoring Committee (IDMC) will review the safety 
recommendations made by the Safety Review Committee (SRC) and will be responsible for 
giving recommendations on continuing, modifying, or stopping the Randomization Phase of the 
study. 
Subject eligibility will be determined up to 28 days prior to randomization. Approximately 
260 eligible subjects will be randomized at a 1:1 ratio to ibrutinib and venetoclax or ibrutinib and 
placebo. Randomization will be stratified by number of prior lines of therapy, ECOG 
performance status (PS), and by TLS risk category through the Interactive Response Technology 
(IRT). 
Initially, subjects at increased risk of TLS will be hospitalized for a minimum of 24 hours (and 
up to 48 hours at the discretion of the investigator) at the start of the 20 mg venetoclax ramp-up 
dose, and again at the start of the 50 mg venetoclax ramp-up dose for monitoring and 
prophylaxis of TLS. The IDMC will review unblinded safety data during the course of the study 
to determine whether continued hospitalization of these subjects during ramp-up remains 
warranted. 
The IDMC will review unblinded safety data including all deaths and any progression associated 
with safety 6-9 months after the initiation of the Randomization Phase to evaluate the safety of 
the combination of ibrutinib and venetoclax/placebo and to confirm that continued dosing with 
the combination is warranted. In addition, the IDMC will review TLS data during the course of 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 


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the study to ascertain whether the continued hospitalization of subjects with high tumor burden 
and/or creatinine clearance <60 mL/min during ramp-up is needed. The composition of the 
IDMC, responsibilities, authorities, and procedures are detailed in a separate IDMC charter. 
1.1.3 Treatment Time and Follow-up Time 
Safety Run-in subjects and TN subjects will be treated with ibrutinib and venetoclax, and 
randomized subjects will be treated with ibrutinib and venetoclax or ibrutinib and placebo for 
approximately 104 weeks followed by ibrutinib monotherapy on both treatment arms until 
progressive disease (PD), unacceptable toxicity or withdrawal of consent. Venetoclax and 
placebo will be discontinued after 104 weeks of treatment regardless of response assessment. 
All enrolled subjects who discontinue study treatment for any reason will be followed for 
progression (if they have not progressed before treatment discontinuation), subsequent anti-
cancer therapy and survival status until study closure. 
1.2 
Endpoints 
Randomized Subjects 
Safety Run-in Subjects 
Primary Efficacy Endpoint 
Progression-free survival (PFS) per investigator 
assessment  
Efficacy Assessments 
 
Overall response rate (ORR) and Duration 
of Response (DOR) per investigator 
assessment  
 
Progression-free survival per investigator 
assessment  
 
Overall Survival (OS) 
Secondary Efficacy Endpoints 
 
Complete response rate (CRR) per investigator 
assessment  
 
Overall Response Rate (ORR) per investigator 
assessment  
 
Minimal residual disease (MRD)-negative 
remission rate in subjects who achieve CR per 
investigator assessment and are MRD-positive at 
baseline 
 
Overall Survival (OS) 
 
Time to next treatment (TTNT) 
 
Time to worsening in FACT-Lym subscale of the 
health-related quality-of-life questionnaire 
(FACT-Lym) 
Exploratory Endpoint 
 
PFS based on investigator assessment after 
initiation of subsequent anti-cancer therapy 
(PFS2) 
Safety Assessments 
 
Frequency, severity, and relatedness of AEs   
 
Frequency, severity and management of TLS  
Safety Assessments 
 
Frequency of TLS and DLTs  
 
 
 
 


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Randomized Subjects 
Safety Run-in Subjects 
 
Frequency of AEs requiring discontinuation of 
study drug or dose reductions, or leading to 
death 
 
Frequency, severity, and relatedness of 
AEs  
 Frequency of AEs causing study drug 
discontinuation, or dose reductions or 
leading to death  
Overall disease assessment is according to Revised Response Criteria for Malignant Lymphoma 
(Cheson 2014, Lugano Classification Criteria) 
 
1.3 
Statistical Hypotheses 
The statistical hypotheses for the primary endpoint (PFS) can be written as follows: 
H0:  SE(t) = SC(t), for all t > 0, where SE(t), and SC(t) are survival functions for the experimental 
and control arms, respectively at all time points t: 
vs. 
H1: The PFS distribution of the experimental treatment group, SE(t), is stochastically larger than 
the control group, SC(t), with strict inequality for some time point t: 
SE (t) ≥ SC(t) for all t ≥ 0, and SE(t) > SC(t) for some t > 0 
These hypotheses will be tested for the primary endpoint using a two-sided stratified log-rank 
test at an alpha level specified in Section 1.6. The source of the stratification factors will be 
based on IRT data. 
1.4 
 Sample Size Determination 
1.4.1 PFS 
The Randomization Phase sample size is powered based on the primary endpoint of PFS. 
Approximately 260 subjects will be randomized at a 1:1 ratio to the ibrutinib + venetoclax arm 
and the ibrutinib + placebo arm. The calculations are based on the following assumptions using 
EAST software Version 6.4.1: 
 
Target hazard ratio is 0.61, which corresponds to an improvement of 9 months in median 
PFS (mPFS) from 14 months to 23 months for the ibrutinib + venetoclax arm compared to 
the ibrutinib + placebo arm. 
 
A total of 134 PFS events will provide approximately 80% power at a one-sided 
significance level of 0.025 for the study. No interim analysis (IA) is planned for PFS. 
 
