Conditions: Leukemia Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 323
Healthy volunteers: no

Brief summary:
This is a multicenter, 2-cohort Phase 2 study assessing both minimal residual disease (MRD)-guided discontinuation and fixed duration therapy with the combination of ibrutinib + venetoclax in subjects with treatment-naïve CLL or SLL.

Detailed description:

Arms:
arm 1: Participants receive 420 mg of single-agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until disease progression or unacceptable toxicity. arm 2: Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase).

Participants with confirmed uMRD are randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, disease progression (PD), or unacceptable toxicity.

After MRD-positive relapse or disease progression (PD) by iwCLL criteria, participants can reintroduce 400 mg venetoclax with a 5-week ramp up. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. arm 3: Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase).

Participants with confirmed uMRD are randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity.

If MRD-positive relapse or PD is confirmed after restaging per iwCLL criteria, participants can first reintroduce oral daily ibrutinib with the option of subsequently reintroducing 400 mg venetoclax with a 5-week ramp up, if subsequent disease relapse per iwCLL criteria occurs after ibrutinib reintroduction. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. arm 4: Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase).

Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity.

In case of confirmed PD after restaging per iwCLL criteria, participants can continue ibrutinib and reintroduce venetoclax treatment. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. arm 5: Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase).

Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase.

Interventions: intervention 1: ibrutinib intervention 2: venetoclax intervention 3: Placebo
Intervention descriptions: intervention 1: ibrutinib administered orally once daily (three 140 mg capsules) intervention 2: venetoclax tablets will be administered orally once daily starting with a 5 week ramp up of 20 mg, 50 mg, 100 mg, 200 mg and 400 mg. After ramp up, venetoclax will be administered at 400 mg. intervention 3: placebo capsules to match ibrutinib administered orally once daily

Protocol document:
Prot_002.pdf: 
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PROTOCOL
TITLE:
Phase 2 study of the combination of ibrutinib plus venetoclax in 
subjects with treatment-naïve chronic lymphocytic leukemia / 
small lymphocytic lymphoma
PROTOCOL NUMBER:
PCYC-1142-CA
STUDY DRUG:
Ibrutinib (PCI-32765)
IND NUMBER:
102,688
EudraCT NUMBER:
2016-002293-12
SPONSOR MEDICAL 
MONITOR:
MD
Pharmacyclics LLC
Phone:
Email:
SPONSOR:
Pharmacyclics LLC 
1000 Gateway Boulevard
South San Francisco,
CA 94080
United States of America
DATE FINAL:
Amendment 1:
Amendment 2:
Amendment 3:
Amendment 4:
05 July 2016
25 September 2017
29 November 2018
11 September 2019
02 December 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.
NCT02910583


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PROTOCOL APPROVAL PAGE
Study Title:
Phase 2 study of the combination of ibrutinib plus venetoclax in 
subjects with treatment naïve chronic lymphocytic leukemia / small 
lymphocytic lymphoma
Study Number:
PCYC-1142-CA
Protocol Date:
05 July 2016
Amendment 1
25 September 2017
Amendment 2
29 November 2018
Amendment 3
11 September 2019
Amendment 4
02 December 2022
I have carefully read Protocol PCYC-1142-CA entitled “Phase 2 study of the combination of 
ibrutinib plus venetoclax in subjects with treatment naïve chronic lymphocytic leukemia / small 
lymphocytic lymphoma” I agree to conduct this study as outlined herein and in compliance with 
Good Clinical Practices (GCP) and all applicable regulatory requirements. Furthermore, 
I understand that the Sponsor, Pharmacyclics, and the Institutional Review Board/Research 
Ethics Board/Independent Ethics Committee (IRB/REB/IEC) must approve any changes to the 
protocol in writing before implementation.
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or methods 
of Pharmacyclics.  All data pertaining to this study will be provided to Pharmacyclics.  
The policy of Pharmacyclics LLC requires that any presentation or publication of study data by 
clinical Investigators be reviewed by Pharmacyclics, before release, as specified in the protocol.
Principal Investigator’s Signature
Date
Print Name
The following Pharmacyclics LLC representative is authorized to sign the protocol and any 
amendments:
Medical Monitor’s Signature
Date
 MD Clinical Science, Pharmacyclics LLC
Electronically signed by:
Reason: Reviewer
Date: Dec 6, 2022 03:07 PST
06-Dec-2022


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TABLE OF CONTENTS
PROTOCOL APPROVAL PAGE ...........................................................................................2
TABLE OF CONTENTS..........................................................................................................3
LIST OF APPENDICES...........................................................................................................9
LIST OF IN-TEXT TABLES AND FIGURES........................................................................9
SYNOPSIS...............................................................................................................................11
ABBREVIATIONS .................................................................................................................24
1.
BACKGROUND .......................................................................................................27
1.1.
Disease/Histology .......................................................................................................27
1.1.1.
Disease Background....................................................................................................27
1.1.2.
Current Treatment Options in Previously Untreated CLL ............................................28
1.2.
Ibrutinib Overview......................................................................................................30
1.2.1.
Summary of Nonclinical Data .....................................................................................30
1.2.1.1. Pharmacology .............................................................................................................30
1.2.1.2. Safety Pharmacology and Toxicology .........................................................................31
1.2.2.
Summary of Clinical Data ...........................................................................................31
1.2.2.1. Pharmacokinetics and Product Metabolism..................................................................31
1.2.3.
Summary of Clinical Safety.........................................................................................32
1.2.3.1. Monotherapy Studies...................................................................................................32
1.2.3.2. Combination Studies ...................................................................................................32
1.2.4.
Risks ...........................................................................................................................33
1.2.4.1. Cardiac Arrhythmias and Cardiac Failure....................................................................33
1.2.4.2. Bleeding-related Events...............................................................................................33
1.2.4.3. Cytopenias ..................................................................................................................34
1.2.4.4. Diarrhea ......................................................................................................................34
1.2.4.5. Infections ....................................................................................................................34
1.2.4.6. Interstitial Lung Disease (ILD)....................................................................................35
1.2.4.7. Leukostasis .................................................................................................................35
1.2.4.8. Lymphocytosis............................................................................................................35
1.2.4.9. Non-melanoma Skin Cancer........................................................................................35
1.2.4.10.Rash............................................................................................................................35
1.2.4.11.Tumor Lysis Syndrome ...............................................................................................35
1.2.4.12.Hypertension...............................................................................................................36
1.3.
Venetoclax Overview..................................................................................................36
1.3.1.
Summary of Nonclinical Data .....................................................................................37
1.3.2.
Summary of Venetoclax Clinical Data.........................................................................37
1.3.2.1. Clinical Pharmacokinetics ...........................................................................................37
1.3.2.2. Summary of Clinical Safety.........................................................................................38
1.3.3.
Risks ...........................................................................................................................38
1.3.3.1. Tumor Lysis Syndrome ...............................................................................................38
1.3.3.2. Neutropenia.................................................................................................................39
1.3.3.3. Immunization..............................................................................................................39
1.4.
Study Rationale...........................................................................................................39
2.
STUDY OBJECTIVE ...............................................................................................43


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2.1.
Primary Objective .......................................................................................................43
2.2.
Secondary Objective(s) ...............................................................................................43
2.2.1.
MRD Cohort ...............................................................................................................43
2.2.2.
Fixed Duration Cohort.................................................................................................43
2.3.
MRD Cohort Exploratory Objectives ..........................................................................44
2.4.
FD Cohort Exploratory Objective................................................................................44
3.
STUDY DESIGN.......................................................................................................44
3.1.
Overview of Study Design ..........................................................................................44
3.1.1.
MRD Cohort: Pre-Randomization Phase .....................................................................45
3.1.2.
MRD Cohort: Randomization Phase (Including Re-introduction Period) .....................46
3.1.3.
Fixed Duration Cohort.................................................................................................48
3.1.4.
Post-PD Follow-Up Phase...........................................................................................48
3.2.
Study Schema; MRD Cohort.......................................................................................49
3.3.
Study Schema; Fixed Duration Cohort ........................................................................50
4.
SUBJECT SELECTION...........................................................................................51
4.1.
Inclusion Criteria.........................................................................................................51
4.2.
Exclusion Criteria........................................................................................................52
5.
TREATMENT OF SUBJECTS ................................................................................54
5.1.
Treatment Allocation and Blinding..............................................................................54
5.2.
Safety Run-in Period ...................................................................................................54
5.2.1.
Dose-Limiting Toxicity (DLT)....................................................................................55
5.2.2.
Baseline TLS Assessment ...........................................................................................56
5.3.
Study Treatment..........................................................................................................56
5.3.1.
Pre-Randomization Phase............................................................................................56
5.3.2.
Randomization Phase ..................................................................................................57
5.3.2.1. Randomization Phase – MRD-negative Subjects (Double-blind) .................................58
5.3.2.2. Randomization Phase – MRD-Positive Subjects (Open-Label) ....................................58
5.3.3.
Fixed Duration Cohort.................................................................................................59
5.3.4.
Baseline TLS Assessment ...........................................................................................61
5.4.
Study Medication ........................................................................................................61
5.4.1.
Ibrutinib ......................................................................................................................61
5.4.1.1. Formulation/Packaging/Storage...................................................................................61
5.4.1.2. Dose and Administration.............................................................................................61
5.4.1.3. Overdose.....................................................................................................................62
5.4.1.4. Dose Modification for Adverse Reactions ...................................................................62
5.4.1.5. Leukocytosis/Leukostasis............................................................................................64
5.4.1.6. Dose Modification for Hepatic-Impaired Subjects .......................................................64
5.4.2.
Venetoclax (ABT-199)................................................................................................64
5.4.2.1. Formulation/Packaging/Storage...................................................................................64
5.4.2.2. Prophylaxis and Management of Tumor Lysis Syndrome............................................65
5.4.2.3. Dose and Administration.............................................................................................67
5.4.2.4. Overdose.....................................................................................................................68
5.4.2.5. Dose Modification for Adverse Reactions ...................................................................68
5.4.2.6. Management of Neutropenia .......................................................................................70
5.4.2.7. Management of Hematologic Toxicities Other Than Neutropenia or Lymphopenia .....70
5.4.2.8. Management of Non-Hematologic Toxicity.................................................................70


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5.4.2.9. Management of Decrease in Spermatogenesis .............................................................70
5.4.2.10.Embryo-Fetal Toxicity ................................................................................................70
5.4.2.11.Immunization..............................................................................................................71
5.5.
Criteria for Permanent Discontinuation of Study Drug ................................................71
6.
CONCOMITANT MEDICATIONS/PROCEDURES.............................................71
6.1.
Permitted Concomitant Medications............................................................................71
6.2.
Medications to Be Used with Caution..........................................................................72
6.2.1.
Drugs That May Alter Ibrutinib and/or Venetoclax Plasma Concentrations .................72
6.2.1.1. Concomitant Use with Ibrutinib...................................................................................72
6.2.1.2. Concomitant Use with Venetoclax...............................................................................73
6.2.2.
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib....................73
6.2.3.
Drugs That May Have Their Plasma Concentrations Altered by Venetoclax................74
6.2.4.
Antiplatelet Agents and Anticoagulants.......................................................................74
6.3.
Prohibited Concomitant Medications and Products......................................................74
6.3.1.
Prohibited Concomitant Medications and Products for Ibrutinib and/or Venetoclax.....74
6.4.
Guidelines for Ibrutinib Management with Surgeries or Procedures.............................75
6.4.1.
Minor Surgical Procedures ..........................................................................................75
6.4.2.
Major Surgical Procedures ..........................................................................................75
6.4.3.
Emergency Procedures................................................................................................75
7.
STUDY EVALUATIONS .........................................................................................76
7.1.
Description of Procedures ...........................................................................................76
7.1.1.
Assessments................................................................................................................76
7.1.1.1. ICF..............................................................................................................................76
7.1.1.2. Confirm Eligibility......................................................................................................76
7.1.1.3. Medical History and Demographics.............................................................................76
7.1.1.4. Prior and Concomitant Medications.............................................................................76
7.1.1.5. Adverse Events ...........................................................................................................76
7.1.1.6. Physical Examination..................................................................................................77
7.1.1.7. ECOG .........................................................................................................................77
7.1.1.8. Vital Signs ..................................................................................................................77
7.1.1.9. Tumor Lysis Syndrome (TLS) Risk Assessment..........................................................77
7.1.1.10.Tumor Lysis Syndrome (TLS) Prophylaxis .................................................................77
7.1.2.
Laboratory...................................................................................................................78
7.1.2.1. Hematology.................................................................................................................78
7.1.2.2. Chemistry (Serum)......................................................................................................78
7.1.2.3. Coagulation Studies.....................................................................................................78
7.1.2.4. Hepatitis Serologies.....................................................................................................78
7.1.2.5. Serum β2-microglobulin..............................................................................................78
7.1.2.6. Pregnancy Test............................................................................................................78
7.1.3.
Diagnostics/Procedures ...............................................................................................79
7.1.3.1. ECG............................................................................................................................79
7.1.3.2. CT/MRI ......................................................................................................................79
7.1.3.3. Bone Marrow Biopsies and Aspirate ...........................................................................79
7.1.3.4. FISH Assays ...............................................................................................................83
7.1.3.5. Karyotype ...................................................................................................................83
7.1.4.
Pharmacokinetics/
.....................................................................................83




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8.2.1.7. Cycle 16 Day 1 Visit .................................................................................................102
8.2.2.
Cycle 17 Randomization Visit and Every 3 Cycles Thereafter...................................103
8.2.3.
Suspected MRD-positive Relapse Visit (Any Time)..................................................104
8.3.
Fixed Duration Cohort...............................................................................................104
8.3.1.
Treatment Visits........................................................................................................105
8.3.1.1. Cycle 1 Day 1 (C1D1) Visit ......................................................................................105
8.3.1.2. Cycles 2 and 3 Visits.................................................................................................106
8.3.1.3. Cycle 4 Visits............................................................................................................106
8.3.1.3.1.
Pre-Cycle 4 (Pre-initiation of Venetoclax)........................................................106
8.3.1.3.2.
Cycle 4 Week 1 Day 1 .....................................................................................107
8.3.1.3.3.
Cycle 4 Week 1 Day 2 .....................................................................................107
8.3.1.3.4.
Cycle 4 (Week 2 – Week 4) Visits....................................................................108
8.3.1.3.5.
Cycle 4 Week 2 Day 2 .....................................................................................108
8.3.1.4. Cycle 5 Visits............................................................................................................109
8.3.1.4.1.
Cycle 5 Week 1 and Week 3 Visits ..................................................................109
8.3.1.5. Cycle 6 – Cycle 9 Visits ............................................................................................109
8.3.1.6. Cycle 10 and Cycle 13 Visits.....................................................................................110
8.3.2.
Fixed Duration Cohort: Post treatment visits .............................................................111
8.4.
Reintroduction of Study Drug (MRD and FD Cohorts)..............................................111
8.5.
Suspected PD Visit (Any Time) ................................................................................114
8.6.
Suspected CR Visit ...................................................................................................115
8.7.
End-of-Treatment Visit .............................................................................................115
8.8.
Response Follow-Up Visits .......................................................................................115
8.9.
Post-PD Follow-Up Phase.........................................................................................116
9.
SUBJECT COMPLETION AND WITHDRAWAL..............................................116
9.1.
Completion ...............................................................................................................116
9.2.
Withdrawal from Study Treatment ............................................................................116
9.3.
Withdrawal from Study.............................................................................................117
10.
STATISTICAL METHODS AND ANALYSIS .....................................................117
10.1.
Subject Information...................................................................................................118
10.2.
Endpoints..................................................................................................................118
10.2.1.
MRD Cohort:............................................................................................................118
10.2.2.
Fixed Duration Cohort:..............................................................................................119
10.3.
Sample Size Determination .......................................................................................119
10.4.
Efficacy Analysis ......................................................................................................120
10.4.1.
MRD-Negative Response Rate..................................................................................120
10.4.2.
Disease-Free Survival (DFS).....................................................................................120
10.4.3.
Overall Response Rate (ORR)...................................................................................121
10.4.4.
Complete Response Rate (CRR)................................................................................121
10.4.5.
Duration of Response (DOR) ....................................................................................121
10.4.6.
Progression-Free Survival (PFS) ...............................................................................121
10.4.7.
Overall Survival (OS)................................................................................................122
10.4.8.
Tumor Lysis Syndrome (TLS) Risk Reduction Rate..................................................122




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LIST OF APPENDICES
Appendix A.
Schedule of Assessments for MRD cohort........................................................146
Appendix B.
Schedule of Assessments for Fixed Duration Cohort........................................151
Appendix C.
Schedule of Assessments for Reintroduction of Ibrutinib (MRD and FD Cohorts)
........................................................................................................................155
Appendix D.
Schedule of Assessments for Reintroduction of Venetoclax (MRD Cohort only)
........................................................................................................................157
Appendix E.
Schedule of Assessments for Reintroduction of Ibrutinib + Venetoclax (FD 
Cohort only).....................................................................................................159
Appendix F.
ECOG Status Scores ........................................................................................161
Appendix G.
Sample List of Cautionary Medications............................................................162
Appendix H.
TLS Risk Category ..........................................................................................164
Appendix I.
Howard Criteria1 for Laboratory and Clinical TLS ...........................................165
Appendix J.
Example of Recommendations for Initial Management of Electrolyte 
Abnormalities and Prevention of Tumor Lysis Syndrome (TLS) ......................166
Appendix K.
Child-Pugh Score for Subjects with Liver Impairment......................................170
Appendix L.
Hematologic Adverse Event Grading Scheme (Hallek 2008)............................171
Appendix M. Rai Staging ......................................................................................................172
LIST OF IN-TEXT TABLES AND FIGURES
Tables
Table 1.
Dose De-Escalation Schedule for Safety Run-in.................................................55
Table 2.
Ibrutinib/ Placebo Dose Modifications for Events not Specified in Table 3.........63
Table 3.
Ibrutinib/Placebo Dose Modifications for Cardiac Failure or Cardiac Arrhythmias
..........................................................................................................................64
Table 4.
TLS Prophylaxis Based on Tumor Burden from Clinical Trial Data (consider all 
co-morbidities before final determination of prophylaxis and monitoring 
schedule)............................................................................................................66
Table 5.
Venetoclax Recommended Dose Modifications for Toxicitiesa...........................69
Table 6.
Dose Modification for Toxicity during Venetoclax Treatment............................69
Table 7.
Management of Potential Ibrutinib and Venetoclax Interactions with CYP3A 
Inhibitors ...........................................................................................................73
Table 8.
Overall Response Assessment............................................................................80
Table 9.
MRD cohort: Bone Marrow Biopsy and Aspirate Collection Times for Clinical 
Response............................................................................................................80
Table 10.
Fixed Duration cohort: Bone Marrow Biopsy and Aspirate Collection Times for 
Clinical Response...............................................................................................80


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Table 11.
MRD Cohort: MRD Sample Collection Schedule...............................................82
Table 12.
Fixed Duration Cohort: MRD Sample Collection Schedule ................................83
Table 13.
Pharmacokinetic Sample Schedule for Ibrutinib and Venetoclax (MRD Cohort 
Only) .................................................................................................................84
Table 14.
Evaluable Parameter Requirements....................................................................89
Table 15.
Criteria for Clinical Response Categories...........................................................90
Figures
Figure 1.
Venetoclax Dose Ramp-up.................................................................................57
Figure 2.
Reintroduction of Ibrutinib or Venetoclax for MRD Cohort ...............................59
Figure 3.
Reintroduction of Ibrutinib or I+V Therapy for FD Cohort.................................61


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SYNOPSIS
Study Title:
Phase 2 study of the combination of ibrutinib plus venetoclax in 
subjects with treatment naïve chronic lymphocytic leukemia (CLL) / 
small lymphocytic lymphoma (SLL)
Protocol Number:
PCYC-1142-CA
Study Phase:
2
Study Duration:
Estimated to be 12 years
Investigational Product 
and Reference Therapy:
Ibrutinib will be supplied as 140 mg hard gelatin capsules for oral (PO) 
administration.
Venetoclax will be supplied as 10 mg, 50 mg, and 100 mg film coated 
tablets for oral (PO) administration.
Objectives:
MRD Cohort
Primary Objective:
To evaluate if discontinuing ibrutinib, in the setting of a confirmed 
MRD-negative response with the combination of ibrutinib + venetoclax, 
allows for a treatment holiday as assessed by 1-year disease-free 
survival (DFS).
Secondary Objectives:
To evaluate:

Minimal Residual Disease (MRD) – negative rate

Overall response rate (ORR)

Complete response rate (Complete Response [CR], and CR with 
incomplete marrow recovery [CRi])

Duration of response (DOR)

Tumor Lysis Syndrome (TLS) risk reduction

Progression free survival (PFS)

Overall survival (OS)

Pharmacokinetics of ibrutinib and venetoclax when dosed in 
combination

Safety and tolerability


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Fixed Duration Cohort
Primary Objective:
To evaluate the depth of response with the combination of ibrutinib + 
venetoclax administered for a fixed duration of therapy by assessment 
of complete response (CR/CRi) rate.
Secondary Objectives:
To evaluate:

Duration of Response (DOR)

Minimal Residual Disease (MRD)-negative rate 

Overall response rate (ORR)

Tumor Lysis Syndrome (TLS) risk reduction

Progression free survival (PFS)

Overall survival (OS)

Safety and tolerability
Study Design:
This is a multicenter, 2-cohort Phase 2 study assessing both MRD-
guided discontinuation and fixed duration therapy with the combination 
of ibrutinib + venetoclax in subjects with treatment-naïve CLL or SLL.
The study consists of an MRD cohort and a Fixed Duration cohort.
All subjects who discontinue treatment in the absence of disease 
progression will remain on study until confirmed disease progression or 
until study closure. All subjects who discontinue for disease progression 
will be followed for survival and subsequent anti-cancer therapies.
Details of the sequentially designed and enrolled MRD and Fixed 
Duration cohorts are below.
1.
MRD Cohort:


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The MRD cohort portion of the study consists of a pre-randomization 
phase (combination treatment phase), an MRD-guided randomization 
phase, and a post-PD follow-up phase. Please see Section 3.1 for full 
explanation of study design.
Investigator assessment of disease overall response and progression will 
be based upon IWCLL criteria (Hallek 2008, Hallek 2012, 
Hallek 2013). Imaging will be collected and stored centrally.
The primary analysis will be performed at the point that all randomized 
subjects have had the opportunity to complete approximately 12 cycles 
of randomized treatment or follow-up. All safety and efficacy endpoints 
will be analyzed at the time of the primary analysis. After the primary 
analysis, the Sponsor may elect to discontinue follow-up of specific 
MRD cohort treatment arms on PCYC-1142-CA. Subjects who are on 
ibrutinib at the time of study arm closure may be offered a separate 
extension study to continue ibrutinib.
Pre-randomization Phase
Approximately 150 subjects will be enrolled into this phase. The 
subjects will receive single-agent ibrutinib for 3 cycles followed by 
ibrutinib + venetoclax combination treatment for at least 12 cycles.
The safety of ibrutinib + venetoclax combination therapy will be 
assessed by a Data Review Committee (DRC). Approximately 
12 subjects will be enrolled in a Safety Run-in Period to assess 
tolerability in the first 6 evaluable subjects who complete venetoclax 
dose escalation (3 cycles of ibrutinib treatment followed by the addition 
of venetoclax administered by standard 5-week dose ramp-up, plus an 
additional week of follow up). Enrollment will be held until the safety 
and tolerability of the combination therapy is confirmed by the DRC.
Subjects will be assessed for MRD status in peripheral blood (PB) every 
3 cycles starting after completion of 6 cycles (C7D1), and in bone 
marrow (BM) aspirate after completion of Cycle 15 (C16D1). MRD 
assessment will be performed using flow cytometry with a sensitivity of 
≥10-4. An early assessment of the MRD-negative response rate for the 
combination therapy will be assessed among the first 30 subjects who 
complete 9 cycles of combination treatment. The sample size may be 
adjusted accordingly based on this early assessment to adequately 
power for the Randomization Phase primary endpoint.
MRD-negative response for randomization purposes must be confirmed 
serially over at least 3 cycles and is required to demonstrate negativity 
in both the bone marrow and peripheral blood.
Randomization Phase
Eligible subjects will be randomized in a 1:1 ratio based on their MRD 
status (see below). Subjects will be stratified by immunoglobulin 
heavy-chain variable region (IGHV) status in each randomization strata.


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Randomization Phase - MRD-negative subjects (Double-blind):
Eligible subjects who achieve a confirmed MRD-negative response and 
who continue on ibrutinib will be randomized to receive blinded 
treatment of ibrutinib (venetoclax discontinued) vs placebo (ibrutinib
and venetoclax discontinued). The randomization will be stratified by 
IGHV status. Subjects will be assessed for disease-free survival as 
measured by continued MRD-negative response without progression or 
death at least 1 year after randomization. MRD status will be evaluated 
every 3 cycles in PB. MRD should also be reassessed in BM aspirate 
after an additional 12 cycles. 
Randomization Phase - MRD-positive subjects (Open-label):
Those subjects who do not achieve a confirmed MRD-negative 
response after 12 cycles of the combination and continue on treatment 
will be randomized to receive open label treatment of ibrutinib + 
venetoclax vs ibrutinib alone (venetoclax discontinued). The 
randomization will be stratified by IGHV status. Subjects will be 
assessed for MRD-negative response. MRD status will be evaluated 
every 3 cycles in PB. MRD should also be reassessed in BM aspirate 
after an additional 12 cycles and at any time in subjects who become 
MRD-negative in PB. For subjects receiving ibrutinib + venetoclax, 
venetoclax can be administered for up to approximately 2 years per 
treatment course, until PD or unacceptable toxicity, or until this arm’s 
study closure, whichever is earlier. Subjects who are continuing on 
ibrutinib at the time of study arm closure may be offered a separate 
extension study to continue ibrutinib. 
Reintroduction of therapy:
MRD-negative randomized subjects who experience confirmed 
MRD--positive relapse and/or confirmed disease progression may have 
their randomization unblinded, and may receive reintroduced therapy as 
follows: 
Placebo subjects: Subjects on the placebo arm will be offered the 
opportunity to reintroduce ibrutinib to assess if they can benefit from 
single-agent ibrutinib under the following circumstances:

For confirmed MRD-positive relapse and/or for disease 
progression by International Workshop on Chronic Lymphocytic 
Leukemia (IWCLL) criteria, subjects will receive ibrutinib until 
PD or unacceptable toxicity. Ibrutinib reintroduced subjects who 
subsequently have confirmed disease progression by IWCLL 
criteria may continue ibrutinib and add venetoclax per standard 
dose ramp up
Ibrutinib subjects: Subjects on the ibrutinib arm will be offered the 
opportunity to continue ibrutinib and reintroduce venetoclax treatment 
under the following circumstances:

For confirmed MRD-positive relapse and/or for confirmed 
disease progression by IWCLL criteria, subjects can continue 
ibrutinib and add venetoclax, per standard dose ramp up


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MRD-positive randomized subjects can receive reintroduced therapy as 
follows: 
Ibrutinib only subjects: Subjects on the ibrutinib arm will be offered the 
opportunity to continue ibrutinib and reintroduce venetoclax treatment 
per standard dose ramp up under the following circumstances:

For confirmed disease progression by IWCLL criteria, subjects 
will receive ibrutinib and venetoclax
For MRD-negative and MRD-positive subjects who have reintroduced 
venetoclax, venetoclax can be administered for up to 2 years per 
treatment course, until PD or unacceptable toxicity, or until these arms’
study closure, whichever is earlier. Subjects who are continuing on 
ibrutinib at time of study arm closure may be offered a separate 
extension study to continue ibrutinib.
Post-PD Follow-up Phase:
Subjects who have confirmed disease progression by IWCLL criteria 
and have discontinued study treatment will be followed for survival 
status and subsequent anti-cancer therapy until study closure. 
2. Fixed Duration Cohort
Approximately 125 subjects without del17p will be enrolled into this 
cohort sequentially after the MRD cohort. Subjects will receive 
15 cycles of open label therapy consisting of single-agent ibrutinib for 
3 cycles followed by ibrutinib + venetoclax combination treatment for 
12 cycles. 
Investigator assessment of tumor response and progression will be 
based upon IWCLL criteria (Hallek 2008, Hallek 2012, Hallek 2013).
Imaging will be collected and stored centrally.
Subjects will be assessed for MRD status in peripheral blood (PB) every 
3 cycles starting after completion of 6 cycles (C7D1), and in bone 
marrow (BM) aspirate after completion of 9 cycles (C10D1) and 
3 months after completion of the fixed duration of therapy (ie, C19) or 
earlier if BM is obtained per clinical indication. MRD assessments will 
be performed using flow cytometry with a sensitivity of ≥10-4. The 
primary analysis will be performed when a clinically meaningful 
evaluation of durable CR rate (12 months or longer) can be assessed in 
the study population. FD Cohort subjects will be followed for 
approximately  10 years. Subjects who are continuing on ibrutinib at FD 
cohort study closure may be offered a separate extension study to 
continue ibrutinib.
Reintroduction of therapy:
Subjects with confirmed progression by IWCLL criteria after 
completion of the fixed duration regimen can be retreated with 
continuous single agent ibrutinib, or retreatment with the ibrutinib + 
venetoclax fixed duration treatment regimen may be considered based 
on Investigator’s clinical discretion and Medical Monitor approval.


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Post-PD Follow-up Phase:
Subjects will be followed for progression, overall survival (OS), and 
use of subsequent anticancer agents until study closure.
Population:
Subjects who have treatment-naive CLL or SLL with active disease 
requiring therapy
Centers:
Multiple, US vs. ex-US 
Inclusion Criteria:
Refer to Section 4 for the 
complete and detailed list of 
inclusion/exclusion criteria.
Disease Related
1.
Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria 
(Hallek 2008).
2.
Active disease meeting at least 1 of the following IWCLL criteria 
(Hallek 2008) for requiring treatment:

Evidence of progressive marrow failure as manifested by the 
development of, or worsening of, anemia and/or 
thrombocytopenia

Massive, progressive, or symptomatic splenomegaly

Massive nodes or progressive or symptomatic 
lymphadenopathy

Progressive lymphocytosis

Constitutional symptoms
3.
Measurable nodal disease by computed tomography (CT).
Laboratory
4.
Adequate hematologic function independent of transfusion and 
growth factor support for at least 7 days, (with the exception of 
pegylated G-CSF [pegfilgrastim] and darbopoeitin which require at 
least 14 days) prior to screening laboratory assessment defined as: 

Absolute neutrophil count (ANC) >750/µL (750 cells/mm3 or 
0.75 x 109/L)  

Platelet count >30,000 /µL (30,000 cells/mm3 or 30 x 109/L). 

Hemoglobin >8.0 g/dL
5.
Adequate hepatic and renal function defined as:

Serum aspartate transaminase (AST) or alanine transaminase 
(ALT) ≤3.0 x upper limit of normal (ULN)

Creatinine Clearance (CrCl) ≥60 mL/min 
(eg, as estimated by Cockcroft-Gault)

Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s 
syndrome or of non-hepatic origin)
6.
Prothrombin time (PT)/International normal ratio (INR) 
<1.5 x ULN and PTT (activated partial thromboplastin time 
[aPTT]) <1.5 x ULN (unless abnormalities are unrelated to 
coagulopathy or bleeding disorder). 