 
 
 


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 
Assuming an enrollment rate of approximately 10-11 subjects per month, the accrual is 
projected to complete approximately 21 months from the first subject in. The actual length 
of the study and the time to the primary analysis will depend on the actual enrollment rate 
and the number of events that occur. 
1.4.2 OS 
 Target hazard ratio is 0.65, which corresponds to an improvement of ~16 months in median 
OS (mOS) from 30 months to 46.2 months for the ibrutinib + venetoclax arm compared to 
the ibrutinib + placebo arm. 
 A total of 155 OS events would provide ~76% power at a one-sided significance level of 
0.025 adjusting for one interim analysis based on group sequential design with Lan-DeMets 
spending function with O'Brien-Fleming1 boundary. 
 It is anticipated that 112 and 155 OS events will be observed at the interim analysis (at 
~40 months corresponding to the timing of the primary PFS analysis) and at the final 
analysis (at ~57 months), respectively. The level of significance for each analysis is 
described in Section 1.6.2. 
 The calculation for OS is based on a log-rank test using EAST software version 6.5. 
1.5 
Planned Analysis 
The effect size (HR) assumptions of PFS and OS did not consider potential impact of COVID-19 
deaths when the study was initiated. In alignment with the FDA guidance2 (Statistical 
Considerations for Clinical Trials During the COVID-19 Public Health Emergency, June 2020), 
in order to mitigate the potential impact on the key efficacy endpoints due to COVID-19, the 
follow-up will be extended to accrue more events as described in Section 1.5.1 and Section 1.5.2 
below than the originally planned event numbers (134 events for PFS and 155 events for OS). 
1.5.1 Primary PFS Analysis and Interim OS Analysis 
The primary PFS analysis will be conducted after approximately 150 PFS events have been 
observed. No interim analysis is planned for PFS. 
An interim analysis (IA) is planned for OS at the time of the primary PFS analysis. 
1.5.2 Final OS Analysis 
The final OS analysis will be conducted after the last subject was followed for at least 5 years or 
approximately 170 OS events are observed, whichever occurs first. 
At the time of the final OS analysis, a CSR addendum will be provided. 
 
 
 
 


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1.6 
Testing Procedure and Level of Significance 
1.6.1 Adjustment of Multiplicity for Multiple Endpoints: 
The one-sided Type I Family Wise Error Rate (FWER) will be controlled at 0.025 by a closed 
testing procedure for testing the primary endpoint (PFS) and key secondary endpoints. The 
following key secondary endpoints will be tested only if the primary endpoint (PFS) reaches 
statistical significance (1-sided 0.025) and will be ranked and tested at 1-sided statistical 
significance of 0.025 sequentially in the hierarchical order below: 
1) 
CR rate per investigator assessment 
2) 
Time to next treatment* 
3) 
OS  
4) 
ORR per investigator assessment 
A secondary endpoint with a lower rank cannot be tested until the preceding endpoint achieves 
statistical significance. 
*For US regulatory purposes, time to next treatment will be tested after OS as the third endpoint 
in the hierarchical order. 
At the time of the primary PFS analysis, an interim analysis is planned for OS. Statistical 
significance level for each OS analysis is described in Section 1.6.2. ORR will be tested at 
1-sided 0.025 using the primary PFS analysis data cut when OS significance is achieved. 
1.6.2 Adjustment of Multiplicity for Multiple OS Analyses 
To maintain a 1-sided overall significance level of 0.025 for OS, assuming the final OS analysis 
is based on 170 events, the significance level of the OS final analysis will be adjusted for the OS 
interim analysis as follows based on Haybittle-Peto boundary instead of O'Brien Fleming 
boundary as specified in the protocol (Protocol Section 10.3). The actual boundary for the OS 
final analysis will be based on actual number of OS events at the time of the OS final analysis. 
Analysis 
# of OS Events  
Significance level 
(1-sided p-value) 
Observed Hazard 
Ratio/Superiority Boundary 
IA 
Agnostic to number of events 
0.0005 
< 0.550 
FA 
170 (assumed) 
0.024983 
< 0.740 
 
 
 
 
 


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1.7 
Blinding and Randomization Methods 
1.7.1 Blinding Method 
Subjects, investigators, and the Sponsor's study team members will remain blinded to the 
treatment assignment in the randomization phase. The investigator will not be provided with 
randomization codes nor the treatment assigned and received. The codes will be maintained 
within the IRT System, which has the functionality to allow the investigator to break the blind 
for an individual subject if necessary, to appropriately manage or treat the subject. Data that may 
potentially unblind the treatment assignment (e.g., study drug plasma concentrations) will be 
handled with special care to ensure that the integrity of the blind is maintained and the potential 
for bias is minimized. 
1.7.2 Randomization Method 
The randomization of the treatment assignment will be stratified by the following factors and 
implemented using the IRT System: 
 
Number of prior lines of therapy (1-2 vs. ≥ 3) 
 
ECOG performance status (0-1 vs. 2) 
 
TLS category (low risk vs. increased risk) 
Within each of the eight randomization strata, subjects will be randomly assigned at a 1:1 ratio to 
the two treatment arms based on permuted block size. 
 
 
 
 


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2 
GENERAL ANALYSIS CONSIDERATION 
The statistical analysis sections in this SAP are mainly for the double-blind Randomization 
Phase. All data collected for the subjects in the SRI portion will only be summarized with 
descriptive statistics or listed separately from Phase 3 data. In addition to standard summaries for 
TEAEs, the safety summary included for SRI subjects will be limited in scope to DLTs and TLS. 
Subjects in the randomization phase will be analyzed and summarized by treatment as 
randomized for efficacy endpoints and as treated for safety. 
Subgroup analyses are mainly to evaluate trend and assess the internal consistency of any 
treatment benefit and/or safety signal. Forest plots of hazard ratios and associated confidence 
intervals will be provided for each category of the subgroup variable to show the trend. 
Statistical tests will not be performed for the subgroup analysis. 
General Definitions: 
The date of the first dose of study treatment is defined as the date the subject received the first 
dose of ibrutinib or venetoclax/placebo (whichever occurs first), and the date of the last dose of 
study treatment is defined as the date the subject received the last dose of ibrutinib or 
venetoclax/placebo (whichever occurs later). 
Unless otherwise specified, the baseline value is defined as the last non-missing valid value 
collected prior to the first administration of study treatment. For subjects who have been 
randomized but not treated, the randomization date will be used as the reference date for the 
baseline. 
For the Safety Run-in Period, the TLS/DLT assessment period is defined as the standard Ramp-
up Period with a minimum of 5 weeks. The DLT period ends on the 7th day of 400 mg 
venetoclax. 
2.1 
Analysis Sets 
Intent-to-Treat Population in Randomization Phase 
The intent-to-treat (ITT) population includes all subjects randomized into the study. 
Safety Population 
The safety population (SP) includes all subjects who received at least one dose of study 
treatment (ibrutinib or venetoclax/placebo). 
 
 
 
 


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Safety Run-in Period Evaluable Population 
Subjects who did not complete the TLS and DLT assessment period for any reason other than 
TLS or a DLT or subjects who missed ≥20% of the planned doses of ibrutinib or venetoclax for 
reasons other than toxicity (e.g., non-compliance, withdrawal of consent, or disease progression) 
during the TLS/DLT assessment period will be considered non-evaluable. All other enrolled 
subjects in the Safety Run-in Period will be considered evaluable for the TLS/DLT assessment. 
2.2 
Definition of Subgroups 
Analyses for the baseline subgroups will be performed for selected variables. The baseline 
subgroup variables (Table 1) and the cutoff values are subject to change (if warranted) to better 
represent the data, 
Table 1 
Baseline Subgroups 
Baseline Subgroup 
Definition of Baseline 
Subgroup 
Analysis Type 
Age 
< 65, ≥ 65 
E, S 
Gender  
Male, Female 
E, S 
Race 
White, Non-White 
E, S 
Geographic region 
North America, Europe, 
Asia Pacific 
B, E, S 
Number of prior lines of therapy (1-2 vs. ≥3) per 
CRF 
1-2, ≥ 3 
E 
ECOG performance status per CRF 
0, 1-2 
E 
TLS risk category per CRF 
Low Risk, Increased Risk 
E 
Simplified MIPI score 
Low Risk, Intermediate 
Risk, High Risk 
E 
Bulky tumor (largest long diameter) per investigator 
< 5 cm, ≥ 5 cm 
E 
Enlargement of spleen per investigator 
Yes, No 
E 
Extranodal disease per investigator 
Presence, Absence 
E 
 
 
 
 


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Baseline Subgroup 
Definition of Baseline 
Subgroup 
Analysis Type 
Blastoid variant and/or pleomorphic variant of MCL 
Yes, No 
E 
Blastoid variant of MCL 
Yes, No 
E 
TP53 Mutation 
Mutated, Not Mutated, Not 
Performed/Missing 
E 
Prior stem cell transplant (SCT) 
Yes, No 
E 
Renal function (creatinine clearance) 
< 60 mL/min, ≥ 60 mL/min  
S 
Hepatic function (NCI ODWG definition) 
normal, mild, moderate, 
severe (or normal vs. 
abnormal as appropriate) 
S 
Analysis type:  B=Subject Demographics, Baseline Characteristics, Baseline Disease Characteristics; 
E = Efficacy (PFS); MIPI: MCL International Prognostic Index; MRD: Minimal Residual Disease; NCI 
ODWG: NCI Organ Dysfunction Working Group Liver Function Classification (Ramanathan et al, 
2008); S = Safety (Overview TEAE, TEAE by SOC/PT, Grade 3 or higher TEAE by SOC/PT). 
 
 
 
 


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3 
SUBJECT INFORMATION 
3.1 
Subject Disposition 
Subject enrollment will be summarized by geographic region, country and site. Subject 
disposition for each study drug and for study participation will be tabulated. Overall treatment 
duration and time on study will be summarized by treatment arm. 
The disposition tables will include the following summaries by treatment arm and overall: 
 Analysis populations (all subjects) 
 Enrollment by geographic region, country and investigator (ITT population) 
 Summary of randomization stratification per IRT (ITT population) 
 Study Treatment Disposition and Discontinuation (ITT population) 
 Study Status, Duration of Treatment and Study Exit (ITT population). 
Time on study is calculated based on reverse Kaplan-Meier estimates of the overall survival 
follow-up time (i.e., subjects who died will be censored at the death date for the time on study). 
3.2 
Demographics, Baseline Characteristics, and Baseline Disease Characteristics 
Subject demographics, baseline characteristics, and baseline disease characteristics including but 
not limited to age, gender, race, etc., will be summarized with descriptive statistics for the ITT 
population by treatment arm. 
3.3 
Prior and Concomitant Medications 
Medications will be coded to a generic name and an Anatomical Therapeutic Chemical (ATC) 
class according to the World Health Organization drug dictionary (WHODRUG B3 Mar 2021). 
Prior medications are defined as medications that started prior to the date of the first dose of 
study treatment. Concomitant medications are defined as medications that were taken on 
treatment (i.e., from the date of the first dose of study treatment through the date of the last dose 
of study treatment). 
Concomitant medications will be summarized by ATC class and preferred term (PT) by 
treatment arm based on the Safety Population. Each subject will be counted only once overall, 
for each PT, and for each ATC class. 
The following concomitant medications will be summarized separately: 
 
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 
Anticoagulants and antiplatelet agents 
 
Blood supportive products and intravenous immunoglobulin (IVIG) 
 