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Demographic
7.
Men and women ≥18 and ≤70 year of age.
8.
Eastern Cooperative Oncology Group (ECOG) performance status 
of 0-2.
Ethical/Other
9.
Female subjects who are of non-reproductive potential (ie, post-
menopausal by history no menses for ≥1 year; OR history of 
hysterectomy; OR history of bilateral tubal ligation; OR history of 
bilateral oophorectomy). Female subjects of childbearing potential 
must have a negative serum pregnancy test upon study entry.
10. 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 abstinence1, 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. Male 
subjects must agree to refrain from sperm donation until 90 days 
after the last dose of study drug.
Exclusion Criteria:
1.
Any prior therapy (including but not limited to chemotherapy, 
targeted therapy, immunomodulating therapy, radiotherapy, and/or 
monoclonal antibody) used for treatment of CLL or SLL.
2.
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 the treating 
physician

Adequately treated non-melanoma skin cancer or lentigo 
maligna without current evidence of disease

Adequately treated carcinoma in situ without current evidence 
of disease 
3.
Known or suspected history of Richter’s transformation.
4.
Concurrent administration of >20 mg/day of prednisone within 
7 days of initiation of study drug unless indicated for prophylaxis,
or management of allergic reactions (eg, contrast).
5.
Known hypersensitivity to one or more study drugs.
6.
Known allergy to xanthine oxidase inhibitors and/or rasburicase.
Subjects who are allergic to xanthine oxidase inhibitors and cannot 
receive rasburicase will be excluded.
7.
Vaccinated with live, attenuated vaccines within 4 weeks of first 
dose of study drug.
                                               
1 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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8.
Recent infection requiring systemic treatment that is ongoing or 
was completed ≤14 days before the first dose of study drug, or 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 
infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). 
Subjects who are positive for hepatitis B core antibody, hepatitis B 
surface antigen (HBs Ag), or hepatitis C antibody must have a 
negative polymerase chain reaction (PCR) result before enrollment.  
Those who are PCR positive will be excluded.
12. Major surgery within 4 weeks of 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 
enrollment.
15. Unable to swallow capsules/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. Concomitant use of warfarin or other vitamin K antagonists.
17. Requires treatment with a strong cytochrome P450 (CYP) 3A 
inhibitor (see Appendix G).
18. Currently active, clinically significant hepatic impairment Child-
Pugh Class B or C according to the Child Pugh classification 
(see Appendix K).
19. Lactating or pregnant.
20. Unwilling or unable to participate in all required study evaluations 
and procedures.
21. 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).
22. Uncontrolled autoimmune hemolytic anemia or idiopathic 
thrombocytopenia purpura, such as those subjects with a declining 
hemoglobin level or platelet count secondary to autoimmune 
destruction within the 4 weeks prior to first dose of study drug, or 
the need for daily prednisone >20 mg daily (or corticosteroid 
equivalent) to treat or control the autoimmune disease.




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OR
Placebo

Orally once daily matching placebo capsules (3 capsules)
continuously until confirmed MRD-positive relapse, disease 
progression or unacceptable toxicity
Randomization Phase – MRD-positive subjects:
Ibrutinib + venetoclax

Orally once daily ibrutinib 420 mg (3 capsules) continuously until 
disease progression or unacceptable toxicity
plus

Orally once daily venetoclax 400 mg daily (four 100 mg tablets)
OR
Ibrutinib

Orally once daily ibrutinib 420 mg (3 capsules) continuously until 
disease progression (post reintroduction when applicable) or 
unacceptable toxicity
Reintroduction of ibrutinib or venetoclax:
Upon confirmed MRD-positive relapse in MRD-negative randomized 
subjects or confirmed disease progression by IWCLL criteria in any 
randomized subjects, ibrutinib and/or venetoclax may be reintroduced.
Subjects who are receiving placebo treatment, when MRD-positive 
relapse or disease progression are confirmed, may reintroduce oral daily 
ibrutinib until disease progression or unacceptable toxicity.
Subjects who are receiving oral daily ibrutinib may reintroduce oral 
daily venetoclax. Standard TLS risk assessment, venetoclax dose ramp 
up, and TLS management should be employed at venetoclax 
reintroduction (VENCLEXTA® (venetoclax) prescribing information).
2) Fixed Duration Cohort
Ibrutinib:

Orally once daily ibrutinib 420 mg (3 capsules)

Single-agent lead-in for 3-cycles, then continued in combination 
for 12 additional cycles until completion of Cycle 15

Dose modification for adverse events are specified in 
Section 5.4.1.4
Venetoclax:

Orally once daily venetoclax, with 5-week dose ramp up 
(VENCLEXTA® (venetoclax) prescribing information), to 400 mg 
daily, added to ongoing ibrutinib therapy starting at Cycle 4 and 
continuously for 12 cycles until completion of Cycle 15

Venetoclax and ibrutinib should be dosed together at the same time 
each day with a meal and water


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
Dose modification for adverse events are specified in 
Section 5.4.2.5
NOTE: If dictated by emerging data from this study, the duration of
combined ibrutinib + venetoclax treatment may be modified to ensure 
appropriate risk-benefit is maintained, compared to historical controls 
and other emerging data.
Subjects with confirmed progression by IWCLL criteria after 
completion of the fixed duration regimen can be retreated with 
continuous single agent ibrutinib, or retreatment with the ibrutinib + 
venetoclax fixed duration treatment regimen may be considered based 
on Investigator’s clinical discretion and Medical Monitor’s approval.
Concomitant Therapy:
Refer to Section 6 for information on concomitant therapy.
Safety Plan:
The safety of this study will be monitored in accordance with the 
Sponsor’s Pharmacovigilance Committee procedures. A Data Review 
Committee (DRC) will be organized to assess safety, tolerability, and 
make a recommendation regarding dosing after the Safety Run-in 
Period.
Safety Run-in Period:
Approximately 12 subjects will be enrolled in a Safety Run-in Period, 
defined as the date of first dose of ibrutinib at Cycle 1 Day 1 through 
the DLT evaluation period. The DLT evaluation period is defined as the 
5-week venetoclax dose ramp-up in combination with ibrutinib plus an
additional week of follow up. Enrollment will be held until safety is 
assessed by the DRC in the first 6 evaluable subjects who complete the 
Safety Run-in Period. Subjects’ laboratory results and AEs will be 
reviewed by the DRC. If ≤1 of the first evaluable 6 subjects experience 
a DLT, the study will continue. If 2 of the first 6 evaluable subjects 
experience a DLT, then the DRC will evaluate safety in the next 
3 evaluable subjects. If 3 or more of the 9 subjects experience DLTs, 
the DRC may recommend the dose of the study drug(s) to be de-
escalated as per Table 1 in Section 5.2.1. The study will be deemed safe 
to proceed when 6–9 subjects complete the Safety Run-in Period 
(DLT observation period) and if <33% (≤1 of 6, or ≤2 of 9) of subjects 
experience a DLT.
Any case of clinical TLS during the Safety Run-in Period will trigger a 
DRC review of that subject. Enrollment will be staggered to no more 
than 3 subjects per week during the Safety Run-in Period in order to 
minimize patient exposure and risk during this initial run-in period. A 
follow-up DRC review will occur after all subjects in the Safety Run-in 
Period have either discontinued therapy and/or have completed the DLT 
evaluation period (venetoclax dose ramp-up plus 1-week follow-up), 
then DRC may make a recommendation regarding dosing.


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General Safety Plan:
All subjects will be assessed for TLS risk at baseline and prior to 
commencement of venetoclax dosing using the previously described 
approach based on tumor burden (Seymour 2014), consistent with the
VENCLEXTA® (venetoclax) prescribing information, and noted in 
Section 5.4.2.2. See Section 7.1.1.9 and Section 7.1.1.10 for TLS risk 
assessment and prophylaxis respectively.
Adverse events (AEs) and serious adverse events (SAEs) will be 
reviewed by the Sponsor on an ongoing basis to identify safety 
concerns. The safety will be monitored in accordance with the 
Sponsor’s routine Pharmacovigilance Committee procedures.
Statistical Methods and 
Data Analysis:
1) MRD Cohort
Descriptive statistics and subject listings will be used to summarize the 
data. For continuous variables the number of observations, means, 
standard deviations, medians, and ranges will be reported. For discrete 
variables, frequencies and percentages will be summarized. For time-to-
event variables, Kaplan-Meier estimates will be provided. No 
inferential tests will be performed for pre-randomization phase. The 
primary endpoint, 1-year disease-free rate in MRD-negative 
randomized subjects, will be tested between placebo and ibrutinib arms 
at a 2-sided alpha level of 0.05. Safety endpoints will be summarized 
descriptively based on subjects who received at least one dose of 
treatment.
2) Fixed Duration Cohort
Efficacy analyses will be based on the all-treated population without 
del17p. The 95% confidence interval will be estimated for complete 
response rate and MRD-negative response rate. Duration of response, 
PFS, and OS will be summarized using the Kaplan-Meier method. 
Summaries based on all-treated population will also be presented. 
Safety endpoints will be summarized descriptively based on subjects 
who received at least one dose of treatment.


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Sample Size 
Determination
1) MRD Cohort
The study cohort will be powered based on the Randomization Phase 
primary endpoint of 1-year disease-free rate in MRD-negative 
randomized subjects (ibrutinib vs placebo). The total sample size will 
be based on both MRD-negative response rate from the 
Pre-randomization Phase and the sample size assumption from the 
Randomization Phase.
Sixty randomized subjects with confirmed MRD-negative status will 
provide approximately 80% power to detect a 30% improvement in the 
1--year disease-free rate, assuming the 1-year disease-free rate is 60% 
for the control (placebo) arm, at a 2-sided significance level of 0.05.
Assuming a 40% MRD-negative response rate for the ibrutinib and 
venetoclax combination therapy in the Pre-randomization Phase, 
150 subjects will be enrolled in the Pre-randomization Phase in order to 
have 60 subjects achieving a confirmed MRD-negative response and to 
be randomized. The final sample size may be adjusted based on an early 
assessment of the MRD-negative response rate among the first 30 
subjects who complete 9 cycles of treatment in Pre-randomization 
Phase (See Section 3.1.1).
2) Fixed Duration Cohort
Assuming the CR rate for ibrutinib + venetoclax is 50%, 125 subjects 
without del17p will provide 83% power to ensure the rate is > 37% at 
1-side alpha 0.025. A CR rate of 50% would represent a significant 
improvement compared to the CR rate seen with the fixed duration 
combination of bendamustine + rituximab (31%) and would 
demonstrate a clinically meaningful improvement over the CR rate seen 
with the most effective standard of care fixed duration regimen 
fludarabine, cyclophosphamide, and rituximab (40%) which were 
obtained in the CLL10 study, which included only patients without 
del17p (Eichhorst 2016).


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ABBREVIATIONS
AE
adverse event 
AESI
Adverse Events of Special Interest 
ALT
alanine aminotransferase 
AML
acute myeloid leukemia cells
ANC
absolute neutrophil count 
ASCO
American Society of Clinical Oncology
AST 
aspartate aminotransferase 
AUC
area under the concentration-time curve
BCR
B-cell receptor
BM
bone marrow
BMA
bone marrow aspirate
BR
bendamustine + rituximab
BTK
Bruton’s tyrosine kinase
CI
confidence interval
CIT
chemoimmunotherapy 
CLL
chronic lymphocytic leukemia 
Cmax
maximum observed plasma concentration
CR 
complete response 
CRR
complete response rate
CRi
Complete response with incomplete bone marrow recovery
CrCl
creatinine clearance
CRF
case report form (paper or electronic as appropriate for this study)
CT
Computed Tomography
CTCAE
NCI Common Terminology Criteria for Adverse Events
CTLS
clinical tumor lysis syndrome
CYP
cytochrome P450
del17p
deletion of the short arm of chromosome 17
DFS
Disease-free survival
DLBCL
diffuse large B-cell lymphomas
DLT
dose limiting toxicity
DOR
Duration of Response
DRC
Data Review Committee 
ECOG
Eastern Cooperative Oncology Group
ECG
Electrocardiogram
ECHO
Echocardiogram
EDC
electronic data capture
FCR
fludarabine, cyclophosphamide and rituximab 
FD
Fixed Duration
FDA
Food and Drug Administration


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FISH
fluorescense in situ hybridization
FL
follicular lymphoma
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV 
hepatitis C virus
HIV
human immunodeficiency virus
HIPAA
Health Insurance Portability and Accountability Act
IAC
Interim Analysis Committee
IB
Investigator's Brochure
IBR
Ibrutinib
IC50
concentration that inhibits a process by 50%
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IGHV
immunoglobulin heavy-chain variable region
ILD
interstitial lung disease 
INR
International normal ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
ITT
Intention-to treat
I+V
ibrutinib plus venetoclax combination
IV
intravenous
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
LDH
lactate dehydrogenase
LN
lymph node
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
MRI
Magnetic Resonance Imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
MUGA
Multigated acquisition scan
nPR
nodular partial response 
ORR
overall response rate
OS
overall survival
PB
peripheral blood
PCR
polymerase chain reaction
PD
progressive disease or disease progression


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PFS
progression free survival
P-gp
P-glycoprotein
PK
Pharmacokinetics
PML
progressive multifocal leukoencephalopathy
PO
Oral
PR 
partial response 
PRL
PR with lymphocytosis 
aPTT
activated partial thromboplastin time
PT
prothrombin time 
QD
once daily
QTc
QT interval corrected for heart rate 
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone  
REB
Research Ethics Board
RS
Richter’s syndrome
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SLL
small lymphocytic lymphoma 
t1/2
half-life
Tmax
time to maximum plasma concentration 
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
ULN
upper limit of normal
USPI
United States package insert
VEN
Venetoclax
WM
Waldenström’s macroglobulinemia


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1.
BACKGROUND
1.1.
Disease/Histology
1.1.1.
Disease Background
Chronic lymphocytic leukemia (CLL) is the most frequent form of adult leukemia in the Western 
world. It is a common and incurable condition, characterized by a distinct diversity of clinical 
outcomes ranging from indolent to markedly aggressive (Chiorazzi 2005). With an estimated 
prevalence in the United States of approximately 106,000, it is largely a disease of the elderly. 
The median age at diagnosis is approximately seventy years (SEER 2016).
The predominantly older and co-morbid population, the incurable nature of the condition and the 
diversity of disease variants combine to make CLL an important area of clinical research with an 
urgent need for innovative and novel treatment approaches for many patient sub-types.
Pathologically, CLL is defined by an accumulation of phenotypically distinct mature monoclonal 
B cells in the blood, bone marrow, and secondary lymph organs. Small lymphocytic lymphoma 
(SLL) is a condition possessing similar characteristics but without lymphocytosis and is 
essentially a variant of the same underlying disorder as CLL. Clinically, the two similar 
pathologies constitute one distinct disease (collectively referred to as CLL hereafter) 
(Müller-Hermelink 2001).
The clinical course of CLL is extremely variable, with a significant proportion of patients 
requiring no treatment for decades, whilst more urgent intervention is indicated in others, 
particularly those with progressive, clinically symptomatic disease. Because the majority of 
patients are asymptomatic at presentation and as there is currently no consensus on the optimal 
timing for initiation of treatment (Dighiero 1998), International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) guidelines have been developed to define the clinical contexts 
in which treatment should be commenced (Hallek 2008).
CLL is both pathologically and clinically heterogeneous, resulting in many patient subgroups 
who respond markedly less favorably to currently available treatment strategies, independent of 
age and comorbidity. In particular, one feature which has consistently been associated with the 
worst overall prognosis is deletion of the short arm of chromosome 17 (del17p) and/or a 
mutation of the TP53 tumor suppressor gene. These abnormalities occur in about 7-10% of CLL 
cases at diagnosis (Krober 2002) and this patient subgroup is characterized by rapid disease 
progression, poor response to therapy, and a very limited median overall survival of less than 
three years (Dohner 2000). In addition to del17p/TP53, immunoglobulin heavy-chain variable 
(IGHV) gene somatic hypermutation status (IGHV-MS) is an important prognostic factor. 
Unmutated IGHV, which occurs in about 40-50% of CLL patients, is predictive for time to first 
treatment (Wierda 2011) and is associated with a worse survival (Bulian 2012, Pflug 2014).


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1.1.2.
Current Treatment Options in Previously Untreated CLL
The results of clinical studies in previously untreated CLL have demonstrated major advances in 
therapy over the last decade. The most active regimen described thus far, on the basis of a 
single-center experience at the MD Anderson Cancer Center (Keating 2005) and subsequent 
randomized CLL8 trial (Hallek 2010), is the chemoimmunotherapeutic (CIT) combination of 
fludarabine, cyclophosphamide, and rituximab (FCR). FCR resulted in significant improvement 
in PFS and OS compared with fludarabine and cyclophosphamide alone, with a hazard ratio for 
progression of 0.51 (95% CI: 0.39, 0.67) for patients less than 70 years of age (N = 736) 
(Hallek 2010, Casak 2011). Although numerous subsequent attempts have been made to improve 
on FCR eg, through the addition of mitoxantrone, alemtuzumab or granulocyte macrophage 
colony-stimulating factor (Parikh 2011, Bosch 2009, Reynolds 2012), increasing the dose of 
rituximab (FCR3) (O'Brien 2005), substituting cladribine or pentostatin for fludarabine 
(Wierda 2012, Bryan 2011), or combining rituximab with bendamustine (Fischer 2012) so far 
FCR remains the most active regimen and regarded as a standard of care for young fit first line 
patients (Hillmen 2010).
Despite the improved efficacy of CIT, only 40-45% of patients treated with these approaches 
currently achieve a complete response (CR) and many patients (including those achieving CR) 
eventually relapse (Hallek 2010, Tam 2008, Kay 2007, Fischer 2016). In some patients, CIT has 
resulted in attainment of undetectable minimal residual disease (MRD), defined as detection of 
<1 CLL cell in 10,000 normal leukocytes by either polymerase chain reaction assay or 4 color 
flow cytometry. These MRD-negative remissions are associated with longer PFS and OS
(Bottcher 2012, Strati 2014), however, only 43-49% of patients who are evaluated for MRD 
(27-43% of ITT patients) are able to achieve MRD-negative remissions (Bottcher 2012, 
Strati 2014). Additionally, MRD-negative remissions are achieved in a lower percent of 
unmutated vs mutated IGHV patients post CIT (33% vs 50.7% respectively of those evaluated)
(Thompson 2016). Although some patients derive significant benefit from CIT, fludarabine 
based CIT regimens result in substantial toxicity including profound immunosuppression, 
prolonged cytopenias (which can restrict salvage therapy options at the time of recurrence), and a 
5-10% risk of therapy-related myelodysplasia (MDS) (Tam 2008, Keating 2005, Ferrajoli 2005). 
These toxicities are problematic since most CLL patients are >age 50 at diagnosis and many 
patients have comorbidities that limit their ability to receive CIT (Hallek 2013). Even among 
younger fit CLL patients, >25% are unable to tolerate FCR-based CIT. Phase 3 trial indicate that 
56% of patients experience Grade 3-4 myelosuppression, 25% infectious complication, 47% 
require dose reductions, and >25% of patients are unable to complete the intended 6 cycles of 
FCR induction even with dose reductions (Hallek). While FCR has been a major advance in the 
CLL treatment, it is associated with significant toxicity that limits the benefit of this approach for 
many patients.
Recently, in the RESONATE-2 randomized trial, single-agent ibrutinib (administered daily until 
progression or unacceptable toxicity) demonstrated superior PFS and OS compared to 
chlorambucil in previously untreated CLL patients (Burger 2015). At 18.4 months of follow up, 


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ibrutinib significantly reduced the risk of progression or death by 84% compared to chlorambucil 
(median PFS not reached vs. 18.9 months respectively; hazard ratio, 0.16; P<0.001). Notably, the 
18-month PFS was 89% in both unmutated and mutated IGHV subgroups treated with ibrutinib, 
compared to 47% and 51% in these respective subgroups treated with chlorambucil. 
Additionally, ibrutinib reduced the relative risk of death by 84% (hazard ratio, 0.16; P = 0.001). 
The overall response rate was higher with ibrutinib compared with chlorambucil (86% vs. 35%, 
P<0.001), and the rates of sustained increases from baseline values in the hemoglobin and 
platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 
20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea, and were 
mainly Grade 1-2. At 18.4 months of follow-up, 87% of the patients in the ibrutinib group 
continued on therapy (Burger 2015). Ibrutinib was approved by US FDA in March 2016 based 
on these data for the first line treatment of CLL.
Although ibrutinib has resulted in an improvement in PFS and OS in treatment-naïve patients 
(Burger 2015), and previously treated patients (Byrd 2014), single-agent ibrutinib has rarely 
demonstrated the ability to induce undetectable MRD by PCR or 4 color flow cytometry with a 
sensitivity of <1x10-4. The addition of ibrutinib to bendamustine + rituximab (BR) resulted in a 
higher MRD-negative CR/CRi rate in previously treated CLL patients compared to placebo + BR 
(4.2% vs 1.5% by IRC; 9.3% vs 2.4% by investigator assessment) (Chanan-Khan 2016). The 
MRD-negative rate reached a plateau 9 months after completion of placebo + BR, however 
increased overtime with continued ibrutinib therapy (Fraser 2016).
Phase 1 data of single-agent venetoclax in relapsed CLL or SLL patients (n=56 in the dose 
escalation cohort and n=60 in the expansion cohort) demonstrated reduction of CLL burden in 
the blood, lymph nodes and bone marrow, with a pooled overall response rate (ORR) of 79% 
including 20% CR/CRi (Roberts 2015). The response rate did not differ by risk factors, including 
deletion 17p CLL, resistance to fludarabine, unmutated IGHV, or bulky disease. Importantly, 
35% (6/17) of those patients who achieved CR and were evaluated for MRD in bone marrow 
became MRD-negative. In the dose-escalation cohort, tumor lysis syndrome (TLS) occurred in 
10 of 56 patients (18%), including clinical TLS in 3 patients and laboratory TLS in 7 patients. In 
the expansion cohort, patients received an extended step-wise dose ramp-up schedule with TLS 
prophylaxis and hospitalization according to their level of TLS risk, resulting in no cases of 
clinical TLS and reduced laboratory TLS. Adverse event of any grade that occurred in at least 
20% of patients included diarrhea, upper respiratory tract infection, nausea, neutropenia, fatigue, 
cough, pyrexia, anemia, headache, constipation, and thrombocytopenia. Phase 2 data of single-
agent venetoclax in ultra high-risk relapsed/refractory del17p CLL (N=107) demonstrated a 79% 
ORR including 7.5% CR/CRi (Stilgenbauer 2015). No detectable MRD was observed in 
peripheral blood in 21% of responders with MRD assessments (17% of whole cohort).
Venetoclax received accelerated approval from US FDA in April 2016 based on this data for 
patients with CLL with 17p deletion who have received at least one prior therapy. Venetoclax 
received conditional approval from the European Commissions in December 2016 for the 
treatment of patients with CLL in the presence of 17p deletion or TP53 mutation in adult patient 
who are unsuitable or have failed a B-cell receptor pathway inhibitor, as well as for the treatment 


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of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both 
chemo-immunotherapy and a B-cell receptor pathway inhibitor. Venetoclax, both as a single
agent and in combination with other therapeutic agents, continues to show promising efficacy in
oncology subject populations. The ORR in subjects with CLL/SLL was 74% (IRC-assessed) and 
74% (investigator-assessed) for single-agent venetoclax (Study M12-175 and Study M13-982, 
respectively), ranged from 67% to 57% for subjects with ibrutinib- or idelalisib-resistant CLL in
Study M14-032, and was 86% for venetoclax administered in combination with rituximab 
(Study M13-365).
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 patients with B-cell malignancies.  
Ibrutinib has been approved in many regions, including the (United States) US and (European 
Union) EU, for indications including treatment of patients with mantle cell lymphoma (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 for patients with chronic graft versus host disease (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.
1.2.1.
Summary of Nonclinical Data
1.2.1.1.
Pharmacology 
Ibrutinib was designed as a selective and covalent inhibitor of the BTK (Pan 2007). In vitro, 
ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM). The irreversible binding of 
ibrutinib to cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic 
activity and enhanced selectivity over other kinases that do not contain a cysteine at this position. 
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).
For more detailed and comprehensive information regarding nonclinical pharmacology and 
toxicology, please refer to the current ibrutinib IB.


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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 comprehensive information regarding nonclinical safety pharmacology and 
toxicology, please refer to the current ibrutinib IB.
1.2.2.
Summary of Clinical Data
For the most comprehensive clinical information regarding ibrutinib, please refer to the current 
version of the ibrutinib IB. 
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 to doses increased with substantial intersubject variability. The 
mean half-life (t1/2) of ibrutinib ranged from 4 to 13 hours, with a median time to maximum 
plasma concentration (Tmax) of 2 hours. Taking into account the approximate doubling in mean 
systemic exposure when dosed with food and the favorable safety profile, ibrutinib can be dosed 
with or without food. Ibrutinib is extensively metabolized primarily by cytochrome 
P450 (CYP) 3A4. The on-target effects of 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. Less than 1% of ibrutinib is excreted renally. 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 


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impairment based on NCI organ dysfunction working group (NCI-ODWG) criteria for hepatic 
dysfunction compared to patients with normal hepatic function.
For the most comprehensive information regarding pharmacokinetics (PK) and product 
metabolism, please refer to the current version of the 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 1318 subjects treated with ibrutinib monotherapy in 13 studies 
that have completed primary analysis or final analysis as of the 31 May 2016 cutoff date for the 
current IB update in B-cell malignancies are summarized below.
The most frequently reported treatment-emergent adverse events (TEAEs) in subjects receiving 
ibrutinib as monotherapy (N=1318):
1.2.3.2.
Combination Studies
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies are briefly summarized below. 
Most Frequently Reported 
TEAEs ≥15%a  
Most Frequently Reported 
Grade 3 or 4 TEAEs ≥3%b
Most Frequently Reported 
Serious TEAEs ≥2%c
Diarrhea
Neutropenia
Pneumonia
Fatigue
Pneumonia
Atrial fibrillation
Nausea
Thrombocytopenia
Febrile neutropenia
Cough
Anemia
Pyrexia
Pyrexia
Hypertension
Anemia
Diarrhea
Neutropenia
Atrial fibrillation
Upper respiratory tract infection
Thrombocytopenia
Oedema peripheral
a.
Source is Table 6 of IB (v10), b Source is Table 8 of IB (v10), c Source is Table 9 of IB (v10).


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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=423):
Most Frequently Reported 
TEAEs ≥20%a
Most Frequently Reported 
Grade 3 or 4 TEAEs ≥3%b
Most Frequently Reported 
Serious TEAEs ≥2%c
Neutropenia
Neutropenia
Pneumonia
Diarrhea
Thrombocytopenia
Febrile neutropenia
Nausea
Febrile neutropenia
Atrial fibrillation
Thrombocytopenia
Pneumonia
Pyrexia
Fatigue
Neutrophil count decreased
Cellulitis
Anemia
Anemia
Pyrexia
Fatigue
Hypertension
Diarrhea
a.
Source is Table 10 of IB (v10), b Source is Table 12 of IB (v10), c Source is Table 13 of IB (v10).
1.2.4.
Risks
For the most comprehensive safety information regarding ibrutinib, please refer to the current 
version of the ibrutinib IB.
1.2.4.1.
Cardiac Arrhythmias and Cardiac Failure
Atrial fibrillation, atrial flutter, cardiac failure, and cases of ventricular tachyarrhythmia 
including some fatal events, have been reported in subjects treated with ibrutinib, particularly in 
subjects with cardiac risk factors, hypertension, acute infections, and a previous history of 
cardiac arrhythmia. Periodically monitor subjects clinically for cardiac arrhythmia 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 and cardiac failure which persist, consider the risks 
and benefits of ibrutinib treatment and follow the protocol dose modification guidelines (see 
Section 5.4.1.4).
1.2.4.2.
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, 


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and petechiae; and major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. Initially, subjects were excluded from participation in 
ibrutinib Phase 2 and 3 studies if they required warfarin or other vitamin K antagonists. Warfarin 
or other vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. In an in vitro platelet 
function study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation were 
observed. Use of ibrutinib in subjects requiring other anticoagulants or medications that inhibit 
platelet function may increase the risk of bleeding. Ibrutinib should be held at least 3 to 7 days 
pre-surgery and at least 3 to 7 days post-surgery depending upon the type of surgery and risk of 
bleeding. Subjects with congenital bleeding diathesis have not been studied. See Section 6.2.4
for guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See 
Section 6.4 for guidance on ibrutinib management with surgeries or procedures. 
1.2.4.3.
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. Subjects should be monitored for fever, weakness, or 
easy bruising and/or bleeding.
1.2.4.4.
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 adequate 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 5.4.1.4). 
1.2.4.5.
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 subjects who are 
at increased risk for opportunistic infections (reference Section 6.1). Although causality has not 
been established, cases of progressive multifocal leukoencephalopathy (PML) and hepatitis B 
reactivation have occurred in subjects treated with ibrutinib. Subjects should be monitored for 
signs and symptoms (fever, chills, weakness, confusion, vomiting and jaundice) and appropriate 
therapy should be instituted as indicated.


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1.2.4.6.
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 (see Section 5.4.1.4).
1.2.4.7.
Leukostasis 
There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high 
number of circulating lymphocytes (>400,000/µL) may confer increased risk. For subject and 
ibrutinib management guidance, refer to Section 5.4.1.5.
1.2.4.8.
Lymphocytosis
Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥50% increase from 
baseline and an absolute count >5000/µL), often associated with reduction of lymphadenopathy, 
has been observed in 66% of subjects with CLL/ small lymphocytic lymphoma (SLL) treated 
with ibrutinib. This observed lymphocytosis is a pharmacodynamic effect and should not be 
considered progressive disease in the absence of other clinical findings (Hallek 2008, 
Hallek 2012, Hallek 2013). The onset of isolated lymphocytosis occurs during the first month of
ibrutinib therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks). When 
ibrutinib was administered with chemoimmunotherapy (bendamustine + rituximab [BR]), 
lymphocytosis was 7% with ibrutinib + BR versus 6% with placebo + BR.
1.2.4.9.
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.
1.2.4.10.
Rash
Rash has been commonly reported in subjects treated with either single-agent ibrutinib or in 
combination with chemotherapy. Most rashes were mild to moderate in severity. Isolated cases 
of severe cutaneous adverse reactions (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.
1.2.4.11.
Tumor Lysis Syndrome
There have been reports of tumor lysis syndrome (TLS) events in subjects treated with single-
agent ibrutinib or in combination with chemotherapy. Subjects at risk of TLS are those with 


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comorbidities and/or risk factors such as high tumor burden prior to treatment, increased uric 
acid (hyperuricemia), elevated lactate dehydrogenase (LDH), bulky disease at baseline, and pre-
existing kidney abnormalities.
1.2.4.12.
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.
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 is approved in the US for the treatment of patients with CLL or SLL, with or without 
17p deletion, who have received at least one prior therapy. Venetoclax is also approved in the 
EU and other regions for the treatment of adult patients with CLL when used as monotherapy
the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable or have failed 
a B-cell receptor pathway inhibitor or for the treatment of CLL in the absence of 17p deletion of 
TP53 mutation in adult patients who have failed both chemo-immunotherapy and a B-cell 
receptor pathway inhibitor, and in combination with rituximab for the treatment of adult patients 
with CLL who have received at least one prior therapy. Venetoclax has also been approved in the 
US in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with 
newly-diagnosed acute myeloid leukemia (AML) who are 75 years of age or older, or have other 
medical conditions that prevent the use of standard chemotherapy.
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. Bcl-2 is also overexpressed in acute and chronic 
leukemias. Chronic lymphocytic leukemia (CLL) is a genetic disease where the microRNAs 
miR15a and miR16-1 that negatively regulate the transcription of Bcl-2 are deleted or 
down-regulated, resulting in uncontrolled expression of Bcl-2 (Cimmino 2005, Calin 2008).
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 


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Bcl-2 signaling and rapidly induces multiple hallmarks of apoptotic cell death in 
Bcl-2-dependent human tumor cell lines (venetoclax 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 patient-derived CLL and 
acute myeloid leukemia (AML) cells, and a variety of lymphoma and leukemia cell lines
including B-cell follicular lymphomas (FLs), mantle cell lymphomas (MCLs), diffuse large 
B-cell lymphomas (DLBCLs), AMLs, and multiple myeloma cell lines. Venetoclax was 
especially potent against cell lines expressing high levels of Bcl-2. A detailed discussion of the 
non-clinical toxicology, metabolism, and pharmacology can be found in the venetoclax IB.
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 pharmacokinetics 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 
pharmacokinetics of venetoclax has not been studied in subjects with severe hepatic impairment.
Based on preliminary data from this combination study of ibrutinib and venetoclax in CLL 
(PCYC-1142-CA), venetoclax exposure (AUC) at 400 mg QD appears to be ~1.6-fold higher 
when co-administered with ibrutinib at 420 mg QD (N = 32), compared to historic venetoclax 
single agent exposure. Ibrutinib exposure was similar prior to, and in combination with 
venetoclax administration.  To date, no new safety signals have been identified.
For the most comprehensive information regarding pharmacokinetics (PK) and product 
metabolism, please refer to the current version of the venetoclax IB.