Growth factors 
3.4 
Extent of Exposure to Study Treatment 
Exposure to study treatment will be summarized by treatment arm for the Safety Population. 
Descriptive statistics will be provided for the following data for each study drug (ibrutinib and 
venetoclax/placebo): treatment duration, total cumulative dose administered, dose intensity 
(average daily dose), and relative dose intensity (%) based on the entire treatment period 
(including both the ramp-up period and fixed dose period), and number (%) of subjects with a 
dose reduction or dose hold due to adverse events (AEs). In addition, dose modification of 
venetoclax due to CYP inhibitor will be summarized based on the check box on the Study Drug 
Administration page. 
Planned dose intensity (PDI) for each study drug is calculated as below: 
Ibrutinib: 
Planned dose intensity (PDI) for ibrutinib is 560 mg per day. 
Venetoclax/placebo: 
Regardless of response assessment, Venetoclax/placebo will be discontinued after 104 weeks of 
treatment including 5 weeks of the standard dose ramp-up period (20 mg, 50 mg, 100 mg, 
200 mg, and 400 mg weekly, respectively) and approximately 99 weeks of the fixed dose 
(400 mg) period. 
The planned dose intensity (mg/day) for venetoclax/placebo is calculated as the total amount of 
the planned dose (mg) during the maximum treatment period allowed (104 weeks) divided by the 
duration of the maximum treatment period allowed (104 weeks): 
388.2 𝑚𝑔/𝑑𝑎𝑦 
= (20 + 50 + 100 + 200 + 400) 𝑚𝑔 ×  7 𝑑𝑎𝑦𝑠+  400𝑚𝑔 × (104 × 7 −35) 𝑑𝑎𝑦𝑠 
104 × 7 𝑑𝑎𝑦𝑠
 
For each study drug, the actual dose intensity (ADI) (mg/day) is calculated as the total amount of 
dose (mg) received during the entire treatment period divided by the entire treatment duration 
(day), and the relative dose intensity (RDI) (%) is calculated as the (actual dose intensity/planned 
dose intensity)*100%. 
 
 
 
 


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3.5 
Prior and Subsequent Anti-Cancer Treatments 
Anti-cancer treatment includes anti-cancer drug therapies, anti-cancer radiation, and anti-cancer 
transplant/immunotherapy. 
Prior anti-cancer treatments are anti-cancer treatments received prior to study treatment and will 
be summarized using the ITT population. Subsequent anti-cancer treatments are anti-cancer 
treatments received after the date of the last dose of study treatment and will be summarized 
using the Safety Population. 
3.6 
Visit Impact of Logistical Restriction Due to COVID-19 
Visit impact of logistical restriction due to the COVID-19 pandemic will be summarized by the 
type of impact (missed visit, in person/partial assessment done, and virtual visit/phone call) 
recorded on the Visit Impact CRF page for each treatment arm. 
Information for treatment discontinuation and study exit during the COVID-19 pandemic will be 
listed. 
Analyses or summaries for efficacy and safety data related to COVID-19 are described in 
Section 4.1 and Section 5.1, respectively. 
 
 
 
 


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4 
ANALYSIS FOR EFFICACY ENDPOINTS 
Analyses of efficacy endpoints will be conducted using the ITT population, unless otherwise 
specified. For subgroup, sensitivity, and exploratory analyses, only the analyses that provide 
meaningful information will be presented in the CSR. 
There are three randomization stratification factors as recorded in IRT: prior lines of therapy 
(1-2 vs ≥ 3), ECOG performance status (0-1 vs 2), and TLS risk category (low risk vs. increased 
risk). Since only 9 subjects in total were randomized to the stratum of ECOG performance status 
of 2, stratification by those three factors will result in empty or very small strata. Therefore, all 
stratified tests/analyses will only be based on two randomization stratification factors per IRT: 
prior lines of therapy (1-2 vs ≥ 3) and TLS risk category (low risk vs. increased risk). 
The investigators will perform the overall disease assessment based on the Revised Response 
Criteria for Malignant Lymphoma (Cheson 2014, Lugano Classification3); referred to as 
Cheson 2014 or Lugano Classification Criteria. An Independent Review Committee (IRC) will 
be implemented to conduct the overall disease assessments based on the same criteria. 
The overall disease assessment per the investigators will be used to conduct the primary efficacy 
analyses, and the overall disease assessment per IRC will be used to conduct sensitivity analyses. 
Due to differences in the preferred censoring approach for PFS across jurisdictions, the estimand 
and analyses for PFS will be described separately for the US and other regions (see Section 4.1 
and Section 4.2). 
4.1 
Estimand of the Primary Efficacy Endpoint 
Estimand4 is the clinical quantity of interest to be estimated in this study, which is defined by the 
following five attributes: Population, Study Treatment, Variable/Endpoint, Intercurrent Events 
and Handling Strategies, and Statistical Summary. 
The estimand corresponding to the primary efficacy endpoint (PFS per investigator assessment) 
is the treatment effect in PFS (ibrutinib + venetoclax versus ibrutinib + placebo) in subjects with 
relapsed/refractory MCL in the ITT population, as measured by the earlier occurrence of 
progressive disease per investigator assessment or death, whichever occurs first. 
The attributes of the estimand for the primary analysis of the primary endpoint (PFS per 
investigator assessment) are described below: 
 
 
 
 


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Estimand 
Label 
Attributes of the Estimand 
Treatment 
Population 
Endpoint 
Intercurrent Events* 
Statistical Summary 
PFS 
 ibrutinib+ 
venetoclax 
 ibrutinib+ 
placebo 
ITT 
PFS per 
investigator 
assessment 
 
Discontinuation 
of study 
treatment 
 
Use of 
subsequent anti-
cancer therapy 
 
Death due to 
COVID-19 
Hazard ratio of PFS 
between 
two treatment arms. 
Kaplan-Meier 
estimates of the 
distribution of PFS 
for each treatment 
arm, median PFS and 
their 95% CIs. 
*: Handling strategies for intercurrent events are described in the table below.  
Intercurrent Events 
Handling Strategy for Addressing Intercurrent Events 
Discontinuation of study treatmentTreatment policy strategy: Use time to PD or death, whichever 
occurs first regardless of discontinuation of study treatment. 
Use of subsequent anticancer 
therapy 
Treatment policy strategy: Use time to PD or death, whichever 
occurs first regardless of use of subsequent anti-cancer therapy. 
Hypothetical strategy: Subjects are censored at the last disease 
assessment showing no evidence of PD before the use of subsequent 
anti-cancer therapy. 
Death due to COVID-19 
Composite variable strategy: Ignore COVID-19 and consider a 
(pre-PD) COVID-19-related death a PFS event. 
Hypothetical strategy: Subjects are censored at the last adequate 
disease assessment before (pre-PD) death due to COVID-19 
 
The strategies to handle the three intercurrent events are described as follows: 
Intercurrent Events 
US 
Other Regions 
Discontinuation of study 
treatment
Treatment policy strategy 
Use of subsequent 
anticancer therapy 
Primary analysis: hypothetical 
strategy 
Supplementary analysis: treatment 
policy strategy
Primary analysis: treatment policy 
strategy 
Supplementary analysis: 
hypothetical strategy
Death due to COVID-19 
Primary analysis: composite variable strategy 
Supplementary analysis: hypothetical strategy
 
 
 
 
 


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4.2 
Definitions and Analyses for Efficacy Endpoints  
Table 2 below describes the definitions and analyses for the efficacy endpoints. 
Table 2 
Definitions and Analyses for Efficacy Endpoints 
Efficacy 
Endpoint 
Definition 
Analysis Method 
Primary Endpoint 
PFS 
assessed by 
investigator 
(INV) 
Time from the date of randomization to the 
date of the first documentation of progressive 
disease (PD) or the date of death due to any 
causes, whichever occurs first, regardless of 
study drug discontinuation or use of 
subsequent anti-cancer treatment. Post-
treatment stem cell transplantation, CAR T-
cell therapy, and other cellular therapies are 
not considered subsequent anti-cancer 
treatment for subjects responding to treatment 
(CR or PR) 
 
For the evaluation of disease progression, an 
adequate post-baseline assessment is defined 
as an assessment where there is enough 
evidence to indicate the subject had or had not 
progressed based on Cheson 2014 (Lugano 
Classification Criteria). 
 
In the situation where subjects did not have a 
baseline disease assessment or any adequate 
post-baseline disease assessment, they will be 
censored at the date of randomization. 
Primary Analysis: 
Treatment policy strategy and composite variable 
strategy as listed in Section 4.1 will be 
implemented to address intercurrent events. 
Subjects without a PFS event will be censored at 
the date of the last adequate post-baseline disease 
assessment showing no evidence of disease 
progression. 
For US, additional censoring conventions will be 
implemented [see Sensitivity/Supplementary 
Analyses item 3) below]. 
Stratified log-rank test will be used to test the 
treatment effect between the two treatment arms. 
Stratified Cox regression model with Efron's tie 
handling method will be used to calculate the 
hazard ratio (HR) and its 2-sided 95% confidence 
interval (CI). In addition, Kaplan-Meier (KM) 
curves will be provided for both treatment arms. 
For each treatment arm, the 2-sided 95% 
Brookmeyer-Crowley confidence interval based 
on the log-log-transformed Greenwood variance 
estimate will be calculated for median PFS 
(mPFS); KM estimates at selected landmark 
points will also be provided. 
 
 
 
 


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Sensitivity/Supplementary Analyses: 
1) To address the intercurrent events of use 
of subsequent anticancer therapy, 
hypothetical strategy (subjects who 
received subsequent anti-cancer treatment 
will be censored at the last adequate post-
baseline disease assessment showing no 
evidence of PD prior to the initiation of 
subsequent anti-cancer treatment) is 
implemented. 
2) Subjects who missed two or more 
consecutive overall disease assessments 
(algorithm is described in Appendix 1) 
prior to the PFS event will be censored at 
the last adequate post-baseline disease 
assessment showing no evidence of PD 
prior to the first missed disease 
assessment.  
3) Implement the two censoring conventions 
from items 1) and 2) above. This will be 
the primary analysis only for the US 
regulatory consideration. 
4) Analyses listed under Primary Analysis 
and Sensitivity/Supplementary Analyses 
items 1) - 3) will be repeated for the IRC 
assessment. 
5) To address the intercurrent events of 
COVID-19 deaths, hypothetical strategy 
(Pre-PD deaths due to COVID-19 are 
censored) is implemented. 
6) Unstratified log-rank test and unstratified 
Cox regression model to calculate HR and 
its 2-sided 95% CI; same censoring 
convention as the primary analysis. 
Subgroup Analysis: Hazard ratio and its 95% CI 
from unstratified Cox regression model for each 
subgroup. Same censoring convention as for the 
primary analysis. 
For the US, additional censoring conventions as 
specified for the US primary PFS analysis in item 
3) above will be implemented. 
 
 
 
 


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Efficacy 
Endpoint 
Definition 
Analysis Method 
Secondary Endpoints 
CR Rate per 
INV 
Proportion of subjects achieving a complete 
response (CR) based on the best overall 
response (BOR) per Cheson 2014 (Lugano 
Classification Criteria) recorded since the date 
of randomization until the initiation of 
subsequent anti-cancer treatment or the first 
documentation of progressive disease, 
whichever occurs first. Subjects who did not 
have any post-baseline disease assessments 
will be considered non-responders when 
summarizing CR rate. 
 
For responding subjects who received post-
treatment stem cell transplantation (SCT), 
CAR T-cell therapy, or other cellular 
therapies, BOR will be based on disease 
assessments conducted prior to these 
treatments. 
 