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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 2016, and version 8 of the Investigator’s Brochure, on the basis of data 
available in the AbbVie and Genentech/Roche clinical databases, a total of 2759 subjects have 
been exposed to at least 1 dose of venetoclax in the oncology and immunology development 
programs. A total of 2534 oncology subjects have data available in AbbVie and 
Genentech/Roche studies as of 28 November 2016. Of these 2534, there are 1435 subjects with
CLL/ SLL, 626 subjects with NHL, 178 subjects with MM, 295 with AML. An additional
127 subjects are healthy volunteers. A total of 663 oncology subjects received the drug as 
monotherapy, 1871 have received the drug in combination with other therapies, and 1 subject
received venetoclax as a single dose in a drug-drug interaction study and did not re-enroll into a
subsequent monotherapy study. Additionally, 98 subjects have been exposed to at least 1 dose of 
venetoclax in the AbbVie immunology study, Study M13-093, as of 28 November 2016.
Of the 1435 subjects with CLL/SLL that have been treated in the venetoclax oncology clinical 
program: 416 patients have received venetoclax monotherapy and 1019 have received venetoclax 
in combination with other agents including rituximab, obinutuzumab, and bendamustine.
The safety profile of venetoclax was similar across CLL subjects, including subjects with 17p del 
or TP53 mutation and subjects who have failed prior B-cell receptor inhibitors (BCRi), such as 
ibrutinib and idelalisib. The most common adverse events (incidence >20%) reported for all 
subjects in CLL/SLL monotherapy studies (N=410) were diarrhea (42.2%), neutropenia (41.0%), 
nausea (40.2%), fatigue (30.5%), anemia (28.8%), upper respiratory tract infection (27.3%), and 
thrombocytopenia (20.7%). The most common Grade 3 and above adverse events were 
neutropenia (36.8%), anemia (15.6%), and thrombocytopenia (13.4%). The most common 
serious adverse events were pneumonia (6.8%), malignant neoplasm progression (5.9%), and 
febrile neutropenia (5.4%). The safety profile in combination studies (N=1019) is consistent with 
that observed in monotherapy studies and combination backbone regimens. 
Additional safety and efficacy data are described in detail in the venetoclax IB.
1.3.3.
Risks
1.3.3.1.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is an important risk, particularly in subjects with CLL. Tumor lysis 
syndrome, including fatal events and renal failure requiring dialysis, have occurred in previously 
treated CLL patients with high tumor burden when treated with venetoclax. As a result of 
on-target effects, the potential for TLS with venetoclax was identified early in the program when 
the initial 3 subjects with relapsed/refractory CLL/SLL received starting doses of 100 mg or 
200 mg and experienced TLS, which was reported as an adverse event for each. The starting 
dose was reduced to 50 mg and prophylaxis and monitoring reduced, with 3-week ramp-up. 


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Subsequently, 2 fatal events in the setting of TLS and another event of clinical TLS in subjects 
with CLL/SLL occurred in December 2012. After comprehensive review of all safety data 
available from studies with venetoclax, a revised dosing regimen with a ramp-up period of 
5 weeks and enhanced TLS prophylaxis and monitoring measures were implemented in all CLL 
studies. A subsequent analysis of data from subjects with CLL/SLL following the 
implementation of prophylaxis measures, who completed monotherapy, indicated a marked 
reduction in severity and frequency of TLS when compared to the previous analysis. None of the 
subjects experienced any serious (including fatal) or non-serious event of clinical TLS (CTLS) or 
had study treatment discontinued because of TLS. Overall, the clinical data strongly support that 
the risk of TLS with venetoclax in CLL/SLL subjects is highest when initiating venetoclax 
dosing, especially with a higher initial dose of venetoclax, as well as being greater in subjects 
with a large tumor burden.
The risk of TLS is a continuum based on multiple factors, including tumor burden and 
comorbidities. Reduced renal function (CrCl <80 mL/min) further increases the risk. Patients 
should be assessed for risk and should receive appropriate prophylaxis for TLS, including 
hydration and anti-hyperuricemics. Changes in blood chemistries consistent with TLS that 
require prompt management can occur as early as 6 to 8 hours following the first dose of 
venetoclax and at each dose increase. Monitor blood chemistries and manage abnormalities 
promptly. Interrupt dosing if needed. Employ more intensive measures (intravenous hydration, 
frequent monitoring, and hospitalization) as overall risk increases (see Section 5.4.2.2 for 
Prophylaxis and Management of TLS).
1.3.3.2.
Neutropenia
Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with venetoclax in the 
pivotal previously treated CLL 17p deletion study. Monitor complete blood counts throughout 
the treatment period. Interrupt dosing or reduce dose for severe neutropenia. Consider supportive 
measures including antimicrobials for signs of infection and use of growth factors (eg, G-CSF).
1.3.3.3.
Immunization
Do not administer live attenuated vaccines prior to, during, or after treatment with venetoclax 
until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated 
vaccines during or following venetoclax therapy have not been studied. Advise patients that 
vaccinations may be less effective.
1.4.
Study Rationale
Despite the impressive survival efficacy (90% PFS at 18 months [Burger 2015]; 94.7% 2-year 
survival estimate [IMBRUVICA USPI]) and safety results with single-agent ibrutinib in the 
randomized Phase 3 RESONATE-2 study in previously untreated CLL patients, complete 
responses remain low (Burger 2015, IMBRUVICA® USPI), and broader questions remain
regarding the optimal duration of ibrutinib therapy. This is particularly relevant among younger 


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patients who may not wish to continue therapy indefinitely or in those seeking a drug holiday. In 
such patients, an all oral truncated combination regimen approach with the ability to induce deep 
and durable remissions would be desirable. 
Pre-clinical studies support the combination of ibrutinib with venetoclax, and suggest potential 
enhanced activity vs. each agent alone. Ex vivo experiments in ibrutinib treated CLL patients 
demonstrated that BCL2 expression remains strong throughout the 6 months of ibrutinib 
treatment (Rawstron 2015). In vitro experiments on previously untreated CLL patient samples 
suggest that ibrutinib increases the dependence of CLL cells on BCL-2 (Deng 2015). 
Additionally, ex vivo experiments on CLL cells from patients demonstrated that ibrutinib 
exposure retained sensitivity to venetoclax, that venetoclax induced potent CLL cell death 
(median 62% at week 4) in patients being treated with ibrutinib, and that cytotoxicity was greater 
than each agent alone (Cervantes-Gomez 2015). 
As of the time of protocol design, in the relapsed CLL setting, single-agent venetoclax had 
induced a 79% ORR, including 20% CR in previously treated CLL patients in a Phase 1 study. 
Of the CR patients evaluated for minimal residual disease (MRD) in bone marrow, 35% (or 5% 
of the total study population) became MRD-negative via flow cytometry (Roberts 2015). In a 
Phase 2 study in patients with relapsed deletion 17p CLL, the IRC assessed response was 69% 
including 7.5% CR/CRi, and MRD-negativity in peripheral blood was achieved in 21% (18/85) 
of responders (Stilgenbauer 2015). MRD-negative response in the bone marrow was achieved in 
53% (26/49) of patients, including 75% (15/20) of patients who achieved CR or CRi with the 
combination of venetoclax plus rituximab in previously treated CLL patients (Ma 2015). Clinical 
remission has been maintained after venetoclax discontinuation in six patients who achieved 
MRD-negative CR, with a median follow up of 15 months off therapy (range 4-24 months). 
Despite impressive response rates and the ability to achieve MRD-negativity in some patients, 
PFS has remains relatively short with single-agent venetoclax (66% - 72% at 12-15 months) and 
combination therapy may afford a better long-term outcome (84% PFS at 24 months with 
rituximab in the relapsed setting).
At the time of protocol design, there was little data with venetoclax in treatment naïve CLL. 
Safety run-in results for the ongoing CLL14 study of venetoclax with obinutuzumab 
demonstrated that the combination was tolerable with 15% of patients developing Grade 3-4 
infusion related reactions with obinutuzumab, and 15% developing Grade 3-4 laboratory tumor 
lysis syndrome (TLS) (Fischer 2015). As infusion-related reactions are not a concern with 
ibrutinib, an ibrutinib lead-in to debulk tumor, followed by the combination of ibrutinib with 
venetoclax may afford better tolerability. The combination of ibrutinib with venetoclax may be 
an effective strategy to achieve deep and durable MRD-negative responses in treatment naïve 
CLL patients. The German CLL Study Group is also planning a study of venetoclax, ibrutinib, 
plus obinutuzumab (CLL2-GiVe, NCT02758665) in physically fit previously untreated CLL.
At the time of protocol design, PCYC-1142-CA was the first clinical trial to study the 
combination of ibrutinib + venetoclax (I+V) in subjects with treatment naïve CLL, therefore a 


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Safety Run-in Period will be instituted to evaluate safety and tolerability of the combination, and 
determination of the recommended doses. Additionally, venetoclax will be introduced after 
3 cycles (1 cycle = 28 days) of single-agent ibrutinib lead-in, representing the period after the 
ibrutinib-induced lymphocytosis peak and where most treated subjects will have experienced 
significant reduction in lymphadenopathy. Utilizing the previously published calculations to 
determine TLS risk categories for venetoclax based on tumor burden (Seymour 2014, 
Appendix H as noted in the VENCLEXTA® (venetoclax) prescribing information, TLS risk at 
baseline and at first assessment were calculated utilizing CT scans after 4 cycles of ibrutinib 
from the RESONATE-2 ibrutinib treatment naïve Phase 3 CLL study (N=135) and after 2 cycles 
of ibrutinib in PCYC-1102 Phase 1b/2 treatment naïve cohorts (N=27).The percent of subjects at 
high or moderate-risk for tumor lysis syndrome (TLS) at baseline was reduced from 81% to 59%
after 2-4 cycles of ibrutinib, and the percent of subjects at high-risk for TLS at baseline was 
reduced from 28% to 7% after 2-4 cycles of ibrutinib. Due to transient increase in ALC, a 
minority (5%) of patients increased from low to medium risk at first assessment, however no 
patients increased from low or medium to high risk. For patients with treatment-naïve CLL or 
SLL with CrCl <80 mL/min, 36% (25/69) with medium TLS risk at baseline were reduced to 
low risk by first assessment and 26% (10/30) with high TLS risk at baseline were reduced to low 
risk by first assessment, further reducing the overall percent of patients requiring hospitalization
(Wierda 2017). Therefore, employing a 3-cycle ibrutinib lead-in and sequencing ibrutinib prior 
to venetoclax should provide tumor debulking and convert higher TLS risk subjects to lower 
TLS risk subjects.
At the time of protocol design, preliminary clinical data from an ongoing investigator-initiated 
study of the combination of ibrutinib and venetoclax (I+V) in subjects with high-risk, 
relapsed/refractory CLL (CLARITY Study, ISCRTN: 13751862) indicated that the combination 
is highly effective, with rapid clearance of disease and an acceptable safety profile (presented at 
the American Society of Hematology [ASH] Annual Meeting, December 2017; Hillmen 2017). 
In this study, the ibrutinib lead-in is 8 weeks, after which the ibrutinib + venetoclax (I+V) 
combination starts. Treatment continues for a period of 14 to 26 months, depending on MRD-
negative status. Median baseline CLL burden in PB, as assessed by the MRD assay in the first 
46 subjects, was 54.5 x109/L. This declined down to 0.001 x109/L in the 37 subjects who have 
completed 8 months of therapy (including 6 months of the combination I+V). All evaluable 
subjects at the 8-month time point (38/38) had an objective response (100% ORR), 18/38 (47%) 
achieved CR or CRi. Peripheral blood was MRD negative in 15/38 (37%) and BM was MRD 
negative in 12/38 (32%). The combination of I+V was reported to have an acceptable safety 
profile, with most AEs being Grade 1 or 2. Two biochemical TLS events were reported, but only 
1 case met the definition of laboratory TLS. Dosing of venetoclax was interrupted until the 
biochemical abnormalities resolved and the patients subsequently escalated to 400 mg/day of 
venetoclax.
At the time of protocol design, the Phase 2 investigator-initiated study conducted at the 
University of Texas MD Anderson Cancer Center (Study NCT02756897) is investigating the 
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(n=39) subjects with CLL with at least 1 of the following high-risk features: del17p, mutated 
TP53, del11q, unmutated IGHV, or ≥65 years of age. Subjects are treated with single agent 
ibrutinib (420 mg daily) for 3 months, followed by addition of venetoclax. As presented at the 
American Society of Hematology [ASH] Annual Meeting, December 2017 (Jain 2017), three 
months of single agent ibrutinib therapy reduced the TLS risk category in 31 of 61 evaluable 
subjects (51%). In the 16 subjects with relapsed/refractory CLL who completed at least 6 months 
of combination therapy, 100% had a response (69% CR/CRi), and 13% were MRD-negative in 
BM. In the 20 subjects with treatment naive, high-risk CLL who completed at least 6 months of 
the combination, 100% had a response (75% CR/CRi), and 45% were MRD-negative in BM. 
One patient had laboratory TLS, none had clinical TLS.
Addition of a Fixed Duration cohort to this study is based upon promising preliminary response 
data (CR, ORR, MRD negative rates) for ibrutinib-venetoclax combination therapy from PCYC, 
investigator-sponsored trials, and other investigator-led studies. After 9 cycles of therapy
(6 cycles of I+V combination), 5 of the first 7 subjects in the MRD cohort of this study have 
achieved MRD-negativity (<0.01%) in the peripheral blood with the remaining 2 subjects having 
only 0.01% MRD.
Together, these preliminary data indicate the combination of ibrutinib and venetoclax has the 
potential for use as a fixed duration regimen. The primary objective of this study is to 
demonstrate a high CR rate in reference to historical data with fixed duration 
chemo-immunotherapy, tested in a similar population. This fixed duration I+V regimen would be 
of value for several reasons, particularly given the barriers to MRD testing in the community and 
the acceptance of fixed duration standard chemoimmunotherapy regimens. If effective, the fixed 
duration I+V therapy would also provide benefit to the patient as well as economic benefits 
given the shorter treatment administration, alleviating the need for long-term dose adherence, 
and providing treatment holidays with the option for treatment following progression.
MRD-negative remission is associated with superior PFS and OS with chemoimmunotherapy 
(CIT) in patients with CLL (Thompson 2016), however whether confirmed MRD-negative 
remissions with novel non-CIT regimens will also translate into a survival benefit is not yet 
known. Additionally, it will be important to understand if extended treatment with ibrutinib in 
patients without confirmed MRD negative remissions after 15 cycles can lead to deeper 
responses and attainment of MRD-negativity. This Phase 2 placebo-controlled study will
investigate the activity of ibrutinib plus venetoclax in treatment-naive CLL subjects by assessing 
the ability to achieve complete clinical response, MRD-negative response, and the durability of
response in the setting of ibrutinib discontinuation.  


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2.
STUDY OBJECTIVE
2.1.
Primary Objective
MRD Cohort

To evaluate if discontinuing ibrutinib, in the setting of a confirmed MRD-negative
response with the combination of ibrutinib + venetoclax (I+V), allows for a treatment 
holiday as assessed by 1-year disease-free survival. 1-year disease-free survival is defined 
as continued MRD-negative response without progression or death at least one year after 
randomization.  
Fixed Duration Cohort

To evaluate the depth of response with the combination of ibrutinib + venetoclax (I+V) 
administered for a fixed duration of therapy by assessment of complete response
(CR/CRi) rate.
2.2.
Secondary Objective(s)
2.2.1.
MRD Cohort

Minimal Residual Disease (MRD) - negative rate

Overall response rate (ORR)

Complete response rate (Complete Response [CR], and CR with incomplete marrow 
recovery [CRi])

Duration of response (DOR)

Tumor Lysis Syndrome (TLS) risk reduction

Progression free survival (PFS)

Overall survival (OS)

Pharmacokinetics of ibrutinib and venetoclax when dosed in combination

Safety and tolerability
2.2.2.
Fixed Duration Cohort

Duration of Response (DOR)

Minimal Residual Disease (MRD)-negative rate

Overall response rate (ORR)

Tumor Lysis Syndrome (TLS) risk reduction

Progression free survival (PFS)

Overall survival (OS)

Safety and tolerability


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2.3.
MRD Cohort Exploratory Objectives
2.4.
FD Cohort Exploratory Objective
3.
STUDY DESIGN
3.1.
Overview of Study Design
This is a multicenter, 2-cohort Phase 2 study assessing both MRD-guided discontinuation and 
fixed duration therapy with the combination of ibrutinib + venetoclax in subjects with treatment-
naïve CLL or SLL.
The MRD cohort consists of a pre-randomization phase (combination treatment), an MRD-
guided randomization phase which includes reintroduction of therapy, and post-PD follow-up 
phase.
The Fixed Duration cohort is an open label, 1 arm cohort of ibrutinib + venetoclax combination 
therapy for a fixed duration.
All subjects who discontinue treatment in the absence of disease progression will remain on 
study until confirmed disease progression or until study closure. All subjects who discontinue for 
disease progression will be followed for survival and subsequent anti-cancer therapies.
Investigator assessment of disease overall response and progression will be based upon IWCLL 
criteria with the modification that isolated treatment-related lymphocytosis in the absence of 
other signs or symptoms of disease progression will not be considered PD (Hallek 2008, 
Hallek 2012, Hallek 2013, Cheson 2012). The Investigator will evaluate sites of disease by
radiological imaging, physical examination or other procedures as necessary, review of 
hematology results, disease-related symptoms and bone marrow examinations (where 
appropriate). The same methods of assessment used to assess disease at baseline should be used 
throughout the study. 
Imaging will be collected and stored centrally. Assessment of efficacy may be confirmed based
on evaluation by an Independent Review Committee (IRC). Detailed procedures will be 
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For the MRD cohort, the primary analysis of the randomized phase will be performed at the 
point that all randomized subjects have had the opportunity to complete at least 12 cycles of 
randomized treatment or follow-up. All safety and efficacy endpoints will be analyzed at the 
time of the primary analysis. After the primary analysis, the Sponsor may elect to discontinue 
follow-up of specific MRD cohort treatment arms on PCYC-1142-CA. Subjects who are 
continuing on ibrutinib at time of study arm closure may be offered a separate extension study to 
continue ibrutinib.
For the FD cohort, the primary analysis will be performed when a clinically meaningful 
evaluation of durable CR rate (12 months or longer) can be assessed in the study population. FD 
Cohort subjects will be followed for approximately 10 years. All subjects who are continuing on 
ibrutinib at the time of FD cohort study closure may be offered a separate extension study to 
continue ibrutinib.
The clinical study report for the study will be generated once the primary analyses of both the 
MRD cohort and FD cohorts are completed.
The rationale for the study concept is provided in Section 1.4.
Details of the sequentially designed and enrolled cohorts, MRD cohort and Fixed Duration 
cohort, are below.
3.1.1.
MRD Cohort: Pre-Randomization Phase
Approximately 150 subjects will be enrolled into this phase. The subjects will receive single-
agent ibrutinib for 3 cycles (1 cycle = 28 days) followed by ibrutinib + venetoclax combination 
treatment for at least12 cycles. 
The safety of ibrutinib + venetoclax combination therapy will be assessed by a Data Review 
Committee (DRC). Approximately 12 subjects will be enrolled in a Safety Run-in Period, 
defined as the date of first dose of ibrutinib at Cycle 1 Day 1 through the DLT evaluation period. 
The DLT evaluation period is defined as the 5-week venetoclax dose ramp up in combination 
with ibrutinib, plus an additional week of follow up (6 weeks total). Enrollment will then be held 
until safety is assessed by the DRC in the first 6 evaluable subjects who complete the Safety 
Run-in Period. Subjects’ laboratory results and AEs will be reviewed by the DRC.  If ≤1 of the 
first 6 evaluable subjects experience a DLT, the study will continue. If 2 of the first 6 evaluable 
subjects experience a DLT, then the DRC will evaluate safety in the next 3 evaluable subjects 
(9 subjects total). The study will be deemed safe to proceed when 6–9 subjects complete the 
Safety Run-in Period (DLT evaluation period) and if <33% (≤1 of 6, or ≤2 of 9) of subjects 
experience a DLT. The DRC will meet and review safety data after all 12 subjects in the Safety 
Run-in Period have either discontinued therapy and/or have completed the DLT evaluation 
period (venetoclax dose ramp up plus 1 week follow up), then DRC may make a 
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Subjects will be assessed for MRD status in peripheral blood every 3 cycles on the combination 
therapy starting after completion of Cycle 6 (C7D1), and in bone marrow aspirate after 
completion of Cycle 15 (C16D1). MRD assessment will be performed using flow cytometry with 
a sensitivity of ≥10-4. An early assessment of the MRD-negative response rate of the 
combination therapy will be assessed among the first 30 subjects who complete 9 cycles of 
treatment. The sample size may be adjusted accordingly based on this early assessment to 
adequately power the Randomization Phase primary endpoint.
MRD-negative response for randomization purposes must be confirmed serially over at least 
3 cycles, and is required to demonstrate negativity in both bone marrow and peripheral blood.
Subjects who complete at least 12 cycles of combination therapy and subjects who discontinue 
venetoclax in the Pre-randomization Phase due to reasons other than PD (but continue on 
ibrutinib single agent treatment and achieve confirmed MRD-negativity by the end of Cycle 16) 
are eligible for randomization. Subjects who have discontinued ibrutinib and subjects that are 
MRD-positive and have discontinued venetoclax are not eligible to be randomized but will 
continue the tolerated open label treatment until PD or unacceptable toxicity.
3.1.2.
MRD Cohort: Randomization Phase (Including Re-introduction Period)
Eligible subjects will be randomized in a 1:1 ratio based on their MRD status (see below). 
Subjects will be stratified by immunoglobulin heavy-chain variable region (IGHV) status in each 
randomization strata.
Randomization Phase - MRD-negative subjects (Double-blind):
Eligible subjects who achieve a confirmed MRD-negative response will be randomized to 
receive blinded treatment of ibrutinib (venetoclax discontinued) vs placebo (ibrutinib and 
venetoclax discontinued). The randomization will be stratified by IGHV status. Subjects will be 
assessed for disease-free survival as measured by continued MRD-negative response without 
progression or death at least 1 year after randomization. MRD status will be evaluated every 
3 cycles in PB. MRD should also be reassessed in BM aspirate after an additional 12 cycles.
Randomization Phase - MRD-positive subjects (Open-label):
Those subjects who do not achieve a confirmed MRD-negative response (MRD-positive) after 
12 cycles of the combination will be randomized to receive open label treatment of I+V vs 
ibrutinib alone (venetoclax discontinued). The randomization will be stratified by 
immunoglobulin heavy-chain variable region (IGHV) status. Subjects will subsequently be 
assessed for MRD-negative response. MRD status will be evaluated every 3 cycles in peripheral 
blood. MRD should also be reassessed in BM aspirate after an additional 12 cycles and at any 
time in subjects who become MRD negative in PB. For subjects receiving I+V, venetoclax can 
be administered for up to approximately 2 years per treatment course, until PD or unacceptable
toxicity, or until this arm’s study closure, whichever is earlier. Subjects who are continuing on 


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ibrutinib at time of study arm closure may be offered a separate extension study to continue 
ibrutinib.
Reintroduction of therapy:
Subjects who wish to reintroduce therapy for MRD-positive relapse (see definition in 
Section 7.2.1.4.2) and/or for disease progression must undergo a CT scan for re-staging (unless 
previously done within approximately 6 weeks prior to reintroduction).  For MRD-negative and 
MRD-positive subjects who reintroduce venetoclax, venetoclax can be administered for up to 
2 years per treatment course, until PD or unacceptable toxicity, or until these arms’ study 
closure, whichever is earlier. Subjects who are continuing on ibrutinib at time of study arm 
closure may be offered a separate extension study to continue ibrutinib. Any non-study therapy 
should only be administered following documented IWCLL confirmed PD.
MRD-negative randomized subjects who experience confirmed MRD-positive relapse and/or 
confirmed disease progression may have their randomization unblinded, and receive 
reintroduced therapy as follows: 
Placebo subjects: Subjects on the placebo arm will be offered the opportunity to reintroduce 
ibrutinib to assess if they can benefit from single-agent ibrutinib under the following 
circumstances:
For confirmed MRD-positive relapse and/or for disease progression by IWCLL criteria, subjects 
will receive ibrutinib until PD or unacceptable toxicity. Ibrutinib reintroduced subjects who 
subsequently have confirmed disease progression by IWCLL criteria may continue ibrutinib and 
add venetoclax per standard dose ramp up
Ibrutinib subjects: Subjects on the ibrutinib arm will be offered the opportunity to continue 
ibrutinib and reintroduce venetoclax treatment under the following circumstances:
For confirmed MRD-positive relapse and/or for confirmed disease progression by IWCLL 
criteria, subjects can continue ibrutinib and add venetoclax per standard dose ramp up.
MRD-positive randomized subjects can receive reintroduced therapy as follows: 
Ibrutinib only subjects: Subjects on the ibrutinib arm will be offered the opportunity to continue 
ibrutinib and reintroduce venetoclax treatment per standard dose ramp up under the following 
circumstances:

For confirmed disease progression by IWCLL criteria, subjects can add venetoclax to 
ongoing ibrutinib

For subjects who have confirmed disease progression and reintroduced therapy, a new 
baseline for response assessment will be collected and utilized for calculating time to
next PD on reintroduced therapy.


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3.1.3.
Fixed Duration Cohort
Approximately 125 subjects without del17p will be enrolled into this cohort sequentially after 
the MRD cohort. Subjects will receive 15 cycles of therapy consisting of single-agent ibrutinib 
for 3 cycles followed by ibrutinib + venetoclax combination treatment for 12 cycles. If emerging 
data from this study indicate, the duration of combined ibrutinib + venetoclax treatment may be 
modified to ensure appropriate risk-benefit is maintained, compared to historical controls and 
other emerging data.
All subjects will be assessed for MRD status in peripheral blood (PB) every 3-12 cycles starting 
after completion of 6 cycles (C7D1), and in bone marrow (BM) aspirate after completion of 
9 cycles (C10D1) and 3 months after completion of the fixed duration Cycle 15 (ie, C19), or 
earlier if BM is indicated for confirmation of CR per IWCLL response criteria. MRD 
assessments will be performed using flow cytometry with a sensitivity (lower limit of detection)
of 1 CLL cell in 10,000 leukocytes (10-4). 
Reintroduction of therapy
Subjects with confirmed progression per IWCLL criteria after completion of the fixed duration 
regimen can be retreated with continuous single agent ibrutinib until disease progression or 
unacceptable toxicity because it is an established standard of care for treatment of relapsed CLL. 
For subjects that experience durable efficacy after I+V (ie, time to progression after fixed 
duration regimen is completed of >2 years), the I+V fixed duration treatment regimen may be 
repeated based on Investigator’s clinical discretion and Medical Monitor’s approval.  
Retreatment is for 15 cycles, until PD or unacceptable toxicity, whichever is earlier.
Subjects will be followed for progression, overall survival (OS), and use of subsequent 
anticancer agents until study closure.
3.1.4.
Post-PD Follow-Up Phase
Subjects who have confirmed disease progression by IWCLL criteria and have discontinued 
study treatment will be followed for survival status and subsequent anti-cancer therapy until 
study closure.






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4.
SUBJECT SELECTION 
4.1.
Inclusion Criteria
Prior to enrollment, each potential subject must satisfy all of the following inclusion criteria. 
Disease Related
1. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008).
2. Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) for requiring
treatment:

Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia and/or thrombocytopenia

Massive, progressive, or symptomatic splenomegaly

Massive nodes or progressive or symptomatic lymphadenopathy

Progressive lymphocytosis

Constitutional symptoms
3. Measurable nodal disease by computed tomography (CT).
Laboratory
4. Adequate hematologic function independent of transfusion and growth factor support for at 
least 7 days (with the exception of pegylated G-CSF [pegfilgrastim] and darbopoeitin which 
require at least 14 days) prior to screening laboratory assessment defined as:

Absolute neutrophil count (ANC) >750 cells/µL (750 cells/mm3 or 0.75 x 109/L)

Platelet count >30,000/µL (30,000 cells/mm3 or 30 x 109/L)

Hemoglobin >8.0 g/dL
5. Adequate hepatic and renal function defined as:

Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤3.0 x upper limit of 
normal (ULN)

Creatinine Clearance (CrCl) ≥60 mL/min (eg, as estimated by Cockcroft-Gault)

Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic 
origin)
6. 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).
Demographic
7. Men and women ≥18 and ≤70 years of age.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.


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Ethical/Other
9. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no 
menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR 
history of bilateral oophorectomy). Female subjects of reproductive potential must have a 
negative serum pregnancy test upon study entry.
10. 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, condom, cervical ring, sponge, etc.) during the period of therapy and for 90 days after 
the last dose of study drug. Male subjects must agree to refrain from sperm donation until 
90 days after the last dose of study drug.
4.2.
Exclusion Criteria
To be enrolled in the study, potential subjects must meet NONE of the following exclusion 
criteria:
1. Any prior therapy (including but not limited to chemotherapy, targeted therapy, 
immunomodulating therapy, radiotherapy, and/or monoclonal antibody) used for treatment of 
CLL or SLL.
2. 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 the 
treating physician

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease

Adequately treated carcinoma in situ without evidence of disease
3. Known or suspected history of Richter’s transformation.
4. Concurrent administration of >20 mg/day of prednisone within 7 days of initiation of study 
drug unless indicated for prophylaxis or management of allergic reactions (eg, contrast).
5. Known hypersensitivity to one or more study drugs.
6. Known allergy to xanthine oxidase inhibitors and/or rasburicase. Subjects who are allergic to 
xanthine oxidase inhibitors and cannot receive rasburicase will be excluded.
7. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
8. Recent infection requiring systemic treatment that is ongoing or was completed ≤14 days 
before the first dose of study drug, or any uncontrolled active systemic infection.
                                               
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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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 infection 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.
12. Major surgery within 4 weeks of 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 enrollment.
15. Unable to swallow capsules/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. Concomitant use of warfarin or other vitamin K antagonists.
17. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix G).
18. Currently active, clinically significant hepatic impairment Child-Pugh Class B or C 
according to the Child Pugh classification (Appendix K).
19. Lactating or pregnant.
20. Unwilling or unable to participate in all required study evaluations and procedures.
21. 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).
22. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, such 
as those subjects with a declining hemoglobin level or platelet count secondary to 
autoimmune destruction within the 4 weeks prior to first dose of study drug, or the need for 
daily prednisone >20 mg daily (or corticosteroid equivalent) to treat or control the 
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5.
TREATMENT OF SUBJECTS
MRD Cohort
5.1.
Treatment Allocation and Blinding
Eligible subjects will be enrolled to a pre-randomization phase and receive open-label ibrutinib 
capsules and venetoclax tablets (single-agent ibrutinib for 3 cycles followed by ibrutinib + 
venetoclax combination treatment for at least 12 cycles). Subjects will then be randomized by 
two separate schemes according to MRD status.
Subjects who achieve confirmed MRD-negative response and who continue ibrutinib will be 
randomized to receive double blind study treatment with either placebo or ibrutinib; Subjects 
who do not achieve confirmed MRD-negative response and who continue both study drugs will 
be randomized to receive open label treatment either single-agent ibrutinib or ibrutinib + 
venetoclax combination treatment. In each scheme, the randomization will be in 1:1 ratio and 
stratified by IGHV status.
5.2.
Safety Run-in Period
Approximately 12 subjects will be enrolled in a Safety Run-in Period, defined as the date of first 
dose of ibrutinib at Cycle 1 Day 1 through the DLT evaluation period. The DLT evaluation 
period is defined as the 5-week venetoclax dose ramp-up in combination with ibrutinib, plus an 
additional week of follow-up (6 weeks total). Enrollment will be held until safety is assessed by 
the DRC in the first 6 evaluable subjects who complete the Safety Run-in Period. Subjects will 
be considered evaluable for DLT assessment if they receive at least 85% of the combined 
therapy at the targeted doses during the DLT evaluation period, or if they experience a DLT after 
the first venetoclax dose. Subjects’ laboratory results and AEs will be reviewed by the DRC. If 
≤1 of the first 6 evaluable subjects experience a DLT, the study will continue. If 2 of the first 
6 evaluable subjects experience a DLT, then the DRC will evaluate safety in the next 3 evaluable 
subjects (9 subjects total). The study will be deemed safe to proceed when 6–9 subjects complete 
the Safety Run-in Period and if <33% (≤1 of 6 or ≤2 of 9) of subjects experience a DLT.
Enrollment will be staggered to no more than 3 subjects per week during the Safety Run-in 
Period in order to minimize patient exposure and risk during this initial run in period.
All subjects will be assessed for TLS risk prior to initiation of venetoclax. See Section 7.1.1.9
and Section 7.1.1.10 for TLS risk assessment and prophylaxis respectively. Any case of clinical 
TLS (See Appendix H for TLS criteria) during the Safety Run-in Period will trigger a DRC 
review of that subject. The DRC will meet and review safety data after all subjects in the Safety 
Run-in Period have either discontinued therapy and/or have completed the DLT evaluation 
period (venetoclax dose ramp-up plus 1-week follow-up), then DRC may make a 
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5.2.1.
Dose-Limiting Toxicity (DLT)
Dose-limiting toxicities (DLT) are defined as clinical TLS per the Howard Criteria (Appendix I) 
or any new CTCAE Grade 3 or higher possibly related non-hematologic or Grade 4 hematologic 
adverse event occurring during the DLT evaluation period (defined as the 5-week venetoclax 
dose ramp-up plus 1-week follow-up) with the additional clarifications below (which will be 
considered DLTs): 
Non-hematologic:

Grade 4 diarrhea and vomiting

Grade 3 nausea, vomiting or diarrhea despite maximum medical supportive care and 
persisting >3 days

Grade 3 fatigue persisting >7 days

Grade 3 rash lasting >7 days that does not resolve with appropriate clinical management
Hematologic (per IWCLL Criteria, Appendix L):

Grade 4 neutropenia (ANC <500 µL) lasting for >7 days duration (irrespective of 
adequate growth factor support)

Grade 4 thrombocytopenia that persists for >7 days

Grade 3 thrombocytopenia associated with clinically significant bleeding
If 2 of the first 6 evaluable subjects experience a DLT, then the DRC will evaluate safety in the 
next 3 evaluable subjects. If 3 or more of the 9 subjects experience DLTs, the DRC may 
recommend the dose of the study drug(s) to be de-escalated as shown in Table 1. However, if 
DLTs occur at a lower dose of venetoclax, the DRC may recommend that the protocol be 
amended to adjust the venetoclax dose ramp-up (eg, starting dose or length of ramp-up). If 
modifications are made to the treatment schedule or dose to mitigate dose-limiting toxicity based 
on the number of DLTs during the Safety Run-in Period, safety data will be further assessed in 
an additional 6 evaluable subjects, until the DRC can make a recommendation (provides 
recommended doses for the combination). 
Table 1.
Dose De-Escalation Schedule for Safety Run-in
Dose Level
Ibrutinib Daily dose
Venetoclax (Target dose)
0
420 mg
400 mg
-1
420 mg
300 mg
-2
280 mg
300 mg




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Venetoclax: 

Orally once daily venetoclax, with 5-week dose ramp up, added to ongoing ibrutinib 
therapy starting at Cycle 4 and continued for at least 12 cycles till completion of 
Cycle 16, utilizing the dose ramp-up schedule in Section 5.4.2.3 and Figure 1.
Figure 1.
Venetoclax Dose Ramp-up

Venetoclax and ibrutinib should be dosed together at the same time with a meal and 
water.
○
For subjects not able to swallow all ibrutinib capsules and venetoclax pills at the same 
time, administration should be completed within a 60-minute window. On days of PK 
sample collection (C2D1 and C6D1), ibrutinib and venetoclax should be administered 
at the same time or as close together in time as possible.