To support CR rate, duration of CR is defined 
as time from the date of first documentation of 
CR to the date of first documentation of PD or 
death, whichever occurs first, regardless of the 
use of subsequent anti-cancer treatment. 
Censoring convention is the same as for the 
PFS primary analysis. 
 
For the US, additional censoring conventions 
as specified for the US primary PFS analysis 
in item 3) under Analysis Method will be 
implemented for duration of CR. 
Primary Analysis: 
Rate ratio between the two treatment arms will be 
calculated and tested using the Cochran-Mantel-
Haenszel (CMH) chi-square test stratified by the 
two randomization stratification factors. 
 
Supportive Analysis 
For duration of CR, the KM estimate of median 
and the KM estimates at selected landmark points 
will be provided for each treatment arm. 
ORR per 
INV 
Proportion of subjects achieving a complete 
response (CR) or partial response (PR) based 
on the best overall response (BOR) per Cheson 
2014 (Lugano Classification Criteria) recorded 
since the date of randomization until the 
initiation of subsequent anti-cancer treatment 
or the first documentation of progressive 
disease, whichever occurs first. Subjects who 
Primary Analysis: 
Method is the same as for the CR rate. 
 
Supportive Analysis: 
Same KM estimates described above for duration 
of CR will be provided for DOR. 
 
 
 
 


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Efficacy 
Endpoint 
Definition 
Analysis Method 
did not have any post-baseline disease 
assessments will be considered non-responders 
when summarizing ORR. 
 
To support ORR, duration of response (DOR) 
is defined for the responders (PR or CR) as 
time from the date of initial response (PR or 
CR, whichever occurs first) to the date of first 
documentation of PD or death, whichever 
occurs first, regardless of the use of 
subsequent anticancer therapy. Censoring 
convention is the same as for the PFS primary 
analysis. 
 
For the US, additional censoring conventions 
as specified for the US primary PFS analysis 
in item 3) under Analysis Method will be 
implemented for duration of response. 
Minimal 
Residual 
Disease 
(MRD)-
Negative 
Remission 
Rate  
For CR subjects per investigator only: 
Proportion of subjects achieving an MRD-
negative remission, which is defined as 
undetectable MRD (i.e. less than the lower 
limit of detection for the assay) at documented 
CR in MRD-evaluable subjects (i.e. subjects 
with positive MRD at baseline) as assessed by 
flow cytometry of bone marrow aspirate 
(BMA) and/or peripheral blood (PB)), with 
requirement of a confirmation of MRD-
negativity in subsequent peripheral blood 
samples at least 12 weeks later. 
 
Only subjects with samples collected at both 
baseline and post-baseline are included in the 
denominator when calculating the MRD 
remission rate. 
 
MRD samples collected after the initiation of 
subsequent anticancer therapy will not be used 
for this analysis.
For CR subjects who were MRD-evaluable, the 
MRD-negative remission rate will be calculated 
and tested by Fisher's Exact test for BMA and PB 
separately. 
 
 
 
 


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Efficacy 
Endpoint 
Definition 
Analysis Method 
Overall 
Survival 
(OS) 
Time from the date of randomization to the 
date of death due to any cause. 
Primary Analysis: 
Similar to the primary PFS analysis, composite 
variable strategy (COVID-19 deaths are 
considered OS events) is implemented to address 
the intercurrent events of COVID-19 deaths. 
Subjects without an OS event will be censored at 
the date last known alive. 
Analysis methods are the same as the primary 
PFS analysis. 
Sensitivity/ Supplemental Analyses: 
1) Unstratified log-rank test and unstratified 
Cox regression model to calculate HR 
and its 2-sided 95% CI. 
2) Hypothetical strategy (Subjects who died 
due to COVID-19 are censored at one day 
prior to the death date) is implemented to 
address the intercurrent events of 
COVID-19 deaths 
Time to 
next 
treatment 
(TTNT) 
Time from the date of randomization to the 
date of the initiation of subsequent anti-cancer 
treatment. Post-treatment stem cell 
transplantation, CAR T-cell therapy, or other 
cellular therapies are not considered 
subsequent anti-cancer treatments for subjects 
responding to the treatment (CR or PR). 
Subjects without the use of subsequent anti-
cancer treatment will be censored at the last 
follow-up date for subsequent anti-cancer 
therapy.
Method is the same as for the PFS analysis 
Time to 
worsening 
in FACT-
Lym 
subscale5,6 
Time from the date of randomization to the 
start date of worsening (defined by a ≥5 points 
reduction from baseline) in the Lym Subscale 
or death due to any cause, whichever occurs 
first. 
 
Subjects who have not met the 
definition of worsening will be censored at the 
last non-missing post-baseline PRO 
assessment. Subjects without baseline or post-
baseline assessment will be censored at the 
date of randomization.
Method is the same as for the PFS analysis 
 
 
 
 


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Efficacy 
Endpoint 
Definition 
Analysis Method 
Exploratory Endpoints 
Progression-
free 
Survival 
Based on 
Investigator 
Assessment 
after 
Initiation of 
Subsequent 
Anti-cancer 
Therapy 
(PFS2) 
Time from the date of randomization to the 
date of the earliest of the following three types 
of events: 
• PD per investigator response assessment after 
administration of the first subsequent 
anticancer 
therapy 
• Death at any time on study 
• Initiation of the second subsequent anti-
cancer therapy 
 
Subjects who did not experience a PFS2 event 
will be censored at the last adequate response 
assessment or the last follow-up for 
subsequent anti-cancer therapy (if they no 
longer have response assessments). 
No inferential test will be conducted. 
 
For each treatment arm, the KM estimate of the 
median PFS2 (mPFS2) and the KM estimates at 
selected landmark points will be calculated using 
the same methods as for the primary PFS 
analysis. 
CMH: Cochran-Mantel-Haenszel; CI: confidence interval; CR: complete response; HR: estimate hazard ratio; 
ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: 
partial response. 
 
 
 
 
 


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SAFETY ASSESSMENTS 
Safety data will be summarized by treatment arm based on the Safety Population. 
Adverse events (AEs) will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA 24.1). Severity of AEs will be graded by the investigator according to the 
National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
Version 4.03.  
The treatment-emergent period is defined as the period of time from the date of the first dose of 
study treatment up to 30 days after the date of the last dose of study treatment or the day before 
initiation of subsequent anti-cancer treatment, whichever comes first. 
Treatment-emergent adverse events (TEAEs) are those events that occur or worsen during the 
treatment-emergent period or that are related to the study treatment. 
Adverse Events of Special interest (AESI )as listed below will be summarized by treatment arm: 
 Protocol-defined events of clinical interest including hemorrhagic events and major 
hemorrhage. 
 Other safety observations including other malignancies (including NMSC, NSC, and 
MSC), hypertension ("Hypertension" SMQ narrow), interstitial lung disease ("Interstitial 
lung disease" SMQ narrow), atrial fibrillation (PT = "atrial fibrillation"), cardiac 
arrhythmia ("Cardiac arrhythmias SMQ, excluding PT of "atrial fibrillation"), Cardiac 
failure, ventricular tachyarrhythmia ("Ventricular Tachyarrhythmia" SMQ narrow), 
tumor lysis syndrome ("Tumour lysis syndrome" SMQ narrow), ischemic stroke 
("Ischaemic central nervous system vascular conditions" SMQ narrow), sepsis 
(PTs = "Sepsis", "Bacteraemia", "Fungaemia" or "Septic" (excluding "Septic screen")), 
cytopenias (PTs="Anemia", "Neutropenia", "Febrile Neutropenia", and 
"Thrombocytopenia"), infections including viral reactivation (SOC = "Infection and 
Infestations"), hepatic disorders ( SOC = "Hepatobiliary disorders"), embryo-fetal 
toxicity (SOC = "Pregnancy, puerperium and perinatal conditions"), Diarrhea 
(PT = "Diarrhoea") 
 
All laboratory values will be converted to and reported as international standard (SI) units. Data 
for hematology and biochemistry were collected at the respective local laboratories and will be 
summarized and analyzed by treatment arm. Laboratory parameters will be graded using the NCI 
CTCAE, Version 4.03. Unless otherwise specified, only baseline and post-baseline values 
collected during the treatment-emergent period will be included in the safety analysis. 
The following safety analyses will be conducted to evaluate the use of venetoclax: 
 
 
 
 


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 Infectious pneumonia. 
 TLS evaluated by adverse events of special interest and laboratory TLS per Howard criteria. 
 Liver function abnormalities evaluated by laboratory data per Hy's law. 
 GI Toxicities: No pooling will be done for diarrhea, nausea, and vomiting. 
 For each of the three preferred terms, events leading to treatment discontinuation 
and dose modification (dose reduction and/or dose hold) will be summarized. 
Table 3 
Summary of Safety Assessments 
Assessment 
Type 
Definition   
Analysis 
Methods 
AE 
TEAEs, SAEs, Grade 3 or higher TEAEs, related TEAEs, TEAEs leading 
to treatment discontinuation, TEAEs leading to dose reduction or dose 
hold, TEAEs leading to death, protocol-defined events of special interest 
defined by SMQ terms and other safety observations 
Descriptive 
summary 
statistics and/or 
listings 
Laboratory 
Parameters 
Worst post-baseline toxicity grade for CTCAE-gradable hematology and 
chemistry results.  Abnormalities in creatinine clearance, uric acid levels, 
and liver function tests. Laboratory TLS per Howard Criteria  
Descriptive 
summary 
statistics and/or 
listings 
Vital Signs 
and other 
Observations 
Related to 
Safety 
Blood pressure, heart rate, temperature, and body weight, new or worsened 
eye-related symptoms 
Descriptive 
summary 
statistics and/or 
listings 
AE: adverse event; CTCAE: Common Terminology Criteria for Adverse Events; SAE: serious adverse event; 
TEAE: treatment-emergent adverse event; SMQ: standardized MedDRA (Medical Dictionary for Regulatory 
Activities) query. 
5.1 
Data Summaries for COVID-19 
TEAEs related to a COVID-19 infection will be summarized using the check box on the CRF 
page by treatment arm separately from other TEAEs. Deaths related to COVID-19 will be 
summarized or listed by treatment arm separately from deaths unrelated to COVID-19. COVID-
19 laboratory tests will be listed by treatment arm. 
5.2 
Safety Run-in 
Safety data for Safety Run-in subjects treated with study treatment will be summarized and/or 
listed by the TLS risk category at baseline (Low versus Increased) separately from the 
randomized subjects. 
 
 
 
 


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In addition to standard safety summaries for TEAEs, SAEs, Grade 3 or higher TEAEs, TEAEs 
leading to study drug discontinuation, and TEAEs leading to death, the summary of safety data 
included will be limited in scope to DLTs and TLS. 
 
 
 
 


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6 
TREATMENT-NAÏVE COHORT 
The following data will be summarized for treatment-naïve subjects who were enrolled into the 
study at the time of the primary PFS analysis for subjects with R/R MCL. Data summaries will 
be limited to the followings: 
 Demographics and baseline characteristics 
 Study drug exposure 
 Treatment disposition and subject disposition 
 Treatment-emergent adverse events 
A comprehensive and complete data summary and analysis for treatment-naïve subjects will be 
described in an SAP addendum at the appropriate time prior to primary analysis. 
 