Dose modification for adverse events are specified in Section 5.4.2.5
5.3.2.
Randomization Phase
Subjects will be randomized in a 1:1 ratio based on their MRD status (see below) after at least 
12 cycles of ibrutinib + venetoclax combination therapy. Subjects will be stratified by IGHV 
status in each randomization strata.
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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5.3.2.1.
Randomization Phase – MRD-negative Subjects (Double-blind)
In the Randomization Phase, subjects who are MRD-negative will be randomized in a blinded 
fashion to ibrutinib or placebo.
Ibrutinib

Orally once daily ibrutinib 420 mg (3 capsules) continuously until disease progression
(post reintroduction when applicable) or unacceptable toxicity
OR
Placebo

Orally once daily matching placebo capsules (3 capsules) continuously until confirmed 
MRD-positive relapse, disease progression, or unacceptable toxicity
5.3.2.2.
Randomization Phase – MRD-Positive Subjects (Open-Label)
In the Randomization Phase, subjects who do not achieve confirmed MRD-negative response
(MRD-positive) will be randomized to receive open label treatment of I+V vs ibrutinib alone 
(venetoclax discontinued). For subjects receiving I+V, venetoclax can be administered for up to 
approximately 2 years per treatment course, until PD or unacceptable toxicity, or until this arm’s 
study closure, whichever is earlier. Subjects continuing on ibrutinib at time of study arm closure 
may be offered a separate extension study to continue ibrutinib. The randomization will be 
stratified by IGHV status.
Ibrutinib + Venetoclax

Orally once daily ibrutinib 420 mg (3 capsules) continuously until disease progression or 
unacceptable toxicity
plus

Orally once daily venetoclax 400 mg (four 100 mg tablets) 
OR
Ibrutinib

Orally once daily ibrutinib 420 mg (3 capsules) continuously until disease progression or 
unacceptable toxicity
Reintroduction of Ibrutinib or Venetoclax (MRD Cohort)
Upon confirmed MRD-positive relapse in MRD-negative randomized subjects or confirmed 
disease progression by IWCLL criteria in any randomized subjects, ibrutinib and/or venetoclax 
may be reintroduced (Figure 2).


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Subjects who are receiving placebo treatment, when MRD-positive relapse or disease 
progression are confirmed, may reintroduce oral daily ibrutinib until disease progression or 
unacceptable toxicity.
Subjects who are receiving oral daily ibrutinib, when MRD-positive relapse or disease 
progression are confirmed, may reintroduce oral daily venetoclax. Standard TLS risk assessment, 
venetoclax dose ramp up, and TLS management should be employed at venetoclax 
reintroduction.
For those subjects who were treated with reduced dose(s) of ibrutinib or venetoclax during the 
Pre-randomization or Randomization Treatment Phase, a dose adjustment at the initiation of the 
Reintroduction period may be required, with escalation to full dose as tolerated.
The primary analysis for the MRD cohort will be performed at the point that all randomized 
subjects have had the opportunity to complete at least 12 cycles of randomized treatment or 
follow-up, and at that time the Sponsor may elect to discontinue follow-up of specific MRD 
cohort treatment arms on PCYC-1142-CA. For subjects receiving I+V, venetoclax can be 
administered for up to approximately 2 years per treatment course, until PD or unacceptable 
toxicity, or until these arm’s study closure, whichever is earlier. Subjects who are continuing on 
ibrutinib at the time of study arm closure may be offered a separate extension study to continue 
ibrutinib.
Figure 2.
Reintroduction of Ibrutinib or Venetoclax for MRD Cohort
5.3.3.
Fixed Duration Cohort
Eligible subjects will receive single-agent ibrutinib (420 mg/day PO) as lead-in treatment for 
3 cycles. Starting at Cycle 4, venetoclax will be initiated (with the standard dose ramp up to the 
target dose of 400 mg/d) utilizing the dose ramp-up schedule in Section 5.4.2.3 Figure 1 and 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 


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added to the ibrutinib (420 mg/day PO) regimen. The combination will be administered
continuously for 12 cycles, until completion of Cycle 15 unless discontinued early for toxicity.

Venetoclax and ibrutinib should be dosed together at the same time each day with a meal 
and water
○
For subjects not able to swallow all ibrutinib capsules and venetoclax pills at the same 
time, administration should be completed within a 60-minute window. 
Dose modification for adverse events are specified in Section 5.4.2.5.
NOTE: If dictated by emerging data from this study, the duration of combined ibrutinib + venetoclax 
treatment may be modified to ensure appropriate risk-benefit is maintained, compared to historical 
controls and other emerging data. 
Reintroduction of Ibrutinib or Ibrutinib + Venetoclax (FD Cohort):
Subjects with confirmed progression per IWCLL criteria after completion of the fixed duration 
regimen can be retreated with continuous single agent ibrutinib until disease progression or 
unacceptable toxicity because it is an established standard of care for treatment of relapsed CLL. 
For subjects that experience durable efficacy after I+V (ie, time to progression after fixed 
duration regimen is completed of >2 years), retreatment with the I+V fixed duration treatment 
regimen may be considered based on Investigator’s clinical discretion and Medical Monitor’s 
approval. Retreatment is for 15 cycles, PD or unacceptable toxicity, whichever is earlier
(Figure 3).
For those subjects who were treated with reduced dose(s) of ibrutinib or venetoclax during the 
fixed duration treatment phase, a dose adjustment at the initiation of the Reintroduction period
may be required, with escalation to full doses as tolerated.
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 




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should be taken together at the same time, with 8 ounces of water and with a meal (or within 
30 minutes after the completion of a meal). For subjects not able to swallow all ibrutinib 
capsules and venetoclax tablets at the same time, administration should be completed within a 
60-minute window. The use of strong CYP3A inhibitors/inducers, and grapefruit, Seville 
oranges, and starfruit should be avoided for the duration of the study (Appendix G).
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.
The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is typically 
on an outpatient basis. On days of PK sample collection (C2D1 and C6D1), ibrutinib and 
venetoclax should be administered at the same time or as close together in time as possible in the 
clinic. Ibrutinib will be dispensed to subjects in bottles at each visit. Unused ibrutinib dispensed 
during previous visits must be returned to the site and drug accountability records (Section 12.8) 
updated at each visit. Returned capsules must not be redispensed to anyone.
5.4.1.3.
Overdose
Any dose of study drug administered in excess of that specified in this protocol is considered to 
be an overdose. Signs and symptoms of an overdose that meet any SAE criterion must be 
reported as a SAE in the appropriate time frame and documented as clinical sequelae to an 
overdose.
There is no specific experience in the management of ibrutinib overdose in subjects. No 
maximum tolerated dose (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 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 11.4 for further information regarding AE reporting. 
5.4.1.4.
Dose Modification for Adverse Reactions
The dose of study drug must be modified according to the dose modification guidance in Table 2
and Table 3 if any of the following 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. 

Grade 3 thrombocytopenia (platelets <50,000/µL) in the presence of clinically significant 
bleeding events.

Grade 4 thrombocytopenia (platelets <25,000/µL).


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
Grade 3 or greater non-hematological toxicity (Note: Table 3 includes recommendations 
for cardiac failure and cardiac arrhythmias)

Grade 2 cardiac failure (Table 3)

Any other Grade 4 or unmanageable Grade 3 hematological toxicity.
If clinically indicated, the use of anticoagulants or antiplatelet agents may be considered for the 
thromboprophylaxis of atrial fibrillation (Section 6.2.4).
In the event that the investigator feels deviation from the recommendations above is required, 
please consult the Medical Monitor.
Dose changes must be recorded in the Dose Administration eCRF. Study treatment should be 
discontinued in the event of an ibrutinib-related toxicity requiring dose hold lasting more than 
28 days, unless reviewed and acknowledged by the Medical Monitor.
Note: Temporary withholding of single-agent ibrutinib for as little as 7 days can cause a transient 
worsening of disease and/or of constitutional symptoms. Study drug should be re-started as soon 
as clinically appropriate.
Table 2.
Ibrutinib/ Placebo Dose Modifications for Events not Specified in Table 3
Occurrence
Action to be Taken 
First
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at original 
dose levela
Second
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower
(ie, 280 mg/day for 420 mg/day dose)
Third
Withhold study drug until recovery to Grade ≤1 or baseline; may restart at 1 dose level 
lower
(ie, 140 mg/day for 420 mg/day dose)
Fourth
Discontinue study drug
a.
When resuming treatment, restart at the same or lower dose based on benefit-risk evaluation. If the toxicity reoccurs, reduce 
daily dose by 140 mg.
For required dose modification for hepatic impairment refer to Section 5.4.1.6 and for 
concomitant treatment with CYP3A inhibitors refer to Section 6.2.1.1.


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Table 3.
Ibrutinib/Placebo 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 (2 capsules [ie, 280 mg daily])
Second
Hold study drug until recovery to Grade ≤ 1 or baseline; restart 
at 1 dose level lower (1 capsules [ie, 140 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 (2 capsules [ie, 280 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.
5.4.1.5.
Leukocytosis/Leukostasis
A high number of circulating malignant cells (>400,000/µL) may confer increased risk of 
leukostasis; these subjects should be closely monitored. Administer supportive care such as 
hydration and/or leukophoresis as indicated. Ibrutinib may be temporarily held, and Medical 
Monitor should be contacted.
5.4.1.6.
Dose Modification for Hepatic-Impaired Subjects
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant hepatic 
impairment at the time of screening (Child-Pugh Class B or C) are excluded from study 
participation. For subjects who develop mild liver impairment while on study (Child-Pugh 
Class A), the recommended dose reduction for ibrutinib/placebo is to a level of 280 mg daily 
(two capsules). For subjects who develop moderate liver 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. Monitor subjects for signs of 
toxicity and follow dose modification guidance as needed (Refer to Appendix K).
5.4.2.
Venetoclax (ABT-199)
5.4.2.1.
Formulation/Packaging/Storage 
Venetoclax tablets are provided as film coated tablets containing 10 mg, 50 mg, or 100 mg of 
venetoclax. 
The venetoclax tablets will be packaged in blister packs during initial dose ramp up period and in 
high density polyethylene (HDPE) plastic bottles thereafter to accommodate the study design. 


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Each container will be labeled as required per country requirements. Labels must remain affixed 
to the container.
The venetoclax 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 Pharmacyclics or 
representative.
The tablets must be stored at a controlled room temperature of 15° to 25°C (59° to 77°F).
5.4.2.2.
Prophylaxis and Management of Tumor Lysis Syndrome 
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-week 
ramp-up phase. 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 tumor burden and 
comorbidities. Subjects with high tumor burden are 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.
Subjects at high risk of TLS (at least one lesion ≥10 cm; or at least one lesion ≥5 cm plus
circulating lymphocytes >25,000 cells/µL) will be hospitalized during the first 24-48 hours of 
treatment for TLS monitoring and hydration. Hospitalization should be considered for subjects 
with medium risk of TLS and baseline creatinine clearance <80 mL/min. Hospitalization for 
subjects lacking immediate access to a facility capable of correcting TLS promptly or for 
subjects who are otherwise considered at risk for TLS is allowed at the discretion of the 
investigator.
In all subjects, perform tumor burden assessments, including radiographic evaluation (eg, CT 
scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) and 
correct pre-existing abnormalities prior to initiation of treatment with venetoclax in Cycle 4.
In all subjects, assess patient-specific factors for level of risk of TLS and provide prophylactic 
hydration and anti-hyperuricemics to subjects prior to first dose of venetoclax to reduce risk of 
TLS. Employ more intensive measures (intravenous hydration, frequent monitoring, and 
hospitalization) as overall risk increases. 


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Table 4.
TLS Prophylaxis Based on Tumor Burden from Clinical Trial Data 
(consider all co-morbidities before final determination of prophylaxis and 
monitoring schedule)
Tumor Burden
Prophylaxis
Blood Chemistry Monitoringc,d
Hydrationa
Anti-
hyperuricemics
Setting and Frequency of
Assessments
Low
All LN <5 cm AND 
ALC <25 x109/L
Oral (1.5-2 L)
Allopurinolb
Outpatient

Pre-dose, 6 to 8 hours, 24 hours at 
first dose of 20 mg and 50 mg

Pre-dose at subsequent ramp-up 
doses
Medium
Any LN 5 cm to 
<10 cm
OR
ALC ≥25 x109/L
Oral (1.5-2 L) 
and consider 
additional 
intravenous
Allopurinolb
Outpatient

Pre-dose, 6 to 8 hours, 24 hours at 
first dose of 20 mg and 50 mg

Pre-dose at subsequent ramp-up 
doses

Consider hospitalization for 
subjects with CrCl <80mL/min at 
first dose of 20 mg and 50 mg; see 
below for monitoring in hospital
High
Any LN ≥10 cm
OR
ALC ≥25 x109/L
AND
any LN ≥5 cm 
Oral (1.5-2 L) 
and intravenous 
(150-200 mL/hr 
as tolerated)
Allopurinolb; 
consider 
rasburicase if 
baseline uric acid 
is elevated
In hospital at first dose of 20 mg and 
50 mg

Pre-dose, 4, 8,12 and 24 hours
Outpatient at subsequent ramp-up 
doses

Pre-dose, 6 to 8, and 24 hours
ALC = absolute lymphocyte count; LN = lymph node
a.
Administer intravenous hydration for any patient who cannot tolerate oral hydration.
b.
Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax.
c.
Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time.
d.
For subjects at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose.
A ±30-minute window is acceptable for the 4 and 8 hr chemistry assessments, a ±1 hr window is acceptable for the 12-hour 
chemistry assessments, and a ±2-hour window is acceptable for the 24-hour chemistry assessments.
e.
Hematology and Serum Chemistry may be collected up to 24 hours prior to each venetoclax ramp-up (Cycle 4 Weeks 2-4 
and Cycle 5 Week 1), to allow for flexibility in start of ramp-up dose.  Hematology and serum chemistry can be drawn on 
day of dosing to allow for comparisons, but results are not required before dosing decision is made
Hydration: Ensure adequate hydration prior to initiating therapy with venetoclax and throughout 
the ramp-up phase, especially 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 uric acid reducing agents (eg, allopurinol).
Start 2-3 days prior to initiation of venetoclax; consider continuing through the ramp-up phase. 
Laboratory Assessments:
Pre-dose: Assess blood chemistries (specifically creatinine, uric acid, potassium, phosphorus, 
and calcium) prior to initiating venetoclax to evaluate kidney function and correct pre-existing 
hyperuricemia, hyperkalemia, hyperphosphatemia, or hypocalcemia to normal levels before 


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administering venetoclax. Reassess blood chemistries before starting each subsequent ramp-up 
dose of venetoclax.
Post-dose: For subjects at low or medium risk of TLS, monitor blood chemistries at 6-8 hours 
and at 24 hours after initiating venetoclax at the 20 mg and 50 mg doses. For subjects at high risk 
of TLS, monitor blood chemistries in the hospital at 4, 8, 12, and 24 hours after initiating 
venetoclax at the 20 mg and 50 mg doses; subsequent ramp-up doses can be administered in the 
outpatient setting with monitoring of blood chemistries at 6-8 hours and at 24 hours after 
initiating venetoclax. Electrolyte abnormalities should be corrected promptly. The next dose of 
venetoclax should not be administered until the 24-hour blood chemistry results have been 
evaluated and hyperuricemia, hyperkalemia, hyperphosphatemia, or hypocalcemia are corrected 
to normal levels.
Hospitalization: Based on investigator assessment of TLS risk, subjects at high risk of TLS 
require hospitalization on the day of the first dose of venetoclax 20 mg and 50 mg doses for more 
intensive prophylaxis and monitoring through the first 24 hours. Subsequent ramp-up doses can 
be administered on an outpatient basis; however, hospitalization may be considered based on 
reassessment of risk. See Appendix H for TLS Risk Categories and Appendix J for
Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of Tumor 
Lysis.
5.4.2.3.
Dose and Administration 
Venetoclax tablets are taken orally once daily with a meal and water. Venetoclax tablets should 
be swallowed whole and not chewed, crushed, or broken prior to swallowing. During cycles with 
ibrutinib combination dosing, ibrutinib and venetoclax should be taken together at the same time, 
with 8 ounces of water and with a meal (or within 30 minutes after the completion of a meal). 
For subjects not able to swallow all ibrutinib capsules and venetoclax tablets at the same time, 
administration should be completed within a 60-minute window. If the subject misses a dose of 
venetoclax 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 dose by more than 8 hours, the subject should not take the missed dose and resume the 
usual dosing schedule the following day.
In cases of vomiting after taking venetoclax, no additional dose (tablets) should be taken that 
day. The next dose should be taken at the usual time the following day.
The first dose of venetoclax will be delivered in the clinic (or in the hospital depending on TLS 
risk category) on Cycle 4 Day 1. Seven doses of daily venetoclax must be taken at each dose 
level in the venetoclax dose ramp up, thus each level of the ramp up may require more than 
7 days if doses are missed or held. After completion of the 5-week dose ramp up, subsequent 
dosing is typically on an outpatient basis. On days of PK sample collection (C2D1 and C6D1), 
ibrutinib and venetoclax should be administered at the same time or as close together in time as 
possible in the clinic. Venetoclax will be dispensed to subjects in blister packs through the dose 


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ramp up period, and in bottles at each subsequent visit. Unused venetoclax dispensed during 
previous visits must be returned to the site and drug accountability records (Section 12.8) 
updated at each visit. Returned tablets must not be redispensed to anyone.
Assess subject-specific factors for level of risk of TLS and provide prophylactic hydration and 
anti-hyperuricemics to subjects prior to first dose of venetoclax to reduce risk of TLS. 
Venetoclax will be administered orally once daily (QD) beginning with a dose ramp-up period.  
As shown in Figure 1, the initial venetoclax dose is 20 mg QD. After one week of treatment at 
20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent increases, each after 
one week, to 100 mg QD, 200 mg QD and the maximum dose of 400 mg QD. The 5-week ramp-
up dosing schedule is designed to gradually reduce tumor burden (debulk) and decrease the risk 
of TLS. All study subjects will be categorized in Cycle 3 according to their risk for developing 
TLS. Their dose management including during the dose ramp-up period will be conducted in 
accordance with their risk for developing TLS (see Section 5.4.2.5) and may include dose delay 
and/or dose reduction as required for prophylaxis and management of TLS.
5.4.2.4.
Overdose
There is no specific antidote for venetoclax. For subjects who experience overdose, closely 
monitor and provide appropriate supportive treatment; during ramp-up phase interrupt 
venetoclax and monitor carefully for signs and symptoms of TLS along with other toxicities (see 
Section 1.3.3 and Section 5.4.2). Based on venetoclax large volume of distribution and extensive 
protein binding, dialysis is unlikely to result in significant removal of venetoclax.
5.4.2.5.
Dose Modification for Adverse Reactions
Dosing interruption and/or dose reduction may be required. See Table 5 for dose modifications 
for hematologic and other toxicities related to venetoclax. For subjects who have had a dosing 
interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 
2 weeks when at the daily dose of 400 mg, 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).


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Table 5.
Venetoclax Recommended Dose Modifications for Toxicitiesa
Event
Occurrence 
Action
Tumor Lysis Syndrome
Blood chemistry 
changes or symptoms 
suggestive of TLS (see 
Howard Criteria in 
Appendix I)
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 TLSb, resume at a reduced 
dose following resolution (see Table 6).
Non-Hematologic Toxicities
Grade 3 or 4 non-
hematologic toxicities 
1st occurrence 
Interrupt venetoclax
Once the toxicity has resolved to Grade 1 or baseline 
level, venetoclax therapy may be resumed at the same 
dose. No dose modification is required. 
2nd and 
subsequent 
occurrences 
Interrupt venetoclax.
Follow dose reduction guidelines in Table 6 when 
resuming treatment with venetoclax after resolution. A 
larger dose reduction may occur at the discretion of the 
investigator
Hematologic Toxicities
ANC <1000/µL with 
infection or fever; or 
CTCAE Grade 4 
hematologic toxicities 
(ANC <500/µL, WBC 
<1000/µL, platelets 
<25,000/µL, life 
threatening anemia)
1st occurrence 
Interrupt venetoclax.
To reduce the infection risks associated with 
neutropenia, granulocyte-colony stimulating factor 
(G-CSF) may be administered with venetoclax if 
clinically indicated. Once the toxicity has resolved to 
ANC >1500/µL or baseline level, venetoclax therapy 
may be resumed at the same dose.
2nd and 
subsequent 
occurrence 
Interrupt venetoclax.
Consider using G-CSF as clinically indicated.
Follow dose reduction guidelines in Table 6 when 
resuming treatment with venetoclax after resolution. 
Additional dose reductions may occur at the discretion 
of the physician.
Consider discontinuing venetoclax for subjects who require dose reductions to less than 100 mg for more than 2 weeks.
a.
Adverse reactions were graded using NCI CTCAE version 4.03.
b.
Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or 
sudden death and/or seizures.
Table 6.
Dose Modification for Toxicity during Venetoclax Treatment
Dose at Interruption, mg
Restart Dose, mga
400
300
300
200
200
100
100
50
50
20
20
10
a.
During the ramp-up phase, continue the reduced dose for 1 week before increasing the dose.


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For required dose modification for concomitant treatment with CYP3A inhibitors refer to 
Section 6.2.1.2.
5.4.2.6.
Management of Neutropenia
Nonclinical and clinical experience indicates that venetoclax may cause neutropenia. Subjects 
with a history of neutropenia who have received multiple prior therapies and/or have significant 
bone marrow involvement may be at a particularly high risk.
CTCAE Grade 3 or 4 neutropenia has been reported in patients treated with venetoclax. 
Complete blood counts should be monitored throughout the treatment period. Dose interruptions 
or dose reductions are recommended for subjects with severe neutropenia. Supportive measures 
including antimicrobials for any signs of infection and prophylactic use of growth factors 
(eg, G-CSF) should be considered.
5.4.2.7.
Management of Hematologic Toxicities Other Than Neutropenia or 
Lymphopenia 
Venetoclax treatment should be withheld for any CTCAE Grade 4 hematologic toxicity. Once 
the toxicity has resolved to Grade 1 or baseline level (recovery), venetoclax may be re-started at 
the same dose. If the toxicity recurs, the dose reduction guidelines in Table 5 should be followed 
when resuming study treatment following resolution. Additional dose reductions may occur at 
the discretion of the physician.
5.4.2.8.
Management of Non-Hematologic Toxicity
Venetoclax treatment should be withheld for any clinically relevant CTCAE Grade ≥3 non-
hematologic toxicity. Once the toxicity has resolved to Grade 1 or baseline level (recovery), 
venetoclax may be re-started at the same dose.  If the toxicity recurs, the dose reduction 
guidelines in Table 5 should be followed when resuming study treatment following resolution. 
Additional dose reductions may occur at the discretion of the physician.
5.4.2.9.
Management of Decrease in Spermatogenesis
Venetoclax may cause a decrease in spermatogenesis. Male subjects considering preservation of 
fertility should bank sperm before initiating treatment with venetoclax.
5.4.2.10.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings in animals, venetoclax may cause embryo-fetal 
harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice, 
administration of venetoclax to pregnant animals at exposures equivalent to that observed in 
patients at the recommended dose of 400 mg daily resulted in post-implantation loss and 
decreased fetal weight. There are no adequate and well-controlled studies in pregnant woman 
using venetoclax. Advise females of reproductive potential to avoid pregnancy during treatment. 


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If venetoclax is used during pregnancy or if the subject becomes pregnant while taking 
venetoclax, the subject should be apprised of the potential hazard to the fetus.
5.4.2.11.
Immunization 
The safety and efficacy of immunization with live or attenuated viral vaccines during or 
following venetoclax therapy have not been studied. Immunization with live virus vaccines is not 
recommended during treatment and thereafter until B-cell recovery.
5.5.
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. If a subject discontinues one study drug for reasons other than disease 
progression, the other study drug should be continued per protocol. Refer to Study Design details 
in Section 3.1.1 and Section 3.1.2. For a complete list of criteria for permanent discontinuation of 
study treatment, refer to Section 9.2.
An End-of-Treatment Visit (Section 8.7) is required for all subjects except for those subjects 
who have withdrawn full consent.
6.
CONCOMITANT MEDICATIONS/PROCEDURES
Concomitant therapies must be recorded from the time of ICF signing until 30 days after the last 
dose of study drug.
6.1.
Permitted Concomitant Medications
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted and patient should receive full supportive care during study participation (including 
fluids and electrolyte replacement, and antibiotics when appropriate). Use of neutrophil growth 
factors (filgrastim and pegfilgrastim) or red blood cell growth factors (erythropoietin) is 
permitted per institutional policy and in accordance with the ASCO guidelines (Smith 2006)
except as outlined in Section 6.2 below. Transfusions may be given in accordance with 
institutional policy.
After consultation with the Medical Monitor the following may be considered; localized,
hormonal or bone sparing treatment for non-B-cell malignancies, and localized radiotherapy for 
medical conditions other than the underlying B-cell malignancies.
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 do 
not exceed 100 mg per day of prednisone or equivalent are permitted.


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Treatment for autoimmune cytopenias are permitted for <14 days at doses that do not exceed 
100 mg per day of prednisone or equivalent.
6.2.
Medications to Be Used with Caution
A sample list of cautionary medications with ibrutinib and venetoclax is provided in
Appendix G. Refer to Table 7 below for management of potential ibrutinib and venetoclax 
interactions with CYP3A inhibitors.
6.2.1.
Drugs That May Alter Ibrutinib and/or Venetoclax Plasma Concentrations
6.2.1.1.
Concomitant Use with Ibrutinib
Ibrutinib is metabolized primarily by CYP3A4. Avoid co-administration with strong CYP3A or 
moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. Avoid 
grapefruit and Seville oranges during ibrutinib/placebo treatment, as these contain moderate 
inhibitors of CYP3A (see Section 5.4.1.2).

If a strong CYP3A inhibitor must be used short-term (such as anti-infectives for seven 
days or less), interrupt ibrutinib for the duration of inhibitor use.

If a strong CYP3A inhibitor must be used, the benefit outweighs the risk, and longer term 
dosing is required (for more than 7 days), reduce ibrutinib dose to 140 mg for the 
duration of inhibitor use. 
o
If posaconazole at higher doses (suspension >200 mg twice daily), or IV or 
delayed-release formulations must be used, reduce ibrutinib dose to 140 mg for 
the duration of azole use

If a moderate CYP3A inhibitor must be used, reduce ibrutinib to 280 mg for the duration 
of the inhibitor use.
o
If voriconazole, or doses ≤200 mg twice daily of posaconazole suspension are 
required, reduce ibrutinib dose to 140 mg for the duration of inhibitor use.

No dose adjustment is required in combination with mild inhibitors.

Subjects should be monitored closely for signs of ibrutinib toxicity

After discontinuation of a CYP3A inhibitor, resume previous dose of ibrutinib
Avoid concomitant use of strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, and 
St. John’s Wort) as these medications/products could decrease ibrutinib concentrations. Consider 
alternative agents with less CYP3A induction.
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp).
A list of common CYP3A inhibitors and inducers is provided in Appendix G. For further 
information, please refer to the current version of the ibrutinib IB.


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6.2.1.2.
Concomitant Use with Venetoclax

Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during 
ramp-up phase increases the risk for TLS. Concomitant use of venetoclax with strong 
CYP3A inhibitors at initiation and during ramp-up phase is contraindicated. 

For subjects who have completed the ramp-up phase and are on a steady daily dose of 
venetoclax, reduce the venetoclax dose by at least 75% when used concomitantly with a 
strong CYP3A inhibitor. See Section 6.3.1 for prohibited CYP3A inhibitors.

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 by at least 50%. Monitor subjects more closely for signs of toxicities.

Avoid concomitant use of strong CYP3A inhibitors with venetoclax. Consider alternative 
treatments. If a strong CYP3A inhibitor must be used, reduce the doses of venetoclax by 
at least 75%. Monitor subjects more closely for signs of toxicities.
Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor 2 to 3 days 
after discontinuation of the inhibitor.
A list of common CYP3A inhibitors, CYP3A inducers, and cautionary medications is provided 
in Appendix G.
For preliminary venetoclax PK results with concurrent ibrutinib administration, see 
Section 1.3.2.1. For further information, please refer to the current version of the venetoclax IB.
Table 7.
Management of Potential Ibrutinib and Venetoclax Interactions with 
CYP3A Inhibitors
Inhibitors
Venetoclax
Ibrutinib
Initiation and
Ramp-up Phase
Steady Daily Dose
(After Ramp-up Phase)
At any time
Strong CYP3A 
Inhibitor
Contraindicated
Avoid inhibitor use, 
consider alternate. 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 280 mg
6.2.2.
Drugs That May Have Their Plasma Concentrations Altered by Ibrutinib
In vitro studies indicated that ibrutinib is not a substrate of P-glycoprotein (P-gp), but is a mild 
inhibitor. Ibrutinib is not expected to have systemic drug-drug interactions with P-gp substrates. 


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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. 
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, co-administration 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.
6.2.4.
Antiplatelet Agents and Anticoagulants
Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
Supplements such as fish oil and vitamin E preparations should be avoided. In an in vitro platelet 
function study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation were 
observed. Use of ibrutinib in subjects requiring other anticoagulants or medications that inhibit 
platelet function may increase the risk of bleeding. Subjects with congenital bleeding diathesis 
have not been studied. For guidance on ibrutinib and the use of anticoagulants during 
procedures/surgeries see Section 6.4.
Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation),
consider the risks and benefits of continuing ibrutinib treatment. If therapeutic anticoagulation is 
clinically indicated, treatment with ibrutinib should be held and not be restarted until the subject 
is clinically stable and has no signs of bleeding. Subjects should be observed closely for signs 
and symptoms of bleeding. No dose reduction is required when study drug is restarted.
In a drug-drug interaction study in healthy subjects, administration of a single dose of venetoclax 
with warfarin resulted in an 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.
6.3.
Prohibited Concomitant Medications and Products
6.3.1.
Prohibited Concomitant Medications and Products for Ibrutinib and/or 
Venetoclax
Any non-study protocol related chemotherapy, anti-cancer immunotherapy, experimental 
therapy, or radiotherapy for the underlying B-cell malignancy 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.
Use of strong CYP3A inhibitors is contraindicated during venetoclax initiation and dose 
ramp-up. Subjects may not consume grapefruit or grapefruit products, Seville oranges (including 
marmalade containing Seville oranges) or starfruit within the 3-day period prior to the first 
venetoclax administration and until the last day of treatment is completed due to possible 
CYP3A mediated metabolic interaction.
6.4.
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:
6.4.1.
Minor Surgical Procedures
For minor procedures (such as a central line placement, needle biopsy, lumbar puncture [other 
than shunt reservoir access], thoracentesis, or paracentesis) 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.
6.4.2.
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 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.
6.4.3.
Emergency Procedures
For emergency procedures, ibrutinib should be held as soon as possible and until the surgical site 
is reasonably healed or for at least 7 days after the urgent surgical procedure, whichever is 
longer.