 
 
 


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7 
CHANGES IN THE PROTOCOL-PLANNED ANALYSES  
1. In alignment with the FDA guidance (Statistical Considerations for Clinical Trials During 
the COVID-19 Public Health Emergency, June 2020), in order to mitigate the potential 
impact on key efficacy endpoints due to COVID-19, the follow-up will be extended to 
accrue more events as described in Section 1.5.1 and Section 1.5.2 over the originally 
planned event numbers (134 events for PFS and 155 events for OS). 
2. Change superiority boundary for the interim OS analysis from O'Brien Fleming boundary 
to Haybittle-Peto boundary. 
3. Specify secondary and exploratory endpoints to be included in the CSR. 
4. IRC will be implemented to do the overall disease assessment based on Cheson 2014 
(Lugano Classification Criteria). A sensitivity analysis will be conducted for PFS using 
the IRC assessment. 
5. Since only 9 subjects in total were randomized to the stratum of ECOG performance 
status of 2, stratification by the three randomization stratification factors will lead to 
empty or very small strata. Therefore, all stratified tests/analyses will only be based on 
two randomization stratification factors per IRT: prior lines of therapy (1-2 vs ≥ 3) and 
TLS risk category (low risk vs. increased risk). 
6. The CR rate and ORR will be compared by rate ratio between the two treatment arms 
using CMH chi-square test stratified by the two randomization stratification factors 
instead of by the difference in proportion between the two treatment arms. 
7. The MRD-negative remission rate for CR subjects evaluable for MRD will be compared 
by Fisher's Exact test due to the small sample size. 
 
 
 
 
 
 
 


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8 
APPENDICES 
8.1 
Algorithm for Defining 2 or more Consecutive Assessments Prior to the PFS Event 
This study has 3 planned imaging schedules: every 12 weeks in the first year, every 16 weeks in 
the second and third years, and every 24 weeks afterwards. The exact imaging schedules are 
defined in weeks (see Table 2). Based on the change between the schedules, two transitions of 
the imaging schedule are described as follows: 
1. When the last non-PD assessment occurs at Week 37, the next assessment is planned at 
Week 49 (12 weeks from Week 37) and then at Week 65 (16 weeks from Week 49). 
2. When the last non-PD assessment occurs at Week 129, the next assessment is planned at 
Week 145 (16 weeks from Week 129) and then at Week 169 (24 weeks from Week 145). 
This algorithm has two steps in series: 
1. Step 1 (Columns 2-4 of Table 1): To map the last adequate non-PD assessment to a 
closest scheduled visit based on the study day of the last adequate non-PD assessment 
using the midpoint window (see footnote of Table 1 for details).  Once the assessment is 
mapped to a scheduled visit, the imaging interval for the next two subsequent consecutive 
visits can be decided based on the planned imaging schedule. 
2. Step 2 (column 5 of Table 1): Calculate maximum days allowed for those two subsequent 
visits based on the planned imaging interval plus 7 days based on the protocol-specified 
window (+/- 7 days) for each visit. 
There are five time periods in Table 1 based on three planned imaging schedules and 
two transitions in the imaging schedule. 
Table 1: Algorithm for defining missing two or more consecutive assessments prior to the 
PFS events 
Time 
Period 
 
Last Adequate Non-PD Assessment 
Imaging Schedule for the Two Subsequent 
Consecutive Assessments 
after the Last Adequate Non-PD Assessment 
Maximum Gap& in Days 
Allowed between PFS 
Event and Last Adequate 
Non-PD Assessment 
 
Scheduled Visit  
 
Study Day* 
1
Week 13-Week 25
Day 2- Day 211   
12 weeks (84 days)
182=(84+7)*2
2
Week 37
Day 212 - Day 295 
12 weeks (84 days) &16 weeks (112 days)
210=(84+7) + (112+7)
3
Week 49-Week 113
Day 296 – Day 841  
16 weeks (112 days)
238=(112+7)*2
4
Week 129
Day 842 - Day 953 
16 weeks (112 days) & 24 weeks (168 days)
294=(112+7) + (168+7)
5
Week 145 and higher
Day 954 and higher
24 weeks (168 days)
350=(168+7)*2
*: The visit window for each visit is based on the midpoint between two scheduled visits (i.e. target day +/- half of the planned interval 
between two scheduled visits). However, start day of Week 13 is one day after randomization (Day 2). If the last adequate non-PD 
assessment is the same as or earlier than the midpoint, it will be assigned to the earlier visit, and if the assessment is later than the 
midpoint, it will be assigned to the later visit. Study day is calculated in reference to the randomization date. 
&: A 7-day window is allowed per the protocol for each subsequent visit. 
Visits sharing the same imaging schedules are combined in Time Periods 1, 3, and 5, respectively; details are displayed in Table 2.
 
 
 
 
 




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9 
REFERENCES 
1. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 
1979;35(3):549-556. 
2. FDA Guidance, Statistical Considerations for Clinical Trials During the COVID-19 Public 
Health Emergency, June 2020. 
3. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. 
J Clin Oncol. 2014;32(27):3059-68. 
4. E9 (R1) Statistical principles for clinical trials: Addendum: Estimands and sensitivity 
analysis in clinical trials. Guidance for Industry. Revision 1, May 2021. 
5. Fay J. Hlubocky, Kimberly Webster, John Cashy, Jennifer Beaumont, and David Cella, "The 
Development and Validation of a Measure of Health-Related Quality of Life for Non-
Hodgkin's Lymphoma: The Functional Assessment of Cancer Therapy—Lymphoma (FACT-
Lym)," Lymphoma, vol. 2013, Article ID147176, 9 pages, 2013. doi:10.1155/2013/147176. 
6. Cella D, Webster K, Cashy J, et al. Development of a Measure of Health-Related Quality of 
Life for Non-Hodgkin's Lymphoma Clinical Research: The Functional Assessment of Cancer 
Therapy – Lymphoma (FACT-Lym) [abstract]. ASH. 2005; 106. Abstract 750.