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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 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 prior to first dose on Day 1
(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. The medical history collection period is defined as disease history up 
until first dose. Concurrent medical signs and symptoms must be documented to establish 
baseline severities. A disease history, including the date of initial diagnosis, Rai staging 
(Appendix M) within 28 days of first dose with study drug will be recorded.
7.1.1.4.
Prior and Concomitant Medications
All active medications from the signing of ICF or at least 14 days prior to 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 adverse event (AE) is provided in Section 11.1. The 
occurrence of AE from 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
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 designated clinically significant by the investigator 
will also be documented as 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.
7.1.1.7.
ECOG
The ECOG performance status is provided in Appendix F. Performance status will only be 
collected until disease progression.
7.1.1.8.
Vital Signs
Vital signs will include blood pressure, heart rate, and body temperature after the subject has 
rested in a sitting position for at least 3 minutes.
7.1.1.9.
Tumor Lysis Syndrome (TLS) Risk Assessment
At baseline and prior to initiating venetoclax in Cycle 4, all study subjects will be assessed for 
risk of developing TLS. Ongoing risk of TLS should be assessed at all ramp up visits. The risk of 
TLS is a continuum based on multiple factors, including comorbidities. Subjects with high tumor 
burden (eg, any lymph node with a diameter ≥5 cm or high absolute lymphocyte count (ALC) 
[ALC ≥25 x 109/L]) are at greater risk of TLS when initiating venetoclax. Reduced renal 
function (creatinine clearance [CrCl] <80 mL/min) further increases the risk. The risk may 
decrease as tumor burden decreases with venetoclax treatment.
Tumor burden assessments, including radiographic evaluation (eg, CT scans) as well as blood 
chemistry (creatinine, uric acid, potassium, phosphorus, and calcium) assessments will be 
performed in all subjects prior to initiating venetoclax treatment.
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 5.4.2.2.
7.1.1.10.
Tumor Lysis Syndrome (TLS) Prophylaxis
For subjects at risk of TLS per investigator assessment, the prophylaxis measures listed in 
Section 5.4.2.2 should be followed and more intensive measures (including hospitalization) 
should be employed as overall risk increases. These measures should be performed prior to 
initiating therapy with venetoclax (2-3 days prior to first dose) and throughout the ramp-up 
phase, especially the first day of each ramp-up dose. Refer to Schedule of Assessments 
(Appendix A, Appendix B, Appendix D, and Appendix E) for specific timepoints of 
assessments.


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7.1.2.
Laboratory
7.1.2.1.
Hematology
Hematology parameters will include a complete blood count: white blood cells, red blood cells, 
hemoglobin, hematocrit, platelets, neutrophils, bands, lymphocytes, prolymphocytes, atypical 
lymphocytes (if found on routine CBC review), monocytes, eosinophils, and basophils. 
Hematology samples will be collected and tested by local laboratory.
7.1.2.2.
Chemistry (Serum)
Serum chemistry parameters will include: sodium, potassium, chloride, blood urea nitrogen 
(BUN)/Urea, creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline 
phosphatase, total bilirubin, LDH, phosphate/inorganic phosphorus, uric acid, magnesium, and 
bicarbonate. Chemistry samples will be collected and tested by local laboratory.
7.1.2.3.
Coagulation Studies
Measurement of PT/INR and aPTT will be performed at Screening and Reintroduction using a 
local laboratory.
7.1.2.4.
Hepatitis Serologies
Hepatitis serologies include hepatitis C antibody, hepatitis B surface antibody, hepatitis B core 
antibody, and hepatitis B surface antigen (HBsAg). 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 enrollment. Subjects who are 
HBsAg positive are excluded. Hepatitis serologies will be collected and tested by local 
laboratory.
7.1.2.5.
Serum β2-microglobulin
One blood sample for β2-microglobulin will be collected and tested by local laboratory at C1D1 
and Cycle 10 for subjects in the FD Cohort (see Appendix B).
7.1.2.6.
Pregnancy Test
Serum pregnancy test will be required at Screening by local laboratory only for women of 
childbearing potential. A urine pregnancy test will also be performed on Day 1 prior to first dose. 
If positive, pregnancy must be ruled out by ultrasound to be eligible. This test may be performed 
more frequently if required by local regulatory authorities.


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7.1.3.
Diagnostics/Procedures
7.1.3.1.
ECG
Electrocardiograms should 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.
At Screening, and if clinically indicated during the conduct of the study, 12-lead ECG will be 
done in triplicate (≥1 minute apart) in supine position after resting at least 10 minutes.
Abnormalities noted at Screening should be included in the medical history.
7.1.3.2.
CT/MRI
CT scans of the neck, chest, abdomen and pelvis will be performed throughout the study until 
disease progression is confirmed. MRI may be used to evaluate sites of disease that cannot be 
adequately imaged using CT (in cases where MRI is desirable, the MRI must be obtained at 
baseline and at all subsequent response evaluations). If MRI is required for any other reason, this 
must first be discussed with the study Medical Monitor.
De-identified copies of all imaging will be submitted to the Sponsor or designee.
7.1.3.3.
Bone Marrow Biopsies and Aspirate 
Bone marrow biopsy and aspirate samples will be assessed locally and used for disease 
assessment by Investigator, to confirm complete response, to confirm cytopenic progression
attributable to CLL, and distinguish autoimmune and treatment-related cytopenias. Bone marrow 
components should be evaluated for complete response per 2008 IWCLL criteria including 
relative cellularity for patient’s age, % lymphocytes, and for the presence of B lymphoid 
nodules.
In the MRD cohort: Bone marrow aspirate will be used for MRD assessment by central lab flow 
cytometry at C16D1 and visits with CR assessments. A Cycle 29 bone marrow aspirate should be 
obtained to confirm ongoing MRD-negativity or attainment of new MRD-negativity (see below 
for additional details).
In the Fixed Duration cohort: Bone marrow aspirate will be used for MRD assessment by central 
lab flow cytometry at the following: C10D1, visits with CR assessments, and the C19D1
assessment (3-months after the completion of Cycle 15) (see below for additional details).




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At Screening (MRD and FD Cohorts)
A unilateral bone marrow biopsy must be obtained at Screening or up to 90 days before 
enrollment for disease confirmation.
The following material will be sent to the central laboratory:

Bone marrow trephine (≥1 cm) in a container of neutral buffered formalin (no other 
fixative allowed); NOTE: The bone marrow trephine will be split in half with one portion 
to remain at the site for local assessment and the other half sent to the central laboratory

Bone marrow aspirate
If insufficient marrow biopsy material or slides are available to be submitted, high resolution 
images of the available representative slides should be acquired and submitted instead.
Copies of redacted bone marrow pathology reports for samples reviewed locally will be collected 
and may be reviewed by the Sponsor and/or IRC. 
For Response Evaluation (MRD and FD Cohorts)
At every Overall Response Assessment with a scheduled BM evaluation (Table 9 for MRD 
cohort and Table 10 for FD cohort), or if the subject’s physical examination findings, laboratory 
evaluations, and radiographic evaluations suggest that CR has been achieved in all response 
parameters at other time points (Suspected CR), a bone marrow aspirate and biopsy must be 
obtained to confirm the CR and to evaluate minimal residual disease.
Bone marrow collected to confirm CR must have minimal residual disease (MRD) assessed by 
flow cytometry on the aspirate (see below for more details). In cases where cytopenic 
progression is suspected, the bone marrow aspirate or biopsy should be used to distinguish 
autoimmune and drug-related cytopenias.
The following material will be sent to the central laboratory:

Bone marrow trephine (≥1 cm) in a container of neutral buffered formalin (no other 
fixative allowed) NOTE: The bone marrow trephine will be split in half with one portion 
to remain at the site for local assessment and the other half sent to the central laboratory

Bone marrow aspirate
If insufficient marrow biopsy material or slides are available to be submitted, high resolution
images of the available representative slides should be acquired and submitted instead.
Copies of redacted local bone marrow pathology reports for samples reviewed locally will be 
collected and may be reviewed by the Sponsor and/or IRC.


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Quantitative Minimal Residual Disease (MRD) Assessment by Central lab
A C1D1 PB sample will be submitted for MRD evaluation to establish a baseline 
immunophenotypic profile. Starting from C7D1 on, MRD will be assessed by PB every 
3-12 cycles. Refer to Table 11 and Table 12 for MRD sample collection schedule.
In the MRD Cohort:
A bone marrow aspirate will be collected from all subjects for assessment of MRD status at 
Cycle 16 (±14 days) unless collected previously in those with a documented CR and MRD-neg 
confirmed in BM after the start of study treatment. An additional bone marrow aspirate should be 
collected at Cycle 29 (±14 days) in randomized subjects, and in any subject with MRD-neg
conversion in PB.
In subjects who consent, an additional bone marrow aspirate (after suspected CR or C16) can be 
collected prior to randomization to serially confirm MRD-negativity in the BM compartment.
Table 11.
MRD Cohort: MRD Sample Collection Schedule
C1D1
C7D1
C10D1
C13D1
C16D1
(±14 
days)
C20-
C29D1   
Q3 
cycles
(±14 
days)
C35D1 and 
Q6 cycles 
thereafter
To 
Confirm 
CR
To 
Confirm 
MRD+ 
Relapse
End of 
Treatment
BM 
Aspirate
Xa
X 
(C29) 
a,b,c
X
Peripheral 
Blood
X
X
X
X
X
X
X
X
X
X
a.
Unless collected prior for CR assessment, and were MRD-neg in BM
b.
Collected in randomized subjects, and in any subject w/ MRD-neg conversion in PB
c.
±14 day window applies to BM aspirate only
In the Fixed Duration Cohort:
A bone marrow aspirate will be collected from all subjects for assessment of MRD status at 
Cycle 10 and 3 months after the completion of Cycle 15 (ie, C19). Bone marrow assessments can 
be performed if needed to confirm CR.




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uninterrupted 7 days of dosing. In cases of dose reduction, pharmacokinetic sampling should be 
delayed until completion of an uninterrupted 7 days of consistent dosing.
Pharmacokinetics of ibrutinib and venetoclax when dosed in combination will be also 
determined at steady-state on Day 1 of Cycle 6 at time-points specified in Table 13 below.
Table 13.
Pharmacokinetic Sample Schedule for Ibrutinib and Venetoclax
(MRD Cohort Only)
Study Drug 
PK
Cyclef
Day
Pre-
dose 
PKc & 
Meald
Study 
Drug 
Dosee
Time after ibrutinib or ibrutinib + venetoclax
1 hour
(± 15 min)
2 hour 
(± 15 min)
4 hour 
(± 30 min)
6 hour
(± 30 min)
8 hour
(± 1 h)
Ibrutinib
2a
1
X
X
X
X
X
X
X
Ibrutinib &
Venetoclax
6b
1
X
X
X
X
X
X
X
a.
Ibrutinib single-agent only steady-state PK
b.
Ibrutinib and venetoclax combination steady-state PK
c.
Predose samples should be collected 30 minutes prior to the administration of ibrutinib (lead-in period) or ibrutinib and 
venetoclax (combination period)  
d.
The meal to be completed within 30 minutes
e.
Ibrutinib/venetoclax to be dosed 30 minutes after the start of the meal
f.
PK should only be drawn when ibrutinib (C2), and ibrutinib with venetoclax (C6) are at steady state plasma levels. If any 
dose of ibrutinib and/or venetoclax were withheld in the week prior to C2D1, and C6D1, then PK assessment should be 
rescheduled to the next study visit day after doses have been consistently administered for ≥1 week
Example:
Predose PK --7:00a
Breakfast ----7:00a to 7:30a
Dose ----------7:30a
1 hr PK ------8:30a
2 hr PK ------9:30a
4 hr PK ------11:30a
6 hr PK ------1:30p
8 hr PK ------3:30p
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 during the PK collection period, administration of concomitant medications should be 
recorded.


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Pharmacokinetics Sample Collection for Subjects Treated with a Concomitant CYP3A 
Inhibitor While on Ibrutinib and/or Venetoclax Treatment
For subjects who must start a moderate or strong CYP3A inhibitor while on treatment with 
ibrutinib and/or venetoclax, additional PK blood samples for evaluation of ibrutinib and/or
venetoclax exposure are requested approximately one week post-initiation of concomitant 
CYP3A inhibitor. PK samples will be collected at:

Pre-dose (If possible, sample should be obtained 22-24 hours post the previous day’s 
dose and before dosing on the day of the scheduled visit)

1 hour ± 15 min

2 hours ± 15 min

4 hours ± 30 min

6 hours ± 30 min

8 hours ± 1 h
7.1.4.2.
7.1.4.3.
7.1.4.4.


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7.2.
Efficacy Evaluations
Clinical disease evaluations will include:

Physical examination (which will focus on the presence/absence of size increase/ 
decrease in lymph nodes, liver, and spleen)

Hematologic parameters by CBC performed at a local laboratory

Radiographic evaluation (CT or MRI scan of the neck, chest, abdomen, and pelvis)

Bone marrow biopsy (as appropriate) if there is evidence of CR in the other response 
parameters
If study drug is held before a scheduled clinical response assessment, then the response 
assessment can be delayed up to 4 weeks to allow re-initiation of study drug for 2 weeks (or as 
long as possible) prior to performing scheduled response assessment.
Clinical efficacy assessments, for the purpose of the study result analyses, will be performed by 
Investigators. For response assessments not requiring a CT scan, the Investigator should
evaluate response based on available clinical data, including physical examination and laboratory 
results.  For the MRD and Fixed Duration cohorts, imaging will be collected and stored centrally. 
The Sponsor may utilize IRC for independent review of efficacy with details to be outlined in the 
separate IRC charter.


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MRD Evaluations:
Samples for MRD analysis will be sent to a central laboratory that has a validated flow 
cytometry assay that has a limit of detection of 10-4. MRD will be assessed in the following 
compartments:

Bone marrow 

Peripheral blood
7.2.1.
Definitions
7.2.1.1.
Measurable Disease
Subjects must have at least 1 measurable site of disease to participate in this study. Measurable 
sites of disease are defined as lymph nodes, or lymph node masses. A measurable site of disease 
must be greater than 1.5 cm in the longest diameter. Measurement must be determined by 
imaging evaluation.
Tumor lesions that are situated in a previously irradiated area might or might not be considered 
measurable. If there are tumor lesions in previously irradiated areas and progression has 
occurred, these lesions will be considered measurable. If tumor lesions in previously irradiated 
areas are present and have been stable, then these lesions are not considered measurable. If tumor 
lesions in previously irradiated areas progress during the study, then disease progression will be 
considered as having occurred provided progression is confirmed by the Investigator.
All other sites of disease will be considered assessable. Assessable disease includes objective 
evidence of disease that is identified by radiological imaging, physical examination, or other 
procedures, as necessary, including peripheral blood counts.
7.2.1.2.
Treatment-Related Lymphocytosis
Treatment-related lymphocytosis, for the purposes of this protocol, is defined as an elevation in 
blood lymphocyte count of ≥50% compared to baseline and ≥5000/µL that occurs in the setting 
of unequivocal improvement in at least one other disease-related parameter including lymph 
node size, spleen size, hematologic parameters (hemoglobin or platelet count), or disease-related 
symptoms. Given the known mechanism of action of BCR-inhibiting agents including ibrutinib, 
treatment-related lymphocytosis is an expected and frequent pharmacodynamic phenomenon 
observed with initiation (or re-initiation) of ibrutinib.
Response assessment in CLL subjects treated with novel agents has been clarified by the authors 
of the IWCLL 2008 guidelines and is outlined in the NCCN NHL 2016 guidelines, supporting 
that subjects with isolated lymphocytosis in the setting of improvement in other disease 
parameters should not be considered to have clinical progressive disease or treatment failure 
(Cheson 2012).


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7.2.1.3.
Richter’s Transformation
Richter's syndrome (RS) is lymphomatous transformation to a more aggressive histology in a 
subject with CLL or SLL. RS is most often characterized by the development of high-grade NHL 
or Hodgkin’s disease. Symptoms of Richter’s transformation can include new or progressive 
lymphadenopathy or organomegaly, fever, loss of weight and muscle mass, and other health 
problems. Richter's transformation can be suggested by a CT/PET scan, but should be confirmed 
with a biopsy (eg, lymph node) demonstrating the histologic transformation.
7.2.1.4.
Minimal Residual Disease (MRD)
MRD is a low-level of disease that persists, and which is not detectable with routine imaging nor 
routine laboratory tests, but can be demonstrated in PB or BM with more sensitive flow 
cytometry assays.
7.2.1.4.1.
MRD-Negativity 
MRD-negativity is defined as <1 CLL cell per 10,000 leukocytes (<1 x 10-4), as assessed by flow 
cytometry of a peripheral blood (PB) or bone marrow (BM) aspirate sample. 
Confirmed MRD-negative response for randomization purposes requires MRD-negativity 
serially over at least 3 cycles, with negativity in both BM and PB. Subjects who do not achieve 
confirmed MRD-negative status are not considered to have a MRD-negative response for 
randomization purposes in the MRD cohort. See Section 7.1.3.3 for MRD assessment schedule.
7.2.1.4.2.
MRD-Positive Relapse (MRD Cohort Only)
MRD-positive relapse is defined as an increase in CLL cells ≥1 per 100 leukocytes (≥1 x 10-2) 
confirmed on two separate serial occasions, after a confirmed MRD-negative response, as 
assessed by flow cytometry of a PB or BM aspirate sample. 
7.2.2.
Guidelines for Clinical Disease Evaluation
Objective response will be categorized as CR, CR with incomplete bone marrow recovery (CRi), 
nodular partial response (nPR), partial response (PR), PR with lymphocytosis (PRL), stable 
disease (SD), or progressive disease (PD)—all based upon IWCLL criteria (Hallek 2008, 
Hallek 2012, Hallek 2013, Cheson 2012). All responses must be maintained for at least 2 months 
to be considered confirmed. CRs must be confirmed by bone marrow biopsy/aspirate. Response 
assessments on treatment arms will occur independent of ongoing therapy. For purposes of this 
protocol, 2 months equals 2 cycles (56 days) with each cycle equaling 28 days.
Given the known mechanism of action of BCR-inhibiting agents, including ibrutinib, and the 
treatment-related lymphocytosis frequently observed during treatment with ibrutinib, isolated 
treatment-related lymphocytosis (in absence of other clinical, CT, or laboratory evidence of 
disease progression) will not be considered progressive disease. This approach is supported by 


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both the authors of the IWCLL 2008 and 2017 guidelines (Hallek 2012, Cheson 2012) and the 
NCCN.
The requirement for each parameter at baseline to be evaluable throughout the study is outlined 
in Table 14.
Table 14.
Evaluable Parameter Requirements
Parameter
Requirements to be Evaluable for Response
Measurable Disease (required for all subjects)
Lymph Node >1.5cm
Splenomegaly
Enlarged spleen
Hepatomegaly
Enlarged liver
Absolute Lymphocyte Count (ALC)
≥4,000/µL
Platelets
≤100,000/µL
Absolute Neutrophil Count (ANC)
≤1500/µL
Hemoglobin
≤11.0 g/dL
7.2.3.
Clinical Response Categories
Investigator assessment of response should include physical examination, radiographic imaging, 
and evaluation of blood and marrow (if applicable). For response assessments not requiring a CT 
scan, the Investigator should evaluate response based on available clinical data, including 
physical examinations and laboratory results.  Definition of response for CR, CRi, nPR, PR, PRL
and disease progression will be evaluated by the criteria listed in Table 15. Group A criteria 
define the tumor load and Group B criteria define the function of the hematopoietic system. 
Response must be confirmed by CT when available, and must last at least 2 months without 
transfusional support or growth factor product to be considered a confirmed response.
7.2.3.1.
Complete Response (CR)
All of the following are required for a CR:

No significant lymphadenopathy (>1.5cm) palpable on examination or by CT

No hepatosplenomegaly on examination or by CT

No constitutional symptoms (ie, no fever >38ºC for ≥2 weeks, no ongoing unintentional 
≥10% body weight loss, no night sweats for >1 month without other evidence of 
infection, no fatigue interfering with work or usual activities) attributable to CLL.

Neutrophils >1500/µL, platelets >100,000/μL, and Hgb >11g/dL without recent growth 
factor or transfusions

ALC <4,000/µL


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Marrow aspirate and biopsy must be performed after all other criteria meet the definition of CR. 
To define a CR, the marrow sample must be at least normocellular for age, with less than 30% of 
nucleated cells being lymphocytes. B-lymphoid nodules should be absent.
In addition, in subjects with a CR, MRD should be performed on both peripheral blood and bone 
marrow aspirate to evaluate MRD status.
Table 15.
Criteria for Clinical Response Categories
Parameter
CR
PR
PD
Group A
Lymphadenopathya
None; ≤1.5cm
Decrease ≥50%
increase ≥50%
Hepatomegaly
None
Decrease ≥50%
increase ≥50% or 
new hepatomegaly
Splenomegaly
None
Decrease ≥50%
increase ≥50% or 
new splenomegaly
Blood lymphocytes
<4000/µL
Decrease ≥50% 
from baseline
increase ≥50% 
over baselinec
Marrowb
Normocellular, 
<30% lymphocytes, 
no B lymphoid nodules.
Hypocellular defines CRid
in a patient with cytopenias
Group B
Platelet count
>100,000/µL
>100,000/µL or increase 
≥50% over baseline
Decrease of ≥50% from 
baseline secondary to CLL
Hemoglobin
>11 g/dL
>11g/dL or increase 
≥50% over baseline
Decrease of >2g/dL from 
baseline secondary to CLL
Neutrophils
>1500/µL
>1500/µL or increase 
≥50% over baseline
N/A
a.
Sum of the products of multiple lymph nodes (as evaluated by CT scans) or the longest diameter of one target lymph 
node
b.
This parameter is not relevant for the PD category unless confirming cytopenic progression.
c.
Subjects with treatment-related lymphocytosis should remain on study treatment in the absence of other criteria for 
progressive disease (see Section 7.2.1.2).
d.
Hypocelluar marrow is a CRi when peripheral blood cytopenias not meeting Group B criteria are present. CRi requires at 
least one abnormal Group B criteria.
Note: Group A defines the tumor load and Group B defines the function of the hematopoietic system
CR: all of the criteria need to be met and subjects have to lack disease related constitutional symptoms. 
Bone marrow and aspirate is required to confirm CR.
PR: At least two of the Group A parameters must be met; with two exceptions: 1) subjects who only have 
abnormal lymph nodes at baseline, or 2) subjects who have only abnormal lymph node and abnormal lymphocyte 
count (ALC) at baseline. For these two exceptions, subjects will only need to meet the lymph node response 
criteria. 
In addition to the Group A criteria, all subjects must also have a response in at least one of the Group B criteria.
SD: the absence of PD and the failure to achieve a response.
PD: at least 1 of the above criteria from Group A or B are met or development of transformation to a more 
aggressive histology
Cross reference: Hallek 2008, Hallek et al. June 2012 e-letter, Hallek 2013


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7.2.3.2.
Complete Response with an Incomplete Marrow Recovery (CRi)
Complete response with an incomplete marrow recovery (CRi) is defined as a CR with an 
incomplete recovery of the subject’s bone marrow, manifested by persistent cytopenias. Subjects 
who have a CRi fulfill all criteria for a CR, but continue to have persistent anemia, 
thrombocytopenia, or neutropenia. These cytopenias are due to drug toxicity in the bone marrow 
and are not due to any evidence of CLL. If the marrow is hypocellular, a repeat determination 
should be performed after 4 weeks, or when peripheral blood counts have recovered. However, 
this time interval should not exceed 6 months.
7.2.3.3.
Nodular Partial Response (nPR)
Nodular partial response (nPR) is a response where subjects meet criteria for a CR, but the bone 
marrow biopsy shows that there are still B-lymphoid nodules, which may represent a clonal 
infiltrate. These nodules or aggregates are residual disease and therefore the subject is termed an 
nPR. Immunohistochemistry may be performed to define whether the nodules or aggregates 
comprise primarily T cells, B cells other than CLL cells, or CLL cells. If nodules or aggregates 
are not composed of CLL cells, a CR can be documented provided all other criteria are met.
7.2.3.4.
Partial Response (PR)
At least two of the following parameters must be met; with two exceptions: 1) subjects who only 
have abnormal lymph nodes at baseline, or 2) subjects who have only abnormal lymph node and 
abnormal lymphocyte count (ALC) at baseline. For these two exceptions, subjects will only need 
to meet the lymph node response criteria. 

≥50% decrease in the sum products of up to 6 lymph nodes, a ≥50% decrease in the 
longest diameter of the single lymph node, or normalization of lymphadenopathy when 
compared to baseline.
○
With no new enlarged lymph nodes by physical examination or CT AND no increase 
in any lymph node by CT. Note:  In a small lymph node <2 cm, an increase of less 
than 25% is not considered to be significant.

When abnormal, a ≥50% decrease in the enlargement of the spleen and/or liver from 
baseline or normalization by CT

If abnormal a ≥50% drop in lymphocyte count from baseline or ≤4000/µL
In addition to the criteria above, the subject must also have a response in at least one of the 
following evaluable criteria independent of growth factor support or transfusion.

Neutrophils >1500/µL or ≥50% improvement over baseline

Platelets >100,000/μL or ≥50% improvement over baseline

Hgb >11 g/dL or ≥50% improvement over baseline
* Note: For criterion to be considered in response evaluation, it must have been evaluable at 
baseline


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7.2.3.5.
PR with Lymphocytosis (PRL)
Subjects achieve all PR criteria with the exception of lymphocyte criteria.
7.2.3.6.
Stable Disease (SD)
Not meeting criteria for CR, CRi, nPR, PR, PRL, or progressive disease.
7.2.3.7.
Progressive Disease (PD)
A CT scan is required to evaluate all cases of suspected progressive disease for this protocol 
regardless of the modality of disease progression (eg, lymph node, lymphocytosis, or 
transformation). Progressive disease requires at least ONE of following:

New enlarged nodes >1.5cm, new hepatomegaly or splenomegaly; or other organ 
infiltrates

≥50% increase from nadir in existing lymph node (must reach >1.5 cm in the longest 
diameter) or ≥50% increase from nadir in sum of product of diameters of multiple nodes

≥50% increase from nadir in enlargement of liver or spleen

≥50% increase from the baseline ALC count and at least 5 x 109/L

New cytopenia (hemoglobin or platelets) attributable to CLL. The progression of any 
cytopenia (unrelated to autoimmune cytopenia, drugs, or bleeding), as documented by a 
decrease of Hgb levels from baseline by more than 20 g/L (2 g/dL) or to less than 100 g/L 
(10 g/dL) and lower than baseline, or by a decrease of platelet counts from baseline by 
≥50% or to less than 100 × 109/L (100,000/μL) and lower than baseline in the presence of 
active CLL, defines disease progression ; a marrow biopsy must demonstrate an infiltrate 
of clonal CLL cells if no other evidence of disease progression is present on CT scan.

Transformation to a more aggressive histology (eg, Richter’s Transformation). 
Whenever possible, this diagnosis should be established by biopsy.
Suspected progressive disease (eg, by PE or ALC) must be confirmed by a serial exam at least 
2 weeks later, and confirmed by imaging.
7.2.4.
Hematological Improvement
Hemoglobin and platelet counts will be evaluated.
7.2.5.
Radiographic Images Assessment
Radiological efficacy assessments, for the purpose of the study result analyses, will be performed 
by the Investigator. For the MRD and Fixed Duration cohorts, imaging will be collected and 
stored centrally. The Sponsor may utilize IRC for independent review of efficacy with details to
be outlined in the separate IRC charter.


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The baseline disease assessment will include all areas of known and suspected disease with use 
of the most appropriate and reproducible radiological technique.
Radiological imaging by CT with contrast is required and must include the neck, chest, 
abdomen, and pelvis. Subjects who are intolerant to IV CT contrast agents will have CT scans 
performed with oral contrast. When possible, all subjects should have radiographic tumor 
measurements performed at the participating study center or an acceptable alternate imaging 
facility using an identical imaging protocol and similar equipment. The same imaging equipment 
should be utilized for all scans whenever possible. The same radiologist should be assigned to 
read all the scans for a given subject throughout the study as much as possible.
Magnetic resonance imaging (MRI) may be used to evaluate non-target lesions that cannot be 
adequately imaged using CT (in cases where MRI is desirable, the MRI must be obtained at 
baseline and at all subsequent response evaluations). If MRI is required for any other reason, this 
must be discussed with the study Medical Monitor first.
CT scans will be performed until disease progression regardless of whether or not the subject 
remains on treatment. In the event disease progression is suspected due to physical examination 
or laboratory test, a CT scan must be performed to confirm disease progression.
There must be radiographically measurable disease at Screening (at least one lymph node 
>1.5 cm in the longest diameter) as outlined in Section 7.2.2. If the sole lesion lies within the 
field of prior radiotherapy, there must be evidence of disease progression in that lesion.
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 followed 
throughout the study.
The cranial-caudal measurement of the spleen and longest diameter of the liver will be assessed 
at Screening and all subsequent response evaluations.
7.3.
Suspected Disease Progression
The schedule of assessments is provided in Appendix A and Appendix B. Any suspected case of 
disease progression will prompt procedures performed in a Suspected Disease Progression visit 
(Section 8.5). Disease progression should be confirmed with a CT scan (or MRI, if CT is 
contraindicated) and should be reported to the Sponsor within 24 hours of discovery. If disease 
progression is suspected based on the results of a single examination or a single laboratory 
parameter, this finding should be confirmed by a subsequent evaluation at least 2 weeks later and 
confirmed by imaging.


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Study treatment should be continued and new anti-cancer therapy withheld, if clinically 
appropriate, until disease progression is confirmed by the Investigator. Subjects should continue 
to adhere to all study-related proceduresincluding response evaluations and procedures to 
confirm disease progressionuntil clinical progressive disease is confirmed by the Investigator. 
When disease progression has been confirmed by the Investigator, study treatment should be 
discontinued.
If there is uncertainty regarding whether there is disease progression, the subject should continue 
study treatment and remain under close observation (eg, evaluated at 2-4 week intervals). 
Transient worsening of disease during temporary interruption of study therapy (eg, for drug-
related toxicity, intercurrent illness, or surgery) may not indicate disease progression.  
7.4.
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, Appendix B, Appendix C, Appendix D, and Appendix E) 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 Period
Screening procedures will be performed up to 30 days prior to initiation of study drug, unless 
otherwise specified. All subjects must first read, understand, and sign the IRB/REB/IEC-
approved ICF before any study-specific screening procedures are performed. All study tests and 
procedures should be performed at the study center at which the subject was enrolled and will be 
receiving treatment. After signing the ICF, and being deemed eligible for entry, subjects may be 
enrolled in the study.
8.1.1.
Screening Visit
The following procedures will be performed at the Screening Visit within 30 days prior to 
enrollment unless otherwise noted:

Obtain signed, written informed consent

Medical history including demographic information 

Perform a complete physical examination, including height and weight (may use prior 
height measurement if available in source documents)

Evaluation of ECOG performance status


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
Obtain vital signs (including blood pressure, heart rate, and body temperature) after the 
subject has rested in the sitting position for at least 3 minutes

Obtain triplicate 12 lead ECG (≥1 minute apart) after the subject has been in a supine 
position and resting for at least 10 minutes.

Record concomitant medication history including over-the-counter drugs, vitamins and 
herbs 

Adverse events (record as Medical History on eCRF form)

Imaging by CT or other modality as described in Section 7.1.3.2 (if not performed within 
6 weeks prior to enrollment)

Obtain a bone marrow aspirate and biopsy (if not performed within 90 days prior to
enrollment) (local and central labs [MRD Cohort]; local labs [FD Cohort])

Obtain blood specimens for the following laboratory tests:
○
Hematology
○
Serum chemistry (including creatinine clearance)
○
Coagulation panel (PT/INR, aPTT)
○
Hepatitis serologies 
○
Obtain serum pregnancy test for women of childbearing potential only
8.2.
MRD Cohort
For the MRD cohort, the study is divided into a Screening Phase, a Pre-randomization Treatment 
Phase, a Randomization Phase, and a Post-PD Follow-up Phase. The Schedule of Assessments 
(Appendix A) summarizes the frequency and timing of efficacy, PK, 
 and safety 
measurements applicable to this study. The timing of all visits will be based on using Cycle 1 
Day 1 (C1D1) as the anchor visit and all subsequent visits should use the C1D1 date as the basis 
for scheduling.
MRD Cohort: Pre-Randomization Treatment Phase
Refer to the Schedule of Assessments (Appendix A) for a complete list of procedures to be 
performed at each scheduled study visit.
Following completion of the Screening Visit and once eligibility has been confirmed (per 
inclusion/exclusion criteria), subjects will initiate ibrutinib treatment. Venetoclax will be added 
to ibrutinib treatment and initiated after completion of 3 cycles of ibrutinib. The venetoclax dose 
will be ramped up over 5 weeks per standing dosing recommendations (see Section 5.3.1 for 
ibrutinib and venetoclax dosing).
Subjects who are unable to complete at least 12 cycles of combination therapy will not be 
eligible for Randomization but will continue to follow the same visit schedule until disease 


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progression. After disease progression subjects will enter the Post-PD Follow up Phase 
(Section 8.8).
8.2.1.
Treatment Visits
8.2.1.1.
Cycle 1 Day 1 (C1D1) Visit
Pre-Dose
The following procedures will be performed prior to dosing (within 3 days) of the C1D1 Visit. 
Please note, C1D1 Visit procedures done at Screening will not need to be repeated if done 
within 3 days of first dose with study drug.

Confirm eligibility (per inclusion/exclusion criteria) and enroll subject. Dosing should 
occur within 3 days of confirmation.

Adverse events

Physical examination

Vital signs

ECOG performance status

Concomitant medications

Hematology

Serum chemistry (including creatinine clearance)

Tumor Lysis Risk assessment (use Screening CT and C1D1 ALC. see Appendix H for 
risk assessment categories)


IGHV (if IGHV sample is not informative for any reason, another peripheral blood 
sample should be drawn and sent to the central lab at the next appropriate timepoint)

FISH panel

Karyotype

Buccal Swab

MRD in peripheral blood

Perform urine pregnancy test for women of childbearing potential only
Dosing and Post First Dose

In-clinic administration of ibrutinib 

Dispense ibrutinib for offsite use and provide study drug compliance instructions


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8.2.1.2.
Cycles 2 and 3 Visits
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of each cycle (except for 
CT/MRI): 

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

CT/MRI (to assess response and lymph node sum of the product of the diameters [SPD]
for TLS risk assessment, Cycle 3 only – to be obtained as close to the beginning of 
Cycle 4 as possible, while still allowing for appropriate TLS risk-guided interventions 
including hospitalization if appropriate)

Hematology

Serum chemistry 


Pharmacokinetics sample (Cycle 2 only. See Section 7.1.4.1 for Pharmacokinetics 
Sample Collection Schedule)
Dosing and Post Dose

In-clinic administration of ibrutinib (Cycle 2 only)

Collection of post dose pharmacokinetics samples per Section 7.1.4.1 (Cycle 2 only)

Dispense ibrutinib for offsite use and provide study drug compliance instructions
8.2.1.3.
Cycle 4 Visits
8.2.1.3.1.
Pre-Cycle 4 (Pre-initiation of Venetoclax)
The following procedures will be performed 2-3 days (±3 days) prior to Cycle 4:

Overall response assessment

Hematology

Serum Chemistry

Tumor Lysis Risk assessment (see Appendix H for risk assessment categories)

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk)


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The following procedures will be performed 1 day prior to Cycle 4:

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk)
8.2.1.3.2.
Cycle 4 Week 1 Day 1
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycle 4, Week 1:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

Creatinine clearance (Cockcroft-Gault)

Tumor Lysis Risk assessment (see Appendix H for risk assessment categories)

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk, venetoclax administration setting, and frequency of serum chemistry monitoring 
assessments)

 assays
Dosing and Post First Dose of Venetoclax

In-clinic administration of ibrutinib

In-clinic administration of venetoclax 20 mg for low and medium risk TLS subjects

Consider hospitalization for first dose of venetoclax 20 mg in medium risk TLS subjects 
with a CrCl < 80 mL/min

In-hospital administration of first dose of venetoclax 20 mg for high risk TLS subjects

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions
8.2.1.3.3.
Cycle 4 Week 1 Day 2
Pre-Dose

Adverse events

Hematology 

Serum chemistry 


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
Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk and frequency of serum chemistry monitoring assessments)
8.2.1.3.4.
Cycle 4 (Week 2 – Week 4) Visits
The following procedures will be performed on Day 1 (±3 days) of Cycle 4, Weeks 2, 3, and 4
(coincides with venetoclax standard dose ramp-up of 50 mg (W2D1), 100 mg (W3D1), and 
200 mg (W4D1)
Pre-Dose

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

Creatinine clearance (Cockcroft-Gault)

Tumor Lysis Syndrome Risk assessment (see Appendix H for risk assessment categories)

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk and frequency of serum chemistry monitoring assessments)
Dosing and Post-Dose

In-clinic administration of venetoclax 50 mg (Week 2), 100 mg (Week 3) and 200 mg 
(Week 4) for low and medium TLS risk subjects

Consider hospitalization for first dose of venetoclax 50 mg in medium risk TLS subjects 
with a CrCl < 80 mL/min

In-hospital administration of first dose of venetoclax 50 mg dose at week 2 for high risk 
TLS subjects; in-clinic administration of venetoclax 100 mg (Week 3) and 200 mg 
(Week 4) for high risk TLS subjects

Dispense venetoclax for offsite use and provide study drug compliance instructions
8.2.1.3.5.
Cycle 4 Week 2 Day 2
Pre-Dose

Adverse events

Hematology 

Serum chemistry 


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
Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk and frequency of serum chemistry monitoring assessments)
8.2.1.4.
Cycle 5 Visits
8.2.1.4.1.
Cycle 5 Week 1 and Week 3 Visits
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycle 5, Week 1 and 
Week 3:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

Creatinine clearance (Cockcroft-Gault)

Tumor Lysis Syndrome Risk assessment (see Appendix H for risk assessment categories)
(Week 1 Only)

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk, venetoclax administration setting, and frequency of serum chemistry monitoring 
assessments) (Week 1 Only)
Dosing and Post-Dose

In-clinic administration of venetoclax

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions (Week 1 only)
8.2.1.5.
Cycle 6 – Cycle 9 Visits
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycles 6, 7, 8, and 9:

Adverse events

Concomitant medication

Study drug compliance review


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
Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

Overall response assessment (by PE/CBC Cycle 7 only)

MRD in peripheral blood (Cycle 7 only)

 assays 

Pharmacokinetics sample (Cycle 6 only. See Section 7.1.4.1 for Pharmacokinetics 
Sample Collection Schedule)
Dosing and Post-Dose

In-clinic administration of ibrutinib (Cycle 6 only)

In-clinic administration of venetoclax (Cycle 6 only)

Collection of post dose pharmacokinetics samples per Section 7.1.4.1 (Cycle 6 only)

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions
8.2.1.6.
Cycle 10 & Cycle 13 Visits
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycles 10 and13:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

CT/MRI (Cycle 10 only)

Overall response assessment 

MRD assessment (in peripheral blood)

 assays 


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Post-Dose

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions
8.2.1.7.
Cycle 16 Day 1 Visit
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycle 16:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology

Serum chemistry

CT/MRI

Overall response assessment

Bone marrow biopsy (unless collected prior for CR assessment, and confirmed 
MRD-negative in BM)

MRD assessment (bone marrow aspirate and peripheral blood). Bone marrow aspirate 
can be drawn ±14 days from C16D1.

assays
Post-Dose

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions
MRD Cohort: Randomization Phase
Refer to the Schedule of Assessments (Appendix A) for a complete list of procedures to be 
performed at each scheduled study visit.
At Cycle 17 (following 3 cycles of ibrutinib lead-in, completion of 12 cycles of ibrutinib + 
venetoclax combination treatment, plus 1 cycle to evaluate MRD status) or within 3 days before 
Cycle 17 Day 1 visit, subjects will be randomized based on their MRD status. Randomization 
will occur via Interactive Response Technology (IRT) or alternative system provided by the 
Sponsor.


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MRD-neg subjects will be randomized to either ibrutinib or placebo, and therapy should be 
continued until MRD-positive relapse, disease progression, unacceptable treatment-related 
toxicity, or other reasons outlined in Section 9.2.
Subjects not obtaining confirmed MRD-neg responses (considered MRD-pos) will be
randomized to either ibrutinib + venetoclax or ibrutinib alone. Ibrutinib and/or venetoclax
should be continued until disease progression, unacceptable treatment-related toxicity, or other 
reasons outlined in Section 9.2.
Central labs for MRD assessment will be used to inform randomization strata, and re-
introduction of therapy. Local labs will be used to guide all other dosing-related decisions. In the 
event of rising MRD assessments, or of clinically suspected disease progression, the subject 
should continue to receive study medication, at the discretion of the Investigator, until 
MRD-positive relapse or disease progression is confirmed respectively.
8.2.2.
Cycle 17 Randomization Visit and Every 3 Cycles Thereafter
The following procedures will be performed on Day 1 (±3 days) of Cycles 17 and every 3 cycles 
thereafter (unless indicated otherwise) until disease progression, unacceptable treatment-related 
toxicity, or other reasons outlined in Section 9.2:
Pre-Dose

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

CT/MRI (Cycle 23, Cycle 29, Cycle 35, and then annually thereafter)

Overall response assessment 

Bone marrow biopsy ( ±14 days from C29 unless collected prior for CR assessment, and 
confirmed MRD-negative in BM)

MRD assessment (by PB starting Cycle 20, 23, 26, 29, and every 6 cycles thereafter; by 
bone marrow aspirate [BMA] at Cycle 29 in randomized subjects, and in any subject with 
MRD-neg conversion in PB; BMA can be drawn ±14 days from C29D1.) 

assays 


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Post-Dose

Dispense randomization specific study medication to subject for off-site use and provide 
study drug compliance instructions
8.2.3.
Suspected MRD-positive Relapse Visit (Any Time)
If MRD-positive relapse is suspected, subject should return to clinic as soon as possible and the
following procedures will be performed:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry

Overall response assessment 

MRD assessment (by PB)

 assays
8.3.
Fixed Duration Cohort
Fixed Duration Cohort: Treatment
The Schedule of Assessments (Appendix B) summarizes the frequency and timing of efficacy, 
 and safety measurements applicable to this study. The timing of all visits will be 
based on using Cycle 1 Day 1 (C1D1) as the anchor visit and all subsequent visits should use the 
C1D1 date as the basis for scheduling.
Following completion of the Screening visit and once eligibility has been confirmed (per 
inclusion/exclusion criteria), subjects will initiate ibrutinib treatment. Venetoclax will be added 
to ibrutinib treatment and initiated after completion of 3 cycles of ibrutinib. The venetoclax dose 
will be ramped up over 5 weeks per standard dosing recommendations (see Section 5.3 for 
ibrutinib and venetoclax dosing).
After completion of 15 cycles of treatment, subjects will come off treatment and will continue to 
be followed for efficacy. Subjects that are unable to complete all 12 cycles of combination 
therapy will continue to follow the same visit schedule until disease progression. After disease 
progression, subjects will enter the Post-PD Follow up Phase (Section 8.9).


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8.3.1.
Treatment Visits
8.3.1.1.
Cycle 1 Day 1 (C1D1) Visit
Pre-Dose
The following procedures will be performed prior to dosing (within 3 days) of the C1D1 Visit. 
Please note, C1D1 Visit procedures done at Screening will not need to be repeated if done 
within 3 days of first dose with study drug.

Confirm eligibility (per inclusion/exclusion criteria) and enroll subject. Dosing should 
occur within 3 days of confirmation.

Adverse events

Physical examination

Vital signs

ECOG performance status

Concomitant medications

Hematology

Serum chemistry (including creatinine clearance)

2-microglobulin

Tumor Lysis Risk assessment (use Screening CT and C1D1 ALC. see Appendix H for 
risk assessment categories)

 assays 

IGHV - will be derived from a 
sample (if IGHV result is not informative for 
any reason, another peripheral blood sample should be drawn and sent to the central lab 
at the next appropriate timepoint)

FISH panel

Karyotype

MRD in peripheral blood 

Perform urine pregnancy test for women of childbearing potential only
Dosing and Post First Dose

In-clinic administration of ibrutinib 

Dispense ibrutinib for offsite use and provide study drug compliance instructions


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8.3.1.2.
Cycles 2 and 3 Visits
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of each cycle (except for 
CT/MRI):

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

CT/MRI (to assess response and lymph node sum of the product of the diameters [SPD]
for TLS risk assessment, Cycle 3 only – to be obtained as close to the beginning of 
Cycle 4 as possible, while still allowing for appropriate TLS risk-guided interventions 
including hospitalization if appropriate)

Hematology 

Serum chemistry
Dosing and Post-Dose

In-clinic administration of ibrutinib (Cycle 2 only)

Dispense ibrutinib for offsite use and provide study drug compliance instructions
8.3.1.3.
Cycle 4 Visits
8.3.1.3.1.
Pre-Cycle 4 (Pre-initiation of Venetoclax)
The following procedures will be performed 2-3 days (±3 days) prior to Cycle 4:

Overall response assessment

Hematology

Serum Chemistry

assays 

Tumor Lysis Risk assessment (see Appendix H for risk assessment categories)

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk)
The following procedures will be performed 1 day prior to Cycle 4:

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk)


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8.3.1.3.2.
Cycle 4 Week 1 Day 1
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycle 4, Week 1:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

Creatinine clearance (Cockcroft-Gault)

Tumor Lysis Risk assessment (see Appendix H for risk assessment categories)

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk, venetoclax administration setting, and frequency of serum chemistry monitoring 
assessments)
Dosing and Post First Dose of Venetoclax

In-clinic administration of ibrutinib 

In-clinic administration of venetoclax 20 mg for low and medium risk TLS subjects

Consider hospitalization for first dose of venetoclax 20 mg in medium risk TLS subjects 
with a CrCl < 80 mL/min

In-hospital administration of first dose of venetoclax 20 mg for high risk TLS subjects 

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions
8.3.1.3.3.
Cycle 4 Week 1 Day 2
Pre-Dose

Adverse events

Hematology 

Serum chemistry 

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk and frequency of serum chemistry monitoring assessments)


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8.3.1.3.4.
Cycle 4 (Week 2 – Week 4) Visits
The following procedures will be performed on Day 1 (±3 days) of Cycle 4, Weeks 2, 3, and 4 
(coincides with venetoclax standard dose ramp-up of 50 mg (W2D1), 100 mg (W3D1), and 
200 mg (W4D1):
Pre-Dose

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

Creatinine clearance (Cockcroft-Gault)

Tumor Lysis Syndrome Risk assessment (see Appendix H for risk assessment categories)

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk and frequency of serum chemistry monitoring assessments)
Dosing and Post-Dose

In-clinic administration of venetoclax 50 mg (Week 2), 100 mg (Week 3) and 200 mg 
(Week 4) for low and medium TLS risk subjects

Consider hospitalization for first dose of venetoclax 50 mg in medium risk TLS subjects 
with a CrCl < 80 mL/min

In-hospital administration of first dose of venetoclax 50 mg dose at Week 2 for high risk
TLS subjects; in-clinic administration of venetoclax 100 mg (Week 3) and 200 mg 
(Week 4) for high risk TLS subjects

Dispense venetoclax for offsite use and provide study drug compliance instructions
8.3.1.3.5.
Cycle 4 Week 2 Day 2
Pre-Dose

Adverse events

Hematology 

Serum chemistry 

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk and frequency of serum chemistry monitoring assessments)


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8.3.1.4.
Cycle 5 Visits
8.3.1.4.1.
Cycle 5 Week 1 and Week 3 Visits
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycle 5, Week 1, and 
Week 3:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry 

Creatinine clearance (Cockcroft-Gault)

Tumor Lysis Syndrome Risk assessment (see Appendix H for risk assessment categories) 
(Week 1 Only)

Tumor Lysis Syndrome prophylaxis (see Section 5.4.2.2 for prophylaxis schedule based 
on risk, venetoclax administration setting, and frequency of serum chemistry monitoring 
assessments) (Week 1 Only)
Dosing and Post-Dose

In-clinic administration of venetoclax

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions (Week 1 only)
8.3.1.5.
Cycle 6 – Cycle 9 Visits
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycles 6, 7, 8, and 9:

Adverse events

Concomitant medication

Study drug compliance review

Physical exam

Vital signs

ECOG


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
Hematology 

Serum chemistry 

CT/MRI (Cycle 7 only)

Overall response assessment (Cycle 7 only)

MRD assessment (in peripheral blood Cycle 7 only)
Dosing and Post-Dose

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions
8.3.1.6.
Cycle 10 and Cycle 13 Visits
Pre-Dose
The following procedures will be performed on Day 1 (±3 days) of Cycles 10 and 13:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistry

b2-microglobulin (at Cycle 10 only)

CT/MRI (C10 and C13)

Overall response assessment (by imaging C10 and C13)

MRD assessment (in peripheral blood)

Bone marrow aspirate and biopsy (C10). Bone marrow MRD should be assessed 
whenever a BM aspirate is collected. Bone marrow can be collected ±14 days from 
scheduled C10D1.
Post-Dose

Dispense ibrutinib and venetoclax for offsite use and provide study drug compliance 
instructions


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8.3.2.
Fixed Duration Cohort: Post treatment visits
For subjects who complete all 15 cycles of fixed duration regimen, the following procedures will 
be performed on Day 1 (±3 days) of Cycles 19 (Post Completion of Cycle 15 therapy), 25, 28, 
31, and every 6 months thereafter (or as indicated below) until disease progression, unacceptable 
treatment-related toxicity, or other reasons outlined in Section 9.2.
Subjects who discontinue treatment before completing the fixed duration regimen will continue 
to come in for response follow-up visits per schedule until confirmed disease progression.

Physical exam

Vital signs

ECOG

Hematology 

Serum chemistries

CT/MRI (Cycle 19, Cycle 25, Cycle 31, and annually thereafter)

Overall response assessment

MRD assessment (by PB at Cycle 19, 25, 28*, 31, and annually thereafter; by PB and 
BMA at Cycle 19; BMA can be drawn ±14 days from C19D1) :

Bone Marrow Biopsy (Cycle 19 only)

assays 

* NOTE:  Cycle 28 MRD collection is not required for patients who have completed 
these respective visits prior to Amendment 3 site approval and any required reconsent
8.4.
Reintroduction of Study Drug (MRD and FD Cohorts)
Subjects in the MRD cohort who are randomized and subjects in the Fixed Duration cohort who 
complete the fixed duration treatment may have study drug reintroduced if they become MRD 
positive (MRD cohort) or have confirmed progressive disease (either cohort). See 
Section 5.4.2.2, and Section 7.1.1.10 for TLS risk assessment and prophylaxis, respectively
Imaging for restaging is required prior to reintroduction. Medical Monitor approval is required 
prior to reintroduction of any study drug.
Creatinine clearance, Coagulation panel (PT/INR, aPTT) (for ibrutinib reintroduction), IGHV, 
karyotype, FISH, and 
 will be assessed at the first reintroduction visit. Prior to 
reintroduction, ECG and Echo/MUGA will be obtained, and cardiology consultation prior to 
reintroduction should be considered for patients with cardiac comorbid conditions or significant 
cardiac risk factors. The following procedures will be performed prior to reintroduction, and 
every 4 months for the first year, then every 6 months until PD, unless otherwise indicated.

Physical exam

Vital signs and Weight 


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
ECOG

Hematology

Serum chemistry

CT/MRI (refer to Appendix D and Appendix E for specific timepoints)

Overall response assessment Adverse events

Concomitant medications

Study drug compliance review

Bone Marrow assessment (only at visit if needed to confirm CR, or if clinically indicated to 
confirm PD)

Assay 

ECG (prior to reintroduction then as clinically indicated)

Echocardiogram or MUGA scan (prior to reintroduction to allow sufficient time for 
subsequent evaluation and clinical decision making, and then as clinically indicated)
Subjects will follow the schedule for their retreatment as outlined in Appendix C, Appendix D, 
and Appendix E. Retreatment with ibrutinib or venetoclax or combination can be continued for 
the duration indicated, until disease progression as determined by investigator or until they meet 
criteria for withdrawal in Section 9.2. Subjects must meet all of the criteria for reintroduction 
listed below. Per investigator discretion and in communication with medical monitor, initiation 
of reintroduction can be delayed until indication for treatment per IWCLL criteria is present.
Criteria for Reintroduction of Study Drug
Inclusions
1. ECOG Performance Status ≤2
2. Platelet count >30,000/µL (30,000 cells/mm3 or 30 x 109/L) 
3. Adequate hepatic and renal function defined as:
a) Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤3.0 x upper limit of 
normal (ULN)
b) Creatinine Clearance (CrCl) ≥60 mL/min (eg, as estimated by Cockcroft-Gault)
c) Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic 
origin)
4. 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). 
5. Female subjects of reproductive potential must have a negative serum pregnancy test upon 
study entry.
6. 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 


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intrauterine devices [IUDs], complete abstinence3, or sterilized partner) and a barrier method 
(eg, condom, cervical ring, sponge, etc.) during the period of therapy and for 90 days after 
the last dose of study drug. Male subjects must agree to refrain from sperm donation until 
90 days after the last dose of study drug.
Exclusions
1. Development of other malignancies, except: 
a) Malignancy treated with curative intent and with no known active disease present and felt 
to be at low risk for recurrence by the treating physician
b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease
c) Adequately treated carcinoma in situ without evidence of disease 
2. Known or suspected history of Richter’s transformation.
3. Recent infection requiring systemic treatment that is ongoing or any uncontrolled active 
systemic infection.
4. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
5. Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety.
6. 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.
7. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix G). 
8. Currently active, clinically significant hepatic impairment Child-Pugh Class B or C 
according to the Child Pugh classification (Appendix K).
9. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura, or the 
need for daily prednisone >20 mg daily (or corticosteroid equivalent) to treat or control the
autoimmune disease.
                                               
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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Categories of Reintroduction
Ibrutinib: Appendix C

Subjects in the MRD cohort who are MRD-negative and have been randomized to
placebo; OR

Subjects in the Fixed Duration cohort who have completed the fixed duration of 
treatment.
Venetoclax: Appendix D

Subjects in the MRD cohort who are MRD-positive and have been randomized to 
ibrutinib only; OR

Subjects in the MRD cohort who are in MRD-negative arms and have previously had 
ibrutinib reintroduced.
Ibrutinib + venetoclax: Appendix E

Subjects in the Fixed Duration cohort who have completed the fixed duration of 
treatment (subjects will take combination for the same fixed duration in the protocol 
[15 months]).
8.5.
Suspected PD Visit (Any Time)
The following procedures will be performed when Disease Progression is suspected:

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

CT/MRI scan (For confirmation of PD)

Bone marrow biopsy/aspirate as clinically indicated

Overall response assessment 

Hematology

Serum chemistry

 assays (MRD and FD cohort, including with bone marrow biopsy when 
obtained)


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8.6.
Suspected CR Visit
The following procedures will be performed (along with regularly scheduled study assessments) 
when Complete Response by imaging is suspected:

Bone marrow biopsy and aspirate (for CR confirmation)

 assays (MRD cohort only)

MRD assessment (by PB and bone marrow aspirate)
8.7.
End-of-Treatment Visit
The following will be performed 30 (±3) days after discontinuation of therapy (if the assessments 
do not coincide with regularly scheduled study assessments) or at start of new anticancer 
therapy, whichever occurs earlier. For the Fixed Duration Cohort, if subject completes fixed 
duration regimen, this visit will take place at Cycle 17 Day 1.

Adverse events

Concomitant medications

Study drug compliance review

Physical exam

Vital signs

ECOG

Hematology

Serum chemistry 

MRD (peripheral blood)

 assays (MRD cohort only)
Subjects that withdraw from treatment for reasons other than clinical progressive disease in 
either cohort should continue to participate in ongoing Response Follow-Up visits until 
confirmed disease progression.
8.8.
Response Follow-Up Visits
Subjects who discontinue treatment for reasons other than disease progression will continue to 
come in every 3 months (or per assigned treatment schedule) until disease progression or study 
closure, whichever is earlier. Subjects will undergo the following procedures:

Physical exam

Vital signs

ECOG

Hematology

Serum Chemistry


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
MRD (peripheral blood) every 6 months for one year, then annually thereafter until 
initiation of subsequent anti-cancer therapy

Overall Response Assessment

CT/MRI scan (every 6 months for one year, then annually thereafter)

Other malignancies

Any subsequent anti-cancer therapy
If an alternative anti-cancer therapy is initiated, response to all subsequent anti-cancer therapies 
including best overall response for each regimen, whether the subject progressed following each 
regimen, and date of PD if applicable will be assessed.
8.9.
Post-PD Follow-Up Phase
Once subjects experience disease progression and discontinue study treatment, they will be 
contacted approximately every 3 months (±14 days), or as needed, by clinic visit or telephone to 
assess survival and the use of alternative anti-cancer therapy (response to all subsequent 
anti-cancer therapies including best overall response for each regimen, whether the subject 
progressed following each regimen, and date of PD if applicable), and other malignancies.
Subjects will be contacted until death, subject withdrawal, lost to follow-up, or study termination 
by the Sponsor, whichever occurs first.
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 study. 
9.2.
Withdrawal from Study Treatment
Study treatment will be discontinued in the event of any of the following events:

Confirmed progressive disease

Unacceptable toxicity: an intercurrent illness or AE that prevents further study drug 
administration  

Withdrawal of consent for treatment by subject

Investigator decision (such as chronic noncompliance, significant protocol deviation, or 
best interest of the subject)

Study termination by Sponsor

Subject becomes pregnant

Death


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Subjects in the Randomization Phase of the MRD cohort or subjects in the Fixed Duration cohort 
who elect to not reintroduce therapy after confirmed PD, or have a confirmed PD after 
reintroduction of therapy, will be withdrawn from study treatment.
All subjects, regardless of reason for discontinuation of study treatment will undergo an 
End -of -Treatment Visit and be followed for progression and survival. 
The investigator should notify the Sponsor within 24 hours if a subject discontinues ibrutinib 
and/or venetoclax treatment due to disease progression and should provide documentation of 
disease progression for review by the Sponsor’s Medical Monitor. If a subject shows signs of 
disease progression on physical examination or laboratory assessment, the subject may continue 
study treatment until disease progression is confirmed. These subjects should stay in the study to 
be followed for survival. 
9.3.
Withdrawal from Study
Withdrawal from study (including all follow-up) will occur under the following circumstances:

Death

Withdrawal of consent for follow-up observation by the subject

Lost to follow-up

Study termination by Sponsor
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.
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 the testing procedure for the secondary endpoints will be 
provided in the Statistical Analysis Plan (SAP).


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10.1.
Subject Information
The analysis populations are defined as:
All treated populations: defined as all enrolled subjects who received at least 1 dose of study 
drug in either the MRD cohort or the Fixed Duration cohort and will be used in both efficacy and 
safety analysis.
MRD-negative randomized population: defined as all subjects in the MRD cohort who achieve 
confirmed MRD-negative response at the end of the pre-randomization phase and are 
randomized to either placebo arm or ibrutinib arm for the double-blind treatment. Subjects in this 
population will be analyzed according to the treatment to which they are randomized.    
MRD-positive randomized population: defined as all subjects in the MRD cohort who do not 
achieve confirmed MRD-negative response at the end of the pre-randomization phase and are 
randomized to either single-agent ibrutinib arm or ibrutinib + venetoclax combination treatment 
arm for a prolonged open label treatment. Subjects in this population will be analyzed according 
to the treatment to which they are randomized.    
Pharmacokinetic-evaluable population: defined as all enrolled subjects who received at least 
1 dose of study drug and had at least 1 pharmacokinetic sample obtained post-treatment in 
pre-randomization phase.
 population: defined as all enrolled subjects whose 
 is available.
10.2.
Endpoints 
10.2.1.
MRD Cohort:
Primary Endpoint:

1-year disease-free rate in MRD-negative randomized subjects
Secondary Endpoints:

MRD-negative response rate

Overall response rate

Complete response rate (CR / CRi)

Duration of response

TLS risk reduction

Progression free survival

Overall survival

Pharmacokinetics of ibrutinib and venetoclax when dosed in combination

Safety and tolerability


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Exploratory Endpoints:
10.2.2.
Fixed Duration Cohort:
Primary Endpoint:

Complete response (CR/CRi) rate
Secondary Endpoints:

Duration of response

MRD-negative response rate

Overall response rate

TLS risk reduction

Progression free survival

Overall survival

Safety and tolerability
Exploratory Endpoints:
10.3.
Sample Size Determination
MRD Cohort
The study will be powered based on the primary endpoint of randomization phase, 1-year 
disease-free rate in MRD-negative randomized subjects (ibrutinib vs placebo). The total sample 
size will be based on both MRD-negativity clinical response rate from the Pre-randomization 
Phase and the sample size assumption from Randomization Phase.
Sixty randomized subjects with confirmed MRD-negative status will provide approximately 80% 
power to detect a 30% improvement in the 1-year disease-free rate, assuming the 1-year 
disease-free rate is 60% for the control (placebo) arm, at a 2-sided significant level of 0.05.


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Assuming a 40% MRD-negative response rate for the ibrutinib and venetoclax combination 
therapy in the Pre-randomization Phase, 150 subjects will be enrolled in the Pre-randomization 
Phase in order to have 60 subjects achieve confirmed MRD-negative response and to be 
randomized. Final sample size may be adjusted based on an early assessment of the 
MRD-negative response rate among the first 30 subjects who complete 9 cycles of treatment in 
Pre-randomization Phase (See Section 3.1.1).
Fixed Duration Cohort
Assuming the CR rate for ibrutinib + venetoclax is 50%, 125 subjects without del17p will 
provide 83% power to ensure the rate is > 37% at 1-side alpha 0.025. A CR rate of 50% would 
represent meaningful improvement compared to the CR rate seen with the fixed duration 
combination of bendamustine + rituximab (31%), and would be an improvement over the CR 
rate seen with the standard of care fixed duration regimen fludarabine, cyclophosphamide and 
rituximab (40%) which were obtained in the CLL10 study, which included only patients without 
del17p (Eichhorst 2016).
10.4.
Efficacy Analysis 
In general, the MRD cohort and the Fixed Duration cohort will be analyzed separately. Analysis 
details will be provided in the SAP.
Descriptive statistics and subject listings will be used to summarize the data. For continuous 
variables, the number of observations, means, standard deviations, medians, and ranges will be 
reported. For discrete variables, frequency will be summarized and the 95% confidence interval 
will be estimated. For time-to-event variables, Kaplan-Meier estimates will be provided. No 
inferential tests will be performed for pre-randomization phase. The primary endpoint, 1-year 
disease-free rate in MRD-negative randomized subjects, will be tested between placebo and 
ibrutinib arms at a 2-sided alpha level of 0.05 All the stratified analyses will be based on the 
randomization stratification factor, immunoglobulin heavy-chain variable region (IGHV) status.
10.4.1.
MRD-Negative Response Rate 
MRD-negative response rate is defined as the proportion of subjects who achieve 
MRD-negativity (definition in Section 7.2.1.4). 
In the MRD cohort, and the Fixed Duration cohort, MRD-negative response rate is the secondary 
endpoint. The analysis of MRD negativity will be based on the all treated population. 
 
will be summarized as an 
exploratory analysis.
10.4.2.
Disease-Free Survival (DFS)  
Disease-free survival (DFS) is the primary endpoint for randomization phase of the MRD cohort 
and will be analyzed in MRD-negative randomized subjects. DFS is defined as the time that 


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subjects remain in MRD-negative status without meeting MRD-positive relapse criteria 
(definition in Section 7.2.1.4.2), or disease progression (assessed by investigator per IWCLL 
2008 criteria) or death from any cause. The primary analysis will be performed when all 
randomized subjects have had the opportunity to complete at least 12 cycles of randomized 
treatment or follow-up. 1-year and 2-year disease-free survival rate will be explored. Analysis 
details will be provided in the SAP.  
10.4.3.
Overall Response Rate (ORR)
Overall response rate (ORR) is defined as the proportion of subjects who achieve a CR, CRi, 
nPR, PR, or PRL as evaluated by investigator using IWCLL 2008 criteria. Subjects who do not 
have any post-baseline response assessment will be considered as non-responders. It is a 
secondary endpoint for the MRD cohort and the Fixed Duration cohort.
 
 as exploratory endpoints. A pooled 
analysis in combination with another dataset (eg, CLL3011; GLOW) may be performed for 
ibrutinib retreatment. Details of the statistical analysis will be described in a separate SAP as 
applicable.
10.4.4.
Complete Response Rate (CRR)
Complete response rate (CRR) is defined as the proportion of subjects who achieve a CR or CRi 
as evaluated by investigator using IWCLL 2008 criteria. Subjects who do not have any 
post-baseline response assessment will be considered as non-responders. It is the primary 
endpoint for the Fixed Duration cohort, and secondary endpoint for the MRD cohort and will be 
summarized in the all treated population.
10.4.5.
Duration of Response (DOR)
Duration of response will be calculated for subjects achieving a response (CR, CRi, nPR, PR) 
based on IWCLL response criteria and defined as the interval between the date of initial 
documentation of a response including PR with lymphocytosis, until disease progression or death 
from any cause, whichever occurs first. Kaplan-Meyer methodology will be used to estimate 
event-free curves, median, and landmark estimates.
10.4.6.
Progression-Free Survival (PFS)  
Progression-free survival (PFS) is defined as the time from the first dose date of study treatment 
until disease progression (per IWCLL 2008 criteria) or death from any cause, whichever occurs 
first. 
In the MRD cohort and the Fixed Duration cohort, PFS is a secondary endpoint and will be 
analyzed in the all treated population. Distribution of PFS will be estimated using Kaplan-Meier 
method. Median PFS, landmark estimates, and their corresponding 95% CI will be provided.


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10.4.7.
Overall Survival (OS)
Overall survival (OS) is defined as the time from the first dose date of study treatment until date 
of death due to any cause. 
In the MRD cohort, and the Fixed Duration cohort, OS is a secondary endpoint and will be 
analyzed in the all treated population. Distribution of OS will be estimated using Kaplan-Meier 
method. Median OS, landmark estimates and their corresponding 95% CI will be provided.
10.4.8.
Tumor Lysis Syndrome (TLS) Risk Reduction Rate
TLS risk reduction rate is defined as the reduction in the proportion of subjects who are at high
risk of TLS after the 3-cycle lead-in of single agent ibrutinib, compared to the proportion of 
patients who are at high risk of TLS at baseline. A reduction in TLS risk from high risk to 
medium or low risk is clinically meaningful because there is a reduction in the extent of TLS 
monitoring and risk of hospitalization. TLS risk category is defined in the protocol in Table 4, 
where Tumor Burden category is equated to TLS risk category. TLS risk reduction is a
secondary endpoint for the MRD cohort and the FD cohort, and will be summarized in the all 
treated population.
10.4.9.
10.4.10.
10.4.11.
Safety Analysis
In the MRD cohort, analysis of safety data will be conducted on the all treated population in pre-
randomization phase and safety population in the randomization phase. An overall summary 
across both pre-randomization and randomization phase may also be provided as appropriate.
The baseline value is defined as the last value collected on or prior to the first dose date of study 
drug. In the Fixed Duration cohort, safety analysis will be based on all treated population.


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The safety variables to be analyzed include exposure of study drugs, AEs, clinical laboratory test 
results (hematology and chemistry), ECOG performance, physical examination, and vital signs 
measurements. 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 the type, 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 30 days following the last dose of
venetoclax, whichever occurs later
AND

The start date of a new anti-cancer therapy.
The treatment-emergent AEs (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,

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) or IWCLL for hematologic toxicity, and drug relationship, as well as 
categorized by system organ class and preferred term. Summaries, listings, datasets, or subject 
narratives may be provided, as appropriate, for those subjects who die, who discontinue 
treatment due to an AE, or who experience a severe AE or a SAE.


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Clinical Laboratory Tests
Laboratory tests will be summarized separately for hematology and serum chemistry. Local 
laboratory results will be standardized using the International System SI unit. Selected 
hematologic and chemistry laboratory parameters are detailed in Section 7.1.2. Hematologic 
parameters including platelet counts, hemoglobin, and neutrophils will be assessed by the 
grading scale for hematologic toxicity in CLL studies in the IWCLL 2008 guidelines. All other 
gradable laboratory parameters will be graded using the NCI CTCAE v4.03. 
Unless otherwise specified, only baseline and post-baseline lab values collected during the 
treatment-emergent period will be included in the analysis. Descriptive statistics will be used.
For selected laboratory parameters, the worst post baseline toxicity grade will be summarized. 
Analysis for hepatic impairment and renal impairment will be provided.
10.5.
Pharmacokinetic Analysis
10.5.1.
Ibrutinib
Ibrutinib and PCI-45227 bioanalytical data will be used in 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 and PK parameters of ibrutinib and PCI-45227 (including, but not limited 
to: Cmax, Tmax, AUClast, and t1/2) at each dosing interval.
Individual and mean plasma ibrutinib and PCI-45227 concentration time profiles will be plotted.
Ibrutinib data from this study may also be combined with data from other studies performed with 
ibrutinib in subjects with hematologic malignancies as part of a population-PK analysis using 
nonlinear mixed effects models. For the population-PK analysis, covariates that could potentially 
correlate with plasma PK parameters will be evaluated. The results of the population-PK 
analyses (if performed) will be presented in a separate report.
Steady-state ibrutinib PK data when administered alone in the lead in period will be compared to 
the data when administered in combination with venetoclax to explore the potential for a 
pharmacokinetic interaction between ibrutinib in combination use with venetoclax. 
Ibrutinib model-derived exposure parameters (PK parameters) may be used to explore PK/PD 
correlation between the exposure of ibrutinib with relevant clinical 
 information to 
assess effectiveness and toxicity.  


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10.5.2.
Venetoclax
Venetoclax bioanalytical data will be used in 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.
Individual and mean plasma venetoclax concentration time profiles will be plotted.
Venetoclax data from this study may also be combined with data from other studies performed 
with ibrutinib in subjects with hematologic malignancies as part of a population-PK analysis 
using nonlinear mixed effects models. For the population-PK analysis, covariates that could 
potentially correlate with plasma PK parameters will be evaluated. The results of the 
population-PK analyses (if performed) will be presented in a separate report.
Venetoclax model-derived exposure parameters (PK parameters) may be used to explore PK/PD 
correlation between the exposure of venetoclax with relevant clinical 
information 
to assess effectiveness and toxicity.
10.6.
 
 
 
Descriptive statistics will be used to summarize these exploratory endpoints. 
The detail will be given in SAP. Results will be presented in a separate report.
10.7.
Data Review Committee (DRC)
A DRC will be established to monitor data in the MRD Cohort Safety Run-in Period (defined as 
the date of first dose of ibrutinib at Cycle 1 Day 1 through the DLT evaluation period) to ensure 
the safety of the subjects enrolled in this novel combination study. The committee will meet 
periodically to review safety data. After the review of the first 6 evaluable subjects who have 
completed the combination of ibrutinib + dose ramp-up of venetoclax with an additional week of 
follow up, the DRC may make recommendations regarding the recommended doses and 
continuation of the study. A follow-up DRC review will occur after all subjects in the Safety 
Run-in Period have either discontinued therapy and/or have completed the venetoclax dose ramp 
up and 1 week follow up, then the DRC may make additional recommendations regarding the 
recommended doses.
The DRC will consist of the Medical Monitor or designee, a Drug Safety representative, a
biostatistician, and at least 2 participating Investigators. 


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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 CLL/SLL" 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).
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.


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
Pre-Planned or Elective Hospitalization: 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. Hospitalization required per 
protocol for subjects at high risk for TLS (high tumor burden, or those with CrCl 
<80 mL/min) are not considered AEs unless the hospitalization is prolonged >24 hours or 
if additional intervention, not described as mandatory prophylaxis in Table 4, is required. 
Elective hospitalizations for social reasons, solely for the administration of therapy, or 
due to long travel distances are also not SAEs.

Diagnostic Testing and Procedures: Testing and procedures should not to 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 serious adverse event (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 unplanned 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 
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 


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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 Hematologic Adverse Event Grading Scheme (Hallek 2008) will be 
used for grading the severity of hematologic AEs. Refer to Appendix L for the grading of 
hematologic AEs.
Definitions found in the Common Terminology Criteria for Adverse Events version 4.03
(CTCAE v4.03) will be used for grading the severity (intensity) of nonhematologic AEs. The 
CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each 
referenced AE. Should a subject experience any AE not listed in the CTCAE v4.03, the 
following grading system should be used to assess severity:

Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities

Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures

Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment

Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be in 
imminent danger of death

Grade 5 (Death related to AE) – experiences which result in subject death
11.1.4.
Causality (Attribution)
The investigator is to assess the causal relation (ie, whether there is a reasonable possibility that 
the study drug 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.


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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 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 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 IB/package insert listed only cerebral vascular accidents. 
"Unexpected" also refers to AEs that are mentioned in the 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)
Occurrence of any special reporting situations should be recorded in the eCRF. If any special 
reporting situation meets the criteria of an AE, it should be recorded on the AEs eCRF. If the AE
is considered serious, it should be recorded on the AEs eCRF as serious and should be reported 
on the Serious Adverse Event Report Form. The Serious Adverse Event Report Form should be 
sent via email or fax to Pharmacyclics 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 


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personnel during subject office visits, detected through physical examination, clinically 
significant laboratory test, or other means, will be recorded in the subject’s medical record and 
on the AEs eCRF 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 in the source documents from the 
time signed and dated ICF is obtained until 30 days following the last dose of study drug. 
Adverse events noted during Screening period will be recorded in Medical History CRF. SAEs 
will be reported to the Sponsor on the SAE Report Form from the time of ICF signing until 30 
days following the last dose of study drug. Both serious and non-serious AEs will be recorded in 
the eCRF from the first dose of study drug until 30 days after the last dose of study drug. In the 
case of subjects who are transferring their ibrutinib treatment from this protocol to another 
ibrutinib treatment protocol, AE collection under this protocol will stop at the time AE collection 
starts under the next protocol.
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. In the case of subjects who are transferring their ibrutinib treatment from this protocol 
to another ibrutinib treatment protocol, SAE collection under this protocol will stop at the time 
SAE collection starts under the next protocol.
Adverse event and SAE collection will also stop at the time any subject starts a subsequent 
anticancer treatment within the first 30 days after discontinuing ibrutinib.
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 assess the relationship of the AE/SAE to the 
study therapy and record their opinion in the CRF. All measures required for AE/SAE
management must be recorded in the source document and reported according to Sponsor 
instructions.


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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 
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 Drug Safety, or designee, within 
24 hours of the discovery of the event or information. Pharmacyclics 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 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/SAEs 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, or a female partner of a male 
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.


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A female 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. A male subject must immediately 
inform the investigator if his partner becomes pregnant from the time of consent to 90 days after 
the last dose of study drug. 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 subject or subject’s partner from the time of consent to 90 days 
after the last dose of study drug must be reported. Any occurrence of pregnancy must be 
recorded on the Pregnancy Report Form Part I and sent via email or fax to Pharmacyclics 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 overall survival.
If observed, enter data in the corresponding eCRF.
11.4.6.
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 Drug Safety, or designee, 
within 24 hours of awareness. 
11.4.6.1.
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.
Events meeting the definition of major hemorrhage will be captured as an event of special 
interest according to Section 11.4.6 above.


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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 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 
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.


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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). 
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 and its 
designees, regulatory agencies, and IRBs/REBs/IECs. As the study Sponsor, Pharmacyclics 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), signed Form FDA 1572 and Financial Disclosures, 
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 and notification of SAEs and related 


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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 and obtain written approval from Pharmacyclics 
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. Pharmacyclics will 
inform the investigator of the date that study records may be destroyed or returned to 
Pharmacyclics.
Pharmacyclics must be notified in advance of, and Pharmacyclics 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 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 case report forms 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 exists within an electronic data capture (EDC) system with controlled access managed 
by Pharmacyclics 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 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 


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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, placebo, and venetoclax 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, placebo, or venetoclax to other investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this protocol without 
prior authorization from Pharmacyclics.
Accountability records for ibrutinib, placebo, and venetoclax must be maintained and readily 
available for 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 accurate 
accountability, the following information must be noted when drug supplies are used during the 
study:
1. Study identification number (PCYC-1142-CA)
2. Subject identification number
3. Lot number(s) of ibrutinib/placebo dispensed for that subject
4. Lot number(s) of venetoclax dispensed for that subject
5. Date and quantity of drug(s) dispensed
6. Any unused drug(s) returned by the subject
At study initiation, the monitor will evaluate and approve the site’s procedure for investigational 
product disposal/destruction to ensure that it complies with Pharmacyclics’ requirements. If the 
site cannot meet Pharmacyclics’ requirements for disposal/destruction, arrangements will be 
made between the site and Pharmacyclics or its representative, for return of unused 
investigational product. Before disposal/destruction, final drug accountability and reconciliation 
will be performed by the monitor if allowed by institutional policy.
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor.
12.9.
Study Monitoring/Audit Requirements
Representatives of Pharmacyclics 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 


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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, 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 included in the 
informed consent and permission form authorizing the use of protected health information.
Pharmacyclics 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 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.
12.10.
Investigator Responsibilities
A complete list of investigator responsibilities is outlined in the clinical trial research agreement 
and the Statement of Investigator Form FDA 1572, 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 


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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 or its authorized representative before the study drug is delivered.
For this study, each investigator and sub-investigator (as designated on the Form FDA1572) will 
provide a personally signed Financial Disclosure Form in accordance with § 21 CFR 54. Each 
investigator will notify Pharmacyclics 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 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 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.


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12.15.
Publication of Study Results
Pharmacyclics 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 reserves the right to preview 
all manuscripts and abstracts related to this study, allowing Pharmacyclics 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 
adjusted upon mutual agreement of the authors and Pharmacyclics 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.
13.
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Willis S, Day CL, Hinds MG, et al. The Bcl-2-regulated apoptotic pathway. J Cell Sci.  
2003;116(Pt 20):4053-6.


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14.
APPENDICES








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Randomization Phase
Study Visits
Randomi-
zation
(1 cycle = 28 days)
Suspected 
MRD-positive
Suspected 
PDs
End-of-
Treatment
Response 
Follow-Up
Post PD
Follow Up
Cycles 17 until disease progression
(every 3 cycles)
As soon as 
possible after 
MRD-positive 
relapse
As soon as 
possible after 
suspected PD
30 Days v
Every 3 
months
Every 3 months
12-lead ECGn
If clinically indicated (eg, subjects with palpitations, lightheadedness)
Survival, including other 
malignancies
X (other 
malignancies)
X
Any new anti-cancer therapy
X
X
Footnote:
a.
Cycle 1 D1: To be collected pre-dose or within +/- 3 days, unless otherwise specified.
b.
Ibrutinib: Day 1 dose of Cycle 1, Cycle 2, Cycles 4 and Cycle 6 should be administered at the investigational site. Subsequent daily doses may be self-administered at home.
c.
Venetoclax: Day 1 dose of Cycle 4 Weeks 1-4, Cycle 5 Week 1 and Cycle 6 should be administered at the investigational site. Subsequent daily doses may be self-
administered at home.
d.
Confirmation of eligibility and enrollment may occur within 3 days of Day 1 of Cycle 1.
e.
Adverse Events: AEs are reported from the time the subject signs the Informed Consent Form until 30 days following last dose of study drug. AEs that occur prior to first 
dose should be entered as Medical History. In addition to all routine AE reporting, all new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies are to be reported as adverse events.
f.
Study Drug Compliance: Includes subject instruction and routine review of study drug diary and evaluation of contents of study drug containers from home administration.
g.
Physical Exam: Height will only be collected in the Screening Period. Vital signs will be collected through end of treatment only. ECOG collected through disease 
progression.
h.
CT Scan: Baseline CT scan can be performed up to 6 weeks prior to enrollment. Cycle 3 CT scan should be performed and assessed prior to starting venetoclax at Cycle 4 and 
are obtained for TLS risk assessment. Cycle 3 CT scans should be obtained as close to the beginning of Cycle 4 as possible, while still allowing for appropriate TLS risk-
guided interventions including hospitalizations if appropriate. Please reference Section 7.1.3.2 for details.
i.
Bone marrow biopsy: should be performed at Screening or up to 90 days before the first dose of study drug before enrollment, Cycle 16 (±14 days) [unless collected prior for 
CR assessment, and confirmed MRD-negative in BM], Cycle 29 (±14 days), and as needed to confirm complete response (CR) or evaluate cytopenia. All bone marrow 
biopsies will be assessed by local laboratory. A portion of bone marrow biopsies collected at 
 should be sent to 
 central lab. 
An additional bone marrow sample will be sent to central laboratory for karyotype (if ALC ≤ 4000) if BM was collected within 90 days prior to screening and at Day 1 of 
reintroduction of study drug (see Section 7.1.3.5). Bone marrow aspirate for 
 will be derived from MRD bone marrow aspirate, no additional sample needs to be 
collected.
j.
MRD Assessment: should be performed in peripheral blood (PB) at Cycle 1, Cycle 7, 10, 13, 16, 20, 23, 26, 29 and every 6 cycles thereafter. MRD assessment confirmation 
by both peripheral blood and bone marrow aspirate (BMA) will be performed at Cycle 16 (±14 days). An additional BMA (after suspected CR or C16) can be collected in 
consented subjects prior to randomization to serially confirm MRD-negativity in the bone marrow compartment.  For all randomized subjects, and any subjects with MRD-
neg conversion in PB, an additional BMA should be collected at Cycle 29 (±14 days).
k.
Local labs: Hematology, chemistry, Creatinine Clearance, Hepatitis serologies (see Section 7.1.2.4), serum and urine pregnancy and Coagulation panel may be performed at 
local labs.
l.
Cytogenetics, FISH panel: If local lab FISH results are not available or if site cannot perform del17p and del11q testing, sample should be sent to Central Lab. 
m.
IGHV: Send to central lab at Cycle 1. If IGHV sample is not informative for any reason, another peripheral blood sample should be drawn and sent to the central lab at the 
next appropriate timepoint. Must have IGHV result in order to be randomized.


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n.
ECG: At Screening, 12-lead ECGs will be done in triplicate (≥1 minute apart). ECG’s may be performed at the investigator’s discretion, particularly in subjects with 
arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea.
o.
PK (ibrutinib): Day 1 of Cycle 2 and Cycle 6: to be collected pre-dose, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose. PK should only be drawn when ibrutinib is at 
steady state plasma levels. If any dose of ibrutinib was withheld in the week prior to C2D1 and/or C6D1, then PK assessments should be rescheduled to the next study visit 
day after doses have been consistently administered for ≥1 week (see Table 12).
p.
PK (venetoclax): Day 1 of Cycle 6: to be collected pre-dose, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours post-dose. PK should only be drawn when venetoclax is at steady 
state plasma levels. If any dose of venetoclax was withheld in the week prior to C6D1, then PK assessments should be rescheduled to the next study visit day after doses have 
been consistently administered for ≥1 week (see Table 12).
q.
Tumor Lysis Syndrome Risk Assessment: Please see Appendix H for risk assessment categories. For baseline risk assessment, use Screening CT and C1D1 ALC.
r.
Tumor Lysis Syndrome Prophylaxis: Please see Section 5.4.2.2 for TLS prophylaxis schedule, venetoclax administration setting and frequency of serum chemistry monitoring
assessments.
s.
Suspected PD: Follow same procedures in Pre-Randomization and Randomization phases.
t.
Reintroduction: Reintroduce ibrutinib (MRD-negative placebo arm) if MRD-positive relapse or IWCLL confirmed disease progression. Reintroduce venetoclax (MRD-
negative ibrutinib arm) per standard dose ramp up if MRD-positive relapse or IWCLL confirmed disease progression. Reintroduce venetoclax (MRD-positive ibrutinib arm) 
per standard dose ramp up if IWCLL confirmed disease progression.
u.
Hematology and Serum Chemistry may be collected up to 24 hours prior to each venetoclax ramp-up (Cycle 4 Weeks 2-4 and Cycle 5 Week 1), to allow for flexibility in start 
of ramp-up dose.  Hematology and serum chemistry can be drawn on day of dosing to allow for comparisons, but results are not required before dosing decision is made. For 
subjects at high risk for TLS, additional hematology and serum chemistry samples will need to be collected 6-8 and 24 hours post-1st dose at Cycle 4 Weeks 3 and 4, and 
Cycle 5 Week 1 as part of TLS risk assessment.  Please see Table 4 for serum chemistry monitoring assessments.
v.
End-of-Treatment Visit: may be sooner if subject is scheduled to start a new anti-cancer treatment.
w.
Karyotype: will be assessed from peripheral blood or bone marrow aspirate samples.












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Footnote:
a.
Adverse Events: AEs are reported from the time the subject restarts study drug until 30 days following last dose of study drug. In addition to all routine AE reporting, all new 
malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported as adverse events.
b.
Study Drug Compliance: Includes subject instruction and routine review of study drug diary and evaluation of contents of study drug containers from home administration
c.
Physical Exam: Vital signs will be collected through end of treatment only. ECOG collected through disease progression.
d.
CT Scan: CT scans should be performed approximately within 6 weeks of reintroduction for restaging, at the end of 4 months, at the end of 12 months, and annually 
thereafter, and as clinically indicated. Please reference Section 7.1.3.2 for details.
e.
Cytogenetics, FISH panel: Central lab if local FISH lab results are not available or if site cannot perform del17p and del11q testing.
f.
IGHV sample will be derived from one of the 
samples collected.
g.
Karyotype: will be assessed from peripheral blood or bone marrow aspirate samples.
h.
Local labs: Hematology, chemistry, Creatinine Clearance, and Coagulation panel may be performed at local labs.
i.
ECG: 12-lead ECGs will be done in triplicate (≥1 minute apart) before reintroduction. In addition, ECG’s may be performed at the investigator’s discretion, particularly in 
subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea.
j.
ECHO or MUGA scan should be obtained prior to reintroduction (to allow sufficient time for subject evaluation) and then as clinically indicated.
k.
End-of-Treatment Visit: may be sooner if subject is scheduled to start a new anti-cancer treatment.




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Footnote:
a.
Day 1: To be collected pre-dose or within +/- 3 days, unless otherwise specified. FISH, Karyotype, IGHV, and 
 only on Week 1 D1
b.
Venetoclax: Day 1 dose of Cycle 4 Weeks 1-4, and Cycle 5 Week 1 should be administered at the investigational site.  Subsequent daily doses may be self-administered at 
home.
c.
Adverse Events: Aes are reported from the time the subject restarts study drug until 30 days following last dose of study drug. In addition to all routine AE reporting, all new 
malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported as adverse events.
d.
Study Drug Compliance: Includes subject instruction and routine review of study drug diary and evaluation of contents of study drug containers from home administration
e.
Physical Exam: Vital signs will be collected through end of treatment only. ECOG collected through disease progression. 
f.
CT Scan: CT scans should be performed prior to reintroduction for restaging, at the end of 4 months, at the end of 12 months, and annually thereafter, and as clinically 
indicated. C4 CT Scan should be collected at C4D-3, while still allowing for appropriate TLS risk-guided interventions including hospitalizations if appropriate.  
g.
Cytogenetics, FISH panel: Central lab if local FISH lab results are not available or if site cannot perform del17p and del11q testing. 
h.
Tumor Lysis Syndrome Risk Assessment: Please see Appendix H for risk assessment categories. For baseline risk assessment, use Screening CT and C1D1 ALC.
i.
Tumor Lysis Syndrome Prophylaxis: Please see Section 5.4.2.2 for TLS prophylaxis schedule,  administration setting and frequency of serum chemistry monitoring 
assessments.
j.
Hematology and Serum Chemistry may be collected up to 24 hours prior to each  ramp-up (Cycle 4 Weeks 1-4 and Cycle 5 Week 1), to allow for flexibility in start of ramp-
up dose.  Hematology and serum chemistry can be drawn on day of dosing to allow for comparisons, but results are not required before dosing decision is made. For subjects 
at high risk for TLS, additional hematology and serum chemistry samples will need to be collected 6-8 and 24 hours post-1st dose at Cycle 4 Weeks 3 and 4 and Cycle 5 
Week 1 as part of TLS risk assessment.  Please see Table 4 for serum chemistry monitoring assessments.
k.
IGHV sample will be derived from one of the 
samples collected
Karyotype: will be assessed from peripheral blood or bone marrow aspirate samples.
l.
ECG: 12-lead ECGs will be done in triplicate (≥1 minute apart) before reintroduction. In addition). ECG’s may also be performed at the investigator’s discretion, particularly 
in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea.
m.
ECHO or MUGA scan should be obtained prior to reintroduction (to allow sufficient time for subject evaluation) and then as clinically indicated. 
n.
MRD Assessment: should be performed in peripheral blood (PB) at Cycle 1, Cycle 7, Cycle 10, Cycle 13, End of Treatment (30 days after last dose of study drug or C17), 
C17 for reintroduction (3 months after completion of therapy), C25, C28, C31 and annually thereafter.  MRD assessment confirmation by both peripheral blood and bone 
marrow aspirate (BMA) will be performed at Cycle 10, and C19 (3 months after completion of therapy [±14 days]). Bone marrow aspirate MRD should be performed if bone 
marrow is obtained to confirm CR.
o.
End-of-Treatment Visit: may be sooner if subject is scheduled to start a new anti-cancer treatment.




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4th month
5th month
Every 4 months for 
the first year, then 
every 6 months 
until PD (Day 1 of 
each visit)
Suspected PD 
(as soon as 
possible after 
suspected PD)
End-of-
Treatment
Post PD 
Follow-up 
(Every 
4 months)
Week 1
Weeks 1-2
Wks 3-4
Wks 1 & 3
1st month –
Day 1a
D-3 or 
D-2
D-1
D1
D2
D1
30 Days q
Study Visit Windows
± 3 days
± 3 days (minimum of 7 days at each dose level of 
venetoclax)
± 3 days
Anytime (as soon 
as possible after 
suspected PD)
±3 days
±14 d
Survival, including other
X
Any new anti-cancer therapy
X
12-lead ECGn
X
If clinically indicated 
ECHO or MUGA scano
X
If clinically indicated 
Footnote:
a.
Day 1: To be collected pre-dose or within +/- 3 days, unless otherwise specified
b.
Venetoclax: Day 1 dose of Cycle 4 Weeks 1-4, and Cycle 5 Week 1 should be administered at the investigational site.  Subsequent daily doses may be self-administered at 
home.
c.
Adverse Events: AEs are reported from the time the subject restarts study drug until 30 days following last dose of study drug. In addition to all routine AE reporting, all new 
malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported as adverse events.
d.
Study Drug Compliance: Includes subject instruction and routine review of study drug diary and evaluation of contents of study drug containers from home administration
e.
Physical Exam: Vital signs will be collected through end of treatment only. ECOG collected through disease progression. 
f.
CT Scan: CT scans should be performed approximately within 6 weeks of  reintroduction for restaging, at 4 months, 12 months, and annually thereafter, and as clinically 
indicated. C4 CT Scan should be collected at C4D-3, while still allowing for appropriate TLS risk-guided interventions including hospitalizations if appropriate.  
g.
Cytogenetics, FISH panel: Central lab if local FISH lab results are not available or if site cannot perform del17p and del11q testing. 
h.
Tumor Lysis Syndrome Risk Assessment: Please see Appendix H for risk assessment categories. For baseline risk assessment, use Screening CT and C1D1 ALC.
i.
Tumor Lysis Syndrome Prophylaxis: Please see Section 5.4.2.2 for TLS prophylaxis schedule, venetoclax administration setting and frequency of serum chemistry monitoring 
assessments.
j.
Hematology and Serum Chemistry may be collected up to 24 hours prior to each venetoclax ramp-up (Cycle 4 Weeks 1-4 and Cycle 5 Week 1), to allow for flexibility in start 
of ramp-up dose.  Hematology and serum chemistry can be drawn on day of dosing to allow for comparisons, but results are not required before dosing decision is made. For 
subjects at high risk for TLS, additional hematology and serum chemistry samples will need to be collected 6-8 and 24 hours post-1st dose at Cycle 4 Weeks 3 and 4, and 
Cycle 5 Week 1 as part of TLS risk assessment.  Please see Table 4 for serum chemistry monitoring assessments.
k.
IGHV sample will be derived from one of the 
 samples collected
l.
Karyotype: will be assessed from peripheral blood or bone marrow aspirate samples.
m.
Local labs: Hematology, chemistry, Creatinine Clearance, and Coagulation panel may be performed at local labs
n.
ECG: 12-lead ECGs will be done in triplicate (≥1 minute apart) before reintroduction. In addition, ECG’s may be performed at the investigator’s discretion, particularly in 
subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset of dyspnea.
o.
ECHO or MUGA scan should be obtained prior to reintroduction (to allow sufficient time for subject evaluation) and then as clinically indicated. 
p.
MRD Assessment: should be performed in peripheral blood (PB) at Cycle 1, Cycle 7, Cycle 10, Cycle 13, End of Treatment (30 days after last dose of study drug or C17), 
C17 for reintroduction (3 months after completion of therapy), C25, C28, C31 and annually thereafter.  MRD assessment confirmation by both peripheral blood and bone 
marrow aspirate (BMA) will be performed at Cycle 10, and C19 (3 months after completion of therapy [±14 days]). Bone marrow aspirate MRD should be performed if bone 
marrow is obtained to confirm CR.  
q.
End-of-Treatment Visit: may be sooner if subject is scheduled to start a new anti-cancer treatment.


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Appendix F.
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 June 6, 2008.






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Appendix H.
TLS Risk Category 
For the management of tumor lysis syndrome prophylaxis, subjects will be classified in 3 risk 
categories based on the risk for developing medically concerning TLS with venetoclax 
administration. The Cycle 3 tumor burden assessed by the nodal disease and absolute 
lymphocyte count will be used to define each category as described below:
Low Risk
Medium Risk
High Risk
Lymph Nodes
All measurable 
lymph nodes with 
the largest diameter 
<5 cm by 
radiographic 
assessment
Presence of any 
single measurable 
lymph node with the 
largest diameter
≥5 cm and <10 cm by 
radiologic assessment
A single 
measurable lymph 
node with the 
largest diameter 
≥5 cm by 
radiologic 
assessment.
Any single 
measurable lymph 
node with the 
largest diameter
≥10 cm by 
radiologic 
assessment
AND
OR
AND
Absolute 
Lymphocyte Count
< 25 × 109/L
≥ 25 × 109/L
≥ 25 × 109/L


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Appendix I.
Howard Criteria1 for Laboratory and Clinical TLS
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 tumor lysis syndrome, 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 tumor lysis syndrome requires the 
presence of laboratory tumor lysis syndrome 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 perdeciliter).
‡
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 tumor 
lysis syndrome. Data about acute kidney injury are from Levin, 2007.
1
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011; 364:1844-54


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Appendix J.
Example of 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 notified (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.

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 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.


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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. If further ≥0.2 mmol/L increase in potassium, but 
still <upper limit of normal (ULN), manage as per potassium 
≥ULN. Otherwise recheck.
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.
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) notified 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.
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.


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Abnormality
Management Recommendations1,2
Hyperuricemia
Uric acid ≥ 8.0 mg/dL (476 μmol/L)
Consider rasburicase (0.2 mg/kg as an intravenous infusion 
over 30 minutes).
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.
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).
When rasburicase is used, sodium bicarbonate should not 
be used as this may exacerbate calcium phosphate 
precipitation.
Notify nephrology (or other acute dialysis service).
Recheck potassium, phosphorus, uric acid, calcium and
creatinine.
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.
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 (eg, 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.
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.


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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.

For potassium, admit patient for any increase ≥1.0 mmol/L (1.0 mEq/L), or any level 
> upper limit of normal.
○
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 K.
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
Source:
1.
Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and portal hypertension. 
Philadelphia: Saunders. 1964. pp. 50-64.
2.
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 L.
Hematologic Adverse Event Grading Scheme (Hallek 2008)
An evaluation of the hematologic toxicity in patients with advanced CLL/SLL must consider the
high frequency of marrow involvement and previous exposure to chemotherapy with consequent
medullary compromise at the initiation of therapy. The standard hematologic grading system for
solid tumors cannot, therefore, be directly applied. A substantial proportion of patients would be
considered to have Grade 2 to 4 hematologic toxicity before any therapy is given. Therefore, the
following modified schema will be used to quantitate hematologic deterioration in patients with
CLL/SLL.
Hematologic Grading Scheme
Decrease in Platelets or Hgb (Nadir) 
from Pre-treatment Value, %
ANC/μL (nadir)c
Toxicity Grade
0 - 10%a
≥ 2000
0
11 - 24%a,b
≥ 1500 and < 2000
1
25 - 49%a,b
≥ 1000 and < 1500
2
50 - 74%a,b
≥ 500 and < 1000
3
> 75%a,b
< 500
4
a.
Platelet counts must be below normal levels to be Grades1 to 4. If at any level of decrease, the platelet count falls below 
20×109/L, toxicity will be considered Grade 4. If the baseline platelet count is <20×109/L, platelet toxicity cannot be 
evaluated.
b.
Hemoglobin levels must be below normal levels to be Grades 1 to 4. Baseline and subsequent Hgb values must be 
determined the day of any given transfusion.
c.
If the ANC was <1000/µL before therapy, the patient is not evaluable for toxicity referable to the ANC.


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Appendix M.
Rai Staging
Rai Stage
0
Lymphocytes (L) in blood (>5000/µL)
I
L + enlarged lymph nodes (LN)
II
L + spleen and/or liver (LN positive or negative)
III
L + anemia (Hgb <11g/dL)
IV
L + thrombocytopenia (platelets <100,000/μL)

SAP_001.pdf: 
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Statistical Analysis Plan 
Phase 2 study of the combination of ibrutinib plus venetoclax in subjects with 
treatment-naïve chronic lymphocytic leukemia / small lymphocytic lymphoma
Protocol PCYC-1142-CA
Version:   1.0
Version Date:  Feb 18, 2020 
Confidentiality Statement 
This document contains confidential information of Pharmacyclics, LLC. that must not be disclosed to 
anyone other than the recipient study staffs 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. 
NCT02910583






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Statistical Analysis Plan Approval 
Protocol Number:   
PCYC-1142-CA 
Protocol Title: 
Phase 2 study of the combination of ibrutinib plus venetoclax in subjects with 
treatment-naïve chronic lymphocytic leukemia / small lymphocytic lymphoma 
SAP Version:  
1.0
Date: 
18Feb2020 
By signing below, all parties accept that the analysis methods and data presentations are acceptable 
and that this document is final. 
Date (ddMMMyyyy) 
Date (ddMMMyyyy) 
Date (ddMMMyyyy) 
Date (ddMMMyyyy)  
__________________________
Date (ddMMMyyyy) 
Date (ddMMMyyyy)  


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TABLE OF CONTENTS
ABBREVIATIONS ........................................................................................................................4 
1. 
INTRODUCTION ..................................................................................................................6 
1.1. Study Design ..................................................................................................................6 
1.2. Endpoints .......................................................................................................................9 
1.3. Statistical Hypotheses ....................................................................................................9 
1.4. Sample Size Determination..........................................................................................10 
1.5. Planned Analysis ..........................................................................................................11 
1.5.1. Interim Analysis ..............................................................................................11 
1.5.2. Primary Analysis ............................................................................................12 
1.5.3. Final Analysis .................................................................................................12 
1.6. Testing Procedure and Level of Significance ..............................................................12 
1.7. Blinding and Randomization Methods ........................................................................12 
1.7.1. Blinding Method .............................................................................................12 
1.7.2. Randomization Method ..................................................................................13 
2. 
GENERAL ANALYSIS CONSIDERATION ....................................................................14 
2.1. Analysis Sets ................................................................................................................14 
2.2. Definition of Subgroups ...............................................................................................14 
3. 
SUBJECT INFORMATION................................................................................................15 
3.1. Subject Disposition ......................................................................................................15 
3.2. Demographics and Baseline Characteristics ................................................................15 
3.3. Prior and Concomitant Medications ............................................................................15 
3.4. Extent of Exposure to Study Treatment .......................................................................15 
3.5. Subsequent Antineoplastic Therapies ..........................................................................15 
4. 
ANALYSIS FOR ENDPOINTS ..........................................................................................16 
5. 
SAFETY ASSESSMENTS ...................................................................................................20 
6. 
CHANGES IN PROTOCOL PLANNED ANALYSIS ......................................................21 
7. 
REFERENCES .....................................................................................................................21 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BM 
bone marrow 
CBC 
complete blood count 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CR 
complete response 
CRi 
complete response with incomplete bone marrow recovery 
CRR 
complete response rate 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
disease free survival 
DOCR 
duration of complete response 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
FD 
fixed duration 
Ibr + Ven 
ibrutinib plus venetoclax combination 
IGHV 
immunoglobulin heavy-chain variable region 
IRC 
independent review committee 
IRT 
interactive response technology 
IWCLL 
international workshop on chronic lymphocytic leukemia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
NCI 
National Cancer Institute 
nPR 
nodular partial response  
ORR 
overall response rate 
OS 
overall survival 
PB 
peripheral blood 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic  
PR 
partial response  
PRL 
PR with lymphocytosis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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Abbreviation 
Definition 
SD 
stable disease 
SLL 
small lymphocytic lymphoma 
TEAE 
treatment-emergent adverse events 
TLS 
tumor lysis syndrome 
WHO 
World Health Organization 


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1. INTRODUCTION 
This statistical analysis plan (SAP) lays out key elements including definitions and statistical 
methods for analysis of data in evaluation of efficacy and safety for the PCYC-1142-CA study.  
Analyses of pharmacokinetics (PK) data and exploratory analyses such as for clonal evolution and 
disease-related mechanisms of resistance will be addressed in separate documents.  
Throughout this SAP, “study treatment” and “study drug” are used interchangeably. 
1.1.
Study Design 
This is an international multicenter, 2-cohort Phase 2 study assessing both minimal residual disease 
(MRD)-guided discontinuation and fixed duration (FD) therapy with the combination of ibrutinib + 
venetoclax (‘Ibr + Ven’ hereafter) in subjects with treatment-naïve chronic lymphocytic leukemia 
(CLL) or small lymphocytic lymphoma (SLL). Figure 1 outlines the study design. 
The MRD cohort begins with the same 15-cycle treatment (3 cycles of ibrutinib single agent lead-in 
followed by 12 cycles of Ibr + Ven) as in the FD cohort.  This is followed by 1 cycle of Ibr + Ven 
during which MRD-guided randomization occurs, after which treatment proceeds according to the 
randomization. MRD negativity is assessed by a central laboratory and defined as <1 CLL cell per 
10,000 leukocytes (<1 x 10-4), as assessed by flow cytometry of a peripheral blood (PB) or bone 
marrow (BM) aspirate sample. MRD negativity for randomization purposes must be confirmed 
serially over at least 3 cycles and must be negative in both bone marrow and peripheral blood. 
The randomized treatment for MRD cohort starts from cycle 17 day 1. MRD-negative randomized 
subjects are randomized to receive double blind ibrutinib or placebo and to be treated until MRD 
relapse or disease progression (PD) or unacceptable toxicity. MRD-positive randomized subjects 
are randomized to receive open label ibrutinib or ibrutinib + venetoclax: ibrutinib is to be continued 
until PD or unacceptable toxicity in either arm, while venetoclax can be administered for up to 2 
years cumulatively (including pre-randomization and randomization phases) or until PD or 
unacceptable toxicity, whichever the earliest. 
The FD cohort is an open-label, 1 arm cohort with a fixed duration 15-cycle treatment: 3 cycles of 
ibrutinib single agent lead-in followed by 12 cycles of Ibr + Ven. This cohort was added in Protocol 
Amendment 1 after the completion of MRD cohort enrollment. Each cycle consists of 28 days.  
All subjects who discontinue treatment in the absence of disease progression will remain on 
response follow-up until confirmed PD or until study closure. After PD, subjects will be followed 
for survival and subsequent anti-cancer therapies. Treatment reintroduction is allowed per 
investigator’s discretion for both cohorts as following: 
For MRD cohort, treatment reintroduction is allowed for both arms of MRD-negative randomized 
subjects after MRD-positive relapse and/or PD and for ibrutinib arm only for MRD-positive 


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randomized subjects after PD. For placebo subjects, ibrutinib is to be reintroduced first and 
venetoclax may be added further if subsequently PD on reintroduced ibrutinib. Ibrutinib subjects 
(either MRD-negative randomized or MRD-positive randomized) may continue ibrutinib and 
reintroduce venetoclax treatment. Reintroduced venetoclax can be administered for up to 2 years. 
For FD cohort, subjects with PD after completion of the 15-cycle fixed duration treatment may be 
retreated by, per investigator’s discretion, either continuous single agent ibrutinib until PD or 
unacceptable toxicity, or a repeat of the fixed duration 15-cycle treatment (3 cycles of ibrutinib 
single agent lead-in followed by 12 cycles of Ibr + Ven).  
Investigators and an independent review committee (IRC) perform the response assessments 
independently based on radiological imaging, physical examination or other procedures as 
necessary, hematology results, disease-related symptoms and bone marrow examinations (where 
appropriate). The response evaluations are in accordance with the International Workshop on 
Chronic Lymphocytic Leukemia (IWCLL) guidelines (Hallek 2008) including subsequent 
clarifications (Hallek 2012, Hallek 2013, Cheson 2012).  




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1.2.
Endpoints 
MRD Cohort 
FD Cohort 
Primary Endpoint 
Primary Endpoint
x 1-year disease-free survival (DFS) rate in MRD-
negative randomized subjects 
x Complete response (CR/CRi) rate 
Secondary Endpoints 
Secondary Endpoints
x MRD negativity rate 
x Duration of response 
x Overall response rate 
x MRD negativity rate 
x Complete response rate (CR / CRi) 
x Overall response rate 
x Duration of response 
x TLS risk reduction 
x TLS risk reduction 
x Progression free survival 
x Progression free survival 
x Overall survival 
x Overall survival 
  
Safety Assessments 
Safety Assessments
x Safety and tolerability 
x Safety and tolerability 
Exploratory Endpoints 
Exploratory Endpoints
x
x
x
x
x
x
x
  
1.3.
Statistical Hypotheses  
MRD Cohort
The primary objective of this cohort is to evaluate if discontinuing ibrutinib, in the setting of a 
confirmed MRD-negative response with the combination of ibrutinib + venetoclax (I+V), allows for 
a treatment holiday as assessed by 1-year disease-free survival. 
The statistical hypotheses are as follows:  
H0: The DFS rate at 1-year landmark for experimental treatment group, SI (1), is equal to the 
control group, SC (1):  
SI (1) = SC (1) 
versus 


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H1: The DFS rate at 1-year landmark for experimental treatment group, SI (1), is different from the 
control group, SC (1): 
SI (1)  SC (1) 
7KHVHK\SRWKHVHVZLOOEHWHVWHGDWVLGHGĮOHYHORIXVLQJ]WHVWIRUWKHGLIIHUHQFHRIWZR
proportions based on Kaplan-Meier estimates with standard error of each arm computed using 
Greenwood’s formula. 
FD Cohort 
The primary hypothesis of this cohort is that: Complete response rate (CRR) is > 37% after 12-cycle 
Ibr + Ven treatment. 
The statistical hypotheses are as follows:  
H0&55
versus 
H1: CRR > 37% 
7KHVHK\SRWKHVHVZLOOEHWHVWHGDWVLGHGĮOHYHORIXVLQJDV\PSWRWLFWHVWIRUWKHELQRPLDO
proportion. Since the assumption for sample size and power of this cohort is based on the historical 
data of subjects without del 17p, the formal hypothesis testing will be performed on the non-del 17p 
population (section 2). 
1.4.
Sample Size Determination 
MRD Cohort 
The MRD cohort is powered based on the primary endpoint of randomization phase, 1-year DFS 
rate in MRD-negative randomized subjects (ibrutinib vs placebo). The total sample size will be 
based on both MRD negativity rate from the Pre-randomization Phase and the sample size 
assumption from Randomization Phase. 
Sixty randomized subjects with confirmed MRD negativity will provide approximately 80% power 
to detect a 30% improvement in the 1-year disease-free rate, assuming the 1-year disease-free rate is 
60% for the control (placebo) arm, at a 2-sided significant level of 0.05. 
Assuming a 40% MRD negativity rate for the ibrutinib and venetoclax combination therapy in the 
Pre-randomization Phase, 150 subjects will be enrolled in the Pre-randomization Phase in order to 
have 60 subjects achieve confirmed MRD negativity and to be randomized.  


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FD Cohort 
In the FD cohort, assuming the complete response rate for Ibr + Ven is 50%, 125 subjects without 
del 17p will provide 83% power to ensure the rate is > 37% at 1-side alpha 0.025. A CR rate of 
50% would represent meaningful improvement compared to the CR rate seen with the fixed 
duration combination of bendamustine + rituximab (31%), and would be an improvement over the 
CR rate seen with the standard of care fixed duration regimen fludarabine, cyclophosphamide and 
rituximab (40%) which were obtained in the CLL10 study, which included only patients without del 
17p (Eichhorst 2016). 
The sample size and power calculations were calculated using the software package, East (Cytel 
Software Corp, Cambridge, MA) version 6.3. 
1.5.
Planned Analysis  
1.5.1. Interim Analysis 
No interim analysis was planned or performed for the randomization period of the MRD cohort or 
for the FD cohort. The protocol prespecified analyses for pre-randomization phase of MRD cohort 
were completed as follows: 
The safety of Ibr + Ven regimen was assessed in safety run-in subjects (the first 14 enrolled MRD 
cohort subjects) by Data Review Committee (DRC) consisting of the Medical Monitor or designee, 
a Drug Safety representative, a biostatistician, and at least 2 participating Investigators. DRC 
meetings were held first on 01May2017 and then on 07Nov2017 when the 6th and the last (i.e. the 
14th) safety run-in subjects, respectively, completed the dose limiting toxicity (DLT) evaluation 
period (defined as the 5-week venetoclax dose ramp-up in combination with ibrutinib plus an 
additional week of follow up) respectively. No DLT or TLS occurred in safety run-in subjects. The 
DRC recommended for the study treatment regimen to move forward without modification in both 
meetings.   
To ensure adequate sample size in the MRD-negative randomization, an early assessment of the 
MRD negativity rate with Ibr + Ven was performed when the first 30 subjects completed 9 cycles 
of treatment (6 cycles Ibr + Ven) as of the 30Mar2018 data extraction. MRD negativity in PB was 
achieved in 23 subjects, rate 77% (95% exact binomial confidence interval [CI]: 58% - 90%). The 
first 14 subjects also completed MRD testing in both PB and BM at cycle 16 as needed to assess for 
confirmed MRD negative status. Confirmed MRD negativity was achieved in 11 of 14 subjects, rate 
79% (95% exact binomial CI: 49% - 95%). The sample size assumption was confirmed, and 
enrollment continued as planned (section 1.4).  


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1.5.2. Primary Analysis 
The primary analysis for the MRD cohort will be performed after the last randomized subject has 
the opportunity to receive 1 year of randomized treatment. All safety and efficacy endpoints for 
MRD cohort will be analyzed at the time of the primary analysis.  
The primary analysis for FD cohort will be performed after the last enrolled FD subject has the 
opportunity to be followed for at least 30 cycles (15 cycles of treatment + 15 cycles of post-
treatment follow-up). All safety and efficacy endpoints for FD cohort will be analyzed at the time 
of the primary analysis. A longer-term analysis for selected MRD cohort endpoints will also be 
performed using the same data extraction. 
The CSR of this study will describe analyses of both MRD and FD cohorts based on data extracted 
at the time of FD cohort primary analysis. Results for the primary analysis of MRD cohort with 
earlier data extraction will also be summarized in a report and be documented in the appendix of 
clinical study report (CSR). 
1.5.3. Final Analysis  
After the primary analysis of both cohorts, the Sponsor will continue to follow the FD cohort for 
approximately 5 years after the first subject was enrolled in the cohort and may elect to discontinue 
follow-up of specific treatment arms of MRD cohort. Subjects who are continuing ibrutinib at the 
time of study arm closure may be offered a separate extension study to continue ibrutinib.When the 
study closes, a final analysis will be performed for both cohorts, and a CSR addendum will be 
prepared.  
1.6.
Testing Procedure and Level of Significance  
For both cohorts, hypothesis testing will be performed independently (without multiplicity 
adjustment) for the primary endpoint only.  Other endpoints will be summarized descriptively with 
95% confidence interval (CI) whenever applicable. 
x
Primary endpoint for MRD cohort, 1-year DFS rate in MRD-negative randomized subjects, 
will be tested between placebo and ibrutinib arms at a 2-sided alpha level of 0.05. 
x
Primary endpoint for FD cohort, CRR, will be tested in non-del 17 subjects at a 1-sided 
alpha level of 0.025. 
1.7.
Blinding and Randomization Methods 
1.7.1.
Blinding Method 
The FD cohort and Pre-Randomization phase of MRD cohort are an open label single arm study 
design. 


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MRD cohort subjects who achieve confirmed MRD negativity after completing the 12 cycle Ibr + 
Ven treatment will be randomized and treated in a double blind manner. Subjects, investigator and 
sponsor’s study staffs are all blinded to treatment assignment until subject experiences a confirmed 
MRD-positive relapse or PD event and plans to reintroduce treatment as per protocol. At such time, 
the specific subject and their treating investigator may request unblinding as needed to make 
subsequent treatment decisions. The sponsor’s independent clinician verifies the DFS event criteria 
have been met per protocol and approves unblinding on the Interactive Response Technology (IRT) 
system.  Details are described in the Minimizing Bias Document.   
MRD cohort subjects who do not achieve confirmed MRD negativity after completing the 12 cycle 
Ibr + Ven treatment are to be randomized in an open label manner. Neither the subjects nor the 
investigators are blinded to treatment. However, no aggregated data summary by arm is allowed 
until data are extracted and approved for the primary analysis for MRD cohort.
In addition to investigator assessment, IRC will evaluate the responses for both cohorts 
independently. Members of the IRC are blinded to the study treatment for all subjects. The IRC data 
flow and workflow are detailed in the IRC charter.  
1.7.2.
Randomization Method 
After completing the 12 cycle Ibr + Ven treatment in MRD cohort, subjects will be randomized 
centrally by two separate schemes according to MRD status, each stratified by IGHV status 
(Unmutated vs mutated [including borderline or not evaluable]): 
x
Subjects who achieve confirmed MRD negativity are to be randomized to receive double 
blind study treatment, either placebo or ibrutinib. 
x
Subjects who do not achieve confirmed MRD negativity are to be randomized to receive 
open label treatment, either single agent ibrutinib or Ibr + Ven.  
In each scheme, subjects will be randomized in a 1:1 ratio within each randomization stratum. This 
randomization scheme will be implemented within the IRT system.  


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2. GENERAL ANALYSIS CONSIDERATION 
2.1.
Analysis Sets 
All treated population includes all enrolled subjects who received at least 1 dose of study drug 
(ibrutinib or venetoclax or both). All analysis including baseline, disposition, efficacy and safety 
analysis will be based on this population. 
MRD-negative randomized population: defined as all treated subjects in the MRD Cohort who 
are randomized to the double blind ibrutinib or placebo arms. Subjects in this population will be 
analyzed according to the treatment to which they are randomized. 
MRD-positive randomized population: defined as all treated subjects in the MRD Cohort who are 
randomized to the open label ibrutinib or Ibr + Ven arms. Subjects in this population will be 
analyzed according to the treatment to which they are randomized. 
Non-del 17p population includes subjects of all treated population without del 17p abnormality 
according to non-missing baseline FISH results. The primary analysis of the primary and main 
secondary endpoints for FD cohort will be based on this population. 
2.2.
Definition of Subgroups 
Subgroup analyses will be performed for the selected variables (Table 1) to assess the internal 
consistency of the treatment benefit. The subgroup variables and the cutoff values may be further 
modified if warranted. 
Table 1: Baseline Subgroups 
ECOG = Eastern Cooperative Oncology Group, FISH = Fluorescence in Situ Hybridization,  
NCI ODWG= National Cancer Institute Organ Dysfunction Working Group 
*Classified in 3 categories per hierarchical order (Dohner et al,2000): del 17p, del 11q without del 17p, and all others 
(neither del 17p nor del 11q identified).   
Baseline Characteristics 
Subgroups 
Analysis Type 
Age 
\HDUV\HDUV
xCRR 
xMRD negativity rate 
xAdverse Event 
Gender 
Male, Female 
Race 
White, Non-White 
ECOG score 
0, 1-2  
xCRR 
xMRD negativity rate 
Rai stage  
Stage 0-II, III-IV 
Bulky disease 
LDi <5 cm, >=5 cm 
Del 17p  
Yes, No  
Del 17p or TP53 mutated  
Yes, No  
FISH* 
Del 17p, Del 11q, Others 
IGHV per central lab 
unmutated, mutated 
Creatinine clearance 
P/PLQP/PLQ
x Adverse Event 
NCI ODWG Liver Function Classification 
Normal, Abnormal  


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3. SUBJECT INFORMATION 
Subject information will be summarized descriptively. No inferential tests will be performed. 
3.1.
Subject Disposition 
Subject enrollment will be summarized by region, country, site and by cohort. Subject 
randomization in MRD cohort will be summarized by arm and by stratification factors. Subject 
disposition for each study treatment and for study participation will be tabulated. The overall 
duration of receiving any study treatment and time on study will be summarized correspondingly.  
Time on study is defined in the same way as overall survival with reversed censoring, i.e. subjects 
who died will be censored at death date. The Kaplan-Meier method will be used to estimate the 
median time on study. 
3.2.
Demographics and Baseline Characteristics 
Demographic information and baseline characteristics including but not limited to age, gender, race, 
histology type, time from initial diagnosis, staging, and potential prognostic factors will be 
summarized with descriptive statistics.  
3.3.
Prior and Concomitant Medications 
Medications will be coded to preferred term and Anatomical Therapeutic Chemical (ATC) class 
according to World Health Organization (WHO) Drug dictionary. 
Prior medications are defined as medications that started prior to the first dose date of study drug. 
Concomitant medications are defined as medications that were taken at any time on treatment (i.e. 
from the date of the first dose of study drug through the date of the last dose of study drug).  
Concomitant medications will be summarized by therapeutic class and preferred term in the all 
treated population. The following concomitant medications of special interest will be summarized 
separately: growth factors, blood supportive products and immunoglobulin, CYP3A 
inhibitors/inducers, anticoagulants and/or antiplatelet.   
3.4.
Extent of Exposure to Study Treatment 
Exposure to ibrutinib and venetoclax will be summarized separately for treatment duration and 
dosing information (e.g. total cumulative dose administered, relative dose intensity, ibrutinib or 
venetoclax dose reduction due to adverse events). 
3.5.
Subsequent Antineoplastic Therapies 
Subsequent CLL/SLL antineoplastic agents will be summarized by type of therapies. 


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4. ANALYSIS FOR ENDPOINTS 
All endpoints will be analyzed in both MRD and FD cohorts separately and pooled except DFS for 
MRD cohort only. The definition and analysis methods are the same for both cohorts on the same 
endpoint with some variations on analysis population and analysis period in terms of primary 
analysis vs supportive analysis of the endpoint.   
In general, the analysis population for the primary analysis is the all treated population for the MRD 
cohort and the non-del17p population for FD cohort. All analyses for the FD cohort will be repeated 
on the all treated population as supportive analyses. 
Unless otherwise specified, the analysis period for primary analysis of endpoints is from the first 
dose date of study treatment to the first dose date of subsequent antineoplastic therapy or 
reintroduction of study treatment, whichever occurs earlier, unless otherwise specified. For MRD 
cohort, this is the overall period including pre-randomization phase and randomization phase. All 
by-arm summaries of the MRD cohort are also based on the overall period except DFS analyzed 
within randomization phase only. Summaries for CRR, ORR, MRD negativity rate within the pre-
randomization phase (first 16 cycles) in the all treated population of MRD cohort will be provided 
as supportive analyses.  
Table 2 summarizes the efficacy endpoints and analysis methods to be performed. For subgroup and 
exploratory or supportive analyses, only those providing meaningful information will be presented. 
Table 2: Definitions and Analyses for Endpoints 
Endpoint 
Definition 
Analysis Method 
Primary Endpoint for MRD Cohort (Not Applicable for FD cohort) 
1-year DFS rate in 
MRD-negative 
randomized subjects
DFS will be analyzed in MRD-negative 
randomized subjects and is defined as 
time from randomization date to MRD-
positive relapse [1], or disease 
progression per investigator assessment 
or death from any cause, whichever 
occurred first. Subjects who do not 
experience any DFS event will be 
censored by the last MRD sample date 
with a valid result [2] or the date of last 
adequate disease assessment [3] after 
randomization, whichever occurs 
earlier. If no valid MRD result and no 
adequate disease assessment after 
randomization, DFS will be censored 
on the randomization date. 
Primary  
The 1-year DFS rates will be estimated using 
Kaplan-Meier method and the corresponding 
2-sided 95% CI will be provided. Z test for the 
difference of two proportions will be 
performed based on Kaplan-Meier estimates 
with standard error of each arm computed 
using Greenwood’s formula.  
Supportive 
A log-rank test will be performed for between-
arm comparison of DFS distribution. The 
hazard ratio and its 95% CI based on Cox 
regression model will be calculated.  
The 2-year DFS will be explored when 
median follow-up post randomization >= 2 
years. 


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Endpoint 
Definition 
Analysis Method 
Primary Endpoint for FD Cohort (Secondary Endpoint for MRD cohort)
Complete response rate 
(CRR)
The proportion of subjects achieving a 
best overall response of CR or CRi on 
or prior to initiation of subsequent 
antineoplastic therapy or, if applicable, 
reintroduction of study treatment, 
whichever occurs earlier. 
Primary  
The point estimate of CRR per investigator 
assessment and the corresponding 95% CI 
based on normal approximation to the 
binomial distribution will be provided. In FD 
cohort non-del17p population, p value for 
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asymptotic test for the binomial proportion 
will be calculated.  
Sensitivity 
CRR per IRC assessment.  
Supportive 
1. Duration of complete response (DOCR 
defined as the interval between the date of 
initial CR or CRi until disease progression 
or death from any cause, whichever occurs 
first.) for subjects who achieved CR or CRi. 
2. Durable CRR (defined as proportion of 
subjects with DOCR >= 336 days (12 
cycles)) 
Subgroup (defined in table 1) 
The point estimate of CRR per investigator 
assessment and its 95% CI by normal 
approximation to the binomial distribution for 
each subgroup.
Secondary Endpoints for MRD and FD Cohorts
Overall response rate 
(ORR) 
The proportion of subjects achieving a 
best overall response of CR, CRi, nPR, 
or PR on or prior to initiation of 
subsequent antineoplastic therapy or, if 
applicable, reintroduction of study 
treatment, whichever occurs earlier. 
Primary  
The point estimate of ORR per investigator 
assessment and the corresponding 95% CI 
based on normal approximation to the 
binomial distribution will be provided. 
Sensitivity 
ORR per IRC assessment. 
Duration of response  
(DOR) 
Duration of response will be calculated 
for the subjects achieving a response 
(CR, CRi, nPR, PR) per investigator 
assessment and is defined as time from 
the date of initial response including PR 
with lymphocytosis to the date of 
disease progression or the date of death 
from any cause, whichever occurs first. 
For subjects without documented PD or 
death, DOR was censored at the date of 
last adequate disease assessment.  
Primary 
Kaplan-Meier estimates of median DOR time 
per investigator assessment and landmark 
estimates with 2-sided 95% CIs.  
Sensitivity 
DOR per IRC assessment 


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Endpoint 
Definition 
Analysis Method 
MRD negativity rate 
The proportion of subjects achieving 
MRD negativity which is defined as <1 
CLL cell per 10,000 leukocytes (<1 x 
10-4) as assessed by flow cytometry of a 
peripheral blood (PB) or bone marrow 
(BM) aspirate sample per central 
laboratory on or prior to initiation of 
subsequent antineoplastic therapy or, if 
applicable, reintroduction of study 
treatment, whichever occurs earlier.   
Primary 
The point estimate of MRD negativity rate 
and the corresponding 95% CI based on 
normal approximation to the binomial 
distribution will be provided.  
Sensitivity 
MRD negativity rate by sample type (PB or 
BM)  
Supportive 
MRD negativity rate by best overall response 
categories (CR/CRi, nPR/PR/PRL, and all 
others including non-responders and those off 
study without response assessment). 
Tumor Lysis Syndrome 
(TLS) risk reduction 
The reduction of the proportion of 
subjects who are at high risk of TLS 
after the ibrutinib lead-in compared 
with baseline.   
Primary  
The point estimate of the difference in 
proportions of subjects with high risk of TLS 
(at baseline - after ibrutinib lead in) and the 
corresponding 95% CI (adjusting correlation 
of paired data) will be provided. 
Supportive 
Reduction of the proportion of subjects with 
hospitalization indicated due to tumor lysis 
Syndrome (TLS) risk (i.e. subjects with high 
TLS risk and subjects with medium risk of 
TLS and creatinine clearance <80 mL/min).
Progression Free Survival 
(PFS) 
Time from the date of first study 
treatment to the date of disease 
progression per investigator assessment 
or date of death from any cause, 
whichever occurs first, regardless of the 
use of subsequent antineoplastic 
therapy prior to documented PD or 
death. 
For subjects without documented PD or 
death, PFS will be censored at the date 
of last adequate disease assessment. For 
subjects without adequate disease 
assessment post-baseline, PFS will be 
censored on the date of first study 
treatment.
PFS distribution will be estimated by Kaplan-
Meier method: median PFS and landmark 
estimates with 2-sided 95% CIs will be 
provided.  


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Overall Survival (OS) 
Time from the date of first study 
treatment to the date of death from any 
cause. For subjects who are not known 
to have died at the time of the analysis, 
OS will be censored at the date of last 
known alive.
Kaplan-Meier estimates of median OS time 
and landmark estimates with 2-sided 95% CIs. 
Exploratory Endpoints for MRD and FD Cohorts
>@05'SRVLWLYHUHODSVHLVGHILQHGDVDQLQFUHDVHLQ&//FHOOVSHUOHXNRF\WHV[-2) confirmed on two 
consecutive occasions, after achieving MRD negativity, as assessed by flow cytometry of a PB or BM aspirate sample.  
[2] MRD samples tested within 5 days after collection are considered valid and can be used in DFS analysis.  
[3] Adequate disease assessment is defined as physical examination and CBC, or CBC and CT scan within 56 days of 
each other.


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5. SAFETY ASSESSMENTS 
Safety data will be summarized for the all treated population. Table 3 summarizes the safety 
analyses to be performed. 
Adverse events will be coded in accordance with the MedDRA. Severity of AEs will be graded by 
the investigator according to the NCI-CTCAE v4.03 for non-hematological AEs and IWCLL 2008 
guidelines for hematologic toxicity.  
Treatment emergent period is defined as the period 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 antineoplastic therapy or reintroduction of study treatment, whichever comes first.  
The treatment emergent adverse events (TEAE) are those events that occur or worsen during the 
treatment-emergent period or that are related to the study treatment. Unless otherwise specified, 
only TEAEs will be included in the adverse event summaries. For MRD cohort, TEAEs within first 
16 cycles (pre-randomization phase) and overall treatment emergent period (pre-randomization and 
randomization phase) will be both summarized. 
All laboratory values will be converted to and reported in international system of units (SI). 
Hematologic parameters including platelet counts, hemoglobin, and neutrophils will be assessed by 
the grading scale for hematologic toxicity in CLL studies in the IWCLL 2008 guidelines. All other 
gradable laboratory parameters will be graded using the NCI CTCAE v4.03. Unless otherwise 
specified, only baseline and post-baseline values collected during the treatment-emergent period 
will be included in the safety analysis.
Table 3: Summary of Safety Assessments 
Assessment Type 
Definition   
Analysis Methods 
AE 
TEAEs, SAEs, Grade 3 or worse TEAEs, related 
TEAEs, TEAEs leading to treatment discontinuation, 
TEAEs leading to dose reduction, TEAEs leading to 
death, protocol- defined events of special interest and 
other safety observations.   
Descriptive summary 
statistics and/or listings 
Lab
Worst post-baseline toxicity grade for selected gradable 
hematology and chemistry.  Abnormalities in creatinine 
clearance, uric acid, and liver function. 
Descriptive summary 
statistics and/or listings 
Vital Signs  
Blood pressure, heart rate 
Descriptive summary 
statistics and/or listings 
TEAE= treatment emergent adverse event; SAE= serious adverse event.        


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6. CHANGES IN PROTOCOL PLANNED ANALYSIS 
x
The term “MRD-negative response” was replaced by the phrase “MRD negativity”.
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Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in 
chronic lymphocytic leukemia. J Clin Oncol 2012; 23:2820-22.  
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Hallek M, Cheson BD, Catovsky D, et al.  Response assessment in chronic lymphocytic leukemia treated with 
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23 August 2012. 
Hallek M, Cheson BD, Catovsky D, et al. E-Letter regarding "Guidelines for the diagnosis and treatment 
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Leukemia updating the National Cancer Institute–Working Group 1996 guidelines": Clarification of 
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Hallek M, Cheson BD, Catovsky D, et al. Guidelines for diagnosis, indications for treatment, response 
assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018, 
http://www.bloodjournal.org/content/early/2018/03/14/blood-2017-09-806398. Accessed 19 March 2018. 
Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic 
leukemia. N Engl J Med. 2000;343(26):1910-1916. 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials, Biometrics 1979; 35:549-556